JA-PED | Annual Meeting of the German Society for Pediatric and Adolescent Endocrinology and Diabetology (DGPAED e. V.)

STEROID METABOLISM AND ANDROGEN PRODUCTION IN COMPLETE ANDROGEN INSENSITIVITY SYNDROME: IMPACT OF ANDROGEN RECEPTOR MUTATIONS

Baraah Al Nawasreh ^a , Paul-Martin Holterhus, Alexander Kulle ^a

^a University Hospital Schleswig-Holstein, Department of Pediatric Oncology and Rheumatology, Division of Pediatric Endocrinology and Diabetology, Kiel, Germany

Introduction and Objectives

Differences of sex development (DSD) are congenital conditions with atypical chromosomal, gonadal, or anatomical sex development. In individuals with a 46, XY karyotype and female phenotype, one of the most common causes is Androgen insensitivity syndrome (AIS) (1). AIS caused by mutations in the X-linked androgen receptor (AR) gene impairs AR function. Based on residual AR activity, AIS is classified as partial (PAIS) or complete (CAIS) (2). CAIS shows complete AR loss and female external genitalia. The aim was to identify potential differences in steroid metabolism between CAIS and controls.

Methods

We analysed genital skin fibroblasts (GSF) from molecular proven CAIS individuals with different AR mutations and GSF from male controls. GSFs were cultured in DMEM-based medium at 37°C, 5% CO₂. Cells were seeded in 6-well plates (6×10⁴ cells/2 ml/well) and incubated with testosterone, DHEA, and 17-hydoxyprogesterone (17OHP) at three concentrations (1, 10 and 100 nM). Supernatants were analyzed by LC-MS/MS.

Results

In the CAIS cell lines, DHT production was significantly lower than in controls. After 72 hours of incubation with 100 nM testosterone, CAIS cells lines produced an average of 9.32 ± 12.8 nmol/L (n=5), compared to control cell lines with 28.47 ± 12.63 nM (n=3) (p = 0.049). In contrast, androstenedione (A4) levels were higher in CAIS cells, reaching 55.26 ± 50.35 nM (p < 0.05), compared to 12.65 ± 5.21 nM in controls. These findings may indicate a shift toward back-conversion or incomplete downstream androgen metabolism in CAIS. Highest A4 accumulation occurred in exon 7 mutations (p.Arg856Cys, p.Asn849Lysfs*31), while early stop mutations (p.Gln59Ter, p.Tyr481Ter) showed lower A4, indicating mutation-specific metabolic effects.

Conclusions

This study shows distinct differences in the steroid pathways between CAIS and control GSFs. CAIS cell lines have markedly reduced DHT production and altered androgen profiles, with significantly higher levels of A4. These findings are likely to reflect impaired AR function. It could provide further insight into the consequences of AR mutations and may help to clarify the diversity of hormonal responsiveness.

References

1. Berglund, Agnethe; Johannsen, Trine H.; Stochholm, Kirstine; Viuff, Mette H.; Fedder, Jens; Main, Katharina M.; Gravholt, Claus H. (2016): Incidence, Prevalence, Diagnostic Delay, and Clinical Presentation of Female 46,XY Disorders of Sex Development. In: The Journal of clinical endocrinology and metabolism 101 (12), S. 4532–4540. DOI: 10.1210/jc.2016-2248.

2. Mongan, Nigel P.; Tadokoro-Cuccaro, Rieko; Bunch, Trevor; Hughes, Ieuan A. (2015): Androgen insensitivity syndrome. In: Best practice & research. Clinical endocrinology & metabolism 29 (4), S. 569–580. DOI: 10.1016/j.beem.2015.04.005

THE CHALLENGE OF MANAGING POTENTIAL COELIAC DISEASE (CD) IN TYPE 1 DIABETES (T1D) PATIENTS

Julia August ^a , Stella A. Nagel ^a,b , Lena Kliewer ^a , Ina Ellrichmann ^a , Gunnar Cario ^a , Paul-Martin Holterhus ^,b , Jessica Bokelmann ^a,b

^a University Medical Center, Campus Kiel, Department of Pediatric Oncology and Rheumatology (Pediatrics an Adolescent Medicine I), Pediatric Endocrinology and Diabetology, Kiel, Germany; ^b Medical care center (MVZ), Pediatric Endocrinology and Diabetology, Kiel, Germany

Introduction and Objectives

In T1D the risk of CD is increased (the prevalence is 8%) and regular screening is recommended. Patients with a 10-fold increase in tissue transglutaminase antibodies of type immunoglobulin A (tTG-IgA-AB) usually undergo duodenal biopsy. According to the German Society of Gastroenterology diagnosis without biopsy is possible if tTG-IgA-AB and anti-endomysial antibodies (EMA) are elevated. Screening patients with potential CD poses a special challenge as high antibody titers may regress without CD. We present a group of patients with elevated tTG-IgA-AB-Titers, with and without developing CD.

Methods

A case series of 6 T1D patients with high-titer tTG-IgA-AB was examined. The course of the antibodies was compared over 12 months, in two patients data over 24 months were available. We investigated the titer progression in 4 patients with transient elevation of tTG-IgA-AB and compared the courses of the tTG-IgA-AB titers with 2 patients in whom the diagnosis of CD was confirmed by serology or biopsy.

Results

2 of 6 patients had 10 times elevated tTG-IgA-AB at time of T1D diagnosis decreasing significantly in both after 12 months and 1 patient reached tTG-IgA-AB in the normal range after 2 years. In 2 other patients who developed elevated tTG-IgA-AB over 10 times of the normal value after T1D diagnosis, the antibody titers decreased continously after 12 months and were in 1 patient in the normal range after 2 years, EMA were not tested. The patients were not biopsied, but monitored for symptoms and serologically tested. They did not stop eating gluten. On the other hand, our patient group also includes 2 cases with persistent high-titer antibody elevation (tTG-AB and EMA) with and without CD-specific symptoms, which are referred for further diagnostics as well as biopsy and a gluten-free diet.

Conclusions

In T1D, elevated titers of tTG-IgA-AB occur repeatedly but only some of the patients with elevated tTG-IgA-AB are diagnosed with CD. The phenomenon of temporary progression is still not well understood. Further research and the establishment of a standardized procedure in these cases are desirable in order to spare patients from the necessity of a lifelong gluten-free diet. In our experience, a wait-and-see approach before a diagnosis is made based on elevated antibodies or biopsy may be justified in the absence of specific symptoms of CD by monitoring tTG-IgA-AB and EMA every 3-6 months.

References

Aktualisierte S2k-Leitlinie Zöliakie der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) Dezember 2021 – AWMF-Registernummer: 021-021

Autoren Jörg Felber1*, Hendrik Bläker2, Wolfgang Fischbach3, Sibylle Koletzko4, 5, Martin Laaß6, Nils Lachmann7, Pia Lorenz8, Petra Lynen8, Imke Reese9, Katharina Scherf10, Detlef Schuppan11, 12, Michael Schumann13*

ISPAD Clinical Practice Consensus Guidelines 2022: Other complications and associated conditions in children and adolescents with type 1 diabetes Elke Fröhlich-Reiterer1 | Nancy S. Elbarbary 2 | Kimber Simmons3 | Bruce Buckingham4 | Khadija N. Humayun5 | Jesper Johannsen6,7 | Reinhard W. Holl8 | Shana Betz9 | Farid H. Mahmud10

Concomitant autoantibodies in newly diagnosed diabetic children with transient celiac serology or proven celiac disease Iva Hojsak, Noam Zevit, Orith Waisbourd-Zinman, Yoram Rosenbach, Yael Mozer-Glassberg, Shlomit Shalitin, Moshe Phillip, Raanan ShamirThe Overlap between Type 1 Diabetes and Celiac Disease in Children and the Role of Tissue Transglutaminase-IgA Positivity in Endoscopy Decision Elif Eviz 1, Sinan Sari 2, Nuray Uslu Kizilkan 3, Esra Doger 4, Gul Yesiltepe Mutlu 1, Ödül Eğritaş 2, Cigdem Arikan 3, Aysun Bideci 4, Buket Dalgic 2, Sukru Hatun 1

Potential celiac children: 9-year follow-up on a gluten-containing diet Renata Auricchio 1, Antonella Tosco 1, Emanuela Piccolo 1, Martina Galatola 1, Valentina Izzo 1, Mariantonia Maglio 1, Francesco Paparo 1, Riccardo Troncone 1, Luigi Greco 1

Interpreting positive celiac serology in children with new-onset type 1 diabetes Lydia Ramharack 1, Colin P Hawkes 2 3 4, Paige Coughlin 1, Lionola Juste 1, Sando Ojukwu 2 5 6, Steven M Willi 2 6, Arunjot Singh 1 6

ASSOCIATIONS OF LEPTIN WITH IGF-1 AND IGFBP-3 IN CHILDREN

Pauline Aust ^a , Mandy Vogel ^a , Jürgen Kratzsch ^a , Wieland Kiess ^a

^a Universität Leipzig, LIFE–Leipzig Research Center for Civilization Diseases, Leipzig, Germany

Introduction and Objectives

Leptin, IGF-1, and IGFBP-3 are key regulators of growth and metabolism in children. While a positive association between these hormones has been reported, studies involving large cohorts of healthy children are limited. This study aimed to examine whether leptin is correlated with IGF-1 and IGFBP-3 in children.

Methods

We analyzed 1431 serum samples from 898 healthy children aged 0.25-6 years, participating in the LIFE Child study, a longitudinal cohort study at Leipzig University. Serum concentrations of leptin, IGF-1, and IGFBP-3 were measured via chemiluminescence immunoassay (CLIA). IGF-1, IGFBP-3, leptin, and BMI were transformed into age standard deviation scores (SDS). Age and BMI-SDS were considered potential confounders. Associations between variables of interest were assessed using regression models.

Results

Leptin-SDS showed a strong positive association with IGF-1-SDS (β = 0.22, p < 0.001) and IGFBP-3-SDS (β = 0.15, p < 0.001). These associations were amplified at higher BMI-SDS levels. Age had a small but significant effect on leptin-SDS (β = 0.02, p = 0.032), while sex had no influence on any of the associations.

Conclusions

In early childhood, leptin is positively associated with both IGF-1 and IGFBP-3. This relationship depends on BMI-SDS. Children with higher BMI-SDS exhibit a stronger association between leptin and both components of the IGF system.

HOW SOCIOECONOMIC STATUS IMPACTS THE EFFECTIVENESS OF PAEDIATRIC OBESITY TREATMENT: RESULTS FROM LARGE REGISTRIES IN SWEDEN AND GERMANY

Marie Auzanneau ^a,b , Resthie Putri ^c , Martin Wannack ^d , Pernilla Danielsson ^c , Stefanie Lanzinger ^a,b , Emilia Hagman ^c

^a Ulm University, Institute of Epidemiology and Medical Biometry, Ulm, Germany; ^b German Center for Diabetes Research (DZD), Munich-Neuherberg, Germany; ^c Karolinska Institutet, Division of Pediatrics, Department of Clinical Science, Intervention, and Technology (CLINTEC), Stockholm, Sweden; ^d Charité Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin und Humboldt-Universität zu Berlin, Department of Pediatric Endocrinology and Diabetology, Center for Social-Pediatric Care, Berlin, Germany

Introduction and Objectives

In high-income countries, a lower socioeconomic status (SES) is often associated with higher levels of paediatric obesity and with lower compliance to treatment. However, high-quality evidence based on large and representative populations is lacking and results are inconsistent. Our aim was to evaluate how SES impacts the effectiveness of paediatric obesity treatment over years in two high-income European countries, using longitudinal data from the paediatric obesity treatment registries BORIS (Sweden) and APV (Germany).

Methods

We included children (3–17 years) receiving lifestyle behavioural obesity treatment between 2000–2020. Surgical and pharmacological treatment were excluded. BMI Standard Deviation Scores (BMI SDS) were recorded from the initial visit up to 36 months of treatment. SES comprised data on education, income, and occupation at district level in Germany and individual level in Sweden. We used adjusted regression models to compare the changes in BMI SDS (with repeated measurements) and the probability of no longer having obesity (obesity remission) in the children of highest vs. lowest SES quintile.

Results

Of 32,176 children included (BORIS: 18,588, APV: 13,588), 51% were males. At treatment initiation, the median age was 10.5 years (8.2, 12.7), and the median BMI SDS was 2.80 (2.54, 3.12). Children of the highest SES had significantly lower BMI SDS at baseline compared to those of the lowest (adjusted estimates [95%CI]: 2.81 [2.75 – 2.87] vs. 2.93 [2.87– 2.99], p <0.001). In addition, children of highest SES had the highest decrease in BMI SDS over time, with the greatest difference at 24 months compared to children of the lowest SES (adjusted change: -0.31 [-0.37– -0.25] vs. -0.24 [-0.29 – -0.19], p<0.001). The adjusted probability of obesity remission was the greatest at 36 months for the highest SES: 49.6% [47.7 – 51.4] vs. 41.0% [39.6 – 42.3] in the lowest.

Conclusions

In Sweden and Germany, low SES is not only associated with higher levels of paediatric obesity, but also with a lower decrease of BMI SDS during the first two years of treatment. Even when guideline-conform treatment programs are provided, effectiveness of obesity treatment is significantly reduced in children of lower SES. New concepts are needed to help children of lower SES to enhance compliance and increase the benefit of the treatment.

“LEBEN MIT ADIPOSITAS” – DEVELOPMENT OF A DIGITAL INFORMATION PLATFORM TARGETING CHILDREN AND ADOLESCENTS WITH OBESITY, THEIR PARENTS, AND HEALTH CARE PROVIDERS WITHIN THE FRAMEWORK OF THE GERMAN CENTER FOR CHILD AND ADOLESCENT HEALTH (DZKJ)

Agnes Bauer ^a,d , Stephanie Brandt-Heunemann ^a,d , Sebastian Brötzler ^b,d , Katrin Erlewein ^c,d , Jörg M. Fegert ^c,d , Gerke Jelena ^c,d , Lena Sasse ^b,d , Lea Schmid ^a,d , Aydin Spieler ^b,d , Lena S. Steubl ^b,d , Harald Baumeister ^b,d , Miriam Rassenhofer ^c,d , Martin Wabitsch ^a,d

^a Universitätsklinikum Ulm, Kinder- und Jugendklinik, Sektion Pädiatrische Endokrinologie und Diabetologie, Ulm, Germany; ^b Universität Ulm, Abteilung Klinische Psychologie und Psychotherapie, Ulm, Germany; ^c Universitätsklinikum Ulm, Sektion Kinder- und Jugendlichenpsychotherapie und Verhaltensmedizin, Ulm, Germany; ^d Standort Ulm, Deutsches Zentrum für Kinder- und Jugendgesundheit (DZKJ), Ulm, Germany

Introduction and Objectives

Obesity in childhood and adolescence is a chronic disease with far-reaching consequences. Despite its high prevalence and relevance, a low-threshold, target group-specific, and scientifically sound information platform is lacking. The “Leben mit Adipositas” information platform, being developed at the German Center for Child and Adolescent Health (DZKJ), aims at raising awareness for obesity, presenting evidence-based knowledge in an understandable format, and supporting young people living with obesity, their families and health care professionals in dealing with the disease.

Methods

In order to identify relevant topics, a competitive analysis of existing webpages and systematic literature research on obesity-specific topics in childhood and adolescence were conducted. Starting from this content collection, the overarching website structure and target group-specific topics were defined. Based on an initial platform version, the content and its presentation will be further developed in a participatory manner. Usage data will serve to further optimize usability and dissemination.

Results

The website structure encompasses the four main areas: understanding, living, acting, discovering, and the additional area immediate assistance. A first version of the information platform is currently being developed, featuring an interactive user interface and target group-specific content in texts, images, and videos. Further participatory development involving all three target-groups will gather as the target groups’ needs as their feedback to the first version of the platform.

Conclusions

By mid-2026, an information platform will be created for young people with obesity, their parents, and health care providers, providing information on the background, consequences, treatment options, and coping strategies for obesity. In the future, the platform will serve as the starting point for a research infrastructure.

INVOLVEMENT OF THOSE AFFECTED IN THE EDUCATION OF CHILDREN AND ADOLESCENTS WITH TYPE 1 DIABETES (T1D) – A FOCUS GROUP STUDY

Bettina Berger ^a , Dörte Hilgard ^b , Ekkehart Jenetzky ^a , David Martin ^a , Reinhard Holl ^a

^a University Witten/Herdecke, Department of Health, Witten, Germany; ^b Pediatric Endocrinology and Diabetology, Primary Psychosomatic Care, Witten, Germany

Introduction and Objectives

The proportion of children living with T1D is increasing. Taking responsibility for blood sugar regulation is a challenge even with increasing technical support. According to the guidelines, training is part of the treatment, but is offered less and less. An innovative out-of-hospital training program – GaDiaKi – has received funding from the German Innovation Fund. One challenge in the statutory health insurance system is the partial financing of one of the relevant innovative component: the training assistants who are affected themselves.

Methods

What significance do those affected attach to their role as training assistants in the newly developed GaDiaKi training programme – for the training courses as a whole and for the children and young people?

Methods: Focus group interviews, based on a structured interview guideline, content analysis evaluation, in the context of Zoom meetings in March 2025. The recording and transcription of the recordings was approved.

Results

11 people aged 17 to 35 who are currently or will be working as training assistants in holistic out-of-hospital training programs at Witten Pediatric Diabetology took part in three focus groups. The following codes could be identified: a) Significance of there work for children and adolescents b) Their importance in the diabetes team c) Coping with emotional situations d) Diabetes self-management with and without automated insulin delivery (AID). From the perspective of the training assistants, the inclusion of self -affected training assistances enables a) the children to better integrate the disease into everyday life, b) the diabetes team to concentrate on medical tasks; c) to support the KuJ individually and emotionally d) to cope with diabetes self-management

Conclusions

Training assistants themselves play an indispensable role in the realization of innovative, non-residential training programs for children and adolescents with type 1 diabetes. Long-term funding opportunities for this valuable component of GaDiaKi training must be identified. The innovation fund project that has already been approved requires suitable financing options for the training assistants who are affected themselves, especially if it is taken over into standard care.

References

Hilgard, D., Galler, A., Klinkert, C., Kulzer, B., Saszmann, H., & Holl, R. (2025, May). From group to individual: how paediatric diabetes education is changing in the era of technology. In Endocrine Abstracts (Vol. 110). Bioscientifica.

Berger B, Sethe D, Hilgard D, Martin D, Heusser P. Design of a Self-Management Program for Children Aged 6-12 Years with Type 1 Diabetes Mellitus at the Community Hospital Herdecke, Germany. Complement Med Res. 2017;24(4):255-263. doi: 10.1159/000479532. Epub 2017 Aug 21. PMID: 28848133.

IMPROVED GLYCEMIC CONTROL FOLLOWING TRANSITION FROM MDI OR NON-AUTOMATED PUMP PLUS CGM TO MYLIFE CAMAPS FX SYSTEM: AN EARLY ANALYSIS OF THE DPV REGISTRY DATA

Torben Biester ^a , Johannes Hamann ^b , Andreas Schmidt ^c , Silke Herrlinger ^d , Julia Rohayem ^e , Alexander Eckert ^f,g , Sabine Hofer ^h , DPV

^a Children’s Hospital AUF DER BULT, Diabetes Center for Children and Adolescents, Hanover, Germany; ^b Children’s Hospital St Marien, Landshut, Germany; ^c Christophorus-Kliniken Coesfeld, Diabeteszentrum Dept. of Pediatrics, Coesfeld, Germany; ^d Klinikum Bremen-Mitte, Bremen, Department of Pediatrics, Bremen, Germany; ^e Children’s Hospital of Eastern Switzerland, Department of Pediatric Endocrinology and Diabetology, St.Gallen, Switzerland; ^f Ulm University, Institute of Epidemiology and Medical Biometry, Ulm, Germany; ^g German Centre for Diabetes Research (DZD), Neuherberg, Germany; ^h Medical University of Innsbruck, Department of Pediatrics I, Innsbruck, Austria

Introduction and Objectives

Limited research is available on the transition from multiple daily injections (MDI) or non-automated insulin pump therapy with CGM (SaP) to automated insulin delivery (AID) systems. The DPV registry offers relevant real-world data to assess therapy outcomes in paediatric population.

This analysis aimed to assess changes in glycaemic outcomes among paediatrics who transitioned from MDI with CGM/SaP, to the mylife CamAPS FX system based on DPV data. This AID system has been available since 2022 and consists of the app-based AID algorithm mylife CamAPS FX, the YpsoPump and two CGM brands.

Methods

This study is a retrospective analysis using data until Dec 2023 from the DPV registry. It focused on individuals transitioning to mylife CamAPS FX system from MDI+CGM or CSII+CGM (excluding PLGS) with the following criteria at transition: age <21 y, at least 1 y of T1D, >90 days of CamAPS FX use, HbA1c available before and after the transition. A sub-analysis was conducted for individuals with HbA1c >7% before the transition. Data are presented as median+IQR.

Repeated measures linear and fractional logistic regression models were used to study changes in HbA1c and TIR before vs after switch.

Results

The cohort included 114 individuals. 50 transitioned from MDI+CGM (48% male, age 12.0 [9.0-15.1] y, diabetes duration 1.5 [0.9-2.7] y, BMI-SDS 0.55 [-0.27; 1.29] and 64 from CSII+CGM (56% male, age 10.8 [6.8; 14.8] y, diabetes duration 4.9 [2.3; 7.8] y, BMI-SDS 0.34 [-0.30; 0.91].

HbA1c [%] significantly improved after transition to AID in both groups: from 7.3 [95%-CI: 7.0-7.6] to 6.8 [6.5-7.1] in MDI (p<.001), and from 7.4 [7.2-7.7] to 7.2 [6.9-7.5] in CSII group (p=0.003).

In a subset with an HbA1c >7% before transition, HbA1c decreased in both groups [%]: 7.9 [7.5-8.3] to 7.1 [6.7-7.5] in MDI (n=30; p<.001); 7.8 [7.5-8.2] to 7.5 [7.2-7.9] in CSII group (n=44; p=0.005).

TIR increased by approximately 12 and 11 percentage points in MDI (n=30; p<.001) and CSII (n=38; p<.001) group.

Conclusions

Insulin therapy with the present AID system was associated with improved glycemic outcomes (lower HbA1c and increased TIR) compared to previous therapies (MDI and CSII).

The improvement in glycaemic outcomes was particularly pronounced among individuals who had not previously achieved the general HbA1c target of 7% during prior open-loop therapy.

To evaluate these metrics in a broader population, a higher completeness of CGM data in DPV is needed which is expected for the coming years.

References

Research support to DPV for this analysis provided by Ypsomed Diabetes Care.

REAL-WORLD PERFORMANCE OF THE OMNIPOD® 5 AUTOMATED INSULIN DELIVERY SYSTEM IN CHILDREN AND ADOLESCENTS WITH TYPE 1 DIABETES IN GERMANY

Torben Biester ^a , Dorothee Deiss ^b , Sven Golembowski ^c , Stefanie Liebl ^d , Jantje Weiskorn ^a , Duy Do ^e , Irene Hadjiyianni ^e , Trang Ly ^e

^a Children’s Hospital AUF DER BULT, Diabetes Centre for Children and Adolescents, Hanover, Germany; ^b DRK-Kliniken Berlin Westend, Diabetes Center for Children and Adolescents, Berlin, Germany; ^c Sana Klinikum Lichtenberg, Diabetes Center for Children and Adolescents, Berlin, Germany; ^d KJF Klinikum Josefinum, Division of Pediatric Endocrinology and Diabetology, Dept. of Pediatrics and Adolescent Medicine, Augsburg, Germany; ^e Insulet Corporation, Acton, United States

Introduction and Objectives

The Omnipod® 5 Automated Insulin Delivery (AID) System allows for personalized therapy through customizable glucose targets from 110-150mg/dL (6.1-8.3mmol/L) in 10mg/dL (0.55mmol/L) increments. The System is CE marked for use in individuals ages two years and older with type 1 diabetes (T1D) and has been commercially available in Germany since September 2023. This study aimed to evaluate the real-world performance of the system in children and adolescents with T1D in Germany.

Methods

A retrospective cross-sectional analysis of continuous glucose monitoring (CGM), insulin, and device use data from Omnipod 5 users with T1D (2-17 years) in Germany whose guardian provided consent was conducted for those with sufficient CGM data (≥30 days with ≥1 reading and ≥75% of days with ≥220 readings) between December 1, 2024 to May 20, 2025. Glycemic metrics included time in range (TIR; 70-180mg/dL; 3.9-10.0mmol/L), time below range (TBR; <70mg/dL; <3.9mmol/L), and time in tight range (TITR; 70-140mg/dL; 3.9-7.8mmol/L). Results are shown as median, stratified by age and target setting.

Results

A total of 5,822 users met the inclusion criteria for analysis. TIR was 66% (n=2,814), 66% (n=1,993), and 65% (n=1,015) with use of the 110mg/dL (6.1mmol/L), 120mg/dL (6.7mmol/L), and 130-150mg/dL (7.2-8.3mmol/L) targets, respectively, and TBR was low at 1.6% across all target setting subgroups. Use of the lowest target was associated with some age-related variability in TIR (2-5y: 68% [n=105]; 6-12y: 69% [n=1,169]; 13-17y: 64% [n=1,540]). Across age groups, use of the lowest target was also associated with a high TITR (41-47%), low TBR (1.4-2.3%), and a high percentage of time spent in Automated Mode (94-96%). Among this subgroup, total daily insulin use was 13U, 32U, and 53U for users aged 2-5y, 6-12y, and 13-17y, respectively, and users delivered 4.0-7.6 boluses/day across age groups.

Conclusions

Collectively, these results in >5,800 children and adolescents with T1D in Germany demonstrate that favorable glycemic outcomes can be achieved with Omnipod 5 use in the real world. These findings also support the idea that users seeking to improve TIR should consider decreasing their glucose target toward the lowest setting whenever possible.

THE ROLE OF SCREEN TIME IN PUBERTY TIMING: FINDINGS FROM THE ADOLESCENT BRAIN DEVELOPMENT (ABCD) STUDY

Luise Bläschke ^a , Franka E. Weisner ^a , Anke Hinney ^a,b , Raphael Hirtz ^c , Lars Dinkelbach ^a,d

^a University Hospital Essen, University of Duisburg-Essen, Institute of Sex- and Gender-sensitive Medicine, Essen, Germany; ^b University Hospital Essen, University of Duisburg-Essen, Section of Molecular Genetics in Mental Disorders, Essen, Germany; ^c Helios University Hospital Wuppertal, Witten/Herdecke University, Center for Child and Adolescent Medicine, Essen, Germany; ^d University Hospital Essen, University of Duisburg-Essen, Department of Pediatrics II, Essen, Germany

Introduction and Objectives

During the COVID-19 pandemic, several countries observed a rise in the incidence of precocious puberty. Increased screen time has frequently been proposed as a potential contributing factor [1]. In animal research, experimental exposure to blue light, comparable to that emitted by digital screens, was linked to earlier pubertal onset in rats [2, 3]. This study aimed to examine the association between screen time during late childhood and subsequent puberty timing in 10,875 participants (47.9% female) from the ABCD Study, a longitudinal cohort conducted at 21 sites across the United States.

Methods

To address the research question, two methods were employed. First, linear mixed models (adjusting for sex, age, ethnicity, SES, physical activity, and BMI) assessed the link between daily screen time at baseline (age 9.9 ± 0.6 years) and puberty timing, measured annually via the parent-reported Pubertal Development Scale (PDS) up to the age of 14.1 ± 0.7 years. Second, the cohort was divided into screen time quintiles (h/day: very low [0–1.3], low [1.3–2.0], moderate [2.0–2.8], high [2.8–4.0], very high [ > 4.0]), and the age reaching mid-puberty (PDS stage 3) was compared across groups.

Results

Higher screen time was associated with a younger age at reaching mid-puberty (PDS stage 3): this milestone was reached at 11.8 ± 1.4 years in the very low group, 11.7 ± 1.5 in the low group, 11.7 ± 1.5 in the moderate group, 11.6 ± 1.5 in the high group, and 11.4 ± 1.5 years in the very high screen time group. Likewise, higher screen time at baseline was associated with accelerated pubertal timing–measured as relative puberty status (standard deviation scores) compared to same-aged, same-sex peers–at follow-up years 1–3, with strongest effects at year 2 (age 12.0±0.7) in both males (B [95%CI]= 0.027 [0.013-0.04]) per hour screen time and females (B [95%CI]= 0.042 [0.028, 0.057]). No significant associations were observed at year 4.

Conclusions

Higher screen time in late childhood was linked to earlier puberty. Children with very high screen use reached mid-puberty ∼4.3 months earlier than peers with very low use. Effects were stronger in females and during mid-adolescence and remained robust across models and confounder adjustments. Overall, the findings indicate that screen time in late childhood is associated with accelerated pubertal development and should be considered in parental guidance on children’s screen media use. Further research is needed to determine whether this link is causal or driven by residual confounding.

References

1. Hoskyns, R.B. and S.R. Howard, Effects of the COVID-19 pandemic on the incidence of central precocious puberty; a narrative review. Journal of Pediatric Endocrinology and Metabolism, 2024. 37(2): p. 102-109.

2. Uğurlu, A.K., et al., Is blue light exposure a cause of precocious puberty in male rats? Frontiers in Endocrinology, 2023. 14: p. 1190445.

3. Uğurlu, A.K., et al., Effects of blue light on puberty and ovary in female rats. Journal of clinical research in pediatric endocrinology, 2023. 15(4): p. 365.

HEALTH-RELATED QUALITY OF LIFE OF CHILDREN WITH X-LINKED HYPOPHOSPHATEMIA TREATED WITH BUROSUMAB AND ITS CLINICAL PREDICTORS

Ineke Böckmann ^a , Martin Klein ^b , Michael Obermaier ^b , Helena Mutze ^b , Dirk Schnabel ^c , Dieter Haffner ^a

^a Hanover Medical School, Department of Pediatric Kidney, Liver, Metabolic and Neurological Diseases, Hanover, Germany; ^b Catholic University of Applied Sciences North Rhine Westphalia, Department of Social Sciences, Cologne, Germany; ^c University Medicine Charité Berlin, Center for Chronically Sick Children, Pediatric Endocrinology, Berlin, Germany

Introduction and Objectives

X-linked hypophosphatemia (XLH) is the most common genetic cause of hypophosphatemic rickets resulting in growth failure, leg deformaties, bone pain, tooth abscess, overweight and various other symptoms. Current clinical guidelines recommend treating children with XLH with burosumab, a monoclonal antibody targeting FGF23. The impact of burosumab on health-related quality of life (HRQoL) in XLH-patients and its clinical predictors is largely unknown.

Methods

HRQoL was assessed in 64 pediatric XLH patients (36 female) with a median age of 13.1 years enrolled in a prospective observational study and patient registry in Germany and Switzerland, using the KIDSCREEN-52 questionnaire. Associations between HRQoL and clinical or laboratory parameters were analyzed using Spearman’s rank correlation, stepwise multivariable regression, and receiver operating characteristics (ROC) curve analyses.

Results

Patients received burosumab at a median dose of 0.63 mg/kg every 14 days for 2.8 years. Prior to burosumab, 35 (55%) patients were treated with phosphate salts and active vitamin D (P+VitD). Overall, HRQoL scores were comparable to German reference values. Multiple regression analyses showed an association of burosumab dose with better HRQoL in self-reports (total, physical, psychological, self-perception) and physical well-being in proxy reports. The duration of prior P+VitD treatment was associated with autonomy and parental relation (self-report) and autonomy (proxy). ROC analyses identified burosumab dose as a good predictor of physical well-being in self- (AUC=0.777,95%CI 0.611–0.942, p=0.006) and proxy-reports (AUC=0.744, 95%CI 0.606–0.882, p=0.003) with a cut-off of 0.6 mg/kg/14d.

Conclusions

In this real-world study of pediatric XLH patients, HRQoL was comparable to that of their healthy German peers. Burosumab dosage was positively associated with well-being, with an optimal cut-off value of 0.6 mg/kg/14d. Incorporating HrQoL into the management and adjustment of medication dosage appears to be relevant.

BIOIMPEDANCE IN CHILDREN AND ADOLESCENTS BETWEEN 5 AND 18 yearS OF AGE AND ITS ASSOCIATION WITH OVERWEIGHT AND OBESITY

Klara R.M. Böker ^a , Mandy Vogel ^a,b , Annelie Grundmann ^a , Wieland Kiess ^a,b

^a Universität Leipzig, Medizinische Fakultät, Leipzig, Germany; ^b Deutsches Zentrum für Kinder- und Jugendgesundheit (DZKJ), Leipzig, Germany

Introduction and Objectives

Bioimpedance analysis (BIA) is a widely used and accessible method for estimating fat-free mass (FFM) and fat mass (FM). BIA devices are non-invasive and use resistance and reactance to approximate body composition. Its use in pediatrics is debatable, as there is conflicting evidence about the precision of the measurements (resistance, reactance, and the resulting FFM and FM). Therefore we aim to determine age- and sex-adjusted reference intervals for segmental resistance and reactance measurements. Further, we will evaluate their association with different measures of weight status.

Methods

FM and FFM estimates based on 2,954 BIA measurements (BIACORPUS RX 4000) from 1,547 children and adolescents aged 5–18 years were compared with skinfold-based-estimates using Bland-Altman analysis. We created percentile curves for height-normalized resistance (Rz/H) and reactance (Xc/H) based on age and sex. We used the overall concordance correlation coefficient (OCCC), the concordance correlation coefficient (CCC), and the intraclass correlation coefficient (ICC) to determine the agreement between BIA measurement segments.

Results

Bioimpedance-based FM estimates were lower than skinfold-based estimates, particularly for boys. Further, these discrepancies depended on weight status. The ICC demonstrated ‘excellent’ agreement (ICC >0.9 by Koo and Li) between all segmental measurements. The OCCC and CCC exhibited varying degrees of concordance. The Rz/H and Xc/H percentile curves presented similar age-related and sex-related patterns across all body segments. Rz/H (SDS) and Xc/H (SDS) levels were found to be generally lower in study participants with obesity than in the normal weight reference population.

Conclusions

Rz/H and Xc/H were strongly dependent on age and BMI-SDS. For children of normal weight, estimates of body fat based on BIA and skinfold measurements showed good agreement. However, our results suggest that the current estimation techniques may be inadequate for children and adolescents with severe obesity. This underscores the necessity for a reevaluation of the methods used to estimate body fat in this particular group.

WEEKLY SOMAPACITAN IS EFFECTIVE AND WELL-TOLERATED IN CHILDREN BORN SMALL FOR GESTATIONAL AGE: RANDOMISED PHASE 3 TRIAL

Volker Böttcher ^a , Stefanie Meckes-Ferber ^b , Agnès Linglart ^c , Michael Højby ^d , Carlos A. Longui ^e , Lawrence Silverman ^f , Kenichi Kashimada ^g

^a MVZ Endokrinologikum Frankfurt am Main, Division of Pediatric Endocrinology and Metabolism, Frankfurt, Germany; ^b Novo Nordisk Germany, Medical Affairs Rare Disease, Mayence, Germany; ^c Université Paris-Saclay, Inserm, Hôpital Bicêtre Paris Saclay, Service d’Endocrinologie et Diabète de l’enfant, Le Kremlin-Bicêtre, France; ^d Novo Nordisk A/S, Medical & Science, Rare Disease & Advanced Therapies, Søborg, Denmark; ^e Irmandade da Santa Casa de Misericórdia de São Paulo and Santa Casa de São Paulo School of Medical Sciences, Pediatric Endocrinology Unit, Pediatric Department, São Paulo, Brasil; ^f Goryeb Children’s Hospital, New Jersey, United States; ^g Tokyo Medical and Dental University, Department of Pediatrics and Developmental Biology, Tokyo, Japan

Introduction and Objectives

Persistent short stature in children born small for gestational age (SGA) is treated with daily growth hormone (GH) injections, which can be burdensome for patients and caregivers. Somapacitan is a long-acting reversible albumin-binding GH derivative in development for once-weekly subcutaneous administration in short children born SGA.

Methods

The reported study is a randomised, multi-national, open labelled, and active-controlled parallel group phase 3 study, comprising a 52-week main phase and a two-year extension period (NCT05330325). In total, 142 GH-treatment-naïve, prepubertal short children born SGA (51.4% female) were randomly assigned 2:1:1 to receive somapacitan 0.24 mg/kg/week (n=70), daily GH 0.035 mg/kg/day (n=37), or daily GH 0.067 mg/kg/day (n=35), all administered subcutaneously. There were 140 children that completed 52 weeks of treatment.

Results

The primary endpoint was annualised height velocity (HV) after 52 weeks of treatment. At week 52, estimated mean HV was 11.0 cm/year for somapacitan vs. 9.4 and 11.1 cm/year for daily GH 0.035 and 0.067 mg/kg/day, respectively. Non-inferiority in HV at week 52 of somapacitan compared to both daily GH doses was confirmed (non-inferiority threshold: -1.6 cm/year). Superiority of somapacitan compared to daily GH 0.035 mg/kg/day was achieved (p<0.0001).

IGF-I standard deviation score (SDS) increased for all groups. At week 52, mean (SD) IGF-I SDS was +1.92 (1.17) for somapacitan compared to +1.05 (1.33) and +2.10 (1.33) for daily GH 0.035 and 0.067 mg/kg/day, respectively.

Somapacitan was well tolerated, with no safety or local tolerability issues identified.

Conclusions

In conclusion, HV response after 52 weeks of somapacitan 0.24 mg/kg/week showed superiority to daily GH 0.035 mg/kg/day and non-inferiority to daily GH 0.067 mg/kg/day with a similar safety profile and IGF-I response in treatment-naïve children born SGA.

EFFECTS OF GROWTH HORMONE THERAPY ON MUSCULAR CONSTITUTION IN A CHILD WITH NOONAN SYNDROME

Max Braun, Oliver Semler, Heike Hoyer-Kuhn

Klinik und Poliklinik für Kinder- und Jugendmedizin, Uniklinik Cologne, Spezialambulanz für Hormon- und Skeletterkrankungen, Cologne, Germany

Introduction and Objectives

We have seen a 9 year old girl with Noonan syndrome. The patient and the parents wanted to start a growth hormone therapy. Under the recommended starting dose of 0.066 mg/kg/d for Noonan syndrome the patient developed a papilledema. Also under a lower dose with 0,03 mg/kg/d the patient developed a papilledema. After regression of the papilledema we decided to try a different growth hormone with a even lower starting dose of 0,025 mg/kg/d.

Under this dosage we have seen an improvement of the muscular function and in the IGF-1 scores.

Methods

Growth, IGF-1 and Esslinger Fitness Index (EFI) was measured before and 17 month after starting the treatment with growth hormone with a dosage of 0,025 mg/kg/d.

The EFI is measured using a jump platform and the associated software. In our case, the single two-leg jump (s2LJ) was recorded, which measures the performance of the musculoskeletal system. The reference values are based on a study by Runge et al., in which a value of 100% is given as the mean of the healthy normal population of the respective age.

Results

The patients height improves from 121,8 cm (-3,48 SD) to 130,6 cm (-3,29 SD) and the IGF-1 from 46,7 ug/l (118-448) to 156 ug/l (170-527).

The Esslinger Fitness Index improves from -2,88 SD to -1,28 SD.

The parents report a significant increase in quality of life due to improved muscular function.

Conclusions

Although the increase in height is not significant, the increase in IGF-1 concentration and the improvement in muscle function are clearly demonstrable. The latter, in particular, is more significant for the patient and her parents than the increase in height. Therefore, muscle function and its significance for the patient should also be screened during growth hormone therapy for Noonan syndrome. If necessary, significantly lower doses than those prescribed for Noonan syndrome are possible.

⁶⁸GA-EXENDIN-4 PET FOR SUSPECTED FOCAL CONGENITAL HYPERINSULINISM: HEAD-TO-HEAD COMPARISON WITH ¹⁸F-DOPA PET

Laurina Bühner ^a , Julian Rogasch ^b , Felix Feldhaus ^b , Martin Gotthardt ^d , Steven Warmann ^c , Peter Kühnen ^a , Winfried Brenner ^b , Oliver Blankenstein ^a , Christian Furth ^b

^a Charité - Universitätsmedizin Berlin, Department of Paediatric Endocrinology and Diabetology, Berlin, Germany; ^b Charité - Universitätsmedizin Berlin, Department of Nuclear Medicine, Berlin, Germany; ^c Charité - Universitätsmedizin Berlin, Department of Pediatric Surgery, Berlin, Germany; ^d Radboud University, Department of Nuclear Medicine, Nijmegen, Netherlands

Introduction and Objectives

Congenital hyperinsulinism (CHI) is a critical condition predominantly manifesting in neonates through severe hypoglycemia. Importantly, CHI is differentiated into focal and diffuse forms based on the distribution of affected beta cells. ¹⁸F-DOPA PET CT is currently the standard procedure to differentiate between focal and non-focal forms. However, limited tracer availability and difficulties in detection of so-called giant foci remain challenges.

Recently, ⁶⁸Ga-Exendin-4 PET has been introduced as an alternative tracer within a multicentre trial.¹

Methods

In this study, we aimed to expand on our previous work to further validate the diagnostic performance of ⁶⁸Ga-Exendin-4 PET scans in patients with suspected focal forms of CHI.¹ We performed a retrospective, monocentric analysis of 35 CHI patients consecutively scanned both with ¹⁸F-DOPA PET/CT and ⁶⁸Ga-Exendin-4 PET/MRI. All PET scans were interpreted by four blinded readers. In case of surgery, histopathology was used as a reference standard.

Results

22 of 35 patients (63%) had focal CHI and 13 patients (37%) non-focal CHI according to the reference standard. ¹⁸F-DOPA PET and ⁶⁸Ga-Exendin-4 PET with standardized reading instructions demonstrated comparable sensitivity and specificity for detecting the focal region, with no significant differences observed. All patients diagnosed with focal CHI underwent ⁶⁸Ga-Exendin-4-guided surgery and the diagnosis of focal CHI was confirmed by histopathology.

Conclusions

⁶⁸Ga-Exendin-4 PET is an accurate alternative to ¹⁸F-DOPA PET in distinguishing focal from diffuse CHI. A key advantage of ⁶⁸Ga-Exendin-4 lies in its potential for intraoperative use, facilitating precise surgical localization of focal lesions.² In addition, the broader availability also in low and middle income counties of ⁶⁸Ga-Exendin-4 compared to ¹⁸F-DOPA may significantly improve access to molecular imaging for patients with suspected focal CHI, particularly in centers where ¹⁸F-DOPA PET is not routinely accessible.

References

¹ Boss M, Rottenburger C, Brenner W, et al. ⁶⁸Ga-NODAGA-Exendin-4 PET/CT Improves the Detection of Focal Congenital Hyperinsulinism. J Nucl Med. 2022;63:310-315.

² Kühnen P, Prasad V, Rothe K, et al. ⁶⁸Ga-labelled Exendin for radioguided surgery of intrapancreatic insulin producing lesions in patients with congenital hyperinsulinism: Proof of concept. Submitted.

A RARE CASE OF A PRIMORDIAL DWARFISM – WHAT TO BEAR IN MIND

Nina Captan ^a , Julia Rohayem ^a

^a Children’s Hospital of Eastern Switzerland, Department of Paediatric Endocrinology and Diabetology, St.Gallen, Switzerland

Introduction and Objectives

A 2.5-year-old boy was presented in the outpatient endocrine clinic for primordial dwarfism. The child was born small for gestational age (SGA) with a birth weight of -3.34 SD and a birth length of -5.08 SD. At physical examination he had proportionate short stature (-6.01 SD), microcephaly (-3.11 SD), muscular hypotonia and dysmorphic features, including frontal bossing, a triangular elongated face, low-set ears, deep-set eyes and short fingers. His language acquisition was delayed. Bone age was delayed by 8 months.

Methods

The radiographic features included short and wide long bones, cup-shaped metaphyses and cone-shaped epiphyses. Laboratory tests showed normal parameters including clinical chemistry, hematology and metabolic parameters. Specifically, IGF1, IGFBP3 and cortisol serum levels were normal. Growth hormone deficiency and adrenal insufficiency was in addition excluded by a glucagon stimulation test. Genetic testing revealed a normal male karyotype (46, XY), and genetic analysis was negative for a Silver-Russel syndrome.

Results

After meeting the SGA criteria for a treatment with rhGH, this treatment was initiated. However, no significant catch-up growth was observed and treatment was ceased after 3 years. Genetic re-evaluation was performed using Trio Whole Exome Sequencing. This revealed a pathological homozygous POC1A variant (c.275+2T>Gp.?), that is known to result a nonsense-mediated mRNA decay. This led to a diagnosis of a SOFT syndrome (Short stature, Onychodysplasia, Facial dysmorphism, hypoTrichosis), a monogenic ciliopathy, that is inherited in an autosomal recessive manner (OMIM 614813).

Conclusions

POC1A mutations cause a pathologic multipolar spindle formation, which impairs cell proliferation and induces cellular senescence^1-5. Resistance to IGF1 explains the absence of therapeutic response to growth hormone treatment.

References

1. Shaheen R, Faqeih E, Shamseldin HE, Noche RR, Sunker A, Alshammari MJ, Al-Sheddi T, Adly N, Al-Dosari MS, Megason SG, Al-Husain M, Al-Mohanna F, Alkuraya FS. POC1A truncation mutation causes a ciliopathy in humans characterized by primordial dwarfism. Am J Hum Genet. 2012 Aug 10;91(2):330-6. doi: 10.1016/j.ajhg.2012.05.025. Epub 2012 Jul 26. PMID: 22840364; PMCID: PMC3415549.

2. Koparir A, Karatas OF, Yuceturk B, Yuksel B, Bayrak AO, Gerdan OF, Sagiroglu MS, Gezdirici A, Kirimtay K, Selcuk E, Karabay A, Creighton CJ, Yuksel A, Ozen M. Novel POC1A mutation in primordial dwarfism reveals new insights for centriole biogenesis. Hum Mol Genet. 2015 Oct 1;24(19):5378-87. doi: 10.1093/hmg/ddv261. Epub 2015 Jul 10. PMID: 26162852.

3. Chen JH, Segni M, Payne F, Huang-Doran I, Sleigh A, Adams C; UK10K Consortium; Savage DB, O’Rahilly S, Semple RK, Barroso I. Truncation of POC1A associated with short stature and extreme insulin resistance. J Mol Endocrinol. 2015 Oct;55(2):147-58. doi: 10.1530/JME-15-0090. PMID: 26336158; PMCID: PMC4722288.

4. Perge K, Capel E, Villanueva C, Gautheron J, Diallo S, Auclair M, Rondeau S, Morichon R, Brioude F, Jéru I, Rossi M, Nicolino M, Vigouroux C. Ciliopathy due to POC1A deficiency: clinical and metabolic features, and cellular modeling. Eur J Endocrinol. 2024 Feb 1;190(2):151-164. doi: 10.1093/ejendo/lvae009. PMID: 38245004.

5. Perge K, Capel E, Senée V, Julier C, Vigouroux C, Nicolino M. Ciliopathies are responsible for short stature and insulin resistance: A systematic review of this clinical association regarding SOFT syndrome. Rev Endocr Metab Disord. 2024 Oct;25(5):827-838. doi: 10.1007/s11154-024-09894-w. Epub 2024 Jul 17. PMID: 39017987; PMCID: PMC11470920.

LONG-TERM TREATMENT OF ADRENAL HYPERCORTISOLISM WITH METYRAPONE IN AN INFANT WITH MCCUNE ALBRIGHT SYNDROME (CASE REPORT)

Ayse Nurcan Cebeci ^a , Katja Frederike Gaßmann ^a , Michaela Marx ^a , Pia Ahren ^b , Joachim Woelfle ^a

^a University Hospital Erlangen, Department of Pediatrics and Adolescent Medicine, Erlangen, Germany; ^b Medizinisch Genetisches Zentrum, Munich, Germany

Introduction and Objectives

ACTH-independent hypercortisolism (Cushing Syndrome, CS) in infancy is a rare and early manifestation of McCune Albright Syndrome (MAS). The preferred treatment is bilateral adrenalectomy followed by lifelong glucocorticoid and mineralocorticoid replacement. Here we present the challenges associated with the diagnosis and long-term medical treatment of this rare condition.

Case Report: A 11- months-old boy was referred to our hospital due to failure to thrive.

Methods

CS diagnosis was made based on typical clinical signs (growth retardation, moon facies, elevated blood pressure) and on biochemical findings (elevated serum and urinary cortisol, low ACTH). Ultrasound and MRI gave no evidence for an adrenal tumour, but gave evidence of nephrocalcinosis. The patient exhibited neither café au lait spots nor fibrous dysplasia at diagnosis, however a café au lait spot become visible at 2 years of age. We started a therapy with metyrapone and hydrocortisone (110 mg/kg/d and 8 mg/m²/d, respectively), to which he responded well clinically.

Results

Genetic analysis via Trio-Exome-Sequencing remained inconclusive, whereas analysis via high-sensitive blood circulating cell free DNA (ccfDNA) confirmed a pathogenic GNAS mutation (c.601C>T p.(Arg201Cys)).

In addition, our patient had an unexplained increased GGT activity by the time of diagnosis. Liver enzymes and bilirubin remained in normal range, ALP was slightly elevated, alpha amylase and lipase were normal. During treatment with ursodeoxycholic acid, GGT-levels remained high, in addition CA 19-9 was elevated (162,74 u/ml (N<37)), but decreased during follow-up. No space-occupying lesion was detected despite repeated imaging. Our patient is currently in the 24th month of medical treatment and is tolerating metyrapone well.

Conclusions

In patients with a high clinical suspicion and where a conclusive genetic diagnosis cannot be established, ccfDNA (“liquid biopsy”) should be considered as an informative noninvasive diagnostic method. Metyrapone treatment can represent an alternative to surgery in patients with adrenal CS and was well tolerated in the long term in our patient. The relationship between metyrapone treatment and elevated GGT and CA 19-9 levels remains to be further investigated.

TWO BROTHERS WITH FAMILIAL PALLISTER-HALL SYNDROME (PHS) AND ISOLATED GROWTH HORMON DEFICIENCY (GHD) (CASE REPORT)

Ayse Nurcan Cebeci ^a , Michaela Marx ^a , Petra Schmid-Seibold ^b , Marlene Volz-Fleckenstein ^b , Helmuth-Günther Dörr ^a , Joachim Woelfle ^a

^a Universitätsklinikum Erlangen Kinder- und Jugendklinik, Department of Pediatrics and Adolescent Medicine, Erlangen, Germany; ^b Pediatric Office, Regensburg, Germany

Case Report

PHS is an extremely rare syndrome with an autosomal dominant inheritance due to GLI3 gene mutations. There is a wide spectrum of associated abnomalies including endocrine dysfunction with two characteristic symptoms, hypothalamic hamartoma (HH) and polydactyly (PD).

We report on two brothers with PHS, who were born at term with normal birth sizes. The German parents were non-consanguineous (target height 174 cm; -0.81 SDS), and apart from the maternal history of PD, otherwise healthy. The postnatal psychomotor development was normal.

Case 1: The index case presented at the age of 7 years with short stature (H-SDS -3.4) and PD. Isolated GHD was diagnosed (GH max.: 3.1 µg/L; IGF1 25 ng/ml). MRI brain revealed a HH. The suspected diagnosis of PHS was confirmed by molecular genetic testing, where a heterozygous mutation in the GLI3 gene was found (also in the mother). GH treatment started at CA 7.3. yrs. After one year of GH, the height velocity was 14.8 cm, and H-SDS increased to -1.82. Puberty started spontaneously; Tanner stage G4 was reached at 12.1 yrs. . GH treatment was discontiuned at CA of 14 years (HSDS 0.65).

The repated MRI revealed no increase in the size of the HH under GH treatment. The GH status was reevaluated 19 months after the end of therapy, but GHD was not confirmed (ITT: max GH 11 ng/ml; IGF1 153 ng/ml). We observed no side effects during GH therapy.

Case 2: At the age of 7.1 yrs. (HSDS -2.2), an isolated GHD (GH max.: 3.9 µg/L; IGF1 38 ng/ml) was also diagnosed in the brother. We also assumed PHS due to HH (found by MRI) and PD, but molecular analysis could not confirm the diagnosis. After one year of GH treatment, the height velocity was 9.3 cm, and HSDS increased to -1.37. Puberty started spontaneously at 11.8 years. The last visit of the patient was at the age of 13 years; his height was 154 cm (+ 0.3 SDS); bone age was 13 yrs., and he had puberty Tanner G3.

We report on two brothers with PHS and isolated GHD. PHS was molecular-genetically confirmed in case 1 and in the mother, but not in case 2. On GH therapy, the sizes of the HH did not increase. We speculate that GHD could be transient in patients with PHS.

ELEVATED FREE T4 WITH NORMAL TSH: A CASE OF FAMILIAL DYSALBUMINEMIC HYPERTHYROXINEMIA (FDH) IN A PEDIATRIC PATIENT

Eleftheria Christofi, Julia Rohayem

Children’s Hospital of Eastern Switzerland, Abteilung für pädiatrische Endokrinologie, St.Gallen, Switzerland

Introduction and Objectives

Elevated levels of free T4 (fT4) and free T3 (fT3) are indicative of hyperthyroidism in the presence of suppressed TSH levels. However, if not accompanied by decreased TSH, distinction between true thyroid pathology and other conditions may be challenging. The patient’s clinical status then focuses on typical symptoms of hyperthyroidism such as weight loss, tachycardia, head intolerance and tremor. If the patient is clinically euthyroid, additional diagnostic steps are indicated.

Methods

A 6-year-old girl with a history of obesity (BMI: 33.5 Kg/m2, z-Score: 5.33) was referred to the pediatric endocrinology clinic for further evaluation of abnormal thyroid function tests. Laboratory results revealed elevated levels of free T4 (35.9 pmol/L, reference range: 6.8-18 pmol/L) and free T3 (11.8 pmol/L, reference range: 3.5-6.4 pmol/L), while thyroid-stimulating hormone (TSH) levels were within the normal range (3.01 mIU/L, reference range: 0.25-4 mIU/L). Despite these findings, the patient showed no clinical signs of hyperthyroidism.

Results

Molecular genetic testing was performed to rule out thyroid hormone resistance due to the mismatch between thyroid hormone levels and absence of clinical symptoms.

Thyroid hormone receptor β gene analysis (THRβ) did not reveal any disease-causing variants. However, sequencing of the albumin (ALB) gene identified a pathogenic heterozygous mutation (c.725G> Ap.(Arg242His)(rs75002628)), indicating a familial dysalbuminemic hyperthyroxinemia (FDH). This ALB variant leads to altered thyroid hormone binding to albumin, which does not affect thyroid hormone action in vivo. However, it results in elevated fT4 levels on routine laboratory thyroid hormone assays, due to the increased binding affinity to albumin, thereby giving rise to falsely elevated fT3 and fT4 serum concentrations.

Conclusions

FDH is characterized by an abnormal albumin molecule with an increased affinity for thyroxin; this gives rise to falsely elevated fT3 and fT4 serum concentrations on standard thyroid hormone assays but does not affect TSH-measurements. High fT3 and high fT4 levels, combined with normal TSH and not accompanied by symptoms of hyperthyroidism should prompt genetic testing for thyroid hormone resistance and FDH.

References

Turkkahraman D, Gullu M, Tekin S, Kalkan T. Familial dysalbuminemic hyperthyroxinemia (FDH) due to Arg242 His variant in ALB gene in Turkish children. J Pediatr Endocrinol Metab. 2024 May 14;37(6):532-535. doi: 10.1515/jpem-2023-0506. PMID: 38736368.

FAILURE TO THRIVE AND HYPONATREMIA IN AN EUTROPHIC TERM BORN GIRL – A RARE CASE OF A PSEUDOHYPOALDOSTERONISM TYPE 1A CAUSED BY A PATHOGENIC VARIANT OF NR3C2

Beate Deubzer ^a , Eleftheria Christofi ^a , Daniela Marx-Berger ^b , Julia Rohayem ^a

^a Children’s Hospital of Eastern Switzerland, Pediatric Endocrinology and Diabetology, Sankt Gallen, Switzerland; ^b Children’s Hospital of Eastern Switzerland, Pediatric Nephrology, Sankt Gallen, Switzerland

Introduction and Objectives

In the neonatal period, there is a variety of differential diagnoses for a failure to thrive and electrolyte dysbalances including several inborn endocrine disorders. Diagnostics may be challenging.

Methods

An eutrophic term born of Caucasian non-consanguine parents was admitted at 8 weeks due to a failure to thrive (drop in weight from P97 to P4), vomiting (no diarrhoe) and a low natrium (Na; 127 mmol/l). Her drinking behaviour had worsened lastly. She was fine without relevant dehydratation and her vital signs normal (HR 124 bpm, RR 96/59 mmHg). Na was again low (120 mmol/l), potassium and the pH normal (6.0 mmol/l; pH 7.42). Extended diagnostics were initiated. With a p.o. substitution the serum Na normalized and the girl quickly gained weight. The Na substitution could be finished at 8 month.

Results

A SIADH, cerebral salt wasting and a salt wasting AGS were unlikely, an aldosterone (Al) synthase defect or a Na loss via kidneys, intestine or skin seemed possible. 17 OHP guthrie and sweat-test were normal. Al and renin serum concentrations were excessively elevated (Al 60600 pmol/l, renin 161000 mIU/l), serum cortisol, DHEAS, androstendione and 17-OHP were normal. Urin Na excretion was high normal.

A type 1a pseudohypoaldosteronism (PHA) was suspected, that is characterised by Al resistance only of the kidneys. Molecular genetics confirmed a pathogenic heterozygote variant of the NR3C2 gene in exon 6, c.2453 C>T; p.(Ser818Leu) rs 12192573. It causes the renal a.d. form PHA1a, equivalent to a renal tubular resistance to Al due to a defective mineralocorticoid receptor (MR) protein.

Conclusions

PHA is a rare, but important differential for neonatal failure to thrive. To differentiate clinically between patients with PHA1a and the more severe, multisystem form PHA1b, iontophoresis is helpful. However, genetic testing is crucial for confirmation of the diagnosis. In PHA1a hyponatremia, hyperkalemia and acidosis are typical findings, though the clinical spectrum is very broad. With increasing age, the disease may lessen due to an increase in the MR receptor protein function and compensatory mechanisms of the renal tubules.

References

Geller et al., 2006; PMID 16611713

Gopal-Kotahndapani et al., 2019; PMID 31301676

Riepe et al., 2006; PMID 16954160

PUBERTY TIMING AND COGNITIVE FUNCTIONING: INSIGHTS FROM THE ADOLESCENT BRAIN COGNITIVE DEVELOPMENT (ABCD) STUDY AND MENDELIAN RANDOMIZATION

Lars Dinkelbach ^a,b , Bianca Serio ^d,c , Sofie Valk ^d,c , Franka E. Weisner ^b , Luise Bläschke ^b , Triinu Peters ^e,b , Anke Hinney ^e,b , Börge Schmidt ^f , Raphael Hirtz ^g

^a University Hospital Essen, Department of Pediatrics II, Essen, Germany; ^b University Hospital Essen, Institute of Sex- and Gender-sensitive Medicine, Essen, Germany; ^c Heinrich-Heine-Universität Düsseldorf, Institute of Systems Neuroscience, Medical Faculty, Düsseldorf, Germany; ^d Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany; ^e University Hospital Essen, Section of Molecular Genetics in Mental Disorders, Essen, Germany; ^f University Hospital Essen, Institute for Medical Informatics, Biometry and Epidemiology, Essen, Germany; ^g Helios University Hospital Wuppertal, Witten/Herdecke University, Center for Child and Adolescent Medicine, Wuppertal, Germany

Introduction and Objectives

Puberty represents a crucial phase in neurodevelopment, marked by changes in cognition and behavior. While early puberty timing has been linked to mental health risks, its relationship with cognitive function remains unclear. This study aimed to examine the association between puberty timing and cognitive performance in youth, investigate potential sex-specific effects, and test for causal relationships using Mendelian randomization.

Methods

In 10,174 participants from the ABCD Study, we assessed associations between puberty timing at baseline (age 9.9±0.6 years) and performance on six cognitive tasks at baseline, 2-year, and 4-year follow-ups. Linear-mixed-regression models were calculated separately by sex, adjusting for bodyweight, birthweight, parental income, and race/ethnicity. To probe causal relationships, we performed Mendelian randomization utilizing external Genome Wide Association Study (GWAS) data on age at menarche (N=632,955), male puberty timing (N=205,354), and executive functioning (N=427,037).

Results

In the ABCD study, earlier puberty timing was associated with poorer performance pooled across timepoints on the NIH Toolbox® Picture Memory Task (girls: standardized β=-0.04, 95%-CI [-0.06, -0.01]; boys: β=-0.03, 95%-CI [-0.05, -0.01]), the List Sorting Working Memory Test (girls: β=-0.03, 95%-CI [-0.06, -0.01]; boys: β=-0.04, 95%-CI [-0.06, -0.01]), and the learning of a word list (girls: β=-0.05, 95%-CI [-0.07, -0.02]; boys: β=-0.04, 95%-CI [-0.06, -0.01]). Mendelian randomization indicated better executive functioning with later menarche (b=0.005/year, 95%-CI [0.000, 0.011]); the association with male puberty timing was directionally consistent but non-significant (b=0.012/year, 95%-CI [-0.004, 0.028]).

Conclusions

Findings suggest a small but consistent link between earlier puberty timing and lower cognitive performance, particularly in memory and executive domains. Mendelian randomization supports a causal role, at least in females. Effect sizes were modest, suggesting that puberty timing within the normal range has negligible clinical relevance for cognitive functioning. However, results indicate a mechanism that may be relevant in markedly early puberty, such as central precocious puberty, and highlight the need to examine cognitive effects of puberty suppression with GnRH analogues.

INCREASED RISK OF PSYCHIATRIC DISORDERS IN CENTRAL PRECOCIOUS PUBERTY: A RETROSPECTIVE COHORT STUDY

Lars Dinkelbach ^a,b , Corinna Grasemann ^c , Cordula Kiewert ^d , Lisa Leikeim ^e , Börge Schmidt ^f , Raphael Hirtz ^g

^a Universitätsklinikum Essen, Klinik für Kinderheilkunde II, Essen, Germany; ^b Universitätsklinikum Essen, Institut für Geschlechtersensible Medizin, Essen, Germany; ^c University Medical Center of the Johannes Gutenberg University Mayence, Department of Pediatrics, Member of ENDO-ERN, Mayence, Germany; ^d University Hospital Essen, Division of Pediatric Endocrinology and Diabetes, Member of ENDO-ERN, Essen, Germany; ^e Gesellschaft für Wirtschaftlichkeit und Qualität bei Krankenkassen (GWQ) ServicePlus AG, Health Data Lab, Düsseldorf, Germany; ^f University Hospital Essen, Institute of Medical Informatics, Biometry and Epidemiology, Essen, Germany; ^g Helios University Hospital Wuppertal, Witten/Herdecke University, Center for Child and Adolescent Medicine, Wuppertal, Germany

Introduction and Objectives

Early onset of puberty, even within the physiological range, has been linked to adverse mental health outcomes. However, data on psychiatric risks in children with central precocious puberty (CPP) remain inconclusive due to small sample sizes and methodological differences. This study aimed to evaluate the risk of psychiatric disorders in patients with idiopathic CPP using a large population-based dataset and to describe the timing of these risks relative to the CPP diagnosis.

Methods

This population-based cohort study analyzed anonymized health insurance records from ∼ 6.5 million individuals in Germany between 2010 and 2023. After applying strict validation criteria, 1,094 individuals with idiopathic central precocious puberty (CPP) were identified (91.3% female) and compared with 5,448 controls matched by sex, birth year interval, duration of insurance coverage, and obesity. The frequency of psychiatric diagnoses–including depression, anxiety, oppositional defiant/conduct disorders (ODD/CD), and attention-deficit/hyperactivity disorder (ADHD)–was compared across groups.

Results

Patients with CPP were significantly more likely to be diagnosed with any psychiatric condition (24.7% vs 16.9%; RR = 1.48, 95% CI [1.31, 1.67]), including depression (7.5% vs 4.6%; RR = 1.73, 95% CI [1.37, 2.20]), anxiety disorders (8.0% vs 5.7%; RR = 1.45, 95% CI [1.16, 1.82]), ODD/CD (8.0% vs 4.5%; RR = 1.76, 95% CI [1.39, 2.23]), and ADHD (11.2% vs 7.3%; RR = 1.53, 95% CI [1.27, 1.86]). Notably, ODD/CD incidence was elevated even before CPP diagnosis. For depression and ADHD, incidence rates remained increased for at least eight years after initial CPP diagnosis. Findings persisted across sensitivity and sex-specific analyses.

Conclusions

To the best of our knowledge, this is the first study to (1) present real-world evidence of increased psychiatric risk in patients with CPP on the basis of more than 1,000 patients, (2) describe temporal trends showing elevated rates of depression and ADHD for up to eight years after diagnosis, and (3) report higher psychiatric risk in males with CPP. Caregivers should monitor psychiatric symptoms, even years after diagnosis. Further research is needed to clarify underlying mechanisms and assess long-term mental health outcomes in this vulnerable group.

References

This work has been published: Dinkelbach, L., Grasemann, C., Kiewert, C., Leikeim, L., Schmidt, B., & Hirtz, R. (2025). Central Precocious Puberty and Psychiatric Disorders. JAMA Network Open, 8(6), e2516679-e2516679.

PATIENT AND CAREGIVER EXPERIENCES WITH SETMELANOTIDE TREATMENT IN BARDET-BIEDL SYNDROME – REAL-WORLD EVIDENCE AND A PATIENT SUPPORT PROGRAM

Lars Dinkelbach ^a , Ilja Finkelberg ^a , Ioanna Polichronidou ^a , Tom Hühne ^a , Pia Brensing ^a , Johannes Jägers ^a , Anja Gäckler ^b , Lars Pape ^a , Metin Cetiner ^a

^a University Hospital Essen, University of Duisburg-Essen, Pediatric Clinic II, Department of Pediatric Nephrology, Gastroenterology, Endocrinology and Sonography, Essen, Germany; ^b University Hospital Essen, University of Duisburg-Essen, Department of Nephrology, Essen, Germany

Introduction and Objectives

Bardet-Biedl syndrome (BBS) is a rare genetic disease resulting from dysfunctional cilia, and is marked by numerous symptoms, among which hyperphagia and early-onset obesity, that can adversely impact the quality of life for both patients and caregivers. The MC4R agonist setmelanotide has demonstrated clinically meaningful weight and hunger reductions in patients with obesity due to BBS. In this study, we evaluated real-world patient expectations and experiences before and during treatment with setmelanotide, as well as the use of a patient support program.

Methods

A one-time survey was conducted online to capture the real-world experiences of patients with BBS and their caregivers with setmelanotide treatment and the patient support program, designed to educate patients and caregivers to allow them to administer injections independently. The survey, including yes/no questions, Likert scale questions and free text questions, was fielded from January 2024 to May 2024, involving participants who began treatment between June 2023 and December 2023 at a single centre in Germany.

Results

Ten paediatric, 13 adult patients, and 12 caregivers participated. Prior to treatment, paediatric patients reported insatiable hunger (80%) and obesity (50%) as most prevalent; adults, vision loss and obesity (69% each); caregivers, obesity (92%) and insatiable hunger (83%). Setmelanotide reduced body weight: ≥92% felt less hunger, more satiated, and reported stable or reduced weight. Improvements were noted in mobility, mood, and behaviour. Common side effects included skin pigmentation changes, (initial) vomiting, diarrhoea, and nausea. The personalized support program led to high satisfaction; over half could self-administer by study end. There was high treatment adherence, no patients discontinuing setmelanotide treatment and an excellent rating of the service by all respondents.

Conclusions

This real-world survey of patients with BBS and their caregivers further demonstrated the meaningful benefits of setmelanotide in improving insatiable hunger and obesity. Personalized nursing support at the initiation of treatment onwards can further facilitate high rates of treatment adherence and satisfaction.

DIABETES CARE FOR CHILDREN FROM UKRAINE IN DRESDEN – CURRENT STATUS AND CHALLENGES

Irena Drozd ^a , Gita Gemulla ^a , Andrea Näke ^a , Susen Reichardt ^a , Monika Flury ^a , Karin Lange ^b

^a Faculty of Medicine and University Hospital Carl Gustav Carus, TU Dresden, Department of Paediatric Endocrinology and Diabetology, Dresden, Germany; ^b Hanover Medical School, Medical Psychology, Hanover, Germany

Introduction and Objectives

Since the onset of the war in Ukraine in February 2022, many refugees, including children with type 1 diabetes (T1D), have arrived in Germany. These families often presented with varying diabetes knowledge and limited language proficiency. To address this, the University Hospital Dresden established a dedicated outpatient clinic for Ukrainian children, enabling consultations in their native language. This study aims to characterize this cohort and highlight challenges in its care.

Methods

Clinical and anamnestic data were collected from Ukrainian children with T1D attending the clinic. Data are presented as median (IQR) or as numbers and percentages.

Results

In 2025,15 Ukrainian children with diabetes (53% girls; mean age 12.5 years, range 6.1–17) were treated at our clinic (3.8% of all T1D patients). Median diabetes duration was 3 years [2.1–6.0]. Mean HbA1c decreased from 7.65% at first visit to 6.8% (Dresden 2024 average: 7.1%). Comorbidities occurred in 40% (celiac disease, PKU, thyroiditis, obesity). At presentation, 33.3% used pumps without structured training; none had AID, one a DIY loop. All used CGM; in Ukraine, all therapy costs are privately borne. 53.3% transitioned from MDI to pumps, requiring nearly twice the resources as for German patients. Only 3 families spoke sufficient English; 13 attended German courses, yet interpreter support remained essential. None planned to return, partly due to superior diabetes care in Germany.

Conclusions

Ukrainian children with T1D achieve glycemic control comparable to local patients. Persistent language barriers, even after prolonged residence, demand increased time and personnel resources to ensure optimal care and education.

THE INTERPLAY OF PHYSICAL ACTIVITY AND INSULIN THERAPY MODALITY IN ASSOCIATION WITH GLYCEMIC CONTROL IN TYPE 1 DIABETES

Alexander J. Eckert ^a,b , Marie-Anne Burckhardt ^c , Johanna Hammersen ^d , Jantje Weiskorn ^e , Katrin Wertgen ^f , Laura S. Dock ^g , Manuel Maier ^h , Thomas Haak ⁱ , Stefanie Lanzinger ^j

^a University of Ulm, Institute of Epidemiology and Medical Biometry, Ulm, Germany; ^b German Centre for Diabetes Research (DZD), Neuherberg, Germany; ^c University Children’s Hospital Basel, Pediatric Endocrinology and Diabetology, Basel, Switzerland; ^d University Hospital Erlangen, Department of Pediatrics, Erlangen, Germany; ^e Children’s Hospital Auf der Bult, Hanover, Germany; ^f Kliniken Der Stadt Köln gGmbH, Cologne, Germany; ^g Klinik Favoriten, Wiener Gesundheitsverbund, Vienna, Austria; ^h University Hospital Freiburg, Freiburg, Germany; ⁱ GLG Werner Forßmann Klinikum Eberswalde GmbH, Eberswalde, Germany; ^j Diabetes Clinic Bad Mergentheim, Bad Mergentheim, Germany

Introduction and Objectives

Glycemic control in individuals with type 1 diabetes (T1D) is associated with different insulin therapy modalities such as multiple daily injection (MDI), use of insulin pumps in open-loop (CSII) and automated insulin delivery (AID) as well as several lifestyle factors including physical activity (PA). The aim was to evaluate how the interplay of PA and insulin therapy modality is associated with HbA1c and glycemic markers from continuous glucose monitoring (CGM)-profiles in adolescents with T1D using data from the Diabetes-Patienten-Verlaufsdokumentation (DPV) registry developed in Germany.

Methods

Data from individuals aged 12–21 years with T1D in the DPV registry were analyzed, including CGM profiles and self-reported PA. PA was categorized as low (0-2h/week), moderate (3-4h/week) and high (≥5h/week). We used linear regression for HbA1c comparison and fractional logit regression for time in range (70-180 md/dl, TIR) and time below range (<70 mg/dl, TBR, whole day and nocturnal (00:00-05:59)). Models were adjusted for demographic and clinical covariates and conducted for hourly CGM profiles considering repeated measurements and weighted for the number of daily sensor profiles.

Results

Of 3,070 individuals included, 1,229 (40%) showed low PA, 1,027 (33%) moderate PA, 814 (27%) high PA. 753 (25%) were on MDI, 288 (9%) on CSII, 2,029 (66%) on AID. Median age was 15.1 (IQR: 13.4-16.9) y. with 6.8 (3.1-9.3) y. diabetes duration and 53% males. HbA1c was lower with higher PA and those on MDI, followed by AID and CSII (7.0% [95%-CI 7.0-7.2] (high PA, MDI) to 7.6% [7.4-7.8] (low PA, CSII)). TIR increased with higher PA in the AID (56% [55-57] to 62% [60-63]) and MDI group (53% [52-54] to 58% [56-60]). In the MDI and AID groups higher PA was associated with higher TBR, (MDI: 4.6% [4.3-4.9] to 3.9% [3.6-4.1], AID: 2.6% [2.4-2.8] to 2.0% [1.9-2.2]). Differences in nocturnal TBR were only seen in the MDI group (high PA: 5.7% [5.2-6.2] vs. moderate PA: 4.3% [3.9-4.7], p=0.001).

Conclusions

Higher PA was associated with lower HbA1c and higher TIR in adolescents with T1D on MDI or AID. TBR was lowest in those on AID. Physically active adolescents on MDI had higher TBR over the whole day and during nighttime. In contrast, higher nocturnal TBR in physically active individuals on AID was not observed. No significant differences for HbA1c, TIR or TBR in association with PA were found within the minority of children treated with CSII.

ASSOCIATION BETWEEN THE USE OF LEGAL DRUGS AND METABOLIC OUTCOMES IN ADOLESCENTS AND YOUNG ADULTS WITH TYPE 1 DIABETES

Alexander J. Eckert ^a,b , Michael Meusers ^c , Bettina Gohlke ^d , Susanne Koling ^e , Marcus Riedel ^f

^a University of Ulm, Institute of Epidemiology and Medical Biometry, Ulm, Germany; ^b German Centre for Diabetes Research (DZD), Neuherberg, Germany; ^c Praxis Dr. Arne Schmidt, Praxis für Kinder- und Jugendpsychiatrie und -psychotherapie, Sozialpsychiatrie, Herdecke, Germany; ^d University Children’s Hospitals, Divisions of Pediatric Endocrinology, Bonn, Germany; ^e Johanniter Kliniken, Hamm, Hamm, Germany; ^f DRK-Kliniken Berlin Westend, Berlin, Germany

Introduction and Objectives

Smoking cigarettes and alcohol consumption is associated with metabolic outcomes in type 1 diabetes, but there is less evidence for Tetrahydrocannabinol (THC) consumption and vaping as well as for joint consumption of multiple drugs. The aim was to investigate potential associations between the consumption of legal drugs and metabolic outcomes in adolescents and young adults with T1D.

Methods

Individuals with T1D aged 14–25 years, documented in 2024 in the DPV-registry (n=14,558) and with information on drug use were included (n=1,451). The association between alcohol consumption, smoking cigarettes, vaping and THC-consumption (as binary variables) with body mass index percentiles (BMI-SDS), HbA1c and the odds ratio (OR) for diabetic ketoacidosis (DKA) and severe hypoglycemia with coma (SH-C) was analyzed using linear and logistic regression models. Models were adjusted for age, sex, diabetes duration, migration background, type of diabetes management and physical activity.

Results

Median age (16.2 [IQR: 14.9; 17.4] y.), diabetes duration (6.6 [3.5; 10.2] y.) and sex (53.6% male) of the final cohort were comparable to the group without drug documentation, but migration background (33% vs. 25%) was more frequent and individuals were from larger centers. In the final cohort, 7.2% drank alcohol, 6.8% smoked cigarettes, 9.2% used vaping and 2.6% consumed THC. BMI-SDS was higher in smokers (1.1 [95%-CI: 0.9-1.4] vs. 0.7 [0.6-0.8], p<0.001), but lower in THC-consumers (0.3 [-0.1-0.7] vs. 0.7 [0.7-0.8], 0.023). HbA1c was increased in vapers (8.1% [7.8-8.3] vs. 7.3% [7.2-7.3], p<0.001) and smokers (7.7 [7.4-8.0] vs. 7.3 [7.2-7.3], p=0.004). Higher OR for DKA was found in vapers (OR: 3.6 [1.3-10.0], p=0.016), higher OR for SH-C in THC-consumers (OR: 13.8 [2.3-81.6], p=0.004).

Conclusions

Vaping and THC consumption can be documented in the DPV-registry only since 2024 and therefore the numbers are still relatively small and there might be selection bias to some extent. However, first results hint at a higher association between vaping and glycemic control compared to cigarette smoking and an association between THC-consumption and life-threatening acute complications.

NORMALIZATION OF CENTRAL PRECOCIOUS PUBERTY INCIDENCE FOLLOWING COVID-19 PANDEMIC PEAK: A RETROSPECTIVE STUDY FROM A SINGLE CENTER PEDIATRIC ENDOCRINOLOGY DEPARTMENT, UNIVERSITY HOSPITAL BONN

Maren E. Falkenroth ^a , Bettina Gohlke ^a , Felix Schreiner ^a , Heike Vollbach ^a

^a Zentrum für Kinder- und Jugendmedizin, Uniklinik Bonn, Abteilung für Endokrinologie, Bonn, Germany

Introduction and Objectives

After our center observed an unusual increase in cases of central precocious puberty (CPP) during the Covid-19 pandemic, a gradual decrease in the number of CPP presentations has been noted following the end of the pandemic and the lifting of Covid-related public health measures. In March 2020, German Bundestag declared an “epidemic situation of national significance,” leading to extensive restrictions in public life. Many nationwide measures to contain the COVID-19 pandemic ended in March 2022, while some were reinstated in October 2022. All restrictions were gradually lifted by April 2023.

Methods

Comparison of patients diagnosed with CPP at the Pediatric Endocrinology Department, University Hospital Bonn in the years 2020/2021 with those who presented between 2022 and July 2025.

Results

At our center, the number of confirmed CPP cases remained consistently below 10 patients per year from 2015 to 2019. In 2020, a more than twofold increase (n=23) was observed, followed by an even higher number in 2021 (n=25). This trend was confirmed by a nationwide survey among all German pediatric endocrinology centers. Starting in 2022 (n=11), a gradual decline in case numbers was observed. In 2023 (n=9) and 2024 (n=7), the number of cases returned to pre-pandemic levels. However, in 2025, another increase was noted (n > 10). Comparing the number of cases from 2020/2021 to those from 2022 through July 2025 shows an overall reduction of approximately 60%.

Conclusions

We demonstrate a clear post-pandemic decrease in CPP cases at our center, supporting the hypothesis that the Covid-19 pandemic had a significant impact on the early onset of puberty. A strong temporal association with the implementation and subsequent lifting of public health measures is evident. We continue to assume a multifactorial origin of CPP, with the increased psychosocial stress during the pandemic likely contributing to the observed rise in case numbers during that period.

CATARACT IN ADOLESCENTS WITH TYPE 1 DIABETES

Ann-Kristin Frerking ^a , Mareike Niemeyer ^a , Torben Biester ^a , Jantje Weiskorn ^a , Felix Reschke ^a , Kerstin Kapitzke ^a , Olga Kordonouri ^a

^a Children’s Hospital Auf der Bult, Diabetes Center for Children and Adolescents, Hanover, Germany

Introduction and Objectives

Cataract is a rare but clinically significant ocular complication in adolescents with type 1 diabetes (T1D). Hyperglycemia increases sorbitol levels in the lens, leading to osmotic stress, swelling, and subsequent opacification [1]. A DPV registry analysis from 2022 [2] reported a prevalence of 0.25% and identified multiple risk factors, including adolescent age, female sex, lower BMI-SDS, short duration of T1D (rate peaks at onset), and elevated HbA1c levels, particularly at onset. No association to diabetic ketoacidosis (DKA) DKA was observed.

We describe three adolescents with T1D, who developed cataracts between 2016 and 2025 at our center and compare clinical characteristics with known risk factors.

Cases

Case 1

Onset: 13-year-old female patient, height-SDS +0.18, weight-SDS -1.27, BMI-SDS -1.76, HbA1c >14%, no ketoacidosis

Cataract: diagnosis two months after diabetes onset, at that point HbA1c 9.8%, both eyes affected, surgical treatment

Case 2

Onset: 12-year-old female patient, height-SDS -0.87, weight-SDS -1.27, BMI-SDS -0.93, HbA1c >14%, moderate ketoacidosis (pH 7.18)

Cataract: diagnosis three months before T1D onset, at that point HbA1c not measured, both eyes affected, surgical treatment; one year after operation laser therapy because of new mild cataract

Case 3

Onset: 16-year-old female patient, height -SDS +0.43, weight-SDS -0.35, BMI-SDS -0.65, HbA1c >14%, no ketoacidosis

Cataract: diagnosis three months after T1D onset, at that point HbA1c 7.7%, both eyes affected, surgical treatment

Conclusions

These cases exhibit nearly all known risk factors for cataract development in T1D. As cataracts can lead to amblyopia and permanent vision impairment, early detection is critical. The German guideline of the Association of Scientific Medical Societies [3] recommend ophthalmologic screening from age 11 or five years after T1D onset. Based on our findings, an initial ophthalmological examination at diagnosis or shortly thereafter may help identify pre-existing lens abnormalities, especially in high-risk patients.

References

[1] Reiter UM, Eckert AJ, Dunstheimer D, Bechtold-Dalla Pozza S, Lüllwitz C, Golembowski S, Freff M, Herrlinger S, von dem Berge T, Rehberg M, Lilienthal E, Holl RW. Cataract in children and adolescents with type 1 diabetes. Insights from the German/Austrian DPV registry. Pediatr Diabetes. 2022 May;23(3):362-369. doi: 10.1111/pedi.13316. Epub 2022 Feb 13. PMID: 35064955.

[2] Pollreisz A, Schmidt-Erfurth U. Diabetic cataract-pathogenesis, epidemiology and treatment. J Ophthalmol. 2010;2010:608751. doi: 10.1155/2010/608751. Epub 2010 Jun 17. PMID: 20634936; PMCID: PMC2903955.

[3] German Diabetes Association (DDG), “Therapie des Typ-1-Diabetes” (engl. therapy of diabetes type 1), version 5.1, 2023, https://register.awmf.org/de/leitlinien/detail/057-013

CUSHING’S SYNDROME RESULTING FROM COMBINED GLUCOCORTICOID ADMINISTRATION – A CASE REPORT EMPHASIZING THE NEED FOR COORDINATED PEDIATRIC MANAGEMENT

Katharina Gastberger ^a , Jakob Krämer ^a , Michael Gerstlauer ^b , Desiree Dunstheimer ^a

^a Universitätsklinikum Augsburg, Klinik für Kinder- und Jugendmedizin, Sektion Kinder-Endokrinologie und -Diabetologie, Augsburg, Germany; ^b Universitätsklinikum Augsburg, Klinik für Kinder- und Jugendmedizin, Sektion Kinderpneumonlogie und -allergologie, Augsburg, Germany

Introduction and Objectives

Short stature is a common reason for referral in pediatric endocrinology. Besides growth hormone deficiency, gastrointestinal or nutritional causes, this may be caused by disorders of adrenocortical function, e.g. hypercortisolism. The combination of growth retardation and weight gain is indicative to Cushing’s syndrome (CS). Iatrogenic CS is caused by long and/or extensive glucocorticoid (Glu) exposure and resembles a rare but severe phenomenon in pediatrics.¹ We present the case of a pediatric patient (Pat) suffering from iatrogenic CS with prolonged anamnestic, etologic workup.

Methods

We retrospectely analyzed the clinical course of a 11year old boy with growth failure, weight gain, fatique and recurent syncope, starting a few years after diagnosis of severe bronchial asthma. Endocrine evaluations including salivary cortisol profile, serum cortisol and ATCH stimulating test, were performed. MRI imaging ruled out CNS pathology. Continous or recurrent medication uptake was denied at the first visits. Later, previous treatment histories were reconstructed via medical records and pharmacy invoices.

Results

The Pat exhibited a marked stagnation in growth with hight percentiles plateauing over several months, while weight and BMI percentiles increased significantly (from 30th to 75th). Salivary cortisol leveles were persistently below the detection threshold; both basal serum cortisol and ACTH were reduced. ACTH stimulation failed to elict an adequate cortisol response, confirming adrenal insufficiency. A thorough review of the Pat’s medical history was conducted, as we suspected an iatrogenic CS.

Medication history revealed overlapping prescription of systemic, inhaled and nasal Glu, some not approved for pediatric use, by multiple providers (pediatric, general practitioner, ENT). The onset of endocrine symptoms correlated temporally with peak cumulative steroid exposure.

Conclusions

We adjusted therapy by reducing inhalative steroid and hydrocortison replacement. This case highlights the importance of centralized medical data management and coordinated interdisciplinary care in pediatric chronic Pats. Cumulative Glu exposure - predominantly non-systemic - from fragmented prescriptions led to clinically significant adrenal suppression. Pediatric oversight is essential to ensure age-appropriate pharmacothearpy and to mitigate risks associated with cumulative Glu. Preventive strategies should include integrated case management and enhanced interprofessional communication.

References

¹Covar, R. A., et al. (2000). “Risk factors associated with glucocorticoid-induced adverse effects in children with severe asthma.” J Allergy Clin Immunol 106(4): 651-659.

ENHANCED HUNGER CONTROL AND BODY MASS INDEX STABILIZATION WITH COMBINED SETMELANOTIDE AND SEMAGLUTIDE ADMINISTRATION IN SH2B1-RELATED SEVERE EARLY-ONSET OBESITY: A CASE STUDY

Eleni Giannopoulou ^a,b , Joanna Lerner ^a,c , Kay Winner ^a,b , Melanie Schirmer ^a,d , Stefanie Zorn ^a,d , Julia von Schnurbein ^a,d , Christian Denzer ^a,b , Martin Wabitsch ^a,d

^a University Medical Center Ulm, Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, Ulm, Germany; ^b Center for Rare Endocrine Diseases at the University of Ulm, Ulm, Germany; ^c Ulm University and Ulm University Medical Center, Institute of Human Genetics, Ulm, Germany; ^d German Center for Child and Adolescent Health (DZKJ), Ulm, Germany

Introduction and Objectives

SH2B Adaptor Protein 1 (SH2B1) plays an important role in the leptin–melanocortin pathway. Microdeletions in chromosome 16p11.2, encompassing the SH2B1 gene are linked to severe, early-onset obesity, hyperphagia, developmental delay, and insulin resistance. Up to now, there is no approved, mechanism-based treatment for patients with this condition. We report the 4-year treatment course of an adolescent with severe early-onset obesity due to a heterozygous 16p11.2 deletion encompassing SH2B1, highlighting the effects of setmelanotide alone and in combination with semaglutide.

Methods

The patient (female, 12 years old) presented with hyperphagia and severe obesity, developmental delay, learning and concentration difficulties, and aggressive behavior. At the age of 9 years, treatment with metformin was initiated due to prediabetes, which progressed to type 2 diabetes (T2D) at the age of 12 years. Further screening for comorbidities revealed arterial hypertension, microalbuminuria, obstructive sleep apnea syndrome, dyslipidemia, and steatotic liver disease. Setmelanotide treatment was initiated at the age of 12 ^7/12 years as part of clinical trials (NCT03013543, NCT03651765).

Results

During the first year of setmelanotide treatment, BMI z-score decreased, hunger was well controlled and HbA1c normalized. After month 12, BMI gradually increased, likely influenced by low physical activity and reduced adherence to the lifestyle programme at that time while continuing daily injections of setmelanotide. HbA1c levels increased, prompting the addition of GLP-1 receptor agonists. Combination therapy stabilized BMI and improved glycemic control and hunger regulation. When setmelanotide administration was stopped after 4 years according to study protocol, the patient experienced sudden excessive weight gain and pronounced hyperphagia. Reintroducing setmelanotide alongside semaglutide reversed weight gain and restored effective hunger control.

Conclusions

Long-term body weight regulation in adolescents with monogenic obesity remains challenging. In an adolescent with severe obesity and T2D, due to a 16p11.2 microdeletion, encompassing the SH2B1 gene, combined setmelanotide–semaglutide therapy improved BMI, hunger, and glucose control. An individualized therapeutic approach, including personalized pharmacological regiments in combination with lifestyle intervention and psychological support, should be considered in selected patients with monogenic obesity.

MONOGENIC OBESITY DUE TO MC4R DEFICIENCY: LESSONS FROM A MULTIGENERATIONAL CASE

Eleni Giannopoulou ^a,b , Melanie Schirmer ^a,c , Claudia Nestoris ^d , Stefanie Zorn ^a,c , Stephanie Brandt-Heunemann ^a,c , Julia von Schnurbein ^a,b , Abubakar Moawia ^e , Reiner Siebert ^e,c , Christian Denzer ^a,b , Martin Wabitsch ^a,c

^a University Medical Center Ulm, Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, Ulm, Germany; ^b Center for Rare Endocrine Diseases at the University of Ulm, Ulm, Germany; ^c German Center for Child and Adolescent Health (DZKJ), partner site Ulm, Ulm, Germany; ^d Endokrinologikum Hanover, Hanover, Germany; ^e Ulm University and Ulm University Medical Center, Institute of Human Genetics, Ulm, Germany

Introduction and Objectives

Melanocortin 4 receptor (MC4R) deficiency is the most common monogenic cause of obesity. Patients with monogenic obesity often undergo a frustrating diagnostic and therapeutic odyssey of years of ineffective lifestyle interventions before a causal diagnosis is made. Data from case reports suggest that individuals with obesity caused by MC4R variants can be treated with a glucagon-like peptide-1 (GLP-1) receptor agonist. We report a four-generation family where genetic testing in a child identified a heterozygous, likely pathogenic MC4R variant, also carried by three ancestors.

Methods

The family included a 7-year-old female index patient, her mother, grandmother, and great-grandmother, all with severe early-onset obesity and all carrying the heterozygous MC4R variant c.913C>T; p.Arg305Trp, previously shown to impair receptor function.

Results

The index patient developed severe obesity by age 2 years, with hyperphagia, tall stature, and dyslipidemia. Despite lifestyle interventions, her body mass index (BMI) continued to rise until liraglutide (3.0 mg/day) was initiated at age 8 years, resulting in significant BMI-z-score reduction during the first year of treatment. Subsequently, other family members underwent genetic testing. Her mother, grandmother and great-grandmother, all with a history of early-onset obesity and comorbidities, carried the same variant. Lifelong and severe psychological distress, including stigmatization, in each individual of the four generations was observed.

Conclusions

This case demonstrates the critical role of early genetic testing in children with severe, early-onset obesity, which led to the identification of the same MC4R variant in four family members across four generations. It also underscores how GLP-1 analogues may benefit some patients with monogenic obesity, while emphasizing the need for personalized, multidisciplinary care to mitigate the worsening impact of today’s obesogenic environment on monogenic obesity.

COMPREHENSIVE GENETIC TESTING REVEALS AN INTRONIC HNF1A BRANCH-POINT VARIANT IN A LARGE GERMAN PEDIGREE WITH EARLY-ONSET DIABETES

Eleni Z Giannopoulou ^a,b , Abubakar Moawia ^c , Josef Högel ^c , Joanna Lerner ^c,a , Stefanie Zorn ^a,d , Christian Denzer ^a,b , Reiner Siebert ^c,d , Martin Wabitsch ^a,d

^a University Medical Center Ulm, Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, Ulm, Germany; ^b Center for Rare Endocrine Diseases at the University of Ulm, Ulm, Germany; ^c Ulm University and Ulm University Medical Center, Institute of Human Genetics, Ulm, Germany; ^d German Center for Child and Adolescent Health (DZKJ), partner site Ulm, Ulm, Germany

Introduction and Objectives

Genetic screening for maturity-onset diabetes of the young (MODY) typically involves sequencing of the coding regions of known disease-associated genes. We describe a patient with early-onset diabetes due to an intronic HNF1A variant likely affecting a branching site missed by targeted testing which covered coding regions and exon/intron boundaries.

Methods

Comprehensive genetic testing, including whole-exome-analysis via next generation sequencing (NGS) and additional analysis, focusing on synonymous and (deep-)intronic variants, revealed a heterozygous intronic HNF1A branch-point variant, 14 years after DM diagnosis.

Results

The index patient was diagnosed with DM at the age of 10 years after incidental hyperglycemia, without polyuria, polydipsia, or weight loss. She had a strong family history of early-onset DM. Initial genetic testing for HNF4A, GCK, HNF1A, and HNF1B coding regions (including exon/intron boundaries±20 bp) and MLPA were negative. Sulfonylureas provided good glycemic control until age 16, when insulin was added. At age 18, an expanded targeted NGS panel for MODY was negative. At age 24, comprehensive genetic analysis focusing on (deep-)intronic variants revealed a heterozygous HNF1A variant(c.327-28A>G;p.?) in the patient and four affected relatives. The variant co-segregated with diabetes, and was predicted to affect splicing via branching site disruption, supporting pathogenicity.

Conclusions

Intronic variants can be missed by targeted genetic screening of only coding regions. Expanded genetic testing, including intronic regions, is recommended for young patients with strong family history, non-autoimmune diabetes, and negative standard tests, as it impacts prognosis, treatment, and family counseling.

GLUCOSE METABOLISM IN TURNER SYNDROME (TS) AND SMALL FOR GESTATIONAL AGE (SGA) PATIENTS AT THE TIME OF TRANSITION TO ADULT MEDICAL CARE

Sebastian Gippert ^a , Daniela Choukair ^a , Markus Bettendorf ^a

^a University of Heidelberg, Department of Paediatrics, Division of Paediatric Endocrinology and Diabetology, Heidelberg, Germany

Introduction and Objectives

Among other pathologies, Turner syndrome (TS) is associated with impaired glucose metabolism and high prevalence of type 2 diabetes mellitus (T2D). Patients born small-for-gestational-age (SGA) are also at a higher risk of developing T2D, since birth weight affects glucose tolerance and insulin sensitivity. Both entities are associated with short stature, for which growth hormone therapy (GH) is approved, which effects glucose metabolism. The aim of this study was to analyse their oral glucose tolerance tests (OGTTs) after GH treatment in adolescence.

Methods

We identified all patients between July 2010 and August 2016 with TS and SGA who were transitioned to adult medical care in our endocrine outpatient clinic. All patients received growth hormone therapy. During a standardized examination, HOMA and Hba1c were assessed and an OGTT was performed with all patients. Results are presented as medians and IQRs.

Results

27 patients with TS and 20 patients with SGA (50% female) with a median age of 17.7 years (IQR: 16.7, 20.2) and 16.8 years (IQR: 14.6, 16.8) were included. Median glucose levels in TS patients were 67mg/dl (IQR: 59, 74) at the start of the test, increasing to 132mg/dl at 60min (IQR: 107, 155), decreasing to 100 mg/dl (IQR: 90, 123) after 120min. Median glucose levels in SGA patients were 78mg/dl (IQR: 72, 83) at the start, increasing to 135mg/dl at 60 min (IQR: 108, 149), decreasing to 106mg/dl (IQR: 89, 136) after 120 min. 8 patients (SGA: n=5, 25%; TS: n=3, 11.1%) showed an impaired glucose tolerance (Glucose >140mg/dl at 120min). Insulin resistance (HOMA > 2.3% at the start) was found in 10/20 SGA patients and in 12/27 TS patients. No patient developed overt T2D (HbA1c>6%).

Conclusions

A significant number of patients, particularly those with SGA had impaired glucose tolerance. These findings highlight the importance of screening patients with these endocrine diseases at time of transition and in adult medical care.

IMPACT OF ADHERENCE ON GROWTH OUTCOMES IN CHILDREN WITH GROWTH HORMONE DEFICIENCY: ONE-YEAR REGISTRY DATA RESULTS

Klaus Hartmann ^a , Tillmann Rohrer ^b , Peter H. Kann ^c,d , Tino Schubert ^e

^a biomedpark Medien GmbH, Heidelberg, Germany; ^b Saarland University Medical Center, Department of General Pediatrics and Neonatology, Homburg, Germany; ^c Philipps-Universität Marburg, Fachbereich Medizin, Marburg, Germany; ^d Deutsches Endokrinologisches Versorgungszentrum DEVZ, Frankfurt (Main), Germany; ^e LinkCare GmbH, Ludwigsburg, Germany

Introduction and Objectives

Growth hormone deficiency (GHD) requires several years of treatment with daily injections of GH. The need for daily treatment and the subcutaneous form of application are just two reasons that contribute to an increased risk of nonadherence. The aim of this study is to compare the growth outcomes of non-adherent and adherent children with GHD at one year.

Methods

Using registry data from a single center in Germany, patients with GHD were categorized into nonadherent (adherence < 85%) and adherent (adherence 85-110%) patient groups at one year based on the idea of Cutfield et al. Growth outcomes were compared after the first year of therapy using the decrease in height standard deviation score (ΔHSDS) and growth rate, which is the growth in cm per year. Statistical tests were performed using the nonparametric Spearman rank correlation coefficient and a linear regression model.

Results

126 patient charts contained all necessary adherence and growth information and could be included in the analysis of growth results after one year of therapy. Of these, 102 (81%) were adherent at one year and 24 (19%) were nonadherent. The HSDS was significantly positively correlated with adherence (ρ=0.18) when comparing the group with low adherence after one year. The growth rate was significantly positive correlated as well (ρ=0.28). The results of the linear regression showed a statistical significant positive effect of adherence on growth rate (β=1.03). The diagnosis of adult GHD also had a statistically significant positive effect on growth rate. All other diagnoses showed no significant effect, as did age and sex.

Conclusions

Adherence to treatment is a decisive factor for the growth success in GHD and requires special attention, taking into account the daily injections required over many years. As with other diseases, continuous monitoring and patient education or new treatment methods are necessary to ensure effective treatment.

PREVALENCE AND OUTCOME OF RELATIVE THYROID HORMONE RESISTANCE IN CONGENITAL HYPOTHYROIDISM DURING THE FIRST YEARS OF LIFE – RESULTS FROM THE AQUAPE REGISTRY

Raphael Hirtz ^a,b , Stefanie Lanzinger ^c , Roland Pfäffle ^d , Clemens Kamrath ^e , Susanne Fricke-Otto ^f , Susanne Thiele-Schmitz ^g , Markus Bettendorf ^h , Corinna Grasemann ⁱ , Johannes Dietrich ^j , Mandy Vogel ^k , Alexander Eckert ^c

^a Helios University Hospital Wuppertal, Witten/Herdecke University, Center for Child and Adolescent Medicine, Wuppertal, Germany; ^b University Hospital Essen (2)Institute of Sex- and Gender-sensitive Medicine, Essen, Germany; ^c University of Ulm, Institute of Epidemiology and Medical Biometry, CAQM, Ulm, Germany; ^d University of Leipzig Medical Center, Department of Pediatrics, Leipzig, Germany; ^e University of Freiburg, Center of Child and Adolescent Medicine, Division of Pediatric Endocrinology and Diabetology, Freiburg, Germany; ^f HELIOS Klinikum Krefeld, Centre for Child and Adolescent Health, Krefeld, Germany; ^g St. Louise Women’s and Children’s Hospital, Diabetes Centre for Children and Adolescents, Paderborn, Germany; ^h Heidelberg University Children´s Hospital, Paediatric Endocrinology and Diabetes, Heidelberg, Germany; ⁱ Johannes Gutenberg University Medical School, Department of Pediatrics, Mayence, Germany; ^j St. Josef Hospital, Ruhr University Bochu, Diabetes, Endocrinology and Metabolism Section, Department of Internal Medicine I, Bochum, Germany; ^k University of Leipzig, Leipzig Research Center for Civilization Diseases, LIFE Child, Leipzig, Germany

Introduction and Objectives

Previous studies have used divergent and mostly age-independent TSH cut-off values to define relative resistance of the hypothalamus-pituitary-thyroid axis (RRHPTA) in congenital hypothyroidism (CH), potentially limiting their sensitivity for detecting RRHPTA across different developmental stages. This is particularly important, as the temporal course and clinical significance of RRHPTA remain poorly understood. Case reports suggest its occurrence may be limited to infancy in a subgroup of CH patients, and its impact on neurodevelopmental outcomes is largely unknown.

Methods

We used data from the AQUAPE ‘HypoDok’ registry, including 2108 patients from Germany and Austria. Inclusion required non-syndromic CH, available TSH screening and therapy start data, 5-year follow-up of TSH and fT4, standardized height/weight, and therapy adherence. RRHPTA was defined by TSH >75th percentile and fT4 >97th percentile (based on age- and sex-specific reference data) at least twice within one year in adherent patients. Controls were defined by a TSH level between the 3rd and 75th percentile and an fT4 level between the 3rd and 97th percentile.

Results

Data from 180 participants were eligible for inclusion, with 41.1% (N=74) exhibiting RRPHTA at any time during the study period. RRHPTA was less common during the first year of life (N=2, 1.9%) than during infancy and was most often diagnosed during the second year of life (N=38, 52.1%). The small number of CH patients with RRHPTA during the first year of life was due to a downward shift in the distribution of TSH levels in CH patients, likely driven by generally higher fT4 levels compared to the general population. This conclusion was confirmed by sensitivity analyses using the distribution of TSH and fT4 levels of the CH cohort as a reference. There was no difference between patients with RRHPTA and controls during the study period concerning z-weight, BMI, or z-height and target height.

Conclusions

RRHPTA is a prevalent condition with no significant clinical impact on auxological parameters within the first 5 years of life in this study. However, the analysis of additional measures of relative resistance, such as Jostel’s TSH index or the TSH resistance index, is ongoing and will provide further insights.

URINARY STEROID METABOLOMICS REVEALS DYSREGULATION OF ADRENAL, GONADAL, AND NEUROACTIVE STEROIDS IN ADOLESCENTS WITH DEPRESSIVE SYMPTOMS

Lars Dinkelbach ^a,b , Stefan Wudy ^c , Michaela Hartmann ^c , Lars Libuda ^d , Manuel Föcker ^e , Johannes Hebebrand ^f , Anke Hinney ^b,g , Ute Nöthlings ^h , Ute Alexy ^h , Corinna Grasemann ⁱ , Raphael Hirtz ^j,b

^a University Hospital Essen, University of Duisburg-Essen, Department of Pediatrics II, Essen, Germany; ^b University Hospital Essen, Institute of Sex- and Gender-sensitive Medicine, Essen, Germany; ^c Justus-Liebig-University Hospital, Steroid Research & Mass Spectrometry Unit, Laboratory for Translational Hormone Analytics, Pediatric Endocrinology & Diabetology, Center of Child and Adolescent Medicine, Giessen, Germany; ^d Paderborn University, Institute of Nutrition, Consume and Health, Faculty of Natural Sciences, Paderborn, Germany; ^e LWL University Hospital Hamm, Ruhr University-Bochum, Hospital for Child and Adolescent Psychiatry, Psychotherapy, and Psychosomatics, Hamm, Germany; ^f University Hospital Essen, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Essen, Germany; ^g University Hospital Essen, Section of Molecular Genetics in Mental Disorders, Essen, Germany; ^h University of Bonn, Department of Nutritional and Food Sciences – Nutritional Epidemiology, DONALD Study, Bonn, Germany; ⁱ University Medical Center of the Johannes Gutenberg University Mayence, Department of Paediatric, Mayence, Germany; ^j Helios University Hospital Wuppertal, Witten/Herdecke University, Center for Child and Adolescent Medicine, Wuppertal, Germany

Introduction and Objectives

Steroid hormone profiles in affective disorders suggest hypothalamus-pituitary-adrenal axis dysfunction and may offer novel therapeutic targets. However, existing evidence largely focuses on glucocorticoids.

Methods

This cross-sectional study analyzed the urinary excretion of 39 steroid metabolites (via gas chromatography-mass spectrometry) from 75 adolescent psychiatric patients with depressive symptoms (63 females, age 15.6±1.3 years) and 75 controls from a population-based cohort (64 females, age 15.3±1.3 years), matched for age, sex, and pubertal status.

Results

Patients exhibited significantly elevated excretion rates (µg/24h) of corticosterone metabolites (median=608.4, IQR: 342.4-1208.2 vs. 321.0, IQR: 243.9-443.8), dehydroepiandrosterone (DHEA) metabolites (median=1253.8, IQR: 569.8-2796.2 vs. median=519.5, IQR: 254.0-1028.7), androgen metabolites (median=6721.0, IQR: 4185.6-9395.8 vs. median=3680.4, IQR: 2510.8-5419.0), and individual progesterone metabolites. Glucocorticoid metabolites revealed a pattern resembling a mild Cushing Syndrome. Analyses of enzyme activity ratios via multivariate machine learning identified the urinary metabolite ratio of tetrahydrated 11-deoxycorticosterone (TH-DOC) to corticosterone metabolites as a potential biomarker to distinguish patients from controls.

Conclusions

In conclusion, elevated rates of ACTH-dependent hormones as detected in the urinary steroid metabolome indicate chronic stress in adolescents with depressive symptoms. The TH-DOC-to-corticosterone metabolite ratio may help identify at-risk patients or guide personalized therapies.

VOSORITIDE IN CHILDREN WITH HYPOCHONDROPLASIA: A SERIES OF 8 CASES

Franka Hodde ^a , Geeske Mühlschlegel ^a , Sonja Kloos ^a , Olimpia Manzardo ^a , Marie Ritter ^a , Johanna Weekes ^a , Miriam Schmidts ^b , Clemens Kamrath ^a , Ekkehart Lausch ^b

^a University Hospital Freiburg, Centre of Paediatric and Adolescent Medicine, Division of Paediatric Endocrinology and Diabetology, Freiburg, Germany; ^b University Hospital Freiburg, Centre of Paediatric and Adolescent Medicine, Division of Paediatric Genetics, Freiburg, Germany

Introduction and Objectives

Similar to achondroplasia, the most severe form, hypochondroplasia is also a skeletal dysplasia caused by a mutation in FGFR3, leading to disproportionate short stature with an average final height of 130.8 cm in women and 143.6 cm in men. Initial data from the Phase II study suggest that vosoritide, which is approved for achondroplasia, also leads to an improvement in growth rate in patients with hypochondroplasia. The aim was to retrospectively investigate the influence of vosoritide on growth in children with hypochondroplasia.

Methods

Off-label treatment with vosoritide following individual application and cost coverage. Patients received a weight-adjusted dose of vosoritide of 15 µg/kgBW once daily subcutaneously. Eight children and adolescents (five females) aged 2.8 to 14.9 years at start of therapy were evaluated. Auxological parameters were recorded in a standardized manner during the initial examination and follow-up visits every 3-6 months in our clinic between December 2023 and July 2025. Body height measurements were converted into standard deviation scores (SDS), results are presented as median (range).

Results

After a median treatment duration of 15 months (range: 8;17) with vosoritide, there was an improvement in the median height SDS, which increased from -4.43 (-1.98;-5.31) before treatment to -3.9 (-1.38;-5.03) at last follow-up. The annualized growth rate increased from 4.5 (2.8;6.9) cm/year to 6.3 (0.5;8.1) cm/year. The median height SDS change during the treatment period was 0.47 (0.08;1.16). Apart from a local infection following a non-sterile injection, no side effects have been observed.

Conclusions

Treatment with vosoritide led to an increased growth rate and an improved height in children and adolescents with hypochondroplasia. These results are consistent with those of the Phase II study. Further long-term data are needed to investigate sustained responses to therapy.

References

Dauber A, Zhang A, Kanakatti Shankar R, Boucher K, McCarthy T, Shafaei N, Seaforth R, Castro MG, Dham N, Merchant N. Vosoritide treatment for children with hypochondroplasia: a phase 2 trial. EClinicalMedicine. 2024 Apr 11;71:102591. doi: 10.1016/j.eclinm.2024.102591. PMID: 38813446; PMCID: PMC11133798.

THE IMPACT IN GERMANY OF COVID-19 REGULATIONS ON ADHERENCE TO RECOMBINANT GROWTH HORMONE THERAPY USING A CONNECTED INJECTION DEVICE

Dorna Hogeabri ^a , Paula van Dommelen ^b , Rick Raudszus ^c , Nadine Nazari ^c , Karl Scheithe ^d , Holger Gnann ^d , Berthold Hauffa ^e , Tilman R. Rohrer ^a

^a Universitätsklinikum des Saarlandes, Division of Paediatric Endocrinology and Diabetology, Homburg, Germany; ^b The Netherlands Organization for Applied Scientific Research TNO, Department of Child Health, Leiden, Netherlands; ^c Merck Healthcare Germany GmbH, Medical Affairs Fertility, Endocrinology and General Medicine, Weiterstadt, Germany; ^d GKM Gesellschaft Für Therapieforschung mbH, Department of Biostatistics, Munich, Germany; ^e Universitätsklinikum Duisburg-Essen, Pediatric Endocrinology, Essen, Germany

Introduction and Objectives

During the COVID-19 pandemic, children in Germany experienced increased psychological stress, isolation, and reduced access to healthcare. However, more time at home also allowed families to better support treatment routines. This study investigated the impact of the COVID-19 pandemic and associated government restrictions on adherence to recombinant human growth hormone (r-hGH) therapy in pediatric patients with growth disorders in Germany.

Methods

Adherence data were extracted from the easypod™ connect. Government policy strictness was quantified using the Stringency Index (SI) from Our World in Data. Adherence during a high-restriction pandemic period (16 Dec 2020–28 Feb 2021 with a mean SI ≥70) was compared with the same pre-pandemic interval (16 Dec 2019–28 Feb 2020). Adherence was classified as optimal (≥85%) or suboptimal (<85%). Chi-squared tests assessed differences in adherence overall and by age groups: <11 years and 11–<18 years.

Results

Adherence data were available for 553 patients during the pandemic (62% males, 55% aged <11 years, 58% growth hormone deficiency (GHD), 30% small for gestational age (SGA), 12% Turner syndrome (TS), 1% chronic renal insufficiency (CRI) ) and 535 patients pre-pandemic (61% males, 56% aged <11 years, 60% GHD, 28% SGA, 12% TS, 1% CRI). Mean time on treatment was 3.5 years in both age groups. The proportion of patients with optimal adherence was significantly higher during the pandemic (85%) compared to the pre-pandemic period (80%) (p=0.04). While not statistically significant by age group, optimal adherence was higher during compared to before the pandemic in both age groups: 88% vs. 84% in children <11 years (p=0.19), and 82% vs. 75% in those aged 11–<18 years (p=0.08).

Conclusions

Strict COVID-19 measures were associated with improved adherence to r-hGH therapy in pediatric patients with growth disorders in Germany, likely supported by increased parental involvement and digital health tools. These findings highlight the value of family engagement and connected technologies in promoting long-term treatment adherence beyond the pandemic.

LONGITUDINAL STUDY OF 0–3-YEAR CATCH-UP GROWTH IN GH-TREATED CHILDREN WITH SHORT STATURE BORN SMALL FOR GESTATIONAL AGE (SGA) FROM A LARGE DATABASE (ENIS) IN A HIGH-ADHERENCE SETTING

Dorna Hogeabri ^a , Paula van Dommelen ^b , Rick Raudszus ^c , Nadine Nazari ^c , Karl Scheithe ^d , Holger Gnann ^d , Tilman R. Rohrer ^a , Berthold Hauffa ^e

^a Universitätsklinikum des Saarlandes, Division of Paediatric Endocrinology and Diabetology, Homburg, Germany; ^b The Netherlands Organization for Applied Scientific Research (TNO), Department of Child Health, Leiden, Netherlands; ^c Merck Healthcare Germany GmbH, Medical Affairs Fertility, Endocrinology and General Medicine, Weiterstadt, Germany; ^d GKM Gesellschaft Für Therapieforschung mbH, Department of Biostatistics, Munich, Germany; ^e Universitätsklinikum Duisburg-Essen, Pediatric Endocrinology, Essen, Germany

Introduction and Objectives

Adherence is one of the major determinants of initial response to growth hormone (GH) treatment. Poor adherence negatively affects growth response in the first years of GH treatment. Electronic drug-delivery devices (easypod^TM) that continuously record adherence enable more accurate assessment of its role in early growth response to GH treatment. To quantify the role of adherence relative to other determinants for the 3-year growth response in prepubertal children born small for gestational age (SGA) treated with growth hormone (GH) participating in the German eNIS open label study (Merck).

Methods

Outcome measures: change in height SD score (ΔHSDS) and responsiveness index (IoR), with adj-HSDS (HSDS – target height SDS) as the dependent variable. Inclusion criteria: SGA, GH-naive, known TH, age <10y girls and <12y boys, ≥4 measurements, HSDS < -2 at start, complete growth/adherence data first 3 years. Linear and logistic regression analyses tested the association between adherence and outcome measures, with ΔHSDS adjusted for potential confounders (age at start, start adj-HSDS, birth weight SDS, gestational age (<37 vs ≥37 weeks), GH dose, and GH max.)

Results

In 66 patients meeting the inclusion criteria, three-year GH adherence was high (median 95.1%; Q25–Q75: 87.2–98.3), decreasing slightly over time (first year 97.2%, second year 96.1%, third year 95.9%). Mean adj-HSDS improved from −2.54 to −1.11 by the end of year 3. Mean IoR was lowest in year 1 (mean ± SD 1.61 ± 1.19), rising subsequently. Adherence and ΔHSDS were significantly related in year 1 (adj. B 0.26; p=0.0486), less in years 2–3. The association between adherence (high vs. low) and IoR varied (B = −0.06, p=0.8862 to 0.45, p=0.3152). One missed injection/week predicted a 0.03 HSDS loss in year 1.

Conclusions

Highly adherent users of an electronic drug-delivery device (easypod^TM) born SGA, treated with GH, and longitudinally followed for three treatment years showed a significant positive association between adherence and ΔHSDS in the first treatment year, while the effect of individual variations in adherence appeared to be less pronounced in the following two years.

LONGITUDINAL STUDY OF 0–3-YEAR CATCH-UP GROWTH IN TREATED CHILDREN WITH ISOLATED IDIOPATHIC GROWTH HORMONE DEFICIENCY FROM A LARGE DATABASE (ENIS) IN A HIGH-ADHERENCE SETTING

Dorna Hogeabri ^a , Paula van Dommelen ^b , Rick Raudszus ^c , Nadine Nazari ^c , Karl Scheithe ^d , Holger Gnann ^d , Tilman R. Rohrer ^a , Berthold Hauffa ^e

^a Universitätsklinikum des Saarlandes, Division of Pediatric Endocrinology and Diabetes, Homburg, Germany; ^b The Netherlands Organization for Applied Scientific Research TNO, Department of Child Health, Leiden, Netherlands; ^c Merck Healthcare Germany GmbH, Medical Affairs Fertility, Endocrinology and General Medicine, Weiterstadt, Germany; ^d GKM Gesellschaft Für Therapieforschung mbH, Department of Biostatistics, Munich, Germany; ^e Universitätsklinikum Duisburg-Essen, Pediatric Endocrinology, Essen, Germany

Introduction and Objectives

Adherence is one of the major determinants of the initial response to growth hormone (GH) treatment. Today, electronic drug-delivery devices (easypod^TM) are available that enable continuous monitoring of adherence and allow for a more precise assessment of the relative role of adherence in early growth response to GH treatment.

To quantify the role of adherence, relative to other determinants, in 3-year growth response in prepubertal children with idiopathic isolated GH deficiency (IIGHD) participating in the German eNIS open label study (Merck).

Methods

Outcome measures: change in height SD score (ΔHSDS) and responsiveness index (IoR), with adj-HSDS (HSDS – target height (TH) SDS) as the dependent variable. Inclusion criteria: IIGHD, GH-naive, known TH, age <10y girls and <12y boys, ≥4 measurements, HSDS < -2 at start, complete growth/adherence data first 3 years.

Linear and logistic regression analyses tested the association between adherence and outcome measures, with ΔHSDS adjusted for potential confounders (age at start, start adj-HSDS, birth weight SDS, gestational age (<37 vs ≥37 weeks), GH dose, and GH max.)

Results

In the 40 patients meeting the inclusion criteria, the overall three-year adherence rate (%) was high (median [Q25-Q75]: 97.5 [92.4–99.1]), decreasing only slightly over time (98.5-> 97.1). Mean adjusted HSDS improved from −2.6 at treatment start to −0.9 at the end of the third year. Mean IoR was low in the first year (−0.51), and highest in the second year (0.53). The strongest associations between adherence (categorized as high vs. low) and outcome parameters were observed in the first treatment year (ΔHSDS: adj. B 0.45 (p=0.0768), IoR: B 1.0 (p=0.1093)), with diminishing effects in subsequent years.

Regression data for continuous adherence suggest a loss of treatment effect (−0.08 HSDS) per one missed injection/week over three years.

Conclusions

Users of an electronic drug-delivery device (easypod^TM) with GH-treated IIGHD who were followed longitudinally for three years exhibited high and stable adherence. Individual variations in adherence influenced growth response and enabled estimation of the loss of therapeutic effect from missed injections.

EMPOWER-TRANS* – DEVELOPMENT AND IMPLEMENTATION OF INNOVATIVE, DIGITAL INFORMATION AND TRAINING CONCEPTS FOR CHILDREN AND ADOLESCENTS WITH GENDER INCONGRUENCE/GENDER DYSPHORIA (GI/GD) AND THEIR FAMILIES

Cindy Holland ^a , Corinna Bergelt ^b , Judy Alan Richter ^b , Mel Stiller ^b , Jens Kanthak ^c , Georg Romer ^c , Annette Richter-Unruh ^d,a , And The Empower-Study-Group ^e

^a Universitätsklinik für Kinder- und Jugendmedizin, Universitätsklinikum Ulm, Sektion Pädiatrische Endokrinologie und Diabetologie, Ulm, Germany; ^b Universitätsmedizin Greifswald K.ö.R., Institut für Medizinische Psychologie, Greifswald, Germany; ^c Universitätsklinikum Münster, Klinik für Kinder-und Jugendpsychiatrie, Münster, Germany; ^d MVZ Eberhard und Partner Dortmund Hormonzentrum für Kinder und Jugendliche, Pädiatrische Endokrinologie, Dortmund, Germany; ^e Konsortial- und Kooperationspartner, Verschiedene Einrichtungen, Germany, Germany

Introduction and Objectives

In recent years there has been an increase in children and adolescents whose sex assigned at birth does not match their self-perceived gender identity. This mismatch can lead to distress and may prompt the use of gender reassignment medical treatments (e.g., hormonal and surgical). Care and information are complex and require specialist disciplines. With few specialist centres in Germany, waiting times are long. EMPOWER-TRANS* aims to develop and evaluate a guideline-compliant digital offer to improve early access to information for affected youth and their families.

Methods

The intervention consists of two components: (1) a digital platform providing guideline-compliant information, and (2) a digital training programme enabling topic exploration and exchange with other people affected. The evaluation follows a mixed-methods design with a longitudinal study in the intervention group and a cross-sectional comparison with a historical control group; the target sample size is n=240 for each group. Recruitment of the historical control group takes place in 2025. The intervention phase will commence in Q1 2026 and continue for one year, with evaluation in 2027.

Results

Recruitment for the historical control group began in April 2025. As of 13 August 2025, 125 families had been enrolled; recruitment is ongoing throughout 2025 to reach n=240. The historical control is assembled prior to implementation to enable cross-sectional comparison with the intervention cohort. Data collection continues in 2025. In addition, the second version of the web platform is currently being tested ahead of implementation to ensure readiness for the intervention start in 2026. The intervention group will start in Q1 2026 and will receive the digital information and training offer for one year.

Conclusions

EMPOWER-TRANS* is intended to provide high-quality, guideline-compliant information and training at an early stage. Delivering part of the initial information digitally is expected to streamline pre-consultation processes and may shorten waiting times. If first appointments become shorter because patients are informed in advance, more initial appointments can be offered, which in turn may reduce overall waiting times. The planned evaluation in 2027 will examine effects on information access and care processes.

RETROSPECTIVE ANALYSIS OF PEDIATRIC THYROID NODULES IN SONOGRAPHIC IMAGES BY AMERICAN COLLEGE OF RADIOLOGY THYROID IMAGING REPORTING AND DATA SYSTEM (ACR-TIRADS) AND COMPARISON WITH POSTOPERATIVE HISTOPATHOLOGY

Johannes Hoos ^a , Sebastian Gippert ^a , Matthias Werner ^a , Daniela Choukair ^a , Markus Bettendorf ^a

^a University Hospital Heidelberg, Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, Heidelberg, Germany

Introduction and Objectives

The aim of our study was to estimate the performance of the American College of Radiology Thyroid Imaging Reporting and Data System (ACR-TIRADS) compared to histopathology of hemi or total thyroidectomy to detect malignancy in pediatric thyroid nodules by sonography validated in adulthood but rarely applied in children and adolescents.

Methods

Preoperative sonographic findings of 37 thyroid nodules of 30 pediatric patients with thyroidectomy between 2004 and 2024 were retrospectively evaluated using ACR-TIRADS. Accuracy of predicting malignancy was evaluated compared to histopathologic findings. Nodules were scored regarding sonographic criteria: composition (cystic, solid, spongiform), echogenicity (hypo-, iso- or hyperechoic), shape (wider than tall or vice versa), margin (smooth, ill-defined, irregular, extra thyroidal) and calcifications and grouped to ACR-TIRADS group 1 (0 pt, benign), 2, 3, 4 and 5 (≥7 pt, highly suspicious).

Results

70% (21/30) of all patients were female, 30% (9/30) male, aged 4 to 17 years (mean 12 years). 19 carcinomas (13 female, 6 male, mean age 12,8 years) were found in thyroidectomy samples (17/19 PTC, 1/19 FTC, 1/19 MTC). Median ACR-TIRADS score was 6 points (IQR 6-8) ranging from 2 to 11 points, cancer samples showed a mean of 7,8 points, benign samples a mean of 4,4 points. The highest ACR-TIRADS group 5 showed a positive predictive value of 78,9% in predicting thyroid cancer. An increasing ACR-TIRADS score showed an odds ratio of 2,8 with a ROC-curve AUC of 0,914 (95%CI 0,827 - 1,0) for thyroid cancer. The risk of malignancy in TIRADS group 5 is more than 6 times higher compared to TIRADS group 4 with a ROC-curve AUC of 0,83 (95%CI 0,695 - 0,966), showing high validity of the model.

Conclusions

ACR-TIRADS retrospectively showed a significant predictive value comparable to fine-needle aspiration to identify thyroid cancer in this pediatric cohort compared to histopathology after thyroidectomy. A solid composition, hypoechogenicity and calcifications of thyroid nodules are sonographic criteria with the highest malignancy rate once found simultaneously. This grading system can help to reduce diagnostic related morbidity and identify patients at risk with the need for a definitive surgical treatment. Prospective studies are needed to validate ACR-TIRADS in children and adolescents.

GROWTH OUTCOMES IN CHILDREN WITH ACHONDROPLASIA TREATED WITH NAVEPEGRITIDE: 52-WEEK RESULTS FROM THE APPROACH CLINICAL TRIAL

Heike-Katharina Hoyer-Kuhn *Presenting on behalf of listed authors ^b , Hanne B. Hove ^a , Ciara McDonnell ^c , Carlos A. Bacino ^d , Philippe M. Campeau ^e , Paul L. Hofman ^f , Janet M. Legare ^g , Daniel G. Hoernschemeyer ^h , Josep M. de Bergua Domingo ⁱ , Jennifer Abuzzahab ^j , Bart Degreve ^k , Lærke C. Freiberg ^k , Meng Mao ^l , Allison S. Komirenko ^l , Aimee D. Shu ^l , Ravi Savarirayan ^m,n

^a Copenhagen Rigshospitalet, Center for Rare Disease, Kopenhagen, Denmark; ^b Unilklinik Cologne, Abteilung für Kinder- und Jugendmedizin, Cologne, Germany; ^c University of Dublin, Children´s Health Ireland at Temple Street, Dublin, Irland; ^d Baylor College of Medicine, Houston, United States; ^e CHU Sainte-Justine Research Centre, Montréal, Canada; ^f The Liggins Institute, University of Auckland, Auckland, New Zealand; ^g University of Wisconsin, Childrens Hospital, Madison, United States; ^h University of Missouri, Children´s Hospital, Columbia, United States; ⁱ Unidad de Cirugia Atroscopia, Vithas Vitoria Hospital, Vitoria-Gasteiz, Spain; ^j Children´s Minnesota, Minneapolis, United States; ^k Ascendis Pharma A/S, Hellerup, Denmark; ^l Ascendis Pharma Inc., Palo Alto, United States; ^m Murdoch Children´s Research Institute, Parkville, Australia; ⁿ Royal Children´s Hospital, Parkville, Australia; ^o University of Melbourne, Parkville, Australia

Introduction and Objectives

Navepegritide is an investigational prodrug of C-type natriuretic peptide (CNP), administered subcutaneously once weekly and designed to provide sustained release of active CNP with a low Cmax. Continuous exposure to released CNP stimulates natriuretic peptide receptor B to counteract the constitutively active fibroblast growth factor receptor 3 in achondroplasia (ACH). ApproaCH is a pivotal, randomized, double-blind, placebo-controlled trial evaluating navepegritide in children with ACH.

Methods

Children with ACH (N=84, aged 2-11 years) were stratified by age and sex and randomized 2:1 to receive navepegritide (100 μg/kg/week) or placebo for 52 weeks. The primary endpoint was annualized growth velocity (AGV) at Week 52. Secondary endpoints included ACH-specific height Z-scores. Safety and tolerability were evaluated through treatment-emergent adverse events (TEAEs), including injection site reactions (ISRs), and changes in bone age

Results

Navepegritide was superior to placebo in AGV at Week 52 (least squares mean (LSM) AGV with navepegritide 5.89 cm/year vs 4.41 cm/year with placebo; LSM difference: 1.49 cm/year, p<0.0001). Change from baseline in ACH-specific height Z-score at Week 52 was significantly greater with navepegritide vs placebo (LSM difference 0.28, p<0.0001). Among children aged ≥5 years (n=53), those treated with navepegritide had a higher AGV at Week 52 (LSM difference 1.78 cm/year, p<0.0001) and greater change from baseline in ACH-specific height Z-score (LSM difference 0.31, p<0.0001) vs placebo. Most TEAEs were mild or moderate, with a low rate of ISRs (all mild) across groups. The mean change from baseline in bone age to chronological age ratio was 0.000 for navepegritide and -0.013 for placebo.

Conclusions

Navepegritide demonstrated superiority over placebo in AGV at Week 52 of the ApproaCH trial. Statistically significant improvements in ACH-specific height Z-scores were observed in children treated with navepegritide compared with placebo. These findings suggest navepegritide improves growth in children with ACH while maintaining a safety and tolerability profile comparable to placebo.

BONE2GENE: AI FOR DETECTING RARE BONE DISORDERS FROM X-RAY IMAGES

Behnam Javanmardi ^a , Eike Bolmer ^a , Philipp Schmidt ^b , Peter Krawitz ^a , Klaus Mohnike ^b

^a Universitätsklinikum Bonn, Bonn, Germany; ^b Universitätsklinikum Magdeburg, Magdeburg, Germany

Introduction and Objectives

Diagnosing rare bone diseases (RBDs) is inherently complex, often involving lengthy evaluations and multiple clinical visits. For RBDs with approved therapies, timely and accurate identification is crucial to enable effective treatment. Artificial intelligence (AI)–based image recognition tools such as Bone2Gene (currently under development) has the potential to greatly enhance the diagnostic process and improve outcomes for patients with RBDs.

Methods

We retrospectively gathered 3434 hand radiographs from 876 patients diagnosed with different RBDs associated with short stature, namely achondroplasia, hypochondroplasia, X-linked hypophosphatemic rickets, SHOX-related short stature, pseudohypoparathyroidism, lysosomal storage diseases, and also Silver-Russell, Ulrich-Turner, and Noonan syndromes. We also included 1000 radiographs from non-RBD cases as controls. We used an end-to-end deep convolutional neural network to train a multi-class classifier to differentiate between these disorders based on hand radiographs.

Results

Using five-fold cross validation, the multi-class classifier achieved a balanced accuracy of 73.8% across the RBDs and controls. To further assess diagnostic support, we also evaluated top-k accuracies. The correct disorder was ranked among the top-2 predictions in 87.7% of cases and among the top-3 in 93.1%.

Conclusions

Our result is a proof-of-concept for the power of Bone2Gene image recognition AI in successfully differentiating between multiple RBDs associated with short stature, hence enhancing their diagnostic processes. When deployed at primary care centers or radiology labs, Bone2gene can accelerate the detection and referral of RBD patients to specialists, and when integrated in specialists work routines, it can assist the differential diagnosis.

LONG-TERM METABOLIC, VASCULAR AND RENAL OUTCOME ASSOCIATED WITH DIABETIC KETOACIDOSIS AT ONSET OF TYPE-1-DIABETES IN CHILDREN – DATA FROM THE PROSPECTIVE DPV REGISTRY

Clemens Kamrath ^a , Joachim Rosenbauer ^b,l , Alexander J. Eckert ^c,l , Thomas Kapellen ^d , Andreas Neu ^e , Martin Holder ^f , Peter Bramlage ^g , Stephan Kress ^h , Katharina Laubner ⁱ , Elke Fröhlich-Reiterer ^j , Michael Hauschild ^k , Reinhard W. Holl ^c,l

^a Universitätsklinikum Freiburg, Kinder- und Jugendklinik, Sektion Pädiatrische Endokrinologie und Diabetologie, Freiburg, Germany; ^b Deutsches Diabetes-Zentrum (DDZ) Düsseldorf, Düsseldorf, Germany; ^c Universität Ulm, Institut für Epidemiologie und Biometrie, Ulm, Germany; ^d Universität Leipzig, Kinderklinik, Leipzig, Germany; ^e Universität Tübingen, Kinderklinik, Tübingen, Germany; ^f Olgaspital Stuttgart, Stuttgart, Germany; ^g Institut für Pharmakologie und Präventive Medizin, Cloppenburg, Germany; ^h Vinzentius-Hospital, Landau, Germany; ⁱ Universitätsklinikum Freiburg, Klinik für Innere Medizin II, Abteilung Endokrinologie und Diabetologie, Freiburg, Germany; ^j Univ.-Klinik für Kinder- und Jugendheilkunde, Medizinische Universität Graz, Klinische Abteilung für Allgemeine Pädiatrie, Graz, Austria; ^k Universität Lausanne, Lausanne, Switzerland; ^l Deutsches Zentrum für Diabetesforschung (DZD) Munich-Neuherberg, Munich, Germany

Introduction and Objectives

Diabetic ketoacidosis (DKA) at type-1-diabetes (T1D) onset may negatively affect metabolic, vascular, and renal outcomes, but long-term data are limited. This study analyzed long-term metabolic and renovascular outcomes in children, adolescents, and young adults by DKA at T1D onset.

Methods

We used data from the DPV registry, including T1D patients (≤20 ys) with follow-up data until the 15th year. Longitudinal repeated measurements linear and logistic models estimated glomerular filtration rate (eGFR) using various creatinine-based formulae (CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration), FAS (Full-Age-Spectrum)-age, FAS-height, EKFC (European Kidney Function Consortium), and CKiD (Chronic Kidney Disease in Children)), HbA1c, BMI-SDS, blood pressure, and hypertension rate. Differences between patients with and without DKA (pH < 7.3) were assessed.

Results

We analyzed data from 2590 patients (54.3% male). The median age at last follow-up was 17.6 years, diabetes duration 14.4 years, and age at onset 3.1 years. 715 patients (27.6%) had DKA at diagnosis.

eGFR values did not differ significantly between groups for FAS-age (p=0.70), FAS-height (p=0.07), EKFC (p=0.55), and CKiD (p=0.09). No difference between the groups was observed for microalbuminuria rates (p=0.81).

HbA1c and BMI-SDS were higher over time in the DKA group (p<0.001). Differences were most pronounced in the first two years after diagnosis, decreased over the next six years and stabilized thereafter.

Systolic blood pressure was higher in the DKA group (p=0.013) and hypertension was more frequent in the DKA group over time (p=0.006).

Conclusions

Children who experience DKA at the onset of T1D tend to have poorer long-term metabolic and higher cardiovascular risk. We have not observed any adverse outcome for renal function. However, there could be a longer delay before the eGFR even begins to fall. It should be noted that an observational study cannot demonstrate causality. It is possible that social and economic disadvantage contributed to both DKA at the time of diagnosis and subsequent poorer outcomes.

JUVENILE IDIOPATHIC OSTEOPOROSIS PRESENTING WITH VERTEBRAL FRACTURES AFTER A SEIZURE IN AN ADOLESCENT WITH TYPE 1 DIABETES MELLITUS

Eleni Bualli ^a , Aimilia Kanellopoulou ^a , Gkentiana Misiou ^a , Semik Khodaverdi ^a , Winfried Krill ^a

^a Klinikum Hanau, Abteilung für Kinder- und Jugendmedizin, Hanau, Germany

Introduction and Objectives

Idiopathic juvenile osteoporosis (IJO) is an uncommon cause of bone fragility in otherwise healthy children and adolescents, usually recognized after secondary causes are excluded [1]. We present a 16-year-old with type 1 diabetes mellitus (T1DM) who developed vertebral fractures after a seizure episode during mild hypoglycemia (nadir 60 mg/dL). Our objective is to illustrate a stepwise diagnostic pathway and early management in a patient with dual risk from T1DM and seizure [2].

Methods

An adolescent with T1DM presented after a first seizure during mild hypoglycemia (nadir 60 mg/dL) with thoracic back pain and no thistory of trauma. The initial neurologic work-up ( EEG,brain MRI) was normal. Spine MRI showed compression fractures at T9–T10, L1, and L3. Baseline DXA demonstrated low BMD (Z-score −2.51). Laboratory Evaluation showed low 25-OH vitamin D with normal calcium, phosphate, PTH, and urinary pyridinoline and the endocrine profile was normal excluding secondary Osteoporosis. Tertiary evaluation in Cologne, including molecular genetics, was negative, supporting IJO.

Results

The patient has received three doses of intravenous zoledronic acid at six-month intervals, alongside vitamin D repletion, calcium optimization, and individualized activity guidance, with excellent tolerability. At follow-up, bone mineral density improved (Z-score −1.8) and no additional vertebral fractures were detected. Neurological follow-up supported a high suspicion of epilepsy; lamotrigine was initiated, and no further seizure episodes have occurred to date. The therapeutic plan remains ongoing with scheduled monitoring.

Conclusions

Initiation of bisphosphonates in the management of IJO, combined with vitamin D repletion and individualized physical activity, can improve BMD and reduce the risk of permanent deformities [3]. Nevertheless, bisphosphonate use remains controversial [1,4]. Therefore in patients with T1DM ,epilepsy and thus potential antiepileptic drug–related bone loss, a multidisciplinary approach and longitudinal BMD monitoring are essential [5]. There is al limited evidence on the management of Osteoporosis in young patients; long-term studies are needed to guide optimal therapy.

References

1. Krassas GE. Idiopathic juvenile osteoporosis. Ann N Y Acad Sci. 2000;900:409–12. doi:10.1111/j.1749-6632.2000.tb06253.x

2. Khan TS, Fraser LA. Type 1 diabetes and osteoporosis: from molecular pathways to bone phenotype. J Osteoporos. 2015;2015:174186. doi:10.1155/2015/174186

3. Kızılcan Çetin S, et al. Clinical Characteristics and Treatment Outcomes of Children with Primary Osteoporosis.Turk Arch Pediatr. 2023;58(3):314–321. doi:10.5152/TurkArchPediatr.2023.22248

4. George S, et al. Short-Term Safety of Zoledronic Acid in Young Patients With Bone Disorders: An Extensive Institutional Experience..J Clin Endocrinol Metab. 2015;100(11):4163–71. doi:10.1210/jc.2015-2680

5. Loxton P, et al. Bone Mineral Density and Type 1 Diabetes in Children and Adolescents: A Meta-analysis. Diabetes Care. 2021;44(8):1898–1905. doi:10.2337/dc20-3128

MILD VARIATIONS IN THYROID HORMONE SERUM CONCENTRATIONS SHOW ASSOCIATIONS WITH THE ET 6-6-R DEVELOPMENTAL TEST- RESULTS FROM A POPULATION-BASED PEDIATRIC COHORT IN GERMANY

Ellen L. Keil ^a , Mandy Vogel ^a,d , Wieland Kiess ^a,b , Jürgen Kratzsch ^a,c , Nico Grafe ^a , Juliane Ludwig ^a

^a Universität Leipzig, Leipzig Research Center for Civilization Diseases, LIFE Child, Leipzig, Germany; ^b Universitätsklinikum Leipzig, Abteilung für Kinder- und Jugendmedizin, Leipzig, Germany; ^c Universitätsklinikum Leipzig, Institute for Laboratory Medicine, Leipzig, Germany; ^d Universität Leipzig, Deutsches Zentrum für Kinder- und Jugendgesundheit (DZKJ), Leipzig, Germany

Introduction and Objectives

Thyroid hormones are essential for child development, and untreated hypothyroidism can lead to severe adverse effects, including mental retardation. However, whether or not thyroid hormone variation within the normal range affects developmental tests is not known. Thus, we aimed to investigate associations between physiological variations in thyroid hormone levels and the results of developmental tests in healthy children.

Methods

We included 946 children who completed the Bayley Scales of Infant and Toddler Development (BSID) III, and 1467 children who completed the developmental test for children from six months to six years old (ET 6-6-R). Using regression models, we assessed the association between TSH, FT3, and FT4 and test results as outcomes. In addition, we assessed associations between the subscales and stability across age.

Results

BSID: We found no consistent significant associations between BSID scores and thyroid hormones. ET 6-6-R:Higher TSH-SDS were associated with lower scores in most developmental domains, with effects between ß = -0.13 to ß = -0.23, all ps < .05 except for drawing and social emotional development. After adjusting for age, sex, and mother´s education, only language development reached significance. FT3 was positively associated with all scales but language development. Cognition, Gross and fine motor skills (ß=0.15 to 0.26, ps <.05) reached significance. After adjusting, only fine motor skills remained significant. FT4 showed positive but nonsignificant associations with most scales. Yet, fine motor skills were positively associated with FT4SDS in the multivariable analysis (ß= 0.17, p=0.014).

Conclusions

We could confirm associations between thyroid hormone levels in the physiological range and children´s developmental scores. However, the differences in results between the two developmental tests suggest that the associations between thyroid hormone levels and developmental tests are highly specific to particular aspects of development and even age groups. Therefore, individual measurements have very limited explanatory power.

KNOCKOUT OF PLIN1 IN SGBS CELLS LEADS TO ABERRANT LIPID DROPLET MORPHOLOGY AND IMPAIRED STIMULATION OF LIPOLYSIS

Elisabeth Kindig ^a , Julia Altvater ^a,b , Lena Semelink-Sedlacek ^a,b , Julia von Schnurbein ^a , Pamela Fischer-Posovszky ^c,b , Martin Wabitsch ^a,b , Daniel Tews ^a,b

^a Ulm University Medical Centre, Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, Ulm, Germany; ^b German Centre for Child and Adolescent Health (DZKJ), Partner site Ulm, Ulm, Germany; ^c Ulm University Medical Centre, Experimental Endocrinology and Metabolism Research, Department of Pediatrics and Adolescent Medicine, Ulm, Germany

Introduction and Objectives

Perilipin 1 is the most abundant protein that coats lipid droplets in adipocytes, playing a crucial role in lipid storage. Frameshift variants in the coding PLIN1 gene can lead to familiar partial lipodystrophy type 4, characterized by selective loss of adipose tissue, which results in metabolic abnormalities including insulin resistance and diabetes. To date, there is no known human loss-of-function model for PLIN1. Here, we aim to investigate the role of PLIN1 in human SGBS adipocytes.

Methods

We established a CRISPR-Cas9-mediated knockout of PLIN1 in human SGBS preadipocytes (PLIN1-KO). Impact of PLIN1 deficiency on adipogenesis and cell morphology was measured by qRT-PCR, Western Blot, and immunofluorescence. Effects on adipocyte function were studied using assays for cellular lipolysis, lipogenesis, and energy metabolism.

Results

During adipogenic differentiation of human PLIN1-KO cells, we noted a distinct change in lipid droplet formation compared to control cells. We did not observe major changes in the number of differentiated cells, but cells lacking PLIN1 tend to form larger lipid droplets, yet fewer per cell. Interestingly, PLIN1 deficiency in adipocytes was paralleled by a strong reduction in protein expression of the PLIN1 coregulator Alpha/beta hydrolase domain-containing protein 5 (ABHD5). Measurements of glycerol release in the supernatant throughout the differentiation revealed significantly higher levels of basal lipolysis. Further, cAMP-mediated lipolysis was blunted in PLIN1-KO cells.

Conclusions

We here present a human adipocyte in vitro model of PLIN1 deficiency. Depletion of PLIN1 leads to a functional impairment of lipid storage in human adipocytes, driven by increased basal and reduced stimulated lipolysis which seems to be mediated by ABHD5 inhibition.

SAME SYMPTOMS, DIFFERENT CAUSES: TWO CASES OF INFANTILE HYPERCALCEMIA

Sonja Kloos ^a , Marie Ritter ^a , Olimpia A. Manzardo ^a , Johanna Weekes ^a , Geeske Mühlschlegel ^a , Franka Hodde ^a , Clemens Kamrath ^a

^a University Hospital Freiburg, Centre of Paediatric and Adolescent Medicine, Division of Paediatric Endocrinology and Diabetology, Freiburg, Germany

Introduction and Objectives

Hypercalcemia in infancy is rare, requiring differentiation between metabolic, genetic, and iatrogenic causes. Untreated, it may lead to nephrocalcinosis, renal insufficiency, neurological symptoms and impaired growth. We present two infants with marked hypercalcemia due to distinct causes.

We want to show diagnostic challenges of infantile hypercalcemia by comparing two cases: one with a heterozygous CYP24A1 variant (impairing vitamin D degradation) and one with presumed vitamin D intoxication.

Methods

Case 1: A 3-month-old male referred for conjunctivitis was incidentally found with elevated calcium (3.21 mmol/L; [2,25 - 2,75mmol/L]). Findings included suppressed PTH, normal 25-OH-vitamin D (30ng/mL [20-70ng/ml]) and elevated 1,25-(OH)₂-vitamin D (135 pg/mL; [40-100pg/ml]).

Case 2: A 7-month-old female admitted with vomiting and urinary tract infection. Routine labaratory work-up revealed severe hypercalcemia (3.92 mmol/L; [2,25 - 2,75mmol/L]), suppressed PTH and extremely elevated 25-OH vitamin D (416 ng/mL), while in relative terms 1,25-(OH)₂ vitamin D was only mildly elevated (149 pg/mL).

Results

Treatment included iv fluids, loop diuretics, and discontinuation of vitamin d intake. Case 1 normalized under fluid therapy and furosemide. Genetic testing revealed a heterozygous variant of uncertain significance in the CYP24A1 gene, encoding the vitamin-D-inactivating enzyme. Impaired enzyme activity may cause accumulation of vitamin D metabolites and subsequent transient hypercalcemia even in heterozygous carriers.

Case 2 required PICU care, with gradual normalization of calcium under forced diuresis and a special formula calcium-free diet. The laboratory constellation - hypercalcemia, suppressed PTH, and elevated 25-OH-D - was suggestive of vitamin D intoxication. However, the parents denied oversupplementation. Follow-up showed normalization of calcium and no more neprhocalcinosis.

Conclusions

These cases highlight the importance of considering both genetic and iatrogenic causes of infantile hypercalcemia. Early identification of the underlying cause via laboratory and genetic testing and thorough medication history is essential to avoid unnecessary therapy and prevent long-term complications.

References

Cappelani et al; Hypercalcemia due to CYP24A1 mutations: a systematic descriptive review , Eur J Endocrinol (2021 Dec 10;186(2):137-149)

Collins et al.; Hypervitaminosis D Secondary to a CYP24A1 Loss-of-Function Mutation: An Unusual Cause of Hypercalcemia in Two Siblings, (JBMR Plu. 2023 Aug 8;7(9):e10788)

Carpenter et al.; CYP24A1 loss of function: Clinical phenotype of monoallelic and biallelic mutations, (J Steroid Biochem Mol Biol. 2017 Oct:173:337-340)

Schlingmann; Vitamin D-dependent Hypercalcemia, (Endocrinol Metab Clin North Am 2021 Dec;50(4):729-742)

Marcinowska-Suchowierska et al.; Vitamin D Toxicity-A Clinical Perspective, (Front Endocrinol (Lausanne) 2018 Sep 20:9:550)

GROWTH, WEIGHT, AND GLUCOSE METABOLISM AFTER FONTAN SURGERY

Christina Klozoris ^a , Isabel Engels ^a , Anne Ksellmann ^c , Nicole Müller ^d , Felix Schreiner ^e , Isa Mayer ^f , Bettina Gohlke ^a

^a University Hospital of Bonn, Department of Paediatric Endocrinology and Diabetology, Bonn, Germany; ^b University Hospital of Bonn, Department of Paediatric Endocrinology and Diabetology, Bonn, Germany; ^c University Hospital of Bonn, Department of Paediatric Cardiology, Bonn, Germany; ^d University Hospital of Bonn, Department of Paediatric Cardiology, Bonn, Germany; ^e University Hospital of Bonn, Department of Paediatric Endocrinology and Diabetology, Bonn, Germany; ^f University Hospital of Bonn, Department of Paediatric Endocrinology and Diabetology, Bonn, Germany; ^g University Hospital of Bonn, Department of Paediatric Endocrinology and Diabetology, Bonn, Germany

Introduction and Objectives

Fontan circulation is established in children born with an univentricular heart via cardiac surgeries. After completion, the hearts pumps blood actively to the body while blood returns passively to the lungs bypassing the heart. Because surgery and treatment improved immensely over the last years, life expectancy is still increasing, so it becomes important to monitor and treat long-term consequences.

Methods

In group 1 (106 patients (60 males) >18 yrs) height, weight, and BMI was analysed. In 32 patients (18 males) a longitudinal analysis of growth from before puberty until final height was possible.

In group 2 (21 patients, seven <12 yrs; five between 12-18 yrs, and nine >18 yrs) continuous glucose monitor (CGM) profiles were analysed using a glucose sensor (Free Style Libre 3^R).

Results

Final height-SDS was -0.88 (SD 1.19) and differed significantly from target height (mean-Diff. 4.13 cm (p<0.001). No change during puberty: mean height-SDS prepubertal -0.94 (SD 1.13) vs postpubertal -0.92 (SD 1.16)). BMI-SDS showed an increase from 10 yrs onwards (mean BMI-SDS boys -0.58 (10yrs) vs +0.43 (18yrs); girls from -1.9 to -1.4).

Analysis of the glucose showed that 5/21 (24%) had an HbA1c>5.7% (range, 4.9-6.3%). Time in range (TiR;Glucose 70-180mg/dl) was achieved in 17/21 (80%; TiR in 99-100%). 4/21 (19%) showed a TiR only in 68%, 97% (n=2), 98%. Only 10/21 (48%) had Time in normal range (TnR;Glucose 70-140 mg/dl) in >95%. In n=11 (52%) TitR time was <95 (mean 86%; range, 68-94%). In 3/21 (14%) TnR was seen only in 68,77, and 83% resp. 5/21 (24%) had frequently glucose >180mg/dl.

Conclusions

Improved surgical techniques have led to increased survival after Fontan procedure. Our study confirms that they might develop growth impairment and disturbances in weight development - with both, increased risk of dystrophy and overweight/obesity. We now could show that they are at risk to develop hyperglycaemia. This might be due to impairment of insulin secretion due to damaged pancreas tissue (e.g., venous congestion) or because of a reduced glucose storage. In addition, the frequently observed obesity in our patients might additionally aggravate the alteration in glucose metabolism.

EXPECTATIONS AND FEEDBACK OF PARENTS ON A SUMMER CAMP FOR PRIMARY SCHOOL CHILDREN WITH TYPE 1 DIABETES

Eva Koch ^a , Alena G. Thiele ^a , Annelie Grundmann ^a , Annett Mauer ^a , Vivien Meyer-Bach ^a , Thomas Kapellen ^a

^a Universitätsklinikum Leipzig, Kinderdiabetologie, Leipzig, Germany

Introduction and Objectives

Outpatient diabetes education is an important component of pediatric diabetes care. A key milestone on the path to independent therapy management is school entry. To support children and families during this transition, our center initially offered one-day training sessions. Since 2024 this program was expanded to a five-day summer day camp for preschool and early primary school children. The aim of this study was to evaluate acceptance, benefits, and potential improvements of this format through parental surveys conducted before and after the camp.

Methods

Both surveys included scaled and open-ended questions. The pre-camp survey assessed expectations regarding organization, activities, and costs. In the post- camp survey, parents were asked to evaluate the quality of training, its relevance for therapy management during school time, as well as the camp’s execution and their future expectations for similar summer camps.

Results

This year, 34 children aged 6 to 10 participated in the summer camp. 18 parents completed both surveys. The five-day camp format was highly appreciated by the parents. Particularly valued were the training in diabetes self-management and the opportunity for peer group interactions. Children made new friends and practiced diabetes management in a group setting. The professional supervision by a specialized diabetes care team was highlighted as highly beneficial. However, costs were an issue for some families, and many parents expressed a desire for insurance reimbursement. All parents expressed support for annual training camps for children of this age group.

Conclusions

The five-day day camp is an effective and well-accepted diabetes education format for young children. Both children and parents appreciate the format without overnight stays. Qualified supervision by a specialized team is crucial for parents. Combining education with leisure activities is well received, particularly for teaching practical skills for improving diabetes management and promotes social participation.

PREVALENCE OF DIABETIC CATARACT IN CHILDREN AND ADOLESCENTS WITH NEWLY DIAGNOSED DIABETES MELLITUS TYPE 1

Mariella Krielen ^a , Stephanie Brandt-Heunemann ^a , Arne J. Speidel ^b , Armin Wolf ^b , Martin Wabitsch ^a , Christian Denzer ^a

^a Universitätsklinikum Ulm, Abteilung für pädiatrische Endokrinologie und Diabetologie, Ulm, Germany; ^b Universitätsklinikum Ulm, Klinik für Augenheilkunde, Ulm, Germany

Introduction and Objectives

Diabetes mellitus is one of the most common metabolic disorders in children and adolescents, with the incidence of both type 1 diabetes (T1D) and type 2 diabetes rising globally. Diabetic cataract is a complication with reported prevalence rates ranging from 0.25% to 3.4% in children and adolescents with T1D. We aimed to assess the prevalence of cataracts at the time of T1D diagnosis and to describe associated clinical characteristics in pediatric patients who were diagnosed and treated at a tertiary care center.

Methods

From a total cohort of 449 consecutive patients (<19 years of age) diagnosed with T1D at the Diabetes Center, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, a subset of 141 children and adolescents (31.4%) aged ≥10 years who underwent an ophthalmologic examination within 14 days of diagnosis at the local Department of Ophthalmology were included in the final analysis. Data collected included results from the ophthalmologic assessment and glycated hemoglobin levels (HbA1c, %).

Results

The prevalence of diabetic cataract in our cohort was 4.26% (N = 6). The affected patients included equal numbers of females and males, with a mean age of 12.4±1.5 years (range: 11.1-15.4 years) at diabetes diagnosis. HbA1c levels were significantly higher in patients with a diagnosis of cataract compared to those without (15.8±1 % vs. 12.4±2.5 %, p<0.05). Patients with a diagnosis of cataract demonstrated significantly lower visual acuity compared to those without cataract (p<0.05). Morphological assessment showed that the majority of cataracts (90%) corresponded to the posterior subcapsular type. In 10% of the examined eyes, nuclear cataracts were observed.

Conclusions

The prevalence of diabetic cataract at the time of T1D diagnosis in our pediatric cohort was higher than previously reported in comparable clinical studies. Although current German evidence-based guidelines do not recommend routine cataract screening in asymptomatic children at diagnosis, our findings underscore the potential benefit of early ophthalmologic evaluation in pediatric patients to facilitate timely detection and management of cataracts.

IMPACT OF A MEDITERRANEAN DIET ON INSULIN RESISTANCE IN CHILDHOOD OBESITY

Susanne Kröber, Marlene Rechtsteiner, Leah Tomerius, Dinet Ahmed, Lorenz Greifoner, Susann Weihrauch-Blüher

University Medicine of Halle, Department of Conservative and Operative Pediatrics, Dept. of Ped. I, Halle (Saale), Germany

Introduction and Objectives

Concomitant with the rise in childhood obesity, there has been an increase in associated diseases, such as MetS including impaired glucose homeostasis and insulin resistance (IR). A Mediterranean Diet (MD), rich in low processed, plant-based foods, fibre and unsaturated fats, is associated with reduced risk for metabolic diseases including type 2 diabetes in adults. Although data for children and adolescents are limited, first results confirm a positive impact of a MD. This study aimed to investigate the impact of an MD-based intervention on glucose metabolism and IR in children with obesity.

Methods

Children aged 6-18 years with BMI ≥90th percentile were included in a prospective study. Anthropometric and biochemical parameters were collected at baseline (t0), after three (t1) and six (t2) months. Primary outcomes were fasting glucose, fasting insulin, HbA1c, HOMA-IR and the presence of IR (HOMA-IR>90th percentile). Children and their families received nutritional counselling on a MD at t0, t1 and t2. Adherence to a MD was assessed using the KIDMED Index, ranging from -4 to 12 points, with higher scores indicating better adherence.

Results

To date, 123 children (52 girls; mean BMI-SDS 2.8±0.5; age 12.3±2.8 years; KIDMED score 2.6±2.0; HOMA-IR 5.5±3.2) have completed the intervention. At t0, the presence of IR was observed in 99 children (80.5%). Improvements between t0 and t2 were demonstrated in an increased KIDMED score (∆1.69; p<0.001), as well as decreased fasting glucose (∆-0.17; p<0.001), HbA1c (∆-1.11; p=0.004) and HOMA-IR (∆-0.74; p<0.001). Within six months, eight children (6.5%) achieved a reduction in HOMA-IR to below the 90th percentile, indicating that IR was no longer present.

Conclusions

Our findings suggest that the MD could improve markers of glucose homeostasis and IR in children with obesity, making it a potential nutritional approach for those with disturbed glucose metabolism. Further analyses in a larger study cohort are warranted to prove the correlation and investigate potential confounding factors such as gender, stage of puberty and weight loss. Decisive nutritional factors of MD are to be identified.

Funding: European Union’s Horizon Europe, grant agreement No.101080329

SETMELANOTIDE TREATMENT IN INDIVIDUALS WITH OBESITY AND PHIP VARIANTS: RESULTS FROM THE DAYBREAK TRIAL

Peter Kühnen ^a , Vidhu Thaker ^b , Christopher Still ^c , Douglas Denham ^d , Heidi Shea ^e , Svetlana Ten ^f , Whitney Herring ^g , Dorit Koren ^h , Jill C. Garrison ^h , Fabian Zuiderwijk ^h , Patrick Sleimann ^h , Orit Pinhas-Hamiel ⁱ , Antje Körner ^j , Erica van den Akker ^k

^a Charité - Universitätsmedizin Berlin, Berlin, Germany; ^b Columbia University Irving Medical Center, New York, United States; ^c Geisinger Clinic, Danville, United States; ^d Clinical Trials of Texas, San Antonio, United States; ^e Endocrine Associates of Dallas and Plano, Plano, United States; ^f Ten’s Medical Center, – Pediatric Endocrinology Clinic, Brooklyn, United States; ^g Mississippi Center for Advanced Medicine, Madison, United States; ^h Rhythm Pharmaceuticals, Inc., Boston, United States; ⁱ Tel Aviv University, Pediatric Endocrine and Diabetes Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, Israel; ^j Universitätsklinikum Leipzig, Leipzig, Germany; ^k Erasmus University Medical Center, Rotterdam, Netherlands

Introduction and Objectives

The melanocortin-4 receptor (MC4R) pathway regulates energy balance, hunger, and satiety. DAYBREAK (NCT04963231) was a two-stage clinical trial evaluating setmelanotide in individuals with a variant in ≥1 of 31 MC4R pathway-related genes, including PHIP, which enhances POMC transcription. Deleterious heterozygous PHIP variants are linked to neurodevelopmental issues, behavioural disorders, obesity and dysmorphic features. This is a post hoc analysis of individuals with PHIP variants and obesity.

Methods

DAYBREAK participants aged 6–65 years with a PHIP variant, classified as variant of unknown significance (VUS) or pathogenic/likely pathogenic (P/LP) per ACMG, hyperphagia and BMI ≥40 kg/m² (≥18 yrs) or ≥97th percentile (6–17 yrs) were included.

Those meeting age-related weight loss criteria after 16-week open-label stage 1 (S1) entered 24-week double-blind randomized, placebo-controlled stage 2 (S2).

Participants could restart open-label setmelanotide if BMI rose ≥5% from S2 entry. Primary analyses were performed at S1; hunger was assessed in those ≥12 yrs; S2 analyses were exploratory.

Results

Sixteen individuals with PHIP variants were enrolled (7-58 years). 9 (56.3%) met age-related weight loss criteria. The mean (SD) BMI percent change in the 13 participants who completed S1 was −6.12% (3.62%). For S1 hunger data, 8 of 11 participants with baseline “most hunger” data had Week-16 follow-up and exhibited a mean (SD) score reduction of −3.87 (1.41); 7 participants achieved a score reduction of ≥2. Nine participants entered S2 (5 adults and 4 children). Participants receiving setmelanotide maintained consistent weight loss, whereas those receiving placebo did not. For post S2 data, 8 participants continued on treatment; 5 adult and 3 pediatric participants exhibited a final mean (SD) percentage change in BMI of −14.18% (7.66%) and in BMI Z-score of −0.71 (0.27), respectively.

Conclusions

Clinical response to setmelanotide, a highly selective MC4R agonist, suggests the MC4R pathway is a key biologic driver of obesity in individuals with PHIP variants of interest and merits further investigation.

THYROID AUTOIMMUNITY IN ADOLESCENT DEPRESSION: IS THERE A RELATIONSHIP BETWEEN TPO ANTIBODIES, CNS ANTIBODIES AND DEPRESSION?

Leonie L. Kühner ^a,c , Raphael Hirtz ^b

^a Albert-Ludwigs-Universität Freiburg, Freiburg, Germany; ^b Helios Universitätsklinikum Wuppertal, Kinder- und Jugendmedizin, Wuppertal, Germany; ^c Universitätsklinikum Essen, Institut für Geschlechtersensible Medizin, Essen, Germany

Introduction and Objectives

The role of endocrine-related autoimmunity in adolescent depression remains unclear. This study examined (1) whether thyroid peroxidase (TPO) antibodies are markers of CNS autoimmunity, (2) whether CNS autoimmunity is related to depression, and (3) whether dysregulation of the corticotropic axis is associated with autoimmunity in depressed adolescents.

Methods

Data from two clinical cross-sectional studies, including 360 adolescents (11–19 yrs.) with at least mild depression (BDI-II >13) treated at the Dep. of Child and Adolescent Psychiatry, LVR Essen, were analyzed. CNS and serotonin-specific IgM/IgG antibody titer levels were compared between depressed adolescents with (n = 18) and without (n = 18) elevated TPO antibodies, as well as with healthy controls (n = 38), matched for age, sex and Tanner stage. Multiple regression analyses were conducted to investigate associations between antibody titers, depressive symptom severity and cortisol levels.

Results

While no differences were found between depressed adolescents with and without TPO antibodies regarding absolute level of CNS and serotonin antibody titers (p = .053 to .91), a comparison of depressed adolescents with healthy controls showed significant differences concerning all antibody titers (p < .005). This was confirmed for CNS IgM antibodies with a more stringent cutoff in categorical analysis (p = .003). There was neither a correlation between the severity of depression and the antibody titer levels (p = .36 to .97) nor between antibody and cortisol levels (p = .19 to .92).

Conclusions

The results indicate a possible involvement of CNS IgM antibodies in the etiopathogenesis of adolescent depression, but TPO antibodies do not appear to be markers for CNS autoimmunity. In addition, the study’s significance is limited by the relatively small number of cases. Future studies are needed to investigate the functional relevance of these antibodies based on a reliable number of cases and additional in vivo analyses, such as cell culture models.

CONTINUOUS GLUCOSE MONITORING IN EXTREMELY LOW BIRTH WEIGHT (ELBW) PREMATURE INFANTS A SINGLE-CENTRE REPORT

Christina Künle ^a , Christian Schlunk ^b , Tanja Wadien ^c , Neysan Rafat ^b , Martin Holder ^a

^a Klinikum Stuttgart, Olgahospital, Pädiatrie 2, Diabetologie und Endokrinologie, Stuttgart, Germany; ^b Klinikum Stuttgart, Olgahospital, Pädiatrie 4, Neonatologie, Stuttgart, Germany; ^c Klinikum Stuttgart, Olgahospital, Diabetesberatung, Stuttgart, Germany

Introduction and Objectives

Premature infants with extremely low birth weight (ELBW; < 1200 g birth weight) have a high risk of both hypo- and hyperglycaemia. Both conditions are associated with increased morbidity. To control glucose levels, frequent blood glucose measurements are currently performed, often up to 12 times a day, e.g. in the context of insulin-dependent hyperglycaemia. A few studies have already demonstrated the advantages and problems of continuous glucose monitoring (CGM) in premature infants. To date, most of these studies have been conducted using Medtronic’s ENLITE® sensor.

Methods

Premature infants with a birth weight < 1200 g were included as soon as possible after birth. A Guardian 4® sensor was attached to the lateral thigh in the prone position. It was inserted manually tangentially and then connected to the transmitter. After a 2-hour warm-up phase, glucose levels were continuously read using the Guardian® app on a mobile phone stored on each child’s bedside table. Blood tests were performed as part of routine blood gas analyses and when sensor glucose was < 54 mg/dl or when rapidly rising or falling.

Results

We demonstrate the feasibility and technical problems of CGM using Medtronic’s Guardian 4® sensor and associated Guardian® app in ELBW premature infants in our neonatal intensive care unit. There was good a concordance between the CGM values and the blood measurements, with limitations in the very low range. The use of CGM resulted in a significant reduction in blood measurements and, as a result, the possibility of stricter minimal handling. The measuring system was very well accepted by the nursing staff. Occasional slippage of the measuring filament when placing the sensor and recurring coupling difficulties between the sensor and the app proved to be limiting factors. Birth weight had no influence on the success of the sensor system.

Conclusions

The use of the Guardian 4® system for the care of extremely low birth weight (ELBW) premature infants is a promising method for achieving continuous monitoring of glucose metabolism in these high-risk children. The significant reduction in frequent blood glucose measurements has a very positive effect in terms of strict minimal handling. Greater accuracy in the area of very low blood sugar levels would be helpful. Further applications of this method would then include newborns of mothers with gestational diabetes.

SUSPECTED ACQUIRED GENERALIZED LIPODYSTROPHY FOLLOWING STEM CELL TRANSPLANTATION

Valentina Lahn ^a , Esther Schulz ^a , Johanna Schrum ^c , Jantje Weiskorn ^d

^a Altonaer Kinderkrankenhaus, Department of Paediatrics, Division of Paediatric Endocrinology and Diabetology, Hamburg, Germany; ^b Altonaer Kinderkrankenhaus, Department of Paediatrics, Division of Paediatric Endocrinology and Diabetology, Hamburg, Germany; ^c UKE, Department of Pediatrics and Pediatric Hematology/Oncology, Hamburg, Germany; ^d Children’s Hospital Auf der Bult, Department of Paediatrics, Division of Paediatric Endocrinology and Diabetology, Hanover, Germany

Introduction and Objectives

We report on a 14-year-old female patient with diabetes, as an incidental finding, insulin resistance and massively elevated HOMA index (37), negative autoantibodies and enormous elevated triglycerides with conspicuous fat distribution pattern.

Methods

Severe hypertriglyceridemia (965 mg/dl), steatosis hepatis and increased transaminases (AST 96 U/l; ALT 196 U/l; GGT 199 U/l), HbA1c of 8.8% and massively increased HOMA index (37), total loss of subcutaneous fatty tissue in the extremities, face, and neck since the 2017 HLA-identical bone marrow transplant, which was due to pre-B-ALL. The summarized findings of diabetes, insulin resistance, steatosis hepatis and the abnormal fat distribution pattern, we suspected acquired generalised lipodystrophy following stem cell transplantation.

Results

Consistent with this clinical presentation, the family reported impaired satiety, leptin level was low (12 ng/ml). Due to severe insulin resistance, we started metformin therapy (2 x 500 mg), a nearly euglycemic glucose profile could be achieved (HbA1c 6 % after 6 weeks). It is unclear whether the elevated liver enzymes are a consequence of hepatic steatosis, or if they are the result of an autoimmune hepatitis-like reaction, such as a graft-versus-host reaction following stem cell transplantation. The triglyceride levels, which were significantly elevated at admission, decreased with the dietary change but remained elevated (minimum 350 mg/dl). Fibrates were not an option due to high liver enzymes, and now, also indicated by the diagnosis, leptin therapy has been started.

Conclusions

Leptin is the drug of choice for metabolic disorders in patients with generalized lipodystrophy, as it has a positive effect on elevated triglycerides, liver enzymes, diabetic metabolism and it is hypothesised that leptin therapy will alleviate the lack of satiety, which is a significant source of distress for patients. The effects in these patients remain to be seen.

References

1. https://www.springermedizin.de/lipodystrophiesyndrome-klinische-praesentation-und-management/50526536

2. Sollier C, Vatier C, Capel E, Lascols O, Auclair M, Janmaat S, Fève B, Jéru I, Vigouroux C. Lipodystrophic syndromes: From diagnosis to treatment. Ann Endocrinol (Paris). 2020 Feb;81(1):51-60. doi: 10.1016/j.ando.2019.10.003. Epub 2019 Dec 16. PMID: 31982105.

3. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.02142/full

THE IMPACT OF PRADER-WILLI SYNDROME (PWS) ON CAREGIVERS AND THE HEALTHCARE SYSTEM: A BURDEN OF ILLNESS STUDY DESIGN

Constanze Lämmer ^a , Evelien Gevers ^b , Kathryn Obrynba ^c , Dairine Dempsey ^d , Kristen Yen ^e , Maria Hall ^f , Jackie Lodge ^g , Helen Ramage ^h , Theresa Strong ⁱ , Stacy Ward ^j , Tom Blenkiron ^k , Lorraine Munetsi ^k

^a KJF Josefinum, Sektion Pädiatrische Endokrinologie und Diabetologie, Abteilung Kinder- und Jugendmedizin, Augsburg, Germany; ^b Barts and the London Medical School, London, Great Britain; ^c The Research Institute at Nationwide Children’s Hospital, Columbus, United States; ^d Soleno Therapeutics Europe Ltd., Dublin, Irland; ^e Soleno Therapeutics Inc., Redwood, United States; ^f Maria Hall Consulting, London, Great Britain; ^g PWSA UK, Derby, Great Britain; ^h FPWR UK, Bradford, Great Britain; ⁱ FPWR, Covina, United States; ^j PWSA United States, Sarasota, United States; ^k PRIME HCD, Daresbury, Great Britain

Introduction and Objectives

Prader-Willi syndrome (PWS) is a rare, genetic, neurobehavioural-metabolic disorder characterised by hyperphagia, behavioural and psychological complications. Managing PWS symptoms through strict supervision, behavioural management and specialised supports imposes significant demands on caregivers and healthcare systems. However, data is lacking on the real-world burden of PWS. The objective was to design a study that characterises the clinical, humanistic, and economic burden of PWS on caregivers, families, and the healthcare system.

Study Design

This study is a descriptive, retrospective, cross-sectional, multi-site, micro-costing burden of illness study. The study will be conducted in the United States, UK, France, Germany, and Italy.

To assess the burden of PWS, a retrospective review will be conducted by consenting approximately 330 healthcare professionals (HCPs) who meet the following inclusion criteria: 1) primary specialty in paediatrics, endocrinology, or psychiatry; 2) qualified in their medical specialty for at least three years and 3) personally responsible for the management of patients with PWS.

HCPs who qualify and consent to participate will complete anonymised electronic case record forms (eCRFs) for eligible patients under their care. Patients are eligible for inclusion if they are aged 4 years and over, with a diagnosis of PWS >12 months, and their caregiver is aged 18 years or over and capable of providing informed consent. The eCRF will collect data on PWS disease history, management, and burden during the past 12 months from the date of consultation with the HCP. Aspects captured by the eCRF will include socio-demographics, symptoms, disease history, comorbidities, management, interventions, and care requirements.

HCPs will invite caregivers of these patients to complete corresponding anonymised Patient Public Involvement & Engagement caregiver forms (PPIE-c).

The PPIE-c will capture health-related quality of life (HRQoL) through EuroQoL 5-Dimensions 5-levels (EQ-5D-5L); the Work Productivity and Activity Impairment (WPAI) Questionnaire; the Hyperphagia Questionnaire for Clinical Trials (HQ-CT), the Zarit Burden Interview (ZBI) and the Food Safe Zone (FSZ) Questionnaire. The PPIE-c will help provide insights into the wider impact of PWS on caregivers and families. Key factors to be evaluated include hospitalisations, HCP visits, treatments, PWS-related transportation, specialised equipment, education status, and dietary modifications.

References

This study is sponsored by Soleno Therapeutics, Inc.

Copyright © 2025, Bioscientifica Publisher. Reused with permission.

LONG-TERM EFFICACY RESULTS OF DIAZOXIDE CHOLINE EXTENDED-RELEASE (DCCR) TABLETS IN PARTICIPANTS WITH PRADER-WILLI SYNDROME FROM THE COMPLETED C601 (DESTINY PWS) AND C602 OPEN LABEL EXTENSION (OLE) STUDIES

Constanze Lämmer ^a , Evelien Gevers ^b,c , Nicola Bridges ^d , Jack Yanovski ^e , Eric Felner ^f , Parisa Salehi ^g , Ashley Hall Shoemaker ^h , Amy Fleischman ⁱ , Anthony Goldstone ^j , Moris Angulo ^k , David Stevenson ^l , Kathryn Obrynba ^m , M. Guftar Shaikh ⁿ , Anthony Holland ^o , Verghese Mathew ^p , David Viskochil ^q , Shawn E. McCandless ^r , Lynne Bird ^s,t , Lah Melissa ^u , Virginia Kimonis ^v , Jennifer Abuzzahab ^w , Laura Konczal ^x , Elizabeth Littlejohn ^y , Heidi Shea ^z , Poonam Dharmaraj ^aa , Umi Das ^aa , Jorge Meja Corletto ^ab , John Wilding ^ac , Katerina Harwood ^ad , Kristen Yen ^ae , Raj Gandhi ^ae , Jing Gong ^ae , Patricia Hirano ^ae , Neil Cowen ^ae , Anish Bhatnagar ^ae , Michael Huang ^ae , Merlin Butler ^af , Jennifer Miller ^ag

^a KJF Josefinum, Sektion Pädiatrische Endokrinologie und Diabetologie, Abteilung Kinder- und Jugendmedizin, Augsburg, Germany; ^b Queen Mary University of London, Barts and The London Medical School, Wiliam Harvey Research Institute, Barts and The London Medical School, Wiliam Harvey Research Institute, Centre for Endocrinology, London, Great Britain; ^c Barts Health NHS Trust, Royal London Hospital, Royal London Hospital, London, London, Great Britain; ^d Chelsea and Westminster Hospital NHS Trust, London, Great Britain; ^e National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States; ^f Emory University School of Medicine, Atlanta, United States; ^g Seattle Children’s, Seattle, United States; ^h Vanderbilt University Medical Center, Nashville, Tennessee, United States; ⁱ Boston Children’s Hospital, Boston, United States; ^j Imperial College London Healthcare NHS Trust, London, Great Britain; ^k Good Samaritan Hospital Pediatrics, Babylon, New York, United States; ^l Stanford University, Stanford, CA, United States, Stanford, California, United States; ^m Nationwide Children’s Hospital, Columbus, Ohio, Germany; ⁿ Royal Hospital for Children, Glasgow, Great Britain; ^o University of Cambridge, Cambridge, Great Britain; ^p Hull University Teaching Hospitals NHS Trust, Hull, Great Britain; ^q University of Utah, Salt Lake City, Utah, United States; ^r University of Colorado, Children’s Hospital Colorado, Aurora, Colorado, United States; ^s University of California San Diego, San Diego, California, United States; ^t Rady Children’s Hospital, San Diego, California, United States; ^u Indiana University School of Medicine, Indianapolis, Indiana, United States; ^v University of California, Irvine Medical Center, Irvine, California, United States; ^w Children’s Minnesota, St. Paul, Minnesota, United States; ^x University Hospitals of Cleveland, Cleveland, Ohio, United States; ^y University of Michigan Health-Sparrow, Lansing, Michigan, United States; ^z Endocrine Associates of Dallas, Plano, Texas, United States; ^aa Alder Hey Children’s NHS Foundation Trust, Liverpool, Great Britain; ^ab New York University Langone Hospital, Garden City, New York, United States; ^ac Aintree University Hospital, Liverpool, Great Britain; ^ad St. Joseph’s Children’s Hospital, Paterson, New Jersey, United States; ^ae Soleno Therapeutics, Inc., Redwood City, California, United States; ^af Kansas University Medical Center, Kansas City, Kansas, United States; ^ag University of Florida, Gainesville, Florida, United States

Introduction and Objectives

Prader-Willi syndrome (PWS) is a rare genetic neurobehavioural-metabolic disorder characterised by hyperphagia, behavioral and psychological complications. In Europe, to date, no approved therapies exist for treating hyperphagia in patients with PWS. DCCR is an oral, once-daily medication currently under development for the treatment of PWS. The objectives of these studies were to evaluate the safety and efficacy of DCCR on hyperphagia, behaviour, and metabolic problems in people with PWS after long-term exposure to DCCR. The long-term safety of DCCR was presented previously.

Methods

125 participants with genetically-confirmed PWS ≥4 years of age received daily oral DCCR in Study C601 (International Phase 3, 13-week, double-blind, placebo-controlled study) and its open-label extension, Study C602. The primary endpoint was Hyperphagia Questionnaire for Clinical Trials (HQ-CT) Total Score (0-36) change from Baseline. Other efficacy analyses included the PWS Profile (PWSP) questionnaire, Clinical and Caregiver Global Impressions of Severity (CGI-S, Caregiver CGI-S) and body composition by DEXA. Efficacy endpoints were analysed through 3 years. Metabolic markers were analysed through 1.5 years.

Results

At Baseline, mean (SD) participant age was 13.4 (7.0) years, 55.2% were female, and mean (SD) HQ-CT Total Score was 21.5 (6.7). HQ-CT Total Score change from baseline was statistically significant at all timepoints through 3 years (p<0.0001). HQ-CT scores progressively improved over the first 52 weeks (-6.4 to -9.9 points), were clinically meaningful beginning at Week 26 (reduction by 7 points or more ) and were maintained thereafter (reduction by 10.7 and 11.6 points). There were significant improvements (p<0.001) in all PWSP domains (aggression, anxiety, compulsivity, depression, disordered thinking, and rigidity/irritability) at all timepoints. CGI-S and Caregiver GI-S were significantly reduced (p≤0.0004) at all timepoints. Lean body mass increased progressively and was significant at all timepoints (p<0.0001) (LS mean change [SE] at 3 years: 7.3 kg [0.46]; 40.3% increase from Baseline; p<0.0001).

Conclusions

Long-term administration of DCCR in participants with PWS was associated with statistically significant, clinically meaningful, and durable improvements in hyperphagia, PWS associated behaviours, clinician and caregiver assessments of disease severity, and lean body mass. DCCR appears to offer meaningful therapeutic benefits for people with Prader-Willi syndrome.

References

Copyright © 2024, Silverchair Publisher. Reused with permission.

THE EARLIER, THE BETTER: A MULTIPROFESSIONAL MANAGEMENT APPROACH SIGNIFICANTLY ALTERS BMI IN CHILDREN AND ADOLESCENTS WITH PRADER-WILLI SYNDROME (PWS)

Constanze Lämmer ^a , Uta Werner ^c , Johanna Schnitzlein ^a , Thomas M. Völkl ^a,b

^a KJF Klinikum Josefinum, Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics and Adolescent Medicine, Augsburg, Germany; ^b Friedrich-Alexander-Universität Erlangen-Nürnberg, Medical Faculty, Erlangen, Germany; ^c Helios Klinikum, Children´s Hospital, Hildesheim, Germany

Introduction and Objectives

PWS is a congenital hypothalamic disorder characterized by short stature and obesity resulting from hyperphagia. Despite early growth hormone therapy, a multiprofessional management approach involving endocrinologists, dietitians, psychologists, physical and sports therapists, neuropediatricians, and orthopedic specialists is recommended to improve BMI and body composition. Miller et al. defined age-dependent nutritional phases in PWS. The aim of this study was to analyze the course of BMI within each phase in relation to the initiation of specialized multiprofessional care.

Methods

We conducted a retrospective analysis of n=187 patients (98 f, median age 7.8 yrs) with genetically confirmed PWS. All patients participated in a PWS-specific multiprofessional management program focusing on diet, behavior, and environmental factors. Patients were grouped into the PWS nutritional phases: phase 1a, hypotonia with difficulty feeding (0–9 m), 1b, no difficulty feeding and growing appropriately (9–25 m), 2a, weight increasing without an increase in appetite (2.1–4.5 yrs), 2b, weight increasing with an increase in appetite (4.5–8 yrs), 3, hyperphagic, rarely feels full (8-18 yrs).

Results

Median BMI SDS in phase 3 who initiated our program in phase 1a was 0.68; 0.15 (ns vs. 1a) in phase 1b, 0.98 (ns) in phase 2a, 1.85 (p=0.0064) in phase 2b, and 0.98 (p=0.0192) in phase 3. These findings show that initiation of the program before 4.5 years of age leads to a significantly better BMI SDS. In phase 3, 90.9% of patients who had started in phases 1a/2a had a BMI SDS <2.0, whereas only 54.5% did so with a later start. Similar results were already evident in phase 2b. Among those who presented late in phase 3, no improvement was seen with years of participation: BMI SDS did not change significantly from 3.08 to 3.05, and from 1.06 to 0.57, respectively. Ten out of 187 patients did not have GH therapy, with a BMI SDS of 3.11 compared to 0.20. There was no difference between sexes.

Conclusions

An early start of a PWS-specific multiprofessional management program can limit maximum BMI in adolescence to below +2 SDS in most patients, at our center in 90.9%. Starting after 4.5 years of age, achieving further improvement in BMI becomes increasingly difficult. Early referral to a specialized PWS expert center and coordinated management should be ensured by the local endocrinologist caring for children and adolescents with PWS.

References

Miller JL, Lynn CH, Driscoll DC, Goldstone AP, Gold JA, Kimonis V, Dykens E, Butler MG, Shuster JJ, Driscoll DJ. Nutritional phases in Prader-Willi syndrome. Am J Med Genet A. 2011 May;155A(5):1040-9. doi: 10.1002/ajmg.a.33951.

DELINEATING ALDOSTERONE DEFICIENT STATES BY GC-MS URINARY STEROID METABOTYPING

Huijie Li ^a , Jörn Pons-Kühnemann ^b , Michaela F. Hartmann ^a , Stefan A. Wudy ^a

^a Justus-Liebig-University, Division of Pediatric Endocrinology & Diabetology, Giessen, Germany; ^b Justus-Liebig-University, Medical Statistics, Institute of Medical Informatics, Giessen, Germany

Introduction and Objectives

Disorders of isolated deficient aldosterone action involve insufficient production of aldosterone (aldosterone synthase defects type 1 and type 2 (corticosterone methyl oxidase (CMO) I and II)), and pseudohypoaldosteronism (PHA) featuring end-organ hormone resistance. Aldosterone is a key regulator of sodium-potassium homeostasis and blood pressure. Deficient action is characterized by hypotension, hyponatremia, hyperkalemia, and dehydration. We investigated whether gas chromatographic-mass spectrometric (GC-MS) urinary steroid metabolome analysis allows for delineation of these entities.

Methods

We quantified 44 urinary steroid metabolites from spot urine (µg/L) by targeted GC-MS from 124 infants with aldosterone deficient states (24 CMO I, 26 CMO II, 74 PHA; aged 3–348 days) and 138 matched controls. Relative enzymatic activities were calculated from precursor/product metabolite ratios. Data preprocessing included log2 transformation, Z-score standardization, and quantile normalization, followed by logistic regression and decision tree analysis.

Results

Male patients dominated in all diseases (68%). All entities peaked around the end of the neonatal period (wk4) with CMO manifesting up to six months and PHA extending until the end of the first year of life. Elevated corticosterone metabolite levels distinguished patients best from controls. PHA showed grossly elevated metabolites of aldosterone and its precursors. The ratio between corticosterone and aldosterone metabolites discriminated best between CMO subtypes and PHA. The ratio between 18-hydroxylated corticosterone and aldosterone metabolites differentiated CMO II from CMO I. Decision tree (rpart) analysis identified various sequential classifiers distinguishing controls, PHA, CMO I and CMO II, with high specificity (96%) and sensitivities (97%, 83% and 92%), respectively.

Conclusions

GC-MS urinary steroid metabotyping from spot urine provides a non-invasive and highly reliable new diagnostic tool for delineating aldosterone deficient states in young infants. Various metabolites and metabolite ratios effectively discerned controls, patients with CMO I, CMO II and PHA. The quantitative biomarkers we found allow for a steroid metabolomics based precision medicine approach.

References

• Wudy, S. A., & Hartmann, M. F. (2004). Gas chromatography-mass spectrometry profiling of steroids in times of molecular biology. Hormone and Metabolic Research, 36(06), 415-422.

• Hobler, A., Kagawa, N., Hutter, M. C., Hartmann, M. F., Wudy, S. A., Hannemann, F., & Bernhardt, R. (2012). Human aldosterone synthase: recombinant expression in E. coli and purification enables a detailed biochemical analysis of the protein on the molecular level. The Journal of steroid biochemistry and molecular biology, 132(1-2), 57-65.

• Riepe, F. G. (2013). Pseudohypoaldosteronism. Endocrine development, 24, 86-95.

CASE REPORT OF AN ADOLESCENT WITH A HOMOZYGOUS PROOPIOMELANOCORTIN (POMC) DEFICIENCY

Sabine Linke ^a , Marisa Buss ^a , Bettina Heidtmann ^a

^a Katholisches Kinderkrankenhaus Wilhelmstift, Pädiatrie, Hamburg, Germany

Introduction and Objectives

Monogenic forms of obesity are rare causes of extreme obesity. Typically, obesity develops in infancy. Depending on the specific gene defect, pharmacological treatment with leptin or setmelanotide may be a possibility in some cases.

Methods

We present the case of a 16-year-old boy who developed obesity within his first year of life. His maximum BMI was 48,0kg/m² (BMI-SDS +3,64). After an unremarkable neonatal period, a lack of satiety was already evident in early infancy, along with abnormal eating behavior characterized by uncontrolled consumption of large portions, frequent binge eating and rapid eating.

Results

The boy developed obesity-related comorbidities including hepatic steatosis, insulin resistance and hypertension.

Educational interventions failed to achieve weight stabilization or reduction.

Genetic testing via an obesity panel ultimately revealed a POMC defiency caused by the homozygous variant c.434G>A; p.(Arg145His). Treatment with the MC4 receptor agonist Setmelanotide (2.0 mg subcutaneously per day) was initiated.

After just five weeks of treatment, a weight loss of 7 kg was observed with a current BMI of 45,7 kg/m² (BMI-SDS +3,54).

Side effects included hyperpigmentation, recurrent headaches and local reactions at the injection sites.

Conclusions

POMC deficiency is a rare form of monogenic obesity. Lifelong therapy with setmelanotide is necessary to induce a feeling of satiety and enable weight reduction in affected patients. Lifelong multidisciplinary care for patients and their families is necessary.

DISEASE CONTROL AND LINEAR GROWTH AT ONE YEAR FOLLOW-UP IN A 9 year OLD GIRL WITH CYCLIC CUSHING SYNDROME DUE TO MICRONODULAR ADRENOCORTICAL DISEASE: A CASE REPORT

Olimpia Alice Manzardo ^a , Marie Ritter ^a , Geeske Muehlschlegel ^a , Franka Hodde ^a , Johanna Weekes ^a , Sonja Kloos ^a , Michaela Hartmann ^b , Stefan Wudy ^b , Clemens Kamrath ^a

^a Albert-Ludwigs-Universität Freiburg, Abteilung für Kinder- und Jugendmedizin, Freiburg, Germany; ^b Universitätsklinikum Giessen, Steroid Research & Mass Spectrometry Unit, Laboratory for Translational Hormone Analytics, Pediatric Endocrinology & Diabetology, Center of Child and Adolescent Medicine, Giessen, Germany

Introduction and Objectives

We present the results after one year follow-up of a case of a 9-year-old girl with Cushing syndrome due to micronodular adrenocortical disease.

The currently 9-year-old girl was diagnosed with Cushing’s syndrome at the age of 7 years, after presenting with a rapidly progressing weight gain (BMI increase from the 9th to the 94th percentile), a concomitant deceleration of linear growth (from the 95th to the 59th percentile) and cushingoid habitus with buffalo hump and moon face.

Methods

At diagnosis, ACTH was suppressed while random serum cortisol levels were in the normal range, without evidence of adrenal masses at imaging. Cortisol metabolites excretions in two different 24h-urine analyses showed differing results, one being six-fold elevated and one in the lower range of normal, indicating a cyclic pattern of disease. A high-dose dexamethasone suppression test over 48h showed a paradoxical increase in serum and 24h-urinary cortisol, indicative for primary pigmented nodular adrenocortical disease (PPND).

Results

To date, no genetic alterations were found in ARMC5, KDM1A, PDE11A, PDE88 or PRKAR1A genes. The results of a trio exome sequencing are currently pending.

The patient has since then been treated with the 11-β hydroxylate inhibitor metyrapone to control hypercortisolism as well as low-dose hydrocortisone as a ‘block and replace therapy’, resulting in a rapid improvement of signs and symptoms.

At one year follow up, the patient and family report well-being, a good quality of life and improved school results. Lab results showed normal urinary cortisol metabolite excretion rates. Growth charts show a normalized BMI (57th percentile) and a linear growth at the 90th percentile after an initial catch-up growth after the beginning of treatment.

Conclusions

The diagnosis and treatment of ACTH-independent Cushing syndrome, especially in cyclic disease, are challenging. The only definitive treatment being bilateral adrenalectomy, which carries with it the burden of lifelong adrenal insufficiency. This case demonstrates the effectiveness of conservative treatment in improving signs and symptoms, while also offering patients and their families a good quality of life.

HIGH PREVALENCE OF MONOGENIC SHORT STATURE DISORDERS IN SGA CHILDREN SCHEDULED FOR RHGH TREATMENT

Judith Mayer ^a , Roland Schweizer ^a , Ute Grasshoff ^b , Tobias Haack ^b , Gerhard Binder ^a

^a Universitätsklinikum Tübingen, Abteilung für pädiatrische Endokrinologie, Tübingen, Germany; ^b Universitätsklinikum Tübingen, Institut für Medizinische Genetik und Angewandte Genomik, Tübingen, Germany

Introduction and Objectives

SGA short stature is an indication for growth hormone treatment. Recent studies using comprehensive genetic analyses (Whole Exome Analyses (WES), Whole Genome Analyses (WGS)) suggest that monogenic short stature disorders are present in up to 50% of clinically unsolved SGA cases.

Therefore, we started WES or WGS analysis in all SGA children scheduled for rhGH treatment who had not received a specific diagnosis by other diagnostic means. We now present the results of our new practice.

Methods

Since November 2021, WES or WGS were performed on DNA isolated from blood samples of 29 SGA patients following standard procedures. Variant filtering and interpretation were performed in a phenotype-based prioritisation using disease databases (OMIM, ClinVar, HGMD and LOVD). Five patients born SGA were excluded from WES/WGS in advance: four with clinical and genetic diagnosis of Silver-Russell syndrome and one with Turner syndrome.

Results

In 8 out of 29 (27.7 %) patients, a monogenetic explanation of the growth disorder was detected. Genetic class 4 (probably pathogenic) and class 5 (pathogenic) variants were found in the genes ACAN, COL1A2, FGFR3, TRPS1, FANCA, PTPN11, IGF1R and SMAD4. All patients with positive genetic findings showed subtle phenotypic characteristics consistent with their diagnosis. In four patients with the new diagnoses of osteodysplasia or cancer predisposition (COL1A2, FGFR3, TRPS1, FANCA), decision against rhGH treatment was made together with families.

Conclusions

This single center study confirms a high rate of positive genetic diagnoses in children born SGA without prior clinical diagnosis but scheduled for rhGH treatment. The findings emphasize the importance of comprehensive genetic testing in SGA short stature before rhGH treatment is started.

NEONATAL DIABETES MELLITUS IN A PATIENT WITH SHORT SYNDROME

Luzia Mildner ^a,b , Annett Bläser ^b , Bartelt Heike ^a , Thomas Michael Kapellen ^a

^a Universitätsklinikum Leipzig, Kinderdiabetologie, Leipzig, Germany; ^b Universitätsklinikum Leipzig, Neonatologie, Leipzig, Germany

Introduction and Objectives

Neonatal diabetes mellitus (NDM) is a rare (1 in 89,000 live births) form of mainly monogenic diabetes that occurs within the first six months of life and can be temporary or permanent. Genetic mutations are found in 80% of cases. SHORT syndrome is a rare genetic disorder which may present with diabetes mellitus, typically in later adulthood. It is historically defined by its acronym: short stature, hyperextensible joints, ocular depression, Rieger anomaly, teething anomalies and a characteristic facial phenotype with a triangular face shape. Not all patients show all symptoms.

Case Report

We report on the case of a female, full-term (SGA) newborn who was delivered at 37+0 weeks of gestation by primary caesarean section with a birth weight of 1500 g [Perc.: < 3 ; z-score -0.656 kg], length: 40.0 cm [Perc.: < 3 ], head circumference: 28.5 cm [Perc.: < 3] and with distinct facial abnormalities, manifested in a triangular face shape and a small nose. Postnatal adaptation was normal. Apart from IUGR, oligohydramnios and gestational diabetes, there were no obstetric problems during pregnancy. The parents are non-consanguineous and stated that they had no relevant health problems.

After initially normal blood sugar levels, the newborn developed hyperglycaemia (up to 11.4 mmol/l) and glucosuria from the 13th day of age. Continuous glucose monitoring was initiated, indicating spontaneous normalisation of blood sugar levels on the 23rd day of age. Laboratory tests – including basal insulin, anti-insulin antibodies, liver enzymes and thyroid function parameters – were all within the normal range. Blood gas analysis remained stable. Exome sequencing ultimately identified a heterozygous pathogenic variant (c.1892G>A, p.Arg631Gin) in the PIK3R1 gene on chromosome 5, confirming PIK3R1-associated SHORT syndrome. Due to the spontaneous normalisation of blood glucose levels, no therapeutic intervention was necessary. To date, no recurrence of hyperglycaemia has been observed.

This appears to be only the second reported case of NDM associated with genetically confirmed SHORT syndrome. It expands the known phenotype of SHORT syndrome by demonstrating that diabetes mellitus can manifest as early as the neonatal period. This case highlights the importance of an early genetic diagnosis of neonatal hyperglycaemia, as this enables appropriate clinical management and drug therapy.

CONCURRENT MANIFESTATION OF TYPE 1 DIABETES AND CONGENITAL LONG QT SYNDROMEWITH TORSADES DE POINTES IN A 9-YEAR-OLD GIRL: A PEDIATRIC EMERGENCY CASE

Gkentiana Misiou ^a , Aimilia Kanellopoulou ^a , Eleni Bualli ^a , Winfried Krill ^a , Semik Khodaverdi ^a

^a Klinikum Hanau, Klinik für Kinder- und Jugendmedizin, Hanau, Germany

Introduction and Objectives

QTc prolongation is a known but usually transient finding in pediatric diabetic ketoacidosis (DKA). However, the manifestation of congenital Long QT Syndrome (LQTS) with torsades de pointes (TdP) during DKA is exceedingly rare. We report a case of simultaneous onset of Type 1 Diabetes Mellitus (T1DM) and genetically confirmed LQTS in a child presenting with life-threatening arrhythmias, emphasizing the importance of early ECG monitoring and interdisciplinary management.

Methods

A 9-year-old girl presented with severe DKA and newly diagnosed T1DM. Clinical symptoms included polydipsia, polyuria, weight loss, fatigue and Kussmaul breathing. During initial stabilization, she experienced four episodes of transient loss of consciousness with tonic features and pallor, initially interpreted as seizures. Continuous ECG monitoring revealed torsades de pointes and a QTc of 700 ms. Diagnostic evaluation included labs, EEG, cranial MRI, long-term ECG and genetic testing. Treatment included fluids, insulin, electrolytes and antiarrhythmics.

Results

The patient received intensive care for DKA with IV insulin and rehydration. During these episodes, arrhythmias were identified as TdP with associated convulsive syncope. Esmolol was ineffective; IV metoprolol led to stabilization. Subsequent transition to propranolol and oral Mexiletine was well tolerated. EEG and MRI findings were unremarkable. Genetic testing confirmed pathogenic variants in KCNH2 and SCN5A, consistent with congenital LQTS. The patient was transitioned to subcutaneous intensified insulin therapy and received structured diabetes education with high adherence.

Conclusions

This case highlights the rare but clinically significant interaction between metabolic decompensation in T1DM and underlying channelopathies. Electrolyte shifts during DKA may unmask congenital LQTS, increasing the risk of malignant arrhythmias. Routine ECG monitoring is essential in pediatric DKA, particularly in patients with altered consciousness or seizure-like activity. Timely interdisciplinary management, including genetic evaluation and tailored antiarrhythmic therapy, is critical to ensure safety and long-term prognosis.

References

1. Ahuja N et al. QTc prolongation in pediatric diabetic ketoacidosis. Pediatr Diabetes. 2008.

2. McMullan DM et al. Congenital Long QT Syndrome in Type 1 Diabetes. Pediatr Diabetes. 2020.

3. Goldenberg I et al. Risk Stratification for Sudden Cardiac Death in Congenital LQTS. JACC. 2008.

4. Ogden D et al. Pediatric Torsades de Pointes: Recognizing Electrolyte and Genetic Triggers. PACE. 2017.

CLOUDED VISION – WHEN CATARACT LEADS TO DIAGNOSIS

Johanna Moos ^a , Benita Momm ^a , Bettina Heidtmann ^a

^a Katholisches Kinderkrankenhaus Wilhelmstift, Abteilung für pädiatrische Endokrinologie und Diabetologie, Hamburg, Germany

Introduction and Objectives

Cataract is a rare complication of type 1 diabetes mellitus in children and adolescents.

It is, among other things, associated with female sex, delayed diagnosis and high HbA1c. The underlying causes include osmotic and oxidative stress, which lead to protein aggregation and fiber degeneration within the lens. This process is irreversible and progresses rapidly as seen in the case presented here.

Methods

We present a case of a 9-year-old girl who was referred to our hospital by a pediatrician after a visual impairment was detected by an optician. She had been experiencing increasing physical weakness and vision disorder for several weeks. For the past year, she had polyuria and polydipsia, nocturia, and failure to thrive, but these symptoms had not led to a diagnosis before.

Results

The girl was dehydrated and in reduced general condition. Her BMI was 12.5 kg/m² (< 1st percentile), blood glucose > 500 mg/dl, pH 7.23, base excess -16.5 mmol/l, and HbA1c 18.1%. After i.v. rehydration and insulin therapy, the treatment was switched to ICT. The required insulin dose was high (3,6 IU/kg/day). Due to her visual impairment an immediate consultation with an ophthalmologist was planned. Rapidly loss of vision proceeded and one week after discharge the girl suffered from blindness. An ophthalmologist confirmed the diagnosis of bilateral cataract and a two-stage surgery was performed. Visual acuity is now 100% with the use of corrective glasses. After switching to an AID-system, the latest HbA1c-value was 6.6% and insulin requirement decreased to 0.96 IU/kg/day.

Conclusions

Diabetic cataract is an irreversible complication of type 1 diabetes mellitus and can lead to complete vision loss. This visual impairment can only be cured by surgery. In our case, cataract led to diagnosis, even though symptoms had been present for one year. This case highlights once again the importance of early diagnosis to prevent severe complications.

ADRENAL CRISIS: RESULTS FROM A PARENTAL EDUCATION WORKSHOP

Geeske Mühlschlegel ^a , Marie Ritter ^a , Franka Hodde ^a , Johanna Weekes ^a , Olimpia Manzardo ^a , Clemens Kamrath ^a

^a Clinic for Pediatric and Adolescent Medicine, University Hospital Freiburg, Division of Paediatric Endocrinology and Diabetology, Freiburg, Germany

Introduction and Objectives

Adrenal insufficiency (AI) is rare in children. Lifelong therapy with glucocorticoids is required in all patients. Adrenal crisis (AC) represents a life-threatening condition in patients with AI. Due to the increased need for glucocorticoids during acute stress, parental education in the prevention and management of adrenal crisis is essential.

Methods

We held a workshop for families with children suffering from AI, which included theoretical input and practical training. Furthermore, we conducted an interactive survey to assess the causes of AI in participating families and to find out about their experiences, level of knowledge and sense of security in dealing with an adrenal crisis.

Results

30 families took part in our survey. Main causes of AI were congenital adrenal hyperplasia (43%) and secondary AI (40%). Almost one half (48%) had already experienced an adrenal crisis, with fever and vomiting presenting most common symptoms. 20% of those families had already administered an emergency hydrocortison injection at least once. However, almost half (48%) of the families admitted that there had already been situations where they retrospectively regretted not having injected the emergency hydrocortisone syringe. Two thirds of families experienced situations where medical staff (paramedics and doctors) were not adequately informed about AI or how to manage AC.

Conclusions

AI is a rare disease associated with a 6% risk per year to suffer from a life-threatending AC. Symptoms are frequently hard to differentiate from seasonal infections, especially in younger individuals. Healthcare professionals often have a lack of knowledge about rare AI and even rarer AC, depending on their scope of practice and experience. Training families and patients in the recognition, prevention and management of adrenal crisis is therefore essential to make these patients and their closest caregivers experts in the management of their disease.

References

1. Lousada LM, Mendonca BB, Bachega TASS. Adrenal crisis and mortality rate in adrenal insufficiency and congenital adrenal hyperplasia. Arch Endocrinol Metab. 2021 Nov 3;65(4):488-494.

2. Rushworth RL, Chrisp GL, Bownes S, Torpy DJ, Falhammar H. Adrenal crises in adolescents and young adults. Endocrine. 2022 Jun;77(1):1-10.

CARDIAC MARKERS IN CHILDREN AND ADOLESCENTS WITH TYPE 1 DIABETES MELLITUS AT THE TIME OF ONSET

Sara Musterer ^a,b , Mandy Vogel ^a,b , Wieland Kiess ^a,b , Sandy Richter ^c , Heike Bartelt ^e , Christof Meigen ^a,b , Uta Ceglarek ^d , Anja Willenberg ^d , Ronald Biemann ^d , Thomas Kapellen ^e , Alexandra Kiess ^f

^a Universität Leipzig, Medical Faculty, University Hospital for Children and Adolescents Leipzig, Center for Pediatric Research (CPL), LIFE Child, Leipzig, Germany; ^b Universitätsklinikum Leipzig, German Center for Child and Adolescent Health (DZKJ), partner site Leipzig/ Dresden, Leipzig, Germany; ^c Universität Leipzig, Pediatric Research Center, University Hospital for Children and Adolescents, Department for Child and Adolescent Medicine, Leipzig, Germany; ^d Universität Leipzig, Institute for Laboratory Medicine, Leipzig, Germany; ^e Universitätsklinikum Leipzig, University Hospital for Children and Adolescents Leipzig, Leipzig, Germany; ^f Universitätsklinikum Jena, Department of Child and Adolescent Medicine, Section of Pediatric Cardiology, Jena, Germany

Introduction and Objectives

The incidence of type 1 diabetes mellitus (T1DM) is rising among children and adolescents. Acute metabolic complications such as ketoacidosis at disease onset may lead to early myocardial stress. This study aimed to investigate the association between cardiac biomarkers - high-sensitivity troponin T (hsTnT) and N-terminal pro-b-type natriuretic peptide (NT-proBNP) - and metabolic parameters (HbA1c, pH, glucose and weight change during hospitalization) at the time of T1DM onset to identify patients at risk for early cardiac involvement.

Methods

We included 306 children and adolescents with newly diagnosed T1DM and compared them to an age-, sex-, and BMI-SDS-matched healthy control group from the LIFE Child study (n=1,259). Blood samples were analysed for high-sensitivity troponin T and NT-proBNP concentrations. Values were transformed into sex- and age-adjusted SDS. Associations between biomarkers and metabolic parameters were analysed using descriptive statistic and censored regression models.

Results

Children with recent T1DM showed significantly higher hsTnT levels and lower NT-proBNP levels compared to the control group. HsTnT levels positively correlated with Hemoglobin A1c

in the T1DM group while both hsTnT and NT-proBNP levels were negatively associated with the pH value. A weak positive trend was observed between hsTnT levels and blood glucose

while no association was found with NT-proBNP. In female patients, weight gain during hospitalization was significantly associated with hsTnT levels, suggesting sex-specific responses.

Conclusions

HsTnT and NT-proBNP may serve as early markers of cardiac stress in children with newly diagnosed T1DM. Reduced NT-proBNP levels likely reflects hypovolemia secondary to

ketoacidosis, highlighting the biomarker’s sensitivity to acute volume status. In cases of severe acidosis (pH < 7.2), elevated NT-proBNP concentrations may indicate increased cardiac

strain, suggesting that the response is modulated by the degree of metabolic derangement. Elevated hsTnT in combination with high HbA1c and low pH may reflect early myocardial

strain and could support the need for early cardiological assessment.

References

1. Ogle GD, James S, Dabelea D, Pihoker C, Svennson J, Maniam J, et al. Global estimates of incidence of type 1 diabetes in children and adolescents: Results from the International Diabetes Federation Atlas, 10th edition. Diabetes Res Clin Pract. 2022 Jan;183:109083.

2. Manuwald U, Schoffer O, Kugler J, Riemenschneider H, Kapellen TM, Kiess W, et al. Trends in incidence and prevalence of type 1 diabetes between 1999 and 2019 based on the Childhood Diabetes Registry of Saxony, Germany. PLoS ONE. 2021 Dec 31;16(12):e0262171.

3. Haji M, Erqou S, Fonarow GC, Tcheugui JBE. Type 1 Diabetes and Risk of Heart Failure: A Systematic Review and Meta-analysis. Diabetes Res Clin Pract. 2023 Aug;202:110805.

4. Baden MY, Imagawa A, Iwahashi H, Shimomura I, Awata T, Ikegami H, et al. Risk factors for sudden death and cardiac arrest at the onset of fulminant type 1 diabetes mellitus. Diabetol Int. 2015 Dec 29;7(3):281–8.

5. Türe M, Akın A, Unal E, Kan A, Savaş S. Electrocardiographic data of children with type 1 diabetes mellitus. Cardiol Young. 2022 Jan;32(1):106–10.

6. Hall C. NT-ProBNP: The Mechanism Behind the Marker. J Card Fail. 2005 Jun 1;11(5):S81–3.

7. Katrukha IA. Human cardiac troponin complex. Structure and functions. Biochem Mosc. 2013 Dec;78(13):1447–65.

8. Bohn MK, Steele S, Hall A, Poonia J, Jung B, Adeli K. Cardiac Biomarkers in Pediatrics: An Undervalued Resource. Clin Chem. 2021 Jun 14;hvab063.

9. Clerico A, Aimo A, Cantinotti M. High-sensitivity cardiac troponins in pediatric population. Clin Chem Lab Med CCLM. 2022 Jan 1;60(1):18–32.

10. Saeed M, Tapia G, Ariansen I, Stene LC, Seljeflot I, Tell GS, et al. Serum Galectin-3 and Subsequent Risk of Coronary Heart Disease in Subjects With Childhood-Onset Type 1 Diabetes: A Cohort Study. Diabetes Care. 2021 Mar;44(3):810–6.

11. El Razaky O, El Amrousy D, Elrifaey S, Elgendy M, Ibrahim W. Three-dimensional speckle tracking echocardiography: Is it the magic wand in the diagnosis of subclinical myocardial dysfunction in children with type 1 diabetes mellitus? Echocardiography. 2018;35(10):1657–63.

12. Salem M, El Behery S, Adly A, Khalil D, El Hadidi E. Early predictors of myocardial disease in children and adolescents with type 1 diabetes mellitus. Pediatr Diabetes. 2009 Dec;10(8):513–21.

13. Poojary I, Khalid U, Patra T, Giri J, Al Heyasat A, Basith S, et al. Troponinemia in Patients With Diabetic Ketoacidosis Without Acute Coronary Syndrome. Cureus. 16(5):e61064.

14. Eubanks A, Raza F, Alkhouli M, Glenn AN, Homko C, Kashem A, et al. Clinical significance of troponin elevations in acute decompensated diabetes without clinical acute coronary syndrome. Cardiovasc Diabetol. 2012 Dec 27;11:154.

15. Atabek ME, Pirgon O, Oran B, Erkul I, Kurtoglu S. Increased cardiac troponin I concentration in diabetic ketoacidosis. J Pediatr Endocrinol Metab JPEM. 2004 Aug;17(8):1077–82.

16. Sakou II, Soldatou A, Seretis A, Karanasios E, Paltoglou G, Karavanaki K. Markedly elevated troponin and NT-proBNP and myocardial dysfunction in an adolescent with severe diabetic ketoacidosis: A case report. Clin Pediatr Endocrinol. 2022;31(3):192–8.

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HETEROGENICITY OF NEONATAL DIABETES ONSET, TREATMENT RESPONSE TO GLIBENCLAMIDE AND CLINICAL COURSE DUE TO IDENTICAL KCNJ11 GENE VARIANT – EXPERIENCE FROM ONE PEDIGREE WITH NINE AFFECTED FAMILY MEMBERS

Stella A. Nagel ^a,b , Julia August ^a , Tanja Ottersberg ^a , Silja Robling ^c , Gunnar Cario ^a , Paul-Martin Holterhus ^,b , Jessica Bokelmann ^a,b

^a Department of Pediatric Oncology and Rheumatology, Pediatric Endocrinology and Diabetology, University Hospital of Schleswig-Holstein, UKSH Campus Kiel, Kiel, Germany; ^b Medical care center (MVZ) for Pediatric Endocrinology and Diabetology, University Hospital of Schleswig-Holstein, UKSH Campus Kiel, Kiel, Germany; ^c MGZ, Medical Genetics Center, Munich, Germany

Introduction and Objectives

2.5%-6.5% of pediatric diabetes cases are of monogenetic origin [1]. Activating KCNJ11 mutations prevent KATP channel closure and thus reduce hyperglycemia-induced insulin secretion [2]. The resulting permanent or transient neonatal diabetes shows a large variation of clinical phenotypes [3]. We present 4 family members necessitating different treatment strategies while harboring the identical KCNJ11 gene variant (c.535G>A, p.Glu179Lys) and summarize key points from our experience, including variability in presentation and response to glibenclamide (GBC) and GBC withdrawal trials.

Methods

The index patient (P1) and his mother were diagnosed with KCNJ11-related diabetes by a different hospital (2015), genetic testing was performed in accredited laboratories (Exeter, MGZ Munich). Regular diabetes care was provided at our centre following the 2^nd son’s (P2) birth (2021). 2025 a half-sister (P3) was born. All children receive regular clinical check-ups including evaluation of blood glucose, continuous glucose monitoring profiles (Dexcom G6 sensor) and A1c-measurements. Informed consent for the presentation of these results was obtained.

Results

Age at diagnosis:

• 16 yrs (mother (diagnosed as IDDM, current age (CA) 33 yrs))

• 5 weeks (son, index case (P1), CA 10 yrs)

• 2 weeks (son (P2), CA 4.5 yrs)

• 9 days (daughter (P3), CA 1 month, genetic confirmation pending)

• unknown: 4 maternal siblings & grandmother

Additional features:

• P1: IUGR, attention deficit disorder (iDEND: intermediate developmental delay, NDM syndrome without epilepsy)

• P2: IUGR, anal atresia

Treatment:

• Mother: metformin, insulin (prior to 1^st & during pregnancies), glimepiride

• P1 & P2: initially CSII, GBC

• P3: no insulin, GBC (ongoing)

GBC withdrawal trial:

• At dose requirement (mg/kg/day):

o P1: GBC 0.008, age 8.5 yrs, A1c 6.1%

o P2: GBC 0.015, age 3 yrs, A1c 5.7 %

• After 1.5 yrs off medication:

o P1: A1c 5.9%

o P2: A1c 5.4%

Conclusions

• In families with known KCNJ11 variants GBC trial in lieu of insulin prior to genetic confirmation should be considered

• Effective start GBC dose may be even lower than recommended (mg/kg/day: ISPAD (0.5 [1]), product information (0.2 [4))

• Low maintenance doses warrant GBC withdrawal trial to reduce care burden

• Regular diabetes care should be continued in order to detect any relapse

• A subclinical degree of ß-cell dysfunction (impaired fasting glucose, A1c in pre-diabetes range) not requiring intervention can persist

References

1. Greeley SAW, Polak M, Njølstad PR, et al. ISPAD Clinical Practice Consensus Guidelines 2022: The diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes. 2022;23(8):1188-1211.

2. Gloyn AL, Pearson ER, Antcliff JF, et al. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med. 2004;350(18):1838-1849.

3. Greeley SA, Tucker SE, Naylor RN, Bell GI, Philipson LH. Neonatal diabetes mellitus: a model for personalized medicine. Trends Endocrinol Metab. 2010;21(8):464-472.

4. Amglidia product information [Online]. Available from: https://www.ema.europa.eu/en/documents/product-information/amglidia-epar-product-information_en.pdf [Accessed 23 July 2025].

ESPED STUDY: NEWBORNS WITH DIAGNOSIS OF DIFFERENCES OF SEX DEVELOPMENT DSD INCLUDING THOSE WITH 46,XX AND VIRILIZATION DUE TO CONGENITAL ADRENAL HYPERPLASIA (CAH)

Uta Neumann ^a , Clemens Kamrath ^b , Annette Richter-Unruh ^c

^a Charité - Universitätsmedizin Berlin, Kinderendokrinologie und -Diabetologie, Berlin, Germany; ^b University of Freiburg, Center of Child and Adolescent Medicine, Kinderendokrinologie und -Diabetologie, Freiburg, Germany; ^c MVZ Eberhard und Partner Dortmund Hormonzentrum für Kinder und Jugendl, Kinderendokrinologie und -Diabetologie, Dortmund, Germany

Introduction and Objectives

Differences of Sex Development (DSD) are rare conditions. It is estimated that around 10,000 people are affected in Germany and that around 150 children are born each year (frequency approximately 1:4,500. The primary objective of the study is to determine the prevalence of newborns with DSD during the first 28 days of life. Secondary study objectives are the recording of phenotype, karyotype, molecular genetic examinations, recommendations of centers/specialists for further care/counseling

Methods

“ESPED” is an established instrument for recording the frequency and clinical characterization of rare diseases in Germany. In this study, newborns with DSD (according to [2]), including those with 46,XX and virilization due to CAH and excluding Ullrich-Turner and Klinefelter syndromes, with a date of birth in the survey period and first diagnosis of a DSD within the first 28 days of life, were recorded. Upon notification, a questionnaire was sent out to record the phenotype (external genitalia), ask about genetic examinations and the procedure after leaving the clinic

Results

From 07/2023 to 12/2024, 44 reports were submitted. Of these, 38 questionnaires were received. Of the total cohort of 38 newborns, seven (18 %) were diagnosed with 46,XX CAH, eight (21 %) with 46,XY and pronounced hypospadias, two had chromosomal DSD and for two, no karyotype could be specified. For 17 children, no genetic testing had been arranged, or no results were available at that time. Genetic variants in genes that can cause 46,XY DSD were found in four children. Six children were not assigned a gender at birth

Conclusions

Over a period of 1,5 years, we received records of 38 newborns with DSD. Around 40% were diagnosed with 46,XX and CAH or 46,XY and severe hypospadias. Most families were referred to specialized centers with DSD expertise. Only seven children with virilized genitalia due to 46,XX CAH were reported via the ESPED notification. With an expected number of approx. 35-45 children with 46,XX CAH over 1.5 years, this suggests low response rates. Therefore, no valid conclusions can be drawn about the incidence of DSD

References

https://dserver.bundestag.de/btd/19/279/1927929.pdf

Aktualisierung S2k-Leitlinie „Varianten der Geschlechtsentwicklung“ (AWMF-Registernr. 174-001) Stand: 03/2025

SEVERE H-SYNDROME WITH MULTIORGAN INVOLVEMENT IN A 10-YEAR-OLD PATIENT

Dimitrios Papadimitriou ^a , Dörte Hilgard ^a

^a Praxis Dr. med. Dörte Hilgard, Kinderendokrinologie und -Diabetologie, Witten, Germany

Introduction and Objectives

H syndrome, also known as histiocytosis-lymphadenopathy plus syndrome, is a very rare, autosomal recessive form of histiocytosis characterized by cardiac anomalies, hepatosplenomegaly, hearing loss, hyperpigmentation, hypertrichosis, hypogonadism, facial and skeletal deformities, and in some cases, diabetes mellitus. This case presentation highlights the complex clinical course of a 10-year-old boy with H syndrome and its complications.

Methods

We present a 10-year-old boy who presented with diabetes mellitus and extreme short stature due to genetically confirmed H syndrome (homozygote mutation of the SLC29A3 gene). He also suffered from severe valvular aortic, pulmonary stenosis with subaortic stenosis and tricuspid insufficiency, which led to significant heart failure, with hypertrophy of both ventricles and constrictive pericarditis, which required surgical treatment. A significant anemia delayed the surgery. Other symptoms: hearing loss, facial features, hepatosplenomegaly, hyperpigmentation, lymphadenopathy, hallux valgus.

Results

The present findings underscore the need for early and comprehensive cardiological evaluation in patients with H syndrome, even when cardiac symptoms are initially secondary. The combination of high-grade valvular stenosis on both heart ventricles presents a particular therapeutic challenge. Anemia and short stature could be both direct manifestations of H syndrome and secondary consequences of chronic cardiac stress, making multidisciplinary treatment essential. Diabetes mellitus is treated in an excellent way by CSII. Furthermore, the family receives support from the Bunten Kreis (a community-based care center), which facilitates coordination between the various outpatient and hospital clinics. The interdisciplinary treatment enabled him now to visit school and feel better.

Conclusions

This case report illustrates a difficult and multidisciplinary and multicenter treatment and care of a patient with complex H syndrome. It emphasizes the importance of an interdisciplinary approach to diagnosis and management and good cooperation in such a case to improve the quality of life and prognosis of affected children.

References

1. V. Molho-Pessach, Z. Agha, S. Aamar, B. Glaser, V. Doviner, N. Hiller, D. H. Zangen, A. Raas-Rothschild, Z. Ben-Neriah, S. Shweiki, O. Elpeleg, A. Zlotogorski: The H syndrome: a genodermatosis characterized by indurated, hyperpigmented, and hypertrichotic skin with systemic manifestations. In: Journal of the American Academy of Dermatology, Band 59, Nr. 1, Juli 2008, S. 79–85; doi:10.1016/j.jaad.2008.03.021, PMID 18410979

2. Molho-Pessach V, Ramot Y, Camille F, et al. H syndrome: the first 79 patients. J Am Acad Dermatol. 2014;70:80-88. https://doi.org/10.1016/j.jaad.2013.09.019

3. Farooq M, Moustafa RM, Fujimoto A, et al. Identification of two novel mutations in SLC29A3 encoding an equilibrative nucleoside transporter (hENT3) in two distinct Syrian families with H syndrome: expression studies of SLC29A3 (hENT3) in human skin. Dermatology. 2012;224:277-284. https://doi.org/10.1159/000338886

4. Virginia P. Sybert (2017). Genetic Skin Disorders. Oxford University Press. pp. 182-. ISBN 978-0-19-027648-5

5. Moynihan L M, Bundey SE, Heath D, Jones EL, McHale DP, Mueller RF, Markham, AF, Lench NJ (1998) Autozygosity mapping, to chromosome 11q25, of a rare autosomal recessive syndrome causing histiocytosis, joint contractures, and sensorineural deafness. Am J Hum Genet 62: 1123-1128

6. Dilip, Meena; Chauhan, Payal; Hazarika, Neirita; Kumar Kansal, Naveen (Jan–Feb 2018). “H Syndrome: A Case Report and Review of Literature”. Indian Journal of Dermatology. 63 (1): 7678. doi:10.4103/ijd.IJD_264_17. PMC 5838761. PMID 29527032.

7. Morgan NV, Morris MR, Cangul H, Gleeson D, Straatman-Iwanowska A, Davies N, Keenan S, Pasha S, Rahman F, Gentle D, Vreeswijk MPG, Devilee P, and 10 others. Mutations in SLC29A3, encoding an equilibrative nucleoside transporter ENT3, cause a familial histiocytosis syndrome (Faisalabad histiocytosis) and familial Rosai-Dorfman disease. PLoS Genet. 6: e1000833

ADVANCED GLYCATION END PRODUCTS (AGES) IN CHILDREN AND ADOLESCENTS WITH OBESITY - A POTENTIAL MARKER FOR CARDIOMETABOLIC RISK?

Luise Pudig ^a , Susanne Kroeber ^a , Marlene Rechtsteiner ^a , Andreas Simm ^b , Susann Weihrauch-Blüher ^a

^a Medical Faculty, Martin Luther University Halle-Wittenberg, Abteilung für pädiatrische Endokrinologie und Diabetologie, Halle (Saale), Germany; ^b Medical Faculty, Martin Luther University Halle-Wittenberg, Medical Faculty, Clinic for Heart Surgery, Halle (Saale), Germany

Introduction and Objectives

An increasing number of children and adolescents are affected by obesity, often accompanied by significant comorbidities. Advanced Glycation End Products (AGEs) result from sustained hyperglycemia, and their development is strongly linked to oxidative stress. They are formed through non-enzymatic glycation and oxidation of proteins, lipids, and nucleic acids, ultimately accumulating in tissue. Already proposed as promising biomarkers for determining cardiometabolic risk in adults, studies in children and adolescents are scarce.

Methods

Children and adolescents with obesity (6 - 18 years; BMI ≥ 90. percentile) are enrolled in the ongoing European PAS GRAS study at the University Hospital Halle. Analysis was conducted using data from the study’s baseline examination. Skin-AGE levels were measured transdermally using the AGE Reader mu (version 2.1) via autofluorescence. Anthropometric parameters (body weight, lenthgs, hip- and waist circumferences) were measured following standardized procedures. Waist-to-height ratio (WHtR) was calculated by dividing waist circumference by height and used as an indicator of abdominal obesity.

Results

Data from 185 participants were analyzed (45.9% female; 12.3 ± 2.9 years; BMI-SDS 2.77 ± 0.57). The mean transdermal AGE level was 1.16 (± 0.25). Transdermal AGE levels showed a positive, albeit weak, correlation with both age (Pearson’s r = 0.200, p = 0.006) and BMI-SDS (Pearson’s r = 0.157, p = 0.033). In initial analyses, no significant correlation was found between the HOMA index or WHtR and AGEs. There were no gender differences in AGEs.

Conclusions

To the best of our knowledge, this is the first study examining the relevance of AGEs in children and adolescents with obesity. Early findings suggest a potential positive association of transdermal AGE levels with both, age and BMI-SDS, which is in line with available results from adults. Further research in a larger cohort is required to better understand the potential of AGEs as a non-invasive cardiometabolic risk marker in children with obesity.

References

Funding: Funded by the European Commission Horizon Europe, project PAS GRAS, grant agreement 101080329

Luise Pudig is supported by the junior clinician scientist program at Martin Luther University Halle-Wittenberg.

INSIGHTS INTO GENETIC AND CLINICAL PROFILES OF TRIPLE A SYNDROME IN SUDANESE CHILDREN

Salwa A. Musa ^b,e , Mohamed A. Abdullah ^b,f , Samar Hassan ^b , Eliane Streiff ^a , Franziska Lange ^a , Omer O. Babiker ^d , Areej A. Ibrahim ^g , Hiba A. Elshafie ^c , Angela Hübner ^a , Katrin Köhler ^a , Friederike S. Quitter ^a

^a Universitätsklinik Carl-Gustav-Carus Dresden, Abteilung für pädiatrische Endokrinologie und Diabetologie, Dresden, Germany; ^b Gaafar Ibn Auf Pediatric Tertiary Hospital, Department of Pediatric Endocrinology and Diabetes, Khartoum, Sudan; ^c Ahfad University for Women, Omdurman, Sudan; ^d Omdurman Islamic University, Department of Pediatrics, Faculty of Medicine and Health Sciences, Khartoum, Sudan; ^e Al-Neelain University, Department of Pediatrics and Child Health, Faculty of Medicine, Khartoum, Sudan; ^f University of Khartoum, Department of Pediatrics and Child Health, Faculty of Medicine, Khartoum, Sudan; ^g Prince Mohamed Bin Abdulaziz Hospital- Pediatric Department- Endocrine Division, Madinah, Saudi-Arabia

Introduction and Objectives

Triple A syndrome (OMIM*231550) is a rare autosomal recessive disorder characterized by achalasia, alacrima, adrenal insufficiency, and neurological features. It is caused by functional impairment of the nucleoporin ALADIN due to mutations in the AAAS gene. Limited data exists on triple A syndrome from Sub-Saharan African and Arab countries. Our objective is to perform a comprehensive clinical and genetic study in Sudanese patients diagnosed with triple A syndrome.

Methods

The clinical diagnoses were based on characteristic clinical and laboratory findings. Genetic testing was conducted in 20 families, encompassing 31 patients, revealing six different AAAS mutations.

Results

A previously described mutation in exon 9 (c.934C>T) was present in 35 %, and the known Arabic founder mutation c.1331+1G>A (intron 14) was found in 30 % of the families. In addition, two novel mutations, including an 8 bp-deletion at the exon 4/intron 4 junction (c.394_399+2delCTGTCTGT) and a 1 bp-deletion in exon 9 (c.852delG) were identified.

Conclusions

Genotype-phenotype analyses highlighted significant variability in symptom occurrence, age of onset, and disease severity. Consistent with the high consanguinity rates in Sudan, most mutations (95 %) occurred in a homozygous state. In conclusion, triple A syndrome shows significant variability in phenotypic presentation even among affected individuals within the same family or mutation. Even when patients exhibit only one of the three main symptoms, one should consider the diagnosis of triple A syndrome and perform genetic studies.

MITOCHONDRIAL RESPIRATION IN CHILDREN WITH OBESITY AND INSULIN RESISTANCE OR TYPE 2 DIABETES MELLITUS

Marlene Rechtsteiner ^a , Eugénia Carvalho ^b,c , Samiya Al-Robaiy ^d , Hans Zischka ^e,f , Susanne Kröber ^a , Andreas Simm ^d,g , Paulo Oliveira ^b,c , Susann Weihrauch-Blüher ^a

^a University Medicine Halle, Department of Conservative and Operative Pediatrics, Clinic for of Ped. I, Halle (Saale), Germany; ^b University of Coimbra, CNC-UC, Center for Neuroscience and Cell Biology, Coimbra, Portugal; ^c University of Coimbra, CIBB-UC, Center for Innovative Biomedicine and Biotechnology (CIBB), Coimbra, Portugal; ^d Martin Luther University Halle-Wittenberg, Medical Faculty, Center for Medical Research (ZMG), Halle (Saale), Germany; ^e Helmholtz Munich, Institute of Molecular Toxicology and Pharmacology, Munich, Germany; ^f Technical University Munich, School of Medicine and Health, Institute of Toxicology and Environmental Hygiene, Munich, Germany; ^g Martin-Luther-University Halle-Wittenberg, Medical Faculty, Clinic for Heart Surgery, Halle (Saale), Germany

Introduction and Objectives

The rising prevalence of childhood obesity is leading to an increase in metabolic diseases such as type 2 diabetes mellitus (T2DM) and cardiovascular disease. Mitochondrial dysfunction is increasingly recognised as both, a cause and a consequence of these conditions, contributing to oxidative stress, impaired energy production, and systemic inflammation. Assessing mitochondrial respiration (MR) in peripheral blood mononuclear cells (PBMC) is a minimally invasive method that could potentially be used to predict metabolic health in pediatric populations.

Methods

This study investigated differences in MR rates in children and adolescents with obesity and deteriorating metabolic conditions. The analysis included 162 children and adolescents (6-18 years) with obesity (BMI ≥ 97^th percentile), who were stratified by pubertal stage and insulin resistance (IR, HOMA-IR ≥ 90^th percentile). MR rates were measured via Extracellular Flux Analysis in PBMC. The Bioenergetic Health Index (BHI) was calculated using reserve capacity, ATP-linked, non-mitochondrial, and proton leak oxygen consumption rates as a marker of mitochondrial performance.

Results

Mitochondrial respiration was measured in prepubertal (n = 51; 37.3 % female; 10.0 ± 1.7 years), peripubertal (n = 47; 44.7 % female; 12.3 ± 1.7 years), post-pubertal (n = 52; 51.9 % female; 15.2 ± 1.7 years) and post-pubertal children with manifested T2DM (n = 12; 25 % female; 15.1 years). With increasing pubertal stage, the proportion of participants with IR raised as well (p < 0.001). There were no significant differences in mitochondrial respiration between children with and without IR (p = 0.187), or between the different pubertal stages (p = 0.246). However, the post-pubertal group with T2DM (BHI = 1.61) showed a significantly lower BHI than the post-pubertal group with IR (BHI = 1.89, p = 0.0252), as well as lower coupling efficiency (-7.4 %, p = 0.0013).

Conclusions

Preliminary results suggest an association between T2DM and impaired mitochondrial respiration in PBMC in children. This is characterized by reduced BHI and coupling efficiency indicating impaired ATP synthesis. IR did not appear to decrease MR compared to insulin sensitive children with obesity. Further research and larger cohorts are required to explore the relationships between insulin resistance/prediabetes, T2DM and mitochondrial dysfunction in children and adolescents with obesity.

Funding: European Commission Horizon Europe, project PAS GRAS, no. 101080329; DDG projectfunding 2024

AUTOIMMUNE THYROIDITIS IN PAEDIATRIC DIFFERENTIATED THYROID CARCINOMA: A PROTECTIVE FACTOR AGAINST METASTASIS?

Antje Redlich ^a , Marina Kunstreich ^b , Desiree Dunstheimer ^b , Niklas Aumann ^c , Kerstin Lorenz ^d , Markus Luster ^e , Kurt W. Schmid ^f , Michaela Kuhlen ^b

^a Otto-von-Guericke-University, Department of Paediatrics, Paediatric Haematology/Oncology, Magdeburg, Germany; ^b Faculty of Medicine, University of Augsburg, Paediatrics and Adolescent Medicine, Augsburg, Germany; ^c DIAKOVERE Hospital Hanover, Department of Vascular Surgery, Hanover, Germany; ^d Medical Faculty, Martin Luther University Halle-Wittenberg, Department of Visceral, Vascular and Endocrine Surgery, Halle, Germany; ^e University Hospital Marburg, Department of Nuclear Medicine, Marburg, Germany; ^f University Hospital Essen, University of Duisburg-Essen, Institute of Pathology, Essen, Germany

Introduction and Objectives

The interplay between autoimmune thyroiditis (AIT) and paediatric differentiated thyroid carcinoma (paedDTC) remains incompletely understood. While adult data suggest associations between AIT and tumorigenesis, paediatric-specific insights are scarce. This study explores whether AIT correlates with a less aggressive tumour phenotype and more favourable outcomes in children and adolescents with paedDTC.

Methods

We analysed 401 patients (<18 years) with histopathologically confirmed paedDTC, enrolled in the German Malignant Endocrine Tumour Registry (1997–2024). Patients were stratified by AIT status. Demographic, histopathological, and clinical data were compared, and survival outcomes analysed via Kaplan-Meier estimates.

Results

AIT was present in 16.0% of patients. AIT patients were older at diagnosis (p<0.001) and more often female (p=0.098). Distant metastases occurred significantly less often in AIT patients (7.5% vs. 22.2%, p=0.014). Similarly, histological thyroiditis was associated with less vascular invasion and smaller tumour size. Surveillance led more often to diagnosis in AIT patients (44.2% vs. 28.3%, p=0.022). A trend toward improved event-free survival (EFS) was observed in AIT patients (87.5% vs. 72.1%, p=0.255), though overall survival (OS) was similar (91.8% vs. 86.0%, p=0.167).

Conclusions

Our findings suggest AIT may confer a less aggressive phenotype in paedDTC, reflected in reduced metastatic burden and potentially improved EFS. Routine surveillance in AIT patients may facilitate earlier diagnosis, but underlying biological mechanisms warrant further exploration. These results could inform future risk-adapted treatment strategies and surveillance protocols in this distinct subgroup.

HYPOPHOSPHATEMIC RICKETS WITH PHEX MUTATION WITHOUT RENAL PHOSPHATE WASTING: A DIAGNOSTIC AND THERAPEUTIC CHALLENGE

Susen Reichardt ^a , Joseph Porrmann ^b , Angela Hübner ^a

^a Faculty of Medicine and University Hospital Carl Gustav Carus, TU Dresden, Division of Paediatric Endocrinology and Diabetology, Department of Pediatrics, Dresden, Germany; ^b Faculty of Medicine and University Hospital Carl Gustav Carus, TU Dresden, Department of Clinical Genetics, Dresden, Germany

Family Report

X-linked hypophosphatemia (XLH) is a rare hereditary metabolic disorder caused by pathogenic variants in the PHEX gene. Loss of PHEX function leads to increased secretion of the phosphaturic hormone fibroblast growth factor 23 (FGF23), resulting in renal phosphate wasting, hypophosphatemia, and reduced synthesis of active vitamin D (1,25(OH)₂D).

XLH typically manifests in childhood with impaired bone mineralization leading to rickets and osteomalacia, dental abscesses, disproportionate short stature, and muscle weakness. We report on a family with strong suspicion of familial hypophosphatemic rickets, highlighting the importance of comprehensive genetic diagnostics for diagnosis – even when initial PHEX gene mutation analysis is negative.

The mother of the index patient had multiple childhood surgeries for genua vara. Based on clinical suspicion of XLH, she was treated with calcitriol and phosphate supplements until adolescence. Her daughter and mother also exhibited mild genua vara and persistently elevated alkaline phosphatase (ALP) levels during childhood. However, no mutations were detected in PHEX gene analyses of either the mother or daughter.

The son was referred at age 2 years for refusal to walk, marked anterocurvature and varus deformity of both distal lower legs, and broadened wrists, despite adequate vitamin D supplementation during the first year of life. Radiological findings were consistent with advanced rickets. Laboratory tests revealed marked hypophosphatemia, elevated ALP and parathyroid hormone levels, but no significant renal phosphate loss (normal TpKrea) or vitamin D deficiency. Despite unremarkable whole exome sequencing (WES), oral phosphate, calcitriol, and vitamin D therapy was initiated. However, serum phosphate levels never sufficiently increased despite regular medication. Given strong clinical suspicion of hereditary rickets, whole genome sequencing (WGS) was performed one year later which revealed a hemizygous intragenic deletion of exon 21 of the PHEX gene (ACMG class 4), enabling targeted therapy with burosumab. Despite dose escalation of burosumab up to current 1.5 mg/kg, serum phosphate levels did not increase to the lower normal range. This raises the question of the underlying etiology of the hypophosphatemia and whether the identified PHEX mutation is indeed functionally pathogenic. We intend to escalate burosumab to the maximum dose of 2 mg/kg. Should this fail to elicit a response, further investigations will be required to clarify the mechanism of persistent hypophosphatemia.

References

Haffner D, Emma F, Eastwood DM, Biosse Duplan M, Bacchetta J, Schnabel D, Wicart P, Bockenhauer D, Santos F, Levtchenko E, Harvengt P, Kirchhoff M, Di Rocco F, Chaussain C, Brandi ML, Savendahl L, Briot K, Kamenicky P, Rejnmark L, Linglart A. Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Nat Rev Nephrol. 2019 Jul;15(7):435-455. doi: 10.1038/s41581-019-0152-5. PMID: 31068690; PMCID: PMC7136170.

Schindeler A, Biggin A, Munns CF. Clinical Evidence for the Benefits of Burosumab Therapy for X-Linked Hypophosphatemia (XLH) and Other Conditions in Adults and Children. Front Endocrinol (Lausanne). 2020 May 28;11:338. doi: 10.3389/fendo.2020.00338. PMID: 32547492; PMCID: PMC7271822

MENSTRUAL CYCLE–ASSOCIATED GLYCAEMIC VARIABILITY IN ADOLESCENT FEMALES WITH TYPE 1 DIABETES USING HYBRID CLOSED-LOOP INSULIN DELIVERY

Felix Reschke ^a,c , Nora Struckmeyer ^b , Torben Biester ^a , Ann-Kristin Frerking ^a , Kerstin Kapitzke ^a , Mareike Niemeyer ^a , Jantje Weiskorn ^a , Zlata Vukadinovic-Nikolic ^b , Rebecca Toenne ^c , Olga Kordonouri ^a

^a Kinder- / Jugendkrankenhaus AUF DER BULT, Abteilung für pädiatrische Endokrinologie und Diabetologie, Hanover, Germany; ^b Gynpraxis Hanover, Hanover, Germany; ^c Netzwerk zur Versorgung schwerkranker Kinder und Jugendlicher, Betreuungsnetz, Hanover, Germany

Introduction and Objectives

Hormonal fluctuations during the menstrual cycle can alter insulin sensitivity and glycaemic control in adolescent females with type 1 diabetes (T1D). Although hybrid closed-loop automated insulin delivery (AID) systems improve metabolic outcomes, their adaptability to cyclical insulin resistance remains poorly understood. This study investigates glycaemic variability and insulin demand across menstrual phases in a structured, app-tracked paediatric AID cohort

Methods

We retrospectively analysed 51 adolescent females with T1D (mean age 14.7 ± 1.8 years), using AID ≥6 months. All were ≥1 year post-menarche and diabetes onset, with regular self-reported cycles and no hormonal contraception, PCOS, or endocrine disorders. Menstrual phases were app-tracked across six complete cycles. Metrics included total daily insulin dose (TDD), time in range (TIR), above (TAR), below range (TBR), coefficient of variation (CV), and mean glucose. Linear mixed-effects models were used.

Results

Median HbA1c was 7.2% (IQR 6.8–7.5), and median BMI-SDS was 0.39 (IQR 0.14–0.71).

Luteal vs. follicular phase:

– TDD: +0.10 U/kg/day (95% CI 0.05–0.15, p<0.001)

– TIR: −6.3% (95% CI −9.0 to −3.5, p=0.001)

– TAR: +5.5% (95% CI 2.3–8.7, p=0.01)

– Mean glucose: +12.5 mg/dL (95% CI 5.3–19.7, p=0.01)

– CV: 35.0% (95% CI 32.1–37.6) vs. 39.4% (95% CI 36.2–42.7), p=0.03

TBR showed no significant change (−0.1%, p=0.44). No relevant differences were observed between menstrual and follicular phases (all p>0.10).

Conclusions

Luteal and premenstrual phases are linked to elevated insulin demand and impaired glycaemic stability in adolescent AID users with T1D. Even with closed-loop automation, physiological insulin resistance is not fully compensated. These data underline the need for menstrual-phase–adaptive insulin delivery algorithms and structured counselling to anticipate cycle-related glycaemic variability in paediatric care

References

Wilmot EG, et al. Glycaemic variability: The under-recognized therapeutic target in type 1 diabetes care. Diabetes Obes Metab. 2019;21(12):2599–2608.

Levy CJ, et al. Insulin delivery and glucose variability throughout the menstrual cycle on closed-loop control. Diabetes Technol Ther. 2022;24(5):357–361.

Gamarra E, Trimboli P. Menstrual cycle, glucose control and insulin sensitivity in T1D: A systematic review. J Pers Med. 2023;13(2):374.

SKYBRIGHT REGISTRY STUDY: ANALYSIS OF SAFETY AND EFFECTIVENESS OF LONAPEGSOMATROPIN IN THE FIRST 100 PATIENTS ENROLLED WITH 1 year OF FOLLOW-UP

Anette Richter-Unruh *Presenting on behalf of listed authors ^b , Aristides Maniatis ^a , M Jennifer Abuzzahab ^c , Steven Chernausek ^d , Terri Lipman ^e , Daniel Flynn ^f , Gnanagurudasan Prakasam ^g , Alan Rogol ^h , Eric Huang ⁱ , Pamela Lai ⁱ , Carol Zhao ⁱ , Philippe Backeljauw ^j

^a Rocky Mountain Pediatric Endocrinology, PC, Centennial, United States; ^b MVZ Dr. Eberhard & Partner Dortmund, Dortmund, Germany; ^c Children’s Minnesota, Minneapolis, United States; ^d University of Oklahoma Health Sciences Center, Oklahoma City, United States; ^e University of Pennsylvania School of Nursing, Philadelphia, United States; ^f St. Luke’s Boise Medical Center, Boise, United States; ^g Sutter Memorial Hospital, Sacramento, United States; ^h University of Virginia, Charlottesville, United States; ⁱ Ascendis Pharma, Inc., Palo Alto, United States; ^j Cincinnati Children’s Hospital Medical Center, Cincinnati, United States

Introduction and Objectives

Lonapegsomatropin, a prodrug providing sustained release of active, unmodified somatropin, is FDA- and EC-approved as a once-weekly treatment for pediatric growth hormone deficiency (GHD). The SkybriGHt registry assesses the safety and effectiveness of lonapegsomatropin in the post-marketing setting. Here, we report outcomes in the first 100 enrolled patients who have reached 1 year follow-up in the SkybriGHt registry.

Methods

Patients in the US who were prescribed lonapegsomatropin consistent with routine clinical practice were invited by their healthcare provider to participate in the SkybriGHt study. The decision to treat with lonapegsomatropin was made prior to/independent of any potential study participation. Outcomes evaluated were height standard deviation score (SDS), annualized height velocity (AHV), and IGF-I SDS. Safety was assessed through reporting of adverse events (AEs).

Results

The first 100 patients enrolled with 1 year follow-up were predominantly male (82%) and white (86%); the median (Q1, Q3) age was 10.0 (8.0, 12.0) years; and 59% had been treated with daily GH for median 9.1 months before being prescribed lonapegsomatropin. The median duration of lonapegsomatropin treatment (including treatment before enrollment in SkybriGHt) was 1.8 years (maximum 7.8 years). Median height SDS increased from -0.22 at enrollment to -0.09 and 0.21 at months 6 and 12, respectively. Median AHV at month 12 was 7.8 cm/year. Median IGF-I was 1.3 SDS at enrollment, 1.3 SDS at month 6, and 1.2 SDS at month 12. No serious or severe treatment-emergent AEs occurred, and there were none leading to death or treatment discontinuation.

Conclusions

Patients treated with lonapegsomatropin had an AHV aligned with expectations for age range and duration of GH treatment; median height SDS increased over time. IGF-I SDS remained stable over time. Safety was consistent with prior lonapegsomatropin trials and clinical experience with daily GH. Most patients were white and male, reflecting real-world prescription patterns. Data for the first 100 patients enrolled with 1 year follow-up in the SkybriGHt registry demonstrated safety and effectiveness aligned with prior reports of lonapegsomatropin treatment for pediatric GHD.

CASE REPORT: DELAYED DIAGNOSIS DUE TO LATE TSH-ELEVATION IN A PRETERM INFANT WITH CONGENITAL HYPOTHYROIDISM

Marie Ritter ^a , Franka Hodde ^a , Johanna Weekes ^a , Olimpia Manzardo ^a , Geeske Mühlschlegel ^a , Sonja Kloos ^a , Friederike Hörster ^b , Clemens Kamrath ^a

^a University of Freiburg, Freiburg University Hospital, Department of General Paediatrics and Adolescent Medicine, Section of Paediatric Endocrinology and Diabetology, Freiburg, Germany; ^b University of Heidelberg, Heidelberg University Hospital, Center for Pediatric and Adolescent Medicine, Newbornscreening-Laboratory, Heidelberg, Germany

Introduction and Objectives

We present the case of an extremely preterm infant with congenital hypothyroidism (CH), which was undetected in the first three newborn screenings (NBS).

Methods

The child was born at 24+1 weeks of gestation via c-section due to pathological CTG, weighing 370g. The newborn had a complicated clinical course, including early-onset sepsis and catecholamine therapy, respiratory insufficiency requiring NO ventilation and grade 3 intraventricular haemorrhage. At a corrected age of 35+0 weeks, the child was still dependent on CPAP and showing bradycardia.

Results

The first NBS was taken shortly after birth, before receiving transfusion. The second sample was taken at day three. Two more controls were taken at the corrected age of 26+4 (age 18 days) and 35+1 weeks (age 11 weeks). The first three NBS showed normal TSH-levels (7.4 µU/ml (Ref: 0-15), TSH 2.0 µU/ml, and 6.2 µU/ml, respectively).

The fourth NBS (35+1 weeks) showed an extremely high TSH level of 348 mU/ml. An immediate control confirmed the diagnose of CH (TSH 571 µU/ml, fT3 2.45 pmol/l (Ref: 3 – 9.28), fT4 <1.3 pmol/l(Ref: 11.5 – 28.3)). After diagnosis, a substitution with L-Thyroxin 25µg/d (15µg/kgKG/d) was started immediately.

Conclusions

This case highlights the problem of delayed TSH-elevation in preterm infants, especially those born before 32 weeks of gestation, leading to missed diagnosis of CH and resulting in delayed treatment initialisation. Delayed TSH-elevation in preterm infants has been described to occur between day of life 8 to 48, with a median of 13 days (McGrath et al, J Pediatr 2018). The optimal timing of repeating NBS in preterm children to detect those with CH remains subject to further research.

References

AWMF S2k-Leitlinie Neugeborenen-Screening auf angeborene Stoffwechselstörungen, Endokrinopathien, schwere kombinierte Immundefekte (SCID), Sichelzellkrankheit, 5q-assoziierte spinale Muskelatrophie (SMA) und Mukoviszidose, AWMF-Registernummer: 024/012, abgerufen online in 08/2025

McGrath N et al, Optimal Timing of Repeat Newborn Screening for Congenital Hypothyroidism in Preterm Infants to Detect Delayed Thyroid-Stimulating Hormone Elevation, J Pediatr (2019) Feb:205:77-82. doi: 10.1016/j.jpeds.2018.09.044

Kaluarachchi DC et al, Congenital hypothyroidism with delayed thyroid-stimulating hormone elevation in premature infants born at less than 30 weeks gestation, J Perinatol (2017) 37, 277–282; doi: 10.1038/jp.2016.213

Odenwald B et al, Long-Term Course of Hypothyroidism Detected through Neonatal TSH Screening in a Population-Based Cohort of Very Preterm Infants Born at Less than 32 Weeks of Gestation, Int J Neonatal Screen (2021) Oct 13;7(4):65. doi: 10.3390/ijns7040065.

IMPACT OF MATERNAL DIABETES IN PREGNANCY ON NEONATAL HYPOGLYCEMIA AND PERINATAL OUTCOMES

Marcia Roeper ^a , Henrike Hoermann ^a , Alena Welters ^a , Ertan Mayatepek ^a , Sebastian Kummer ^a , Thomas Meissner ^a

^a Universitätsklinikum Düsseldorf, Klinik für Allgemeine Pädiatrie, Neonatologie und Kinderkardiologie, Düsseldorf, Germany

Introduction and Objectives

Neonatal hypoglycemia is a common complication in newborns with perinatal risk factors, particularly those born to mothers with diabetes mellitus (DM). This prospective cohort study aimed to assess glycemic profiles and other neonatal outcomes in infants of mothers with pregestational or gestational diabetes (GDM), and to investigate differences according to maternal diabetes management.

Methods

Data were combined from three prospective cohorts focused on neonatal hypoglycemia, comprising a total of 1,018 neonates born at ≥35+0 weeks of gestation (857 at-risk neonates and 161 controls). At-risk infants underwent standardized protocols for blood glucose monitoring and management.

Results

Of the cohort, 365 neonates were born to diabetic mothers: 2.7% (n = 10) with type 1 DM, 3.6% (n = 13) with type 2 DM, 65.2% (n = 238) with diet-controlled GDM, and 28.5% (n = 104) with insulin-treated GDM. Infants of insulin-treated mothers had significantly higher mean birth weights (3,522g vs. 3,353g; p < 0.05) and were more often large for gestational age (LGA) (19.8% vs. 9.6%; p < 0.05). Diet-controlled diabetes was linked to increased rates of small for gestational age (SGA) (15.9% vs. 5.6%; p < 0.05). No significant group differences were observed in hypoglycemia frequency or severity, glucose monitoring, iv glucose treatment, NICU admission, or other complications such as late preterm birth, hyperbilirubinemia, respiratory distress, polycythemia, or suspected diabetic fetopathy.

Conclusions

Maternal diabetes influences fetal growth patterns, with insulin treatment associated with an increased risk of LGA and diet-controlled diabetes more often linked to SGA. However, when maternal glycemic control is maintained and neonatal management is standardized, glycemic outcomes and rates of neonatal complications are comparable across different types of maternal diabetes.

ESTABLISHING AGE-BASED REFERENCE VALUES FOR URINARY STEROID METABOLITES IN INFANTS

Eleni I. Sakellari ^a , Michaela F. Hartmann ^a , Stefan A. Wudy ^a

^a Justus Liebig University, Steroid Research and Mass Spectrometry Unit, Laboratory for Translational Hormone Analytics, Division of Pediatric Endocrinology & Diabetology, Center of Child and Adolescent Medicine, Giessen, Germany

Introduction and Objectives

Urinary steroid profiling by gas chromatography–mass spectrometry (GC-MS) is a key diagnostic tool for identifying inborn errors of steroidogenesis. GC-MS offers an easily accessible method for assessing the complete steroid metabolome, providing a holistic view of steroidogenesis, as urinary metabolites reflect both synthesis and catabolism. We aimed to establish normative reference ranges for urinary steroid metabolites during the first year of life,in order to support accurate and early diagnosis in this critical developmental period and to address a major gap in pediatric endocrinology.

Methods

This retrospective study included all infants under 1 year of age evaluated at our center between 2017 and 2021, who had no evidence of metabolic disorders based on urinary steroid excretion. Exclusion criteria were prematurity, corticosteroid therapy, or known syndromic conditions. Only infants with both weight and length between the 5th and 95th percentiles according to WHO growth standards were included. Urine samples were analyzed using GC–MS, measuring a panel of 58 typical neonatal steroid metabolites. Statistical analysis was performed using IBM SPSS Statistics 26.

Results

A total of 145 infants were included (82 males, 56.6%). Patients were stratified into six age groups by postnatal days: 0–30 (n=45), 31–60 (n=24), 61–120 (n=25), 121–180 (n=11), 181–270 (n=20), and 271–365 (n=20). Age- and sex-specific trends in urinary excretion of pregnenolone, progesterone, cortisol, and androgen metabolites were observed, with full numerical data and graphical representations provided in the complete study.

Conclusions

This study establishes reference values for urinary steroid metabolites in infants under one year of age, including critical markers for enzyme defects. These data offer a robust framework for comprehensive adrenal assessment, integrating cortisol production indices and Δ5-steroid profiles to capture both synthesis and catabolism, as well as postnatal involution of the fetal zone. The reference ranges generated have the potential to enhance global diagnostic precision for inborn errors of steroidogenesis. Further validation and expansion through additional studies remain essential.

References

Kamrath C, Wudy SA, Krone N. Steroid biochemistry. Endocr Dev. 2014;27:41-52. doi: 10.1159/000363612.

NOVEL HSD11B2 VARIANT (C.478G>A, P.GLY160SER) IN THREE SIBLINGS WITH APPARENT MINERALOCORTICOID EXCESS SYNDROME: PROOF OF PATHOGENICITY BY GC–MS URINARY STEROID METABOLOMICS

Eleni I. Sakellari ^a,b , Nora Genthner ^a,b , Felicitas Wolf ^a,b , Michaela F. Hartmann ^a , Stefan A. Wudy ^a,b

^a Justus Liebig University, Steroid Research and Mass Spectrometry Unit, Laboratory for Translational Hormone Analytics, Division of Pediatric Endocrinology & Diabetology, Center of Child and Adolescent Medicine, Giessen, Germany; ^b University Children’s Hospital, Justus-Liebig-Universität, Pediatric Endocrinology and Diabetology, Giessen, Germany

Introduction and Objectives

Apparent mineralocorticoid excess (AME) is a rare autosomal recessive disorder caused by pathogenic variants in 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2), leading to impaired inactivation of cortisol to cortisone. We present three siblings, children of consanguineous parents, carrying a novel HSD11B2 variant (c.478G>A, p.Gly160Ser), currently classified as a variant of uncertain significance, with metabolomic findings proving its pathogenicity.

Methods

Clinical presentation, laboratory data, imaging results, and urinary steroid profiles obtained by gas chromatography–mass spectrometry (GC–MS) were reviewed. Total urinary cortisol metabolite excretion (THF+allo-THF+THE) and the (THF+allo−THF)/THE ratio were calculated and compared with age-adjusted reference ranges.

Results

Case 1: A 12-year-old boy presented with headache, muscle weakness, dizziness, and hypertensive crisis (170/123 mmHg). Laboratory tests revealed hypokalemia, metabolic alkalosis, low renin/aldosterone. Imaging demonstrated bilateral nephrocalcinosis, renal cysts, and left ventricular hypertrophy.

Case 2: His 3-year-old brother presented with severe hypertension (175/104 mmHg) with normal electrolytes/imaging.

Case 3: His 10-year-old sister presented with abdominal pain, hypokalemia, and hypertension (156/114 mmHg) with normal imaging.

Urinary steroid analysis showed markedly reduced total cortisol metabolites, <5th percentile, suppressed tetrahydroaldosterone, and elevated (THF+allo-THF)/THE ratios >6 (normal ≤ 2.5).

All patients required spironolactone plus other potent antihypertensives.

Conclusions

A novel HSD11B2 variant (c.478G>A, p.Gly160Ser) was identified in three siblings with severe, early-onset ΑΜΕ. All presented with marked hypertension and the pathognomonic urinary steroid profile on GC–MS analysis, providing decisive biochemical proof of pathogenicity. As AME can hardly be diagnosed by serum or plasma steroid analysis, urinary GC-MS steroid metabolome analysis represents the technique of choice for the delineation of low-renin hypertension.

References

Lu YT, Zhang D, Zhang QY, Zhou ZM, Yang KQ, Zhou XL, Peng F. Apparent mineralocorticoid excess: comprehensive overview of molecular genetics. J Transl Med. 2022 Nov 3;20(1):500. doi: 10.1186/s12967-022-03698-9

Funder JW. Apparent mineralocorticoid excess. J Steroid Biochem Mol Biol. 2017 Jan;165(Pt A):151-153. doi: 10.1016/j.jsbmb.2016.03.010.

GONADOTROPIN-INDEPENDENT PRECOCIOUS PUBERTY (TESTOTOXICOSIS) IN A TWO YEARS OLD BOY – A NEW MUTATION IN LHCGR GENE

Vera Schempp ^a , Felix Schreiner ^a , Martin Heimbrodt ^b , Miriam Elbracht ^c , Bettina Gohlke ^a

^a University Hospital of Bonn, Department of Paediatric Endocrinology and Diabetology, Bonn, Germany; ^b University Hospital of Bonn, Department of Oncology and Haematology, Bonn, Germany; ^c University of Aachen, Centrum of Human Genetics, Aachen, Germany

Introduction and Objectives

A 2.5 years old boy presented growth acceleration (height 106.0 cm; +3.3 SDS), enlarged penis and pubic hair (Tanner P3G2) and normal prepubertal testicular volume (2ml). Testosterone was elevated (3.9ng/ml;norm <0.2ng/ml). Gonadotropins were prepubertal (LH<0.1U/ml, FSH<0.3IU/L). Bone-age was accelerated (7 yrs). Testicular and adrenal ultrasound were unobtrusive. ACTH, 17-OH-Progesterone were in the normal range, and other adrenal hormones were in the normal range. Normal cranial MRI but MRI of adrenals was suspicious for an unilateral small adrenal adenoma and adrenalectomy was performed.

Methods

Adrenalectomy was performed and histology showed no malignancy but confirmed an adenoma. However, thereafter, high testosterone levels with low gonadotropins persisted and the boy showed further growth acceleration and pubertal progress. Four months after the adrenalectomy he presented with Tanner P4G3 and slightly enlarged testis (volume 4ml) and testosterone of 3.22 ng/ml. MRI of the adrenals showed an unremarkable result and with no sign of relapse of the adenoma.

Genetic analysis with exome-based enrichment were performed to exclude suspected high tumour risk syndromes.

Results

Genetics showed no pathogenic or probably pathogenic changes in the genes responsible for hereditary tumour risk syndrome. However, a heterozygous missense variant in the LHCGR gene (NM_000233.4c.1754T>Gp.(Ile585Ser) Chr2:g.48688D43A>C(hg38)) was detected. The clinical relevance of which is currently unclear (variant of uncertain significance - VUC). Nevertheless, because changes in the LHCGR gene can have an inactivating or activating effect on the encoding protein (LH/hCG receptor) and activating pathogenic variants are associated with an autosomal dominant familial form of so-called precocious male puberty (testotoxicosis) comparable to the clinical findings in our patient, bioinformatic classifies the described change as “probably disease-causing”.

Conclusions

The boy suffers from a gonadotropin-independent precocious puberty (testotoxicosis) probably due to a so far not described activating mutation in the LHCGR Gene. Missense-changes nearby have been associated with the disease. Therefore, the region between nucleotide 1624-1741 on exon 11 seems to be a hotspot for point mutations responsible for activation of the LHCGR-Gene.

He was started on an antiandrogen agent and a third-generation aromatase inhibitor.

GLUCAGON-LIKE PEPTIDE-1 (GLP-1) AGONIST TREATMENT AND BARIATRIC SURGERY FOR THE MANAGEMENT OF EARLY-ONSET, SEVERE OBESITY DUE TO TWO HOMOZYGOUS MELANOCORTIN 4 RECEPTOR VARIANTS: A CASE REPORT

Melanie Schirmer ^a,b , Emine A. Cimbek ^c , Susanna Wiegand ^d , Peter Kühnen ^e,f , Leonard Elad ^g , Marko Kornmann ^g , Alexandra Kranzeder ^h , Joanna Lerner ^b,i , Stefanie Zorn ^a,b , Reiner Siebert ^b,i , Julia von Schnurbein ^a , Martin Wabitsch ^a,b

^a Ulm University Medical Center, Endo-ERN Reference Centre, Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, Ulm, Germany; ^b German Center for Child and Adolescent Health (DZKJ), partner site Ulm, Ulm, Germany; ^c Karadeniz Technical University Medical Faculty, Division of Pediatric Endocrinology, Department of Pediatrics, Trabzon, Turkey; ^d Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Center for Chronically Sick Children, Charité, Berlin, Germany; ^e Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department for Paediatric Endocrinology and Diabetology, Berlin, Germany; ^f German Center for Child and Adolescent Health (DZKJ), partner site Berlin, Berlin, Germany; ^g Ulm University Medical Center, Clinic for General and Visceral Surgery, Ulm, Germany; ^h Ulm University Medical Center, Department of Psychosomatic Medicine and Psychotherapy, Department Chronic Inflammatory Bowel Diseases and Eating Disorders, Ulm, Germany; ⁱ Ulm University and Ulm University Medical Center, Institute of Human Genetics, Ulm, Germany

Introduction and Objectives

Biallelic pathogenic variants in the melanocortin 4 receptor (MC4R) gene disrupt satiety regulation, causing early-onset, severe obesity with hyperphagia and poor response to lifestyle interventions [1]. No approved pharmacological treatment exists for these patients, and bariatric surgery outcomes are variable.We report a successful therapeutic intervention in an adolescent with two homozygous MC4R variants, treated with a combination of liraglutide therapy, sleeve gastrectomy, and multidisciplinary care.

Methods

We report a 16-year-old girl with severe obesity (BMI 75.2kg/m²) and multiple metabolic and psychiatric comorbidities. Genetic testing via next-generation sequencing revealed two likely pathogenic, homozygous MC4R variants, each homozygous. Extensive prior lifestyle interventions had failed. After a structured pre-surgery program, the decision for sleeve gastrectomy was endorsed by a multidisciplinary board. Preoperative liraglutide treatment was started to induce weight reduction and resumed postoperatively alongside a structured pre- and postoperative multidisciplinary support program.

Results

In this 16-year-old girl with two homozygous MC4R missense variants (p.Ser85Gly, p.Tyr268His), Liraglutide induced marked appetite suppression and 12.7kg weight loss over 13 weeks pre-surgery. Sleeve gastrectomy was performed leading to further weight loss of 15kg in 1.5 months. Restart of liraglutide 6 weeks post-surgery reduced recurrent hunger and supported further weight loss. At 6 months after surgery, weight decreased from an initial weight of 214.7kg to 158.8kg (−26% total weight reduction), with BMI falling to 59.5kg/m². Comorbidities, including hypertension, impaired glucose tolerance, dyslipidemia, hyperuricemia, and elevated liver enzymes, resolved or improved markedly. After 12 months, sustained weight stability was confirmed by telephone contact after the patient had moved.

Conclusions

In this adolescent girl with severe obesity due to homozygous MC4R-mutations, combining GLP-1 receptor agonist therapy with bariatric surgery and multidisciplinary care resulted in substantial, durable weight loss and remission of comorbidities. Earlier genetic testing might have enabled earlier and better intervention and could possibly have led to a better outcome and a less dramatic course. This case expands the genotypic spectrum of MC4R variants and provides important evidence for successful integrated pharmacological-surgical strategies for monogenic obesity.

References

1. Faccioli, N., Poitou, C., Clément, K., & Dubern, B. (2023). Current Treatments for Patients with Genetic Obesity. Journal of Clinical Research in Pediatric Endocrinology (Vol. 15, Issue 2, pp. 108–119). doi.org/10.4274/jcrpe.galenos.2023.2023-3-2

GENOTYPING AND PHENOTYPING OF PATIENTS WITH MONOALLELIC NTRK2 VARIANTS

Lea Schmid ^a , Stefanie Zorn ^a,b , Julia von Schnurbein ^a , Melanie Schirmer ^a,b , Moawia Abubakar ^c , Margit Klehr-Martinelli ^c , Reiner Siebert ^b , Martin Wabitsch ^a,b

^a Ulm University Medical Centre, Division of Pediatric Endocrinology and Diabetology, Ulm, Germany; ^b German Centre for Child and Adolescent Health (DZKJ), Ulm site, Ulm, Germany; ^c Institute of Human Genetics, Ulm University and Ulm University Medical Centre, Ulm, Germany

Introduction and Objectives

Monoallelic NTRK2 variants in the leptin-melanocortin signalling pathway can cause monogenic obesity. However, comprehensive analyses of genotype-phenotype correlations are lacking. This study investigates genotype-phenotype relationships in patients with monoallelic constitutional NTRK2 variants from the Ulm University Medical Centre as well as those reported in the literature.

Methods

Genotype and phenotype data, including anthropometric, neurological, and clinical characteristics, were collected from nine unpublished patients with eight distinct monoallelic NTRK2 variants diagnosed at Ulm University Medical Centre. These data were complemented by a systematic literature search conducted in three major scientific databases between August and November 2024 that identified 56 patients carrying 35 distinct monoallelic NTRK2 variants. Relevant genotype-phenotype information was extracted from published cases.

Results

Overall, 65 individuals with 42 distinct monoallelic NTRK2 variants were identified. Of these, 65.9% of the NTRK2 variants were classified as variants of uncertain significance. 61.0% of the affected cases presented with obesity. Early childhood growth trajectories in patients from our centre showed severe obesity developing from the age of four years. Neurological symptoms were observed in 88.1% of cases. Remarkably, patients with NTRK2 variants located in the tyrosine kinase or extracellular domains exhibited mild neurological symptoms and obesity, whereas the p.Tyr434Cys variant was associated with severe neurological impairment in the absence of obesity. Treatment with methylphenidate or liraglutide resulted in significant and sustained weight loss in three patients from our centre.

Conclusions

This genotype-phenotype analysis reveals a positive association between NTRK2 variants in the extracellular and tyrosine kinase domains and the presence of mild neurological abnormalities along with obesity, in contrast to the p.Tyr434Cys variant. Methylphenidate and liraglutide represent potential therapeutic approaches for patients with monoallelic NTRK2 variants.

AUTOMATED INSULIN DELIVERY SYSTEM IN AN ONCOLOGY PATIENT

Janina Schmunk ^a , Nikolas Hillenbrand ^a , Antje Allendorf ^a

^a Goethe University Frankfurt, Department of Pediatrics, Division of pediatric diabetology, Frankfurt (Main), Germany

Introduction and Objectives

We report on a 6-year-old patient with acute lymphoblastic leukemia during her third high-dose corticosteroid therapy, who received treatment with an Omnipod 5 (insulin pump) and Dexcom G6 (continuous glucose monitoring) to manage her blood glucose.

In the first two high-dose corticosteroid therapies blood glucose averaged around 250 mg/dl.

However, during the third cycle the patient experienced hyperglycemia up to 800 mg/dl, necessitating hospitalization for continuous intravenous insulin therapy.To shorten the hospital stay we transitioned her treatment to an automated insulin delivery system.

Methods

A target glucose level of 150 mg/dl was set, with corrections above 180 mg/dl. The correction factor was 150 mg/dl and the insulin action duration was 2 hours. The carbohydrate-to-insulin ratio ranged from 0.5 to 1. About 50% of the prior daily insulin requirement was assigned as basal rate, based on age-adapted profiles.

During corticosteroid reduction the correction factor was raised to 200 mg/dl, corrections were given only above this level and bolus insulin for meals was stopped.

Six days after steroid cessation, insulin pump therapy was discontinued due to improved glycemic control.

Results

The patient used the insulin pump for a total of 21 days, thereby avoiding a hospital stay of 14 days.

The average blood glucose level during this period was 257 mg/dl (±87 mg/dl). The time spent within the target glucose range (70-250 mg/dl) was 49%. Elevated values (>250 mg/dl) were observed in 50% of the time. Hypoglycemia (< 69 mg/dl) occurred in only 1% of cases through the function of automatic insulin suspension. The patient received 70% basal insulin and 30% bolus insulin during this period. The need for capillary blood glucose monitoring was minimized and there was reduced need for insulin.

Overall, the patient’s and caregivers’ quality of life improved as both, the length of hospital stay and the insulin infusion pump use were significantly reduced.

Conclusions

The use of automated insulin delivery (AID) systems in oncology patients with therapy-induced dysregulated glucose levels is feasible and allows effective blood glucose control.

This can improve quality of life by reducing hospitalization duration. Furthermore, the risk of hypoglycemia is reduced compared to intravenous or subcutaneous insulin administration, through automatic insulin suspension. This makes a significant difference in the safety of therapy control.

PATIENTS WITH SHOX-DEFICIENCY WITH DAILY GROWTH HORMONE THERAPY: REAL-WORLD EVALUATION FROM THE INSIGHTS-GHT REGISTRY

Dirk Schnabel ^a , Christof Land ^b , Desiree Dunstheimer ^c , Bettina Gohlke ^d , Alexandra Keller ^e , Gerhard Binder ^f , Tilman Rohrer ^g , Thomas Reinehr ^h , Ilonka Kreitschmann-Andermahr ⁱ , Christian Strasburger ^j , David Pittrow ^k,l , Christine Pausch ^l , Joachim Wölfle ^m

^a Charité Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin und Humboldt-Universität zu Berlin, Department of Pediatric Endocrinology and Diabetology, Center for Social-Pediatric Care, Berlin, Germany; ^b Centre for Paediatric and Adolescent Endocrinology, Gauting, Germany; ^c Augsburg University Hospital, Pediatric Endocrinology, Augsburg, Germany; ^d Centre for Paediatrics, Division of Paediatric Endocrinology and Diabetology University Hospital, Bonn, Germany; ^e MVZ Medpoint, Pediatric Endocrinology, Leipzig, Germany; ^f Pediatric Endocrinology, University Hospital, Tübingen, Germany; ^g Pediatric Endocrinology, Saarland University, Medical Cente, Homburg, Germany; ^h Vestische Kinder- und Jugendklinik Datteln, University of Witten/Herdecke, Datteln, Germany; ⁱ University of Duisburg- Essen, Department of Neurosurgery and Spine Surgery, University Hospital Essen, Essen, Germany; ^j Charité Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin und Humboldt-Universität zu Berlin, Department of Endocrinology and Metabolism, Berlin, Germany; ^k Technical University, Institute for Clinical Pharmacology, Dresden, Germany; ^l GWT-TUD, Innovation Centre Real-World Evidence, Dresden, Germany; ^m University Hospital Erlangen, Department of Pediatrics and Adolescent Medicin, Erlangen, Germany

Introduction and Objectives

INSIGHTS-GHT is the world’s first cross-product registry study on growth hormone (GH) therapy in approved indications across patients of all ages. This allows for broad insights into many relevant issues of clinical routine. In this analysis, we focus on paediatric patients with SHOX deficiency which represents one of the most frequent monogenetic causes of short stature and results from mutations in the SHOX gene at the PAR1 region (location Xp22.33 or Yp11.32).

Methods

Since its launch in February 2022, the INSIGHTS-GHT registry has included over 2,100 patients from 30 endocrinology institutions in Germany. We report a first descriptive interim analysis of paediatric patients with genetically confirmed SHOX deficiency receiving daily GH-therapy subcutaneously. For comparison, we analysed pediatric patients with Turner syndrome (TS). The database status of the analysis is 7 July 2025

Results

The analysis included 73 patients; 56.2% were male. Mean gestational age was 38.7 (3.4) weeks, birth weight was -0.4 (0.8) SDS, body length was -0.8 (1.1) SDS, with 9.1% representing SGA births. Among the mothers and fathers of affected patients, height was less than -2 SDS in 39.7% and 35.6% cases, respectively. In 9.6% both parents were affected by short stature. Mean age at initiation of GH therapy was 7.3 (2.9) years, mean height being -2.5 (0.6) SDS, 87.9% prepubertal. GH therapy was started with 39,2 (9,8) µg/kgxd. After >3 yrs of GH therapy, mean delta height was +1.39 (0.71) SDS. In the 142 patients with TS, age at start of treatment was 6.4 (3.1) yrs, 95.6% prepubertal, initial GH dose was 39.6 (10.0) µg/kgxd. After >3 yrs of GH therapy, height SDS increased by +0.74 (0.74) SDS.

Conclusions

Analyses of SHOX patients from the INSIGHTS-GHT registry show that these patients were already shorter at birth compared to the normal population and 65.8% had at least one parent with short stature. Compared to the TS cohort from the same registry with similar age and GH dose by sight, the effect on the height SDS increment was stronger in the SHOX group. These analyses are continuously updated and supplemented. The INSIGHTS-GHT registry is a valuable tool for collecting longitudinal data on the effectiveness and safety of GH therapies.

2 PEDIATRIC CASES OF CALCIUM-SENSING RECEPTOR DEFECTS

Florian J. Schneider ^a , Eva Dammann ^a , Philipp Latzko ^a , Judit Horvath ^b , Angelika Dübbers ^a

^a Universitätsklinikum Münster, Pädiatrische Endokrinologie, Münster, Germany; ^b Universitätsklinikum Münster, Medizinische Genetik, Münster, Germany

Introduction and Objectives

The calcium-sensing receptor (CASR) is mostly expressed in the parathyroid gland and the renal tubule. The receptor helps to normalize blood calcium concentrations by regulating the parathyroid hormone secretion and the urinary calcium secretion. Mutations in the CASR can cause a reset of the serum calcium concentration upwards or downwards. We present two clinical cases of CASR defects: A 10 year old girl presenting with hypocalciuric hypercalcemia (inactivating CASR mutation) with hyperparathyroidism and a 2 week old boy with hypocalciuric hypocalcemia with hypoparathyroidism.

Methods

The female patient (age of initial presentation 10 10/12 years) complained about hair loss, headache, stomach pain and reduced general condition. Elevated calcium levels were detected with elevated levels of the parathyroid hormone. ​​A heterozygous mutation (NM_001178065.2 (CASR): c.472G>Ap.(Gly158Arg)) was found. The male patient (age of initial presentation 2 weeks) presented with hypocalciuric hypocalcemia with hypoparathyroidism. A heterozygous mutation in CASR (c.2234A>Cp.(Gln745Pro) and a heterozygous mutation for NM_000383.4 (AIRE): c.967_979del p.(Leu323Serfs*51) was found.

Results

In the female patient urine calcium and phosphate levels were low. In the ECG there was no arrhythmia and no QTc time abnormalities. In the sonography of the thyroid and parathyroid gland no abnormalities were seen. No nephrocalcinosis was seen. In the scintigraphy of the thyroid there were no MIBI-positive foci. We started treating the patient with a CASR agonist (Cinacalcet). This drug binds on the CASR on the parathyroid. This lowers the treshhold of the calcium receptor and leads to a decreased secretion of the parathyroid hormone. This treatment lead to decreased parathyroid hormone levels and serum calcium levels. We started treating the male patient with active Vitamin D and oral Calcium and the child grew steadily and the calcium normalised. Both improved and developed well.

Conclusions

Further genetic testing in the mother, in the grandmother and the grand-grandmother of the female patient resulted in the same genetic mutation of the CASR. The mutation of the boy was also found in the mother. The AIRE mutation in the boy with hypoparathyroidism is dominant over the CASR mutation usually presenting with hyperparathyroidism. The hypercalcemic effect of the inactivating CASR mutation is thus abolished. We presented two rare cases of CASR mutations in two independent families with completely different clinical presentations.

CAN EVERYONE MANAGE DIABETES? – THE EDUCATIONAL LEVEL OF PARENTS AND GUARDIANS AS AN UNDERESTIMATED COMPLEXITY FACTOR IN PEDIATRIC DIABETOLOGY -

Gerhard Schöpke ^a , Gertraud Mergner-Wudy ^b , Frauke Döll ^c , Andreas Kolbe ^d , Stefan A. Wudy ^a

^a Universitätsklinikum Giessen, Abteilung Pädiatrische Endokrinologie & Diabetologie, Giessen, Germany; ^b Volkshochschule Schwalm-Eder, Programmbereich Sprachen & Lerntreff, Homberg (Efze), Germany; ^c Hans-Rettig-Schule, Universitätsklinikum, Giessen, Germany; ^d Universitätsklinikum Giessen, Sozialer Dienst, Giessen, Germany

Introduction and Objectives

Children who suffer from diabetes mellitus must be supported by their parents or guardians in diabetes management. German law stipulates that legal guardians are responsible for the care of their children. If guardians do not have sufficient knowledge of reading, writing and dealing with numbers and/or do not speak German, this can lead to legal and social problems in therapy and safe diabetes management can be called into question. We investigate what level of education is required to take over the care of diabetic children.

Methods

We conducted a systematic literature search in the PubMed medical database and the Google Scholar internet search engine. We used the PICO search scheme with the keywords: “type 1 diabetes, parents, mother, father, child, adolescent” for (P), “school education, literacy, numeracy” for (C) and “glycemic control” for (O) and obtained seven hits that met our inclusion criteria.

Results

The few available studies describe that the better parents can read, write and calculate, the better is the glycemic metabolic control of their diabetic children. Only two studies used tests to assess the level of education. The influence of language was not investigated in any of the studies. It is not possible to deduce from the results what level of education is required for safe care.

Conclusions

In current situation children and pediatric diabetes teams are the big losers. We show that safe diabetes management is not possible without appropriate education in reading, writing and numeracy. In addition, if the German language is unfamiliar, current legislation puts medical staff under considerable pressure. A lack of education and language barriers create a dilemma that cannot be solved with the resources currently available. All responsible players in the healthcare system must take immediate action to provide ways and means to solve this situation in a timely manner.

DIABETOLOGY MEETS IMMUNOLOGY – A CASE OF DIABETES, HYPOTHYROIDISM, CHRONIC MUCOCUTANEOUS CANDIDIASIS, AND IMMUNODEFICIENCY DUE TO STAT-1 GAIN-OF FUNCTION MUTATION

Sandra Schulte, Ines Marek, Corina Weigel, Johanna Hammersen, Joachim Woelfle

University Hospital Erlangen, Department of Paediatric Diabetology and Metabolic Medicine, Erlangen, Germany

Introduction and Objectives

Case report: A three-year-old girl was transferred to our paediatric intensive care ward for ECMO therapy due to progressive ARDS caused by an influenza B infection. Pre-existing diseases were: status post CMV hepatitis, hypothyroidism, developmental delay, chronic mucocutaneous candidiasis, pancytopenia without signs of malignant diseases in bone-marrow puncture, splenomegaly, and insulin-dependent diabetes mellitus since the age of eight months. Diabetes was autoantibody-negative and due to a genetic variance of unknown significance classicised as MODY 12 in an extern clinic.

Methods

The patient needed ECMO therapy and prolonged intensive care treatment. She showed pronounced pancytopenia and hepatic failure due to HLH-like autoinflammation which responded to glucocorticoid and immunoglobulin treatment. Diabetes management was challenging.

Results

Genetic testing revealed a de novo STAT-1-gain of function mutation (GOF). STAT-1-GOF are part of the IPEX-like syndrome spectrum (IPEX = Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked). Patients with IPEX-like syndromes show clinical symptoms resembling IPEX, but without FOXP3 mutations. Symptoms are broad, e.g., various combinations of autoimmune manifestations, mostly including insulin-dependent diabetes mellitus (IDDM), autoimmune thyroiditis, autoimmune enteropathy, autoimmune cytopenia, and dermatitis, while simultaneous immunodeficiency is possible¹. STAT1-GOF have first been described in 2011 by have been first described by van de Veerdonk et al.². Symptoms and prognosis are very variable, poor outcomes are possible.

Conclusions

To achieve direct modulation of the JAK-STAT signalling pathway our patient was treated off-label with JAK-inhibitor ruxolitinib which improved symptoms. Allogenic stem cell transplantation is under consideration.

Patients with manifestation of IDDM at a very young age who show signs of polyendocrinopathy or multiple autoimmune phenomena should be considered for genetic testing, especially if symptoms are combined with immunodeficiency and/or chronic mucocutaneous candidiasis. In STAT1-GOF causal treatment is available. Allogenic stem cell transplantation might be considered.

References

¹ G. Azizi, R. Yazdani, W. Rae, H. Abolhassani, M. Rojas, A. Aghamohammadi, et al., Monogenic polyautoimmunity in primary immunodeficiency diseases, Autoimmun Rev, 17 (2018), pp. 1028-1039

² van de Veerdonk FL, Plantinga TS, Hoischen A, Smeekens SP, Joosten LAB, Gilissen C, et al. STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N Engl J Med. 2011;365:54–61.

CELIAC DISEASE IN CHILDREN WITH TYPE 1 DIABETES. DOES SCREENING MAKE SENSE? TWENTY-FIVE YEARS OF EXPERIENCE IN A SINGLE CENTER

Roland Schweizer ^a , Julia Bung ^a , David Majer ^a , Franziska Liebrich ^a , Susann Herrlich ^a , Andreas Neu ^a , Julian Ziegler ^a

^a Universitätsklinikum Tübingen, Pädiatrische Diabetologie, Tübingen, Germany

Introduction and Objectives

Children with type 1 diabetes (T1D) have an increased risk of developing additional autoimmune diseases. The risk of developing celiac disease (CD) is 3-4 times higher in children with T1D. Guidelines recommend regular screening for transglutaminase antibodies (TgAb) in T1D children. CD could be an additional burden for T1D children as both diseases affect food intake. We describe the screening practice for CD during the last 25 years in our outpatient clinic in children with T1D.

Methods

We retrospectively analysed the development of CD-specific antibodies in our children with T1D (diabetes onset since 1998). We did not routinely recommend endoscopy when CD-specific antibodies (TgAb, endomysium (EAb), gliadin) were positive and patients had no CD-specific symptoms.

Results

We analysed 304 patients. 122 had CD-specific antibodies. In 98 of them, they disappeared after a short time or had been only slightly elevated. The diagnosis of CD was confirmed in 12. All 12 showed CD-specific symptoms such as failure to thrive, anemia, hypoglycemia or gastrointestinal problems. In 6 patients, even severely elevated EAb and/or TgAb disappeared on average after 7.1 years (range 4.9 to 13.5 years) on gluten-containing diet. The remaining 6 had antibodies without CD-specific symptoms by the end of the observation period. In this group the duration of antibody-positivity was 4 years (range 1.8 to 11.6 years)

Conclusions

We conclude that even highly elevated CD-specific antibodies can disappear in children with T1D and that screening for CD-specific antibodies is therefore only useful in symptomatic children with T1D.

THE IMPACT SURVEY IN GERMANY: TREATMENT PATTERNS IN OSTEOGENESIS IMPERFECTA

Taco van Welzenis ^a , Lena Lande Wekre ^b , Ingunn Westerheim ^a , Cathleen Raggio ^c , Frank Rauch ^d , Tracy Hart ^e , Samantha Prince ^f , Emma Geldman ^f , Oliver Semler ^g

^a Osteogenesis Imperfecta Federation Europe, Heffen, Belgium; ^b Sunnaas Rehabilitation Hospital, TRS National Resource Center for Rare Disorders, Nesodden, Norway; ^c Hospital for Special Surgery, Center for Skeletal Dysplasias / Pediatric Orthopedics, New York, United States; ^d McGill University, Department of Pediatrics, Montréal, Canada; ^e Osteogenesis Imperfecta Foundation, Gaithersburg, United States; ^f Wickenstones Ltd, Oxford, Great Britain; ^g University of Cologne, University Hospital Cologne, Department of Pediatrics, Cologne, Germany

Introduction and Objectives

The treatment landscape of osteogenesis imperfecta (OI)—a rare hereditary connective tissue disorder—is not fully understood. This study aimed to capture real-world insights on pharmacologic interventions in people with OI living in Germany. The IMPACT Survey was developed by the OI Federation Europe, the OI Foundation and an international steering committee of experts to explore the clinical, humanistic and economic impact of OI.

Methods

The survey was fielded online from July–September 2021 and open to individuals with OI, caregivers and close relatives. This descriptive analysis presents findings from 134 adults with OI (mean age 42.6 years; 69.4% female) and caregiver-reported data on children aged ≤18 years with OI (mean age 8.0 years; 44.9% female) living in Germany. Distribution across OI types and severity was spread; the largest proportion of respondents rated their OI severity as moderate (50.7% adults; 50.0% children) or reported their OI as Type I (29.9% adults) or Type III (24.5% children).

Results

Many individuals had experience of vitamin D or calcium supplementation (adults 79.1% and 47.0%; children 98.0% and 51.0%, respectively). Current or prior bisphosphonate use was reported by 57.4% adults and 69.4% children. Of adults currently on bisphosphonates (29 [21.6%]), 34.5% were receiving ibandronate, 20.7% neridronate, 17.2% alendronate, 10.3% zoledronate, and 6.9% risedronate; all children on bisphosphonates (26 [53.1%]) were receiving neridronate.

Current or prior use of other therapies included: muscle relaxants (19.4% adults; 16.7% children), parathyroid hormone (0.7% adults), oestrogen (15.1% adult females), and monoclonal antibodies (e.g., denosumab, romosozumab, setrusumab; 3.7% adults and 16.3% children). Pain medication was regularly used by 26.9% adults and 36.1% children.

Conclusions

The IMPACT Survey provides unique patient-reported perspectives on the German OI treatment landscape highlighting use of a wide-range of medicines. Data indicate common prescription of off-label bisphosphonates in children and adults and emphasise the importance and need of pain management in individuals of all ages.

BONE MORPHOMETRY IN CHILDREN WITH ACHONDROPLASIA TREATED WITH NAVEPEGRITIDE: 52-WEEK RESULTS FROM THE APPROACH CLINICAL TRIAL

Oliver Semler *Presenting on behalf of listed authors ^b , Leanne M. Ward ^a , Daniel G. Hoernschemeyer ^d , Janet M. Legare ^e , Hanne B. Hove ^f , Carlos A. Bacino ^g , Philippe M. Campeau ^h , Paul L. Hofman ⁱ , Josep M. de Bergua Domingo ^j , Jennifer Abuzzahab ^k , Stefan Jackowski ^c , Kevin Smit ^c , Andrew Tice ^c , Sasha Carsen ^c , Meng Mao ^l , Lærke C. Freiberg ^m , Michael Makara ^l , Michael Ominsky ^l , Aimee Shu ^l , Ravi Savarirayan ^n,o , Ciara McDonnell ^q

^a University of Ottawa, Pediatric Bone Health, Ottawa, Canada; ^b Unilklinik Cologne, Abteilung für Kinder- und Jugendmedizin, Cologne, Germany; ^c Children´s Hospital of Eastern Ontario, Ottawa, Canada; ^d University of Missouri, Children´s Hospital, Columbia, United States; ^e University of Wisconsin, School of Medicine and Public Health, Madison, United States; ^f Copenhagen Rigshospitalet, Center for Child and Adolescent Medicine, Kopenhagen, Denmark; ^g Baylor College of Medicine, Houston, United States; ^h CHU Sainte-Justine Research Centre, Research Center, Montréal, Canada; ⁱ The Liggins Institute, University of Auckland, Auckland, Neuseeland; ^j Vithas Vitoria Hospital, Unidad de Cirugia Artroscopia, Vitoria-Gasteiz, Spain; ^k Children´s Minnesota, Minneapolis, United States; ^l Ascendis Pharma Inc., Palo Alto, United States; ^m Ascendis Pharma A/S, Hellerup, Denmark; ⁿ Murdoch Children´s Research Institute, Parkville, Australien; ^o Royal Children´s Hospital, Parkville, Australien; ^p University of Melbourne, Parkville, Australien; ^q University of Dublin, Children´s Health Ireland at Temple Street, Dublin, Irland

Introduction and Objectives

Navepegritide is an investigational prodrug of C-type natriuretic peptide (CNP), administered subcutaneously once weekly and designed to provide sustained release of active CNP with a low Cmax. Continuous exposure to released CNP stimulates natriuretic peptide receptor B to counteract the constitutively active fibroblast growth factor receptor 3 in achondroplasia. We report radiographic findings from ApproaCH, a pivotal randomized, double-blind, placebo-controlled trial evaluating navepegritide in children with achondroplasia.

Methods

Children (N=84, aged 2-11 years) were stratified by age and sex and randomized 2:1 to navepegritide (100 mg/kg/week) or placebo. The primary endpoint was annualized growth velocity (AGV) at Week 52. Changes from baseline at Week 52 in bone morphometry were assessed by blinded, expert central readers.

Results

Navepegritide was superior to placebo in AGV at Week 52 (least squares mean (LSM) AGV 5.89 cm/year vs 4.41 cm/year with placebo; LSM difference (diff): 1.49 cm/year, p<0.0001), with a comparable safety and tolerability profile. Spinal canal dimensions were numerically improved with navepegritide vs placebo across L1-L5, with a significant increase from baseline observed for interpedicular distance at L1 (LSM diff 0.618 mm, p=0.0222). Navepegritide significantly reduced tibia-femoral angle (LSM diff -1.814 degrees, p=0.0094) and lower limb mechanical axis deviation (LSM diff -2.781 mm, p=0.0063) vs placebo, corresponding to a normalization in fibular overgrowth, considered the key cause of leg bowing, as reflected in the reduced fibula-to-tibia ratio (LSM difference -0.016, p=0.0001).

Conclusions

In the ApproaCH trial, once-weekly administration of navepegritide was superior to placebo in AGV and improved aspects of bone morphometry in children with achondroplasia. These findings highlight that navepegritide, which provides continuous exposure to active CNP, may provide benefits beyond promoting linear growth, addressing critical aspects of skeletal dysplasia in achondroplasia.

REFERENCE VALUES FOR OGTT-DERIVED INSULIN INDEXES ENABLE EARLY DETECTION OF EMERGING TYPE 2 DIABETES IN CHILDREN AND YOUNG ADULTS WITH OBESITY

Robert Stein ^a,b , Mandy Vogel ^d,c , Juraj Stanik ^e , Eric Wenzel ^a,b , Ronald Biemann ^f , Jürgen Kratzsch ^f , Klara Meyer ^a,b , Johannes Riedel ^a , Natascha Genge ^a , Elena Sergeyev ^a , Anette Stoltze ^a , Helena Enders-Seidlitz ^g , Susanna Wiegand ^g , Daniel Weghuber ^h , Anders Forslund ⁱ , Peter Bergsten ⁱ , Michael Stumvoll ^j , Roland Pfäffle ^a,c , Wieland Kiess ^a,d , Matthias Blüher ^b,j , Antje Körner ^b,a

^a University of Leipzig, Medical Faculty, University Hospital for Children & Adolescents, Center for Pediatric Research Leipzig, Leipzig, Germany; ^b Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum Munich at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany; ^c German Center for Child and Adolescent Health (DZKJ), partner site Leipzig/Dresden, Leipzig, Germany; ^d University of Leipzig, LIFE–Leipzig Research Center for Civilization Diseases, Leipzig, Germany; ^e Slovak Academy of Sciences, Department of Pediatrics, Medical Faculty at the Comenius University, and DIABGENE Laboratory, Institute of Experimental Endocrinology, Biomedical Research Center, Bratislava, Germany; ^f University of Leipzig, Medical Faculty, Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnosis, Leipzig, Germany; ^g Charité University Hospital, Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnosis, Berlin, Germany; ^h Paracelsus Medical University, Department of Pediatric Endocrinology and Diabetology, Salzburg, Austria; ⁱ Uppsala University, Department of Women’s and Children’s Health, Uppsala, Sweden; ^j University of Leipzig, Department for Endocrinology, Nephrology and Rheumatology, University Medical Center Leipzig, Leipzig, Germany

Introduction and Objectives

The course of type 2 diabetes (T2D) is more severe in children with obesity than in adults. Early identification of children at high risk for diabetes is crucial, but specific pediatric criteria are lacking.

Methods

We established age- and puberty-specific reference values for eight indexes of insulin response during OGTT in 530 healthy participants (1408 observations) aged 6–30 years. Using these cut-offs, we assessed the prevalence and longitudinal stability of insulin resistance in 1876 children with obesity (2846 observations) and analyzed its predictive value for T2D onset through survival analyses.

Results

In patients with obesity, insulin resistance was present in half of preschool children and still affected two-thirds at age 18–30 years. Indexes of insulin secretion outside the reference range remained more stable during subsequent testing (86–89%) than classical diabetes markers (e.g., 2h glucose: 30.0%). Children with insulin resistance had a fourfold increased diabetes risk, with OGTT indexes outperforming fasting indexes (HRs for ISI_Matsuda 4.05 (95% CI 1.83 - 8.93); HOMA-IR 2.56 (95% CI 1.25 - 5.24)). Using our new cut-offs, we identified twice as many future diabetics at baseline compared to conventional prediabetes markers (82.4% with pathological ISI_Matsuda vs. 39.2% with impaired glucose tolerance). Findings were validated in independent cohorts from Germany, Austria and Sweden.

Conclusions

OGTT-derived references enable earlier, more sensitive detection of children at high risk for T2D than conventional diabetes markers and fasting indexes. Children with obesity and hyperinsulinemia require close monitoring and rigorous treatment to prevent diabetes.

LONG-TERM OUTCOME AFTER CRANIOPHARYNGIOMA IN CHILDHOOD: THE ROLE OF TREATMENT IN SPECIALIZED CENTERS

Nele Tacke ^a , Carsten Friedrich ^b , Martin Schuhmann ^c , Joachim Woelfle ^d , Gerhard Binder ^a

^a University Children’s Hospital Tübingen, Department of Pediatric Endocrinology, Tübingen, Germany; ^b University Children’s Hospital, Carl Von Ossietzky Universität, Klinikum Oldenburg, Department of Pediatrics and Pediatric Hematology/Oncology, Oldenburg, Germany; ^c University Hospital, Section of Pediatric Neurosurgery, Department of Neurosurgery, Tübingen, Germany; ^d University Hospital Erlangen, Department of Paediatrics and Adolescent Medicine, Erlangen, Germany

Introduction and Objectives

Craniopharyngioma is a rare sellar tumor associated with poor outcomes, particularly severe hypothalamic obesity. The aim of this retrospective study was to compare the outcome of patients treated in two specialized university hospitals (surgery & long-term care) with the overall outcome in Germany documented in the German Craniopharyngioma Registry. The primary endpoint was the BMI at the last follow-up in pediatric care.

Methods

All patients with craniopharyngioma diagnosed between 2000 and 2020 with follow-up >1y were identified from two specialized pediatric centers (SC). Data from the German craniopharyngioma registry (REG; centers excluded) served as comparison. Age and BMI at surgery, number/type of surgeries, radiotherapy, age and BMI at last follow-up were recorded. BMI was calculated as percentage of the P95 value (%BMI_P95), as this correlates better with fat mass in severely overweight children than SDS-LMS. Data are given as median and quartiles. Mann-Whitney U and Chi-squared analyses were performed.

Results

The follow-up time was 7.8y (5.3-10.5) in 54 SC patients and 6.3y (3.3-9.0) in 178 REG patients, with last follow-up at 18.6y (15.5-20.2) in SC and 17.3y (13.7-20.0) in REG. Transsphenoidal surgery rates were higher (37.7 vs. 17.4%) and radiotherapy rates lower at SC (31.5 vs. 51.4%).

At last follow-up, 37.0% of the patients in SC were obese, but 57.9% in REG. %BMI_P95 was 92.8 (77.8-118.4) in SC, but 108.1 (90.4-131.4) in REG, with higher post-surgical increase of %BMI_P95 in REG (P=0.021). Height SDS at last follow-up was not different: -0.06 (-1.01-0.73) in SC and -0.09 (-0.89-0.77) in REG. Initial transsphenoidal surgery (P<0.001) and no radiationtherapy (P=0.007) were associated with less post-interventional obesity unlike age at surgery, relapse surgery and pre-interventional obesity.

Conclusions

Factors associated with hypothalamic obesity were identified. Data of this study suggest that children with craniopharyngioma benefit significantly from treatment in specialized centers.

PREDICTING DYSFUNCTIONAL PARENTING IN PARENTS OF CHILDREN AND ADOLESCENTS WITH TYPE 1 DIABETES

Alessa Thomas ^a , Su-Jong Kim-Dorner ^a , Olga Kordonouri ^b , Bettina Heidtmann ^c , Thomas Kapellen ^d,e , Simone von Sengbusch ^f , Roland Schweizer ^g , Karin Lange ^a , Heike Saßmann ^a

^a Medizinische Hochschule Hanover, Medizinische Psychologie, Hanover, Germany; ^b Kinder- / Jugendkrankenhaus AUF DER BULT, Klinik für Diabetologie, Endokrinologie und Allgemeine Pädiatrie, Hanover, Germany; ^c Katholisches Kinderkrankenhaus Wilhelmstift, Pädiatrie, Diabetologie, Endokrinologie, Hamburg, Germany; ^d Universitätsklinikum Leipzig, Diabeteszentrum Dept. of Pediatrics, Leipzig, Germany; ^e MEDIAN Jugendhaus, Pädiatrie, Bad Kösen, Germany; ^f University Hospital Schleswig-Holstein, Klinik für Kinder- und Jugendmedizin, Lübeck, Germany; ^g Universitätsklinikum Tübingen, Klinik für Kinderheilkunde III, Tübingen, Germany

Introduction and Objectives

Parents of a child with type 1 diabetes (T1D) may experience more potential conflict situations due to daily disease management (1). Parenting style describes the way parents react to these disciplinary situations regarding appropriateness, harshness or consistency. Increased dysfunctional parenting behavior is known to be associated with children’s mental health and development (2). This study examined psychosocial factors that predict dysfunctional parenting behaviors (laxness and overreactivity) in parents of children and adolescents with T1D.

Methods

This multicenter cross-sectional survey was conducted across five pediatric diabetes centers in Germany (Bad Kösen, Hamburg, Hanover, Lübeck, and Tübingen) (January 2021– December 2022). Parents of children aged 7–18 years with T1D completed the German versions of the short form of the Parenting Scale (EFB-K) (3), the Patient Health Questionnaire (PHQ-9) (4), the parent version of the Problem Areas in Diabetes Survey (P-PAID) (5,6) and the Quality of Marriage Index (QMI) (7). Using linear regression, we examined the contribution of demographic variables and PROs to laxness and overreactivity.

Results

Data from 677 parents were analyzed (77.1% mothers). The parents’ and children’s average ages were 43.9 (± 6.3) and 12.4 (± 2.8) years, respectively. Higher parental age (p ≤ .01) and greater diabetes burden (p ≤ .05) as well as fewer than 12 years of parental school education (p ≤ .001) predicted significantly increased laxness behavior in parents. Younger age in children (p ≤ .05), greater parental diabetes burden (p ≤ .001), more depressive symptoms (p ≤ .001), and lower relationship quality (p ≤ .05) were predictive of higher level of overreactivity.

Conclusions

Psychosocial factors predicted elevated dysfunctional parenting behavior, e.g. laxness and overreactivity in parents of children and adolescents with T1D. Signs of dysfunctional parenting should not be overlooked during a diabetes consultation. Parents at risk should be offered parental counselling.

References

¹Kobos, E., Rojkowska, S., Szewczyk, A. et al. Burden of care and a sense of loneliness in caregivers of children with type 1 diabetes. a cross-sectional study. BioPsychoSocial Med 17, 34 (2023). https://doi.org/10.1186/s13030-023-00291-4

²Jun Hyung Kim, Wolfgang Schulz, Tanja Zimmermann, Kurt Hahlweg. Parent–child interactions and child outcomes: Evidence from randomized intervention. Labour Economics, 2018, 54: 152-171, ISSN 0927-5371. https://doi.org/10.1016/j.labeco.2018.08.003.

³Miller Y. Erziehung von Kindern im Kindergartenalter. Erziehungsverhalten und Kompetenzüberzeugungen von Eltern und der Zusammenhang zu kindlichen Verhaltensstörungen. Dissertation. Braunschweig: Technische Universität, 2001.

⁴Kroenke, K, Spitzer, RL, Williams, JB. The PHQ-9: validity of a brief depression severity measure. J. Gen. Intern. Med., 2001;9:606–613. https://doi.org/10.1046/j.1525-1497.2001.016009606.x

⁵Kim-Dorner, S, Saßmann, H, Framme, JR, Heidtmann, B, Kapellen, TM, Kordonouri, O et al. Psychometric properties of the German versions of the Problem Areas in Diabetes Scale for Children (PAID-C) with Type 1 Diabetes and Their Parents (P-PAID-C). Psychol. Assess., 2024;9:e38–e50. https://doi.org/10.1037/pas0001338

⁶Saßmann, H, Kim-Dorner, S,J., Framme, J, Heidtmann, B, Kapellen, T, Kordonouri, O et al. Psychometric Properties of the German Teen and Parent Versions of the Problem Areas in Diabetes Scale (PAID). Psychol. Assess., 2023: 35(7), e31–e42. https://doi.org/10.1037/pas0001243

⁷Zimmermann, T, de Zwaan, M, Heinrichs, N. The German version of the Quality of Marriage Index: Psychometric properties in a representative sample and population-based norms. PLoS One, 2019;2:e0212758. https://doi.org/10.1371/journal.pone.0212758

EFFECTS OF ADHERENCE TO A MEDITERRANEAN DIET ON ANTHROPOMETRIC OUTCOMES IN CHILDREN WITH OVERWEIGHT AND OBESITY

Leah Tomerius ^a , Marlene Rechtsteiner ^a , Susanne Kröber ^a , Dinet Ahmed ^a , Lorenz Greifoner ^a , Susann Weihrauch-Blüher ^a

^a University Medicine Halle, Department of Conservative and Operative Pediatrics, Clinic for of Ped. I, Halle (Saale), Germany

Introduction and Objectives

Childhood obesity is affecting the physical and mental health of children and adolescents, as well as their overall quality of life. In particular, abdominal obesity is recognized as a significant risk factor for the Metabolic Syndrome. There is growing evidence that adherence to a Mediterranean diet (MD) has positive impact on cardiometabolic risk factors in adults. However, data in children and adolescents with obesity are limited to date. We thus aimed to investigate the effect of adherence to MD on anthropometric parameters in childhood obesity.

Methods

Children and adolescents (6-18 years) with BMI >90^th percentile were included in the study. Anthropometric parameters were measured at baseline(t0), after 3(t1) and 6(t2) months. The BMI-SDS (age/sex-adjusted) was used to assess the extent of obesity. Waist-to-height-ratio (WHtR) was used to estimate abdominal obesity, with values >0.5 indicating elevated cardiovascular risk. At all three appointments the families received a dietary counselling based on the MD. MD adherence was assessed using the validated KIDMED score (range: -4 to+12 points), with higher scores indicating better adherence.

Results

To date, 125 children and adolescents (age 12.3±2.8 years; 57.6 % female, mean BMI-SDS 2.77±0.54, mean KIDMED score 2.6±2.0) have completed the intervention. KIDMED score increased significantly after six months (∆1.67; p<0.001). In parallel, a significant reduction was observed in BMI-SDS at t2 compared to t0 (∆-0.12; p<0.001). BMI-SDS reduction ≥ -0.2 was achieved in 28% and moderate improvement (≥ -0.1) or stabilization (-0.09-0.1) in 61% of the participants. WHtR decreased significantly between t0 and t2 (∆-0.03; p<0.001), and the proportion of children with a WHtR < 0.5 increased from 3.2% to 11.4%.

Conclusions

An increase in the KIDMED score along with improvements in BMI-SDS and WHtR suggests positive effects of MD on anthropometric parameters that reflect general and abdominal obesity as well as cardiovascular risk in children and adolescents with obesity. Further investigations on potential confounding factors, together with research in a larger study cohort, are warranted.

Funding: Funded by the European Commission Horizon Europe, project PAS GRAS, grant agreement 101080329

THE CLINICAL APPROACH TO CHILD AND ADOLESCENT PATIENTS WITH LIPODYSTROPHY: A SERIES OF INTERNATIONAL CASE DISCUSSIONS

Martin Wabitsch ^a , Rebecca J. Brown ^b , Baris Akinci ^c , Saif Al Yaarubi ^d , Elise Bismuth ^e , Marco Cappa ^f , Asma Deeb ^g , Clemens Kamrath ^h , Carla Musso ⁱ , Nivedita Patni ^j , Flavia Prodam ^k , Rachel Williams ^l,m

^a University Medical Center, German Center for Child and Adolescent Health (DZKJ), Ulm site, Department of Pediatrics and Adolescent Medicine, Division of Pediatric Endocrinology and Diabetes, Ulm, Germany; ^b National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States; ^c Dokuz Eylul University Health Campus, Izmir Biomedicine and Genome Center & DEPARK, Izmir, Turkey; ^d Oman Medical Specialty Board, Pediatric Endocrinology, Muscat, Oman; ^e Assistance Publique-Hôpitaux de Paris, Robert Debré Hospital, Department of Pediatric Endocrinology, Paris, France; ^f Bambino Gesù Children’s Hospital, IRCCS, Research Unit for Innovative Therapies in Endocrinopathies, Rome, Italy; ^g Khalifa University, Sheikh Shakhbout Medical City and College of Medicine and Health Sciences, Division of Paediatric Endocrine, Abu Dhabi, United Arab Emirates; ^h University Hospital Freiburg, Centre of Child and Adolescent Medicine, Department of General Pediatrics and Neonatology, Freiburg, Germany; ⁱ Hospital Universitario Fundación Favaloro, Buenos Aires, Argentina; ^j UT Southwestern Medical Center, Department of Pediatrics, Division of Pediatric Endocrinology, Dallas, United States; ^k University of Eastern Piedmont, Department of Health Sciences, Unit of Endocrinology, Novara, Italy; ^l Cambridge University Hospitals, NHS Foundation Trust, Cambridge, Great Britain; ^m Nottingham Children’s Hospital, Nottingham, Great Britain

Introduction and Objectives

Lipodystrophy syndromes comprise a group of rare endocrine disorders characterized by the generalized or partial loss of adipose tissue. Affected individuals frequently display absolute or relative reductions in leptin, a key adipokine regulator of hunger-satiety signaling, and are predisposed to a range of metabolic and end-organ complications, often from a young age. To assist clinicians with limited experience of managing young patients with lipodystrophy syndromes, we describe our clinical approach to a series of pediatric patients with this rare disease.

Methods

The clinical history, diagnosis, disease management and follow-up care of 10 international pediatric patients with lipodystrophy syndromes are presented. Teaching points from each case study are also provided. Most of these cases are based on patients from our clinics with certain details changed to protect privacy. Others represent hypothetical scenarios based on our clinical experience supported by review of the medial literature and are included here for educational purposes.

Results

Our patients illustrate the broad phenotypic spectrum of lipodystrophy syndromes that can manifest early in life. We highlight the importance of timely and accurate diagnosis in guiding early disease management strategies to help reduce the risk of comorbidities. The challenges faced by clinicians managing pediatric patients with lipodystrophy syndromes and how these challenges may differ from adult patients are also explored.

Conclusions

The cases presented by us may assist clinical teams to promptly diagnose and holistically manage young patients with lipodystrophy syndromes and help optimize clinical outcomes as they transition to adult care.

DAYBREAK TRIAL: SETMELANOTIDE VS PLACEBO IN PATIENTS WITH MELANOCORTIN-4 RECEPTOR PATHWAY VARIANTS

Martin Wabitsch ^a , Gloria Ortiz ^b , Svetlana Ten ^c , Whitney Herring ^d , Elif A. Oral ^e , Orit Prinhas-Hamiel ^f , Nina Rosano ^g , Dorit Koren ^h , Hak-Myung Lee ^h , Jill C. Garrison ⁱ , Olga Ohayon ^j , Patrick Sleimann ^k , Erica van den Akker ^m , Jesús Argente ⁿ , Sadaf Farooqi ^o

^a University of Ulm, Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, Ulm, Germany; ^b Rio Grande Valley Endocrine Center, McAllen, United States; ^c Ten’s Medical Center, Pediatric Endocrinology Clinic, Brooklyn, United States; ^d Mississippi Center for Advanced Medicine, Madison, United States; ^e Tel Aviv University, Pediatric Endocrine and Diabetes Unit, Lily Safra Children’s Hospital, Sheba Medical Cente, Tel Hashomer, Israel; ^f University of Michigan, Ann Arbor, United States; ^g UMass Chan Medical School, Worcester, United States; ^h Rhythm Pharmaceuticals, Inc., Boston, United States; ⁱ Rhythm Pharmaceuticals, Inc., Boston, United States; ^j Rhythm Pharmaceuticals, Inc., Boston, United States; ^k Rhythm Pharmaceuticals, Inc., Boston, United States; ^l Rhythm Pharmaceuticals, Inc., Boston, United States; ^m Erasmus University Medical Center, Division of Pediatric Endocrinology, Department of Pediatrics, Sophia Children’s Hospital and Obesity Center CGG, Rotterdam, Netherlands; ⁿ Universidad Autónoma de Madrid, Hospital Infantil Universitario Niño Jesús; CIBER fisiopatología de la obesidad y nutrición, Instituto de Salud Carlos III, Madrid, Spain; ^o University of Cambridge, Wellcome-MRC Institute of Metabolic Science and NIHR Cambridge Biomedical Research Centre, Cambridge, Great Britain

Introduction and Objectives

DAYBREAK (NCT04963231) was a two-stage clinical trial of setmelanotide in patients with a variant in ≥1 of 31 genes associated with the melanocortin-4 receptor (MC4R) pathway, which regulates energy balance, hunger and satiety.

Methods

Patients aged 6-65 years with hyperphagia and BMI ≥40 kg/m² (≥18 years) or ≥97th percentile (6-17 years) carrying eligible variants were enrolled. Those meeting age-related weight loss criteria after 16-week open-label stage 1 (S1) entered 24-week double-blind, randomized, placebo-controlled stage 2 (S2). Patients could restart open-label setmelanotide if BMI increased by ≥5% from S2 entry. Primary analyses were performed at S1; S2 analyses, shown here, were exploratory or ad hoc. Genotype-specific analyses were limited by the small number of placebo-treated patients.

Results

After S1, 49 patients with PHIP, PLXNA(1-4), SEMA3(A-G), SIM1, MAGEL2, TBX3, or RPGRIP1L variants were randomised 2:1 to receive setmelanotide or placebo; 39 patients completed S2. A higher proportion of patients in the setmelanotide arm achieved or maintained 5% BMI reduction from study baseline to the end of S2 (27/32 on setmelanotide [84.4%] vs 5/17 on placebo [29.4%];P=0.001). Mean percent BMI change from baseline to S2 study end was −12.4% (SD 8.0%; range 1.2%-35.0%) in the continuous setmelanotide arm. Results of gene-specific cohort analyses were consistent with trends observed in S1; individuals with PHIP variants, which can lead to obesity by disrupting POMC transcription,maintained a consistent weight loss response. Setmelanotide was well tolerated with no new safety concerns.

Conclusions

The results from randomised withdrawal from setmelanotide support the efficacy of setmelanotide in patients with variants in MC4R pathway genes and gene families identified in the open-label first stage of DAYBREAK and suggest these variants may be targets for setmelanotide therapy.

EFFICACY AND SAFETY OF SETMELANOTIDE IN ACQUIRED HYPOTHALAMIC OBESITY: RESULTS FROM A DOUBLE-BLIND, MULTICENTER, PLACEBO-CONTROLLED, RANDOMIZED PHASE 3 TRIAL

Martin Wabitsch ^a , Susan A. Philips ^b , Hanneke M. van Santen ^c , Jill Hamilton ^d , Ashley H. Shoemaker ^e , Shana E. McCormack ^f , Jennifer Abuzzahab ^g , Mehul T. Dattani ^h , Tomohiro Tanaka ⁱ , Cecilia Scimia ^j , Guojun Yuan ^j , Hermann L. Müller ^k , Christian L. Roth ^l , Jennifer Miller ^m

^a University of Ulm, Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, Ulm, Germany; ^b University of California San Diego/Rady Children’s Hospital, Pediatric Endocrinology, San Diego, United States; ^c University Medical Center Utrecht, Wilhelmina Children’s Hospital, Princess Máxima Center for Pediatric Oncology; Department of Pediatric Endocrinology, Utrecht, Netherlands; ^d University of Toronto, Hospital for Sick Children, Division of Endocrinology, Department of Paediatrics, Toronto, Canada; ^e Vanderbilt University Medical Center, Ian Burr Division of Endocrinology and Diabetes, Nashville, United States; ^f Perelman School of Medicine at the University of Pennsylvania, Children’s Hospital of Philadelphia, Division of Pediatric Endocrinology and Diabetes, Philadelphia, United States; ^g Children’s Minnesota, Pediatric Endocrinology and Diabetes, St. Paul, United States; ^h UCL GOS Institute of Child Health, Genetics and Genomic Medicine Research and Teaching Department, Department of Paediatric Endocrinology, Great Ormond Street Children’s Hospital, London, Great Britain; ⁱ Nagoya City University, Gastroenterology and Metabolism, Graduate School of Medical Sciences and Medical School, Nagoya, Japan; ^j Rhythm Pharmaceuticals, Inc., Boston, United States; ^k University Children’s Hospital, Carl Von Ossietzky Universität, Klinikum Oldenburg, Department of Pediatrics and Pediatric Hematology/Oncology, Oldenburg, Germany; ^l University of Washington, Seattle Children’s Research Institute, Division of Endocrinology, Department of Pediatrics, Seattle, United States; ^m University of Florida, College of Medicine, Pediatric Endocrinology, Department of Pediatrics, Gainsville, United States

Introduction and Objectives

Hypothalamicmelanocortin-4 receptor (MC4R) signaling is crucial for regulating hunger, satiety, and energy expenditure. Tumor/treatment-induced or traumatic brain injury to the hypothalamus can lead to hyperphagia and acquired hypothalamic obesity (aHO), for which no approved treatments exist. We present results of an international phase 3 trial of the MC4R agonist setmelanotide in aHO (NCT05774756), including patients aged ≥4 years with BMI ≥95th percentile (4-17 years) or ≥30 kg/m² (≥18 years).

Methods

Patients were randomized 2:1 to setmelanotide (SET, n=81) or placebo (PBO, n=39) for up to 60 weeks. 14 patients discontinued treatment. Patients were 60.0% female; mean [SD] age, 19.9 [13.8] years; BMI (≥18 years) 41.2 [9.7] kg/m² or BMI z-score (<18 years) 3.61 [1.66]. The primary endpoint was a modified intent-to-treat analysis of the mean percent (standard error [SE]) change in BMI at 52 weeks. Secondary endpoints included proportion of patients with ≥5% BMI reduction and change in weekly average of maximal daily hunger score (scored 0-10 in patients ≥12 years). Safety was also assessed.

Results

Mean percent (SE) change in BMI at 52 weekswas -16.5% (1.4%) for SET vs +3.3% (2.0%) for PBO; PBO-adjusted difference of -19.8% (95% CI: -24.6%, -15.1%; P<0.0001). 79.5% (SET) vs 10.4% (PBO) patients received a ≥5% BMI reduction (P<0.0001). Maximal daily hunger score reduced by −2.68 (0.28) for SET vs -1.24 (0.40) for PBO (P=0.003). 81 (100%, SET) vs 35 (89.7%, PBO) patients reported AEs; most commonly skin hyperpigmentation (55.6% vs 7.7%), nausea (50.6% vs 30.8%), vomiting (39.5% vs 17.9%), and headache (38.3% vs 30.8%). In the SET arm, one treatment-unrelated death due to seizures and one serious treatment-related AE of hypernatremia occurred due to vomiting and desmopressin intolerance; SET was resumed 2 days after hospital discharge

Conclusions

In the largest randomized, placebo-controlled trial in aHO to date, setmelanotide demonstrated significant effects over placebo in the primary and key secondary efficacy endpoints at 52 weeks, with no new safety signals. Setmelanotide may represent an important treatment option for patients with aHO aged ≥4 years, for which currently no approved treatments exist.

UNUSUAL TORTICOLLIS IN A GIRL WITH ACHONDROPLASIA

Katja Wechsung ^a , Anke Schmermer ^a,b , Carl Cristoph Goetzke ^b , Dirk Schnabel ^a

^a Charité - Universitätsmedizin Berlin, SPZ Interdisziplinär Bereich Endokrinologie, Berlin, Germany; ^b Charité - Universitätsmedizin Berlin, SPZ Interdisziplinär Bereich Rheumatologie, Berlin, Germany

Introduction and Objectives

Achondroplasia is a rare skeletal dysplasia due to a FGFR3 mutation that leads to disproportionate bone growth. Vosoritide is approved to ameliorate the resulting severe short stature. Further Achondroplasia-associated complications include foramen magnum stenosis, sleep apnea, muscular hypotonia and recurrent otitis media in infancy as well as spinal stenosis, thoracolumbar kyphosis and obesity in adolescents and adults.

Methods

We report the case of a 4-year-old girl with Achondroplasia who developed a sudden torticollis with no history of trauma or infection. Her medical history was remarkable for a VP Shunt implantation (age 5 months), decompression surgery for foramen magnum (10 months) and start of Vosoritide (2 years). The MRI of the head and spine showed slight ventricular over drainage. The VP Shunt was revised because of valve disfunction. The X-ray of the cervical spine showed no sign of atlantoaxial instability. After a shunt revision the symptoms improved but head rotation remained reduced.

Results

At the age of 6 years she developed swelling of both knees and morning stiffness leading to rheumatology referral. A rheumathoid factor-negative polyarthritis was diagnosed and treated with Methylprednisolone, Methotrexate and Adalimumab. Retrospectively an effusion in the atlantoaxial joint was present in the MRI since the onset of clinical complaints. Torticollis can be the first presentation of cervical spine arthritis. The typical cervical disorders associated with Achondroplasia are foramen magnum stenosis and spinal stenosis which did not explain the symptoms of the patient. While atlantoaxial instability is associated with certain skeletal dysplasia it is unusual in Achondroplasia. No association of vosoritide treatment and autoimmune conditions have been described yet.

Conclusions

Trauma, malignancy, infection and autoimmune conditions have to be included in the differential diagnosis of spinal complaints in children with skeletal dysplasia that are not typical for the genetic condition. Rheumatoid arthritis is the most common inflammatory disease affecting the craniovertebral junction. It is challenging to evaluate unusual complaints in children with rare genetic disorders who are treated with orphan drugs.

PREVALENCE OF LOW AND ELEVATED HIGH-DENSITY LIPOPROTEIN CHOLESTEROL LEVELS IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS WITH TYPE 1 DIABETES – RESULTS FROM THE PROSPECTIVE DPV REGISTRY

Johanna Weekes ^a , Alexander J. Eckert ^b,c , Jantje Weiskorn ^d , Marianne Becker ^e , Silvia Müther ^f , Andrea Näke ^g , Maria Fritsch ^h , Eggert Lilienthal ⁱ , Susanne Büsing ^j , Stefanie Lanzinger ^b,c , Clemens Kamrath ^a

^a Universitätsklinikum Freiburg, Section of Paediatric Endocrinology and Diabetology, Freiburg, Germany; ^b Universität Ulm, Institut für Epidemiologie und medizinische Biometrie, ZIBMT, Forschergruppe computergestütztes Qualitätsmanagement in der Medizin, Ulm, Germany; ^c German Center for Diabetes Research (DZD), Munich-Neuherberg, Germany; ^d Children’s Hospital Auf der Bult, Hanover, Germany; ^e Centre Hospitalier de Luxembourg, Department of Pediatric Endocrinology and Diabetology, Luxembourg, Luxemburg; ^f DRK Kliniken Berlin Westend, Diabetes Center for Children and Adolescents, Berlin, Germany; ^g Faculty of Medicine and University Hospital Carl Gustav Carus, TU Dresden, Department of Paediatrics, Division of Paediatric Endocrinology and Diabetology, Dresden, Germany; ^h Medical University Graz, Department of Paediatrics and Adolescent Medicine, Graz, Austria; ⁱ University Hospital St Josef Bochum, Department of Paediatrics, Bochum, Germany; ^j Christliches Kinderhospital Osnabrück, Osnabrück, Germany

Introduction and Objectives

Individuals with type 1 diabetes (T1D) have an increased cardiovascular risk. A U-shaped association in adults has been shown between high density lipoprotein cholesterol (HDL-C) and increased cardiovascular risk, with higher risk in subjects with low (< 35 mg/dl) and also with elevated (>80 mg/dl) concentrations. However, the number of children and adolescents affected is unknown. This study aimed to determine the number of children, adolescents and young adults with T1D and with elevated and low HDL-C, and its associations with demographics and cardiovascular risk factors.

Methods

Data from children and adolescents aged 0.5-<25 years with T1D and diabetes duration of more than one year from the DPV registry were evaluated. Adjusted linear and logistic regression models were used to examine associations of HDL-C with sex, age, diabetes duration, body mass index (BMI), HbA1c, lipids and blood pressure (BP). BMI and BP were analysed as age and sex related standard deviation scores (SDS).

Results

HDL-C levels of 8824 children were analysed. 92 patients (1.0%) had HDL-C below 35 mg/dL, 8140 patients (92.0%) had HDL-C between 35 and 80 mg/dL, and 616 patients (7.0%) had HDL-C above 80 mg/dL. Females had significantly higher HDL-C levels than males and children aged 6-<12 years had highest HDL-C concentrations. Diabetes duration as well as HbA1c levels were not associated with HDL-C levels, whereas BMI-SDS was highest in the low HDL-C group (mean [95%-CI]: 1.2 [1.0-1.4]) compared to those with normal (0.6 [0.6-0.7]) or high HDL-C (0.3 [0.2-0.4], all P<0.001). Patients with elevated HDL-C had significantly higher systolic BP-SDS (0.8 [0.7-0.9]) than patients with normal HDL-C (0.7 [0.7-0.7], P=0.026), whereas diastolic BP-SDS was not associated with HDL-C.

Conclusions

A significant number of individuals with T1D had elevated HDL-C levels, which might be associated with an increased risk of cardiovascular disease. Elevated HDL-C was seven times more common than low HDL-C levels. Elevated HDL-C levels were associated with increased systolic blood pressure, whereas diabetes duration and metabolic control were not related to HDL-C levels. High HDL-C levels may be an under-recognized risk factor in children and adolescents with T1D.

References

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• Trimarco, V., R. Izzo, C. Morisco, P. Mone, M. Virginia Manzi, A. Falco, D. Pacella, P. Gallo, M. Lembo, G. Santulli, and B. Trimarco. 2022. ‘High HDL (High-Density Lipoprotein) Cholesterol Increases Cardiovascular Risk in Hypertensive Patients’, Hypertension, 79: 2355-63.

• Hirata, A., D. Sugiyama, M. Watanabe, A. Tamakoshi, H. Iso, K. Kotani, M. Kiyama, M. Yamada, S. Ishikawa, Y. Murakami, K. Miura, H. Ueshima, and T. Okamura. 2018. ‘Association of extremely high levels of high-density lipoprotein cholesterol with cardiovascular mortality in a pooled analysis of 9 cohort studies including 43,407 individuals: The EPOCH-JAPAN study’, J Clin Lipidol, 12: 674-84.e5.

• Madsen, C. M., A. Varbo, and B. G. Nordestgaard. 2017. ‘Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: two prospective cohort studies’, Eur Heart J, 38: 2478-86.

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ANALYSIS OF THE PEDIATRIC LIPODYSTROPHY COHORT FROM THE ECLIP REGISTRY

Jantje Weiskorn ^a , Gabriele Nagel ^h , Baris Akinci ^d , David Araújo-Vilar ⁱ , Giovanni Ceccarini ^g , Antía Fernández-Pombo ⁱ , Nadezhda Frolkova ^e , Alessandra Gambineri ^f , Lavinia Palladino ^g , Flavia Prodam ^c , Ermelinda Santos Silva ^b , Marina Shestakova ^e , Martin Wabitsch ^h , Julia von Schnurbein ^h

^a Kinderkrankenhaus AUF DER BULT, Abteilung für pädiatrische Endokrinologie und Diabetologie, Hanover, Germany; ^b Centro Materno-Infantil do Norte, Abteilung für pädiatrische Endokrinologie, Porto, Portugal; ^c Università del Piemonte Orientale, Department of Health Sciences, Piemonte, Italy; ^d Dokuz Eylul University School of Medicine, Department of Endocrinology and Metabolism, Izmir, Izmir, Turkey; ^e Endocrinology Research Centre Moscow, Endocrinology Research Centre Moscow, Moscow, Russia; ^f U.O. Endocrinologia Pagotto Bologna, Abteilung für Endokrinologie, Bolonga, Italy; ^g Universita di Pisa, Abteilung für Endokrinologie, Pisa, Italy; ^h Universitätsklinikum Ulm, Abteilung für pädiatrische Endokrinologie und Diabetologie, Ulm, Germany; ⁱ University of Santiago de Compostela, Abteilung für Endokrinologie, Santiago de Compostela, Spain

Introduction and Objectives

Lipodystrophy syndromes (LD) are rare diseases characterized by the loss of subcutaneous adipose tissue, which leads to metabolic disorders such as dyslipidemia, insulin resistance, diabetes, and fatty liver disease. The ECLip Registry (European Consortium for Lipodystrophy) is a multicenter, longitudinal observational study that records all LD patients (except those with HIV-associated forms) across Europe. This study aims to analyze the pediatric LD cohort in the ECLip Registry.

Methods

All pediatric patients recruited into the ECLip registry between December 2017 and January 2025 were analyzed. Inclusion criteria for the analysis were: manifestation < 18 years of age, at least 2 documented visits with the first visit < 18 years of age, and the second follow-up visit < 21 years of age. The LD subtypes were classified into five different groups: congenital generalized LD (CGL), familial partial LD (FPLD), acquired generalized LD (AGL), acquired partial LD (APL), and other subtypes.

Results

A total of 60 patients (68% female, median age 11 [IQR: 8.0-15.0]) were included in the study: 43% with CGL, 7% with AGL, 17% with FPLD, 15% with APL, and 18% with other subtypes. The most prevalent comorbidities were fatty liver disease (77%), dyslipidemia (60%), diabetes (38%), cardiac hypertrophy/ conduction disorders (28%), albuminuria (30%), and arterial hypertension (13%). The most commonly used medications were metreleptin (38%), oral antidiabetic agents (32%), antihypertensive agents (22%), lipid-lowering agents (18%), insulin (15%), and cardiac medications (17%). On average, patients took 1.1 agents at the first visit and 1.5 at the last visit. The median time from first symptom to diagnosis was one year for patients with CGL and three years for patients with FPLD.

Conclusions

Lipodystrophy syndromes are associated with a significant disease burden, even during childhood and adolescence. Despite increased awareness, there is still a long latency period between the appearance of the first symptom and diagnosis. International registries, such as the ECLip Registry, facilitate characterizing the clinical course and disease progression of rare diseases, such as lipodystrophy (LD). Additionally, conclusions can be drawn about the quality of care, including diagnostic gaps and medication use.

CARDIAC BIOMARKERS IN DIABETIC KETOACIDOSIS AT ONSET OF TYPE 1 DIABETES IN CHILDREN AND ADOLESCENTS

Jantje Weiskorn ^a , Sophia Hotze ^b , Alexander von Gise ^a , Olga Kordonouri ^a

^a Kinder- / Jugendkrankenhaus AUF DER BULT, Abteilung für pädiatrische Endokrinologie, Diabetologie und klinische Forschung, Hanover, Germany; ^b Medizinische Hochschule Hanover, Germany

Introduction and Objectives

Diabetic ketoacidosis (DKA), an acute complication of type 1 diabetes (T1D), may be associated with cardiac involvement. Increases in cardiac biomarkers and cardiac dysfunction have mainly been reported in adults with T1D. However, data on children are lacking. This study aimed to evaluate cardiac complications at the onset of T1D in young patients.

Methods

A prospective study was conducted on patients < 18 years with onset of T1D between 01/2024 and 03/2025. Cardiac biomarkers (troponin I [0–60 ng/L] and NT-proBNP [5–200 ng/L]) were assessed before and 24h after treatment. DKA status was monitored (pH <7.30 or bicarbonate <18 mmol/l: moderate DKA; pH <7.10: severe DKA). Blood gas analysis, electrolytes, HbA1c, glucose, osmolality, fluid management, and complications such as hypokalaemia and hypoglycaemia were also monitored. Group differences were tested using the Mann–Whitney U test or the X² test (significance level: two-sided p<.05).

Results

81 patients (60% male; median age 9.8 years, IQR 5.2–14.1) were included, of whom 43 (53.1%) had DKA. Cardiac biomarkers were higher in patients with DKA than without [troponin I: 5.7 (4.1–10.8) vs. 3.9 (3.9–4.6) ng/L, p<.001; NT-proBNP: 87.0 (41.0–231.0) vs. 40.0 (16.8–69.0) ng/L, p=.002). These biomarkers were positively associated with the severity of DKA (both p<.001). Elevated levels were still present at 24h [troponin I: 5.3 (4.2–8.8) vs. 3.9 (3.9–4.5) ng/L, p<.001] or had increased further [NT-proBNP: 229.0 (88.0–539.0) vs. 63.5 (30.0–95.0) ng/L, p<.001]. Baseline pH was inversely associated with baseline and 24h troponin I (p<.001, each) and NT-proBNP (p<.001, each). There was no significant correlation between 24h infusion volume, HbA1c, glucose and gender, and cardiac biomarkers.

Conclusions

This study found differences in cardiac biomarkers in young patients with and without DKA at the onset of T1D. Troponin I elevation was more pronounced according to the severity of DKA. NT-proBNP was initially elevated and increased further, particularly in patients with DKA, but there was no association with infusion volume. Glycaemic status was not associated with increased cardiac biomarkers. Further analysis is required to determine whether these changes are self-limiting. Long-term follow-up is required to evaluate these patients’ outcomes, even in the presence of subclinical changes.

THE TWO FACES OF THE HNF4A MUTATION

Jantje Weiskorn ^a , Sebastian Kummer ^b , Olga Kordonouri ^a

^a Kinderkrankenhaus AUF DER BULT, Abteilung für pädiatrische Endokrinologie, Diabetologie und klinische Forschung, Hanover, Germany; ^b Universitätsklinikum Düsseldorf, Abteilung für pädiatrische Endokrinologie und Diabetologie, Düsseldorf, Germany

Introduction and Objectives

Congenital hyperinsulinism is a rare disease. It is typically caused by the permanent depolarization of beta cells due to mutations in the KCNJ11 or ABCC8 genes. These high insulin levels lead to recurrent hypoglycemia. Gain-of-function mutations in the GLUT1, HNF4A, or HNF1A genes are less common and are associated with a milder tendency toward hypoglycemia.

Methods

Report of a mature, macrosomic newborn of a diabetic mother and a tendency toward hypoglycemia during the first days of life. Initially, this tendency was considered as an adjustment disorder. Due to the persistence, diagnostics were performed, revealing suspected hyperinsulinism (glucose 45mg/dL, insulin 4.7mU/ml). Treatment consisted of a glucose infusion and meals every 2-4 hours. This resulted in borderline glucose levels but no severe hypoglycemiaFH: Mother, treated with insulin since age 10 years, HbA1c level of 4.9-5.2% during pregnancy. Uncle and grandmother (maternal) have diabetes.

Results

A genetic diagnosis revealed evidence of HNF4A-associated congenital hyperinsulinism. At one year of age, when frequent meals were still necessary, a prolonged fasting test was performed, resulting in a blood glucose drop of less than 60 mg/dl and only slight ketogenesis (beta-hydroxybutyrate maximum of 0.5 mmol/l). To achieve age-appropriate fasting phases, diazoxide therapy was initiated at a dosage of 5 mg/kg body weight. This normalized the meal frequency to three main meals and two to three snacks, and avoided nighttime meals. Genetic diagnostics were also performed on the mother, uncle and grandmother confirming an HNF4A mutation.

Conclusions

Mutations in the HNF4A gene can cause hyperinsulinism or monogenic diabetes. In addition to malformations of the liver and kidneys, family members’ diagnoses of type 1 or type 2 diabetes must also be re-evaluated. Since this form of congenital hyperinsulinism is associated with the later onset of monogenetic diabetes, HbA1c monitoring should be performed, even in cases of self-limiting progression.

THE SEX-SPECIFIC ROLE OF ADRENAL ANDROGENS IN YOUTH PSYCHOPATHOLOGY

Franka E. Weisner ^a , Bianca Serio ^b,c , Sofie Valk ^b,c , Luise Bläschke ^a , Anke Hinney ^a,d , Raphael Hirtz ^e , Lars Dinkelbach ^a,f

^a University Hospital Essen, University of Duisburg-Essen, Institute of Sex- and Gender-sensitive Medicine, Essen, Germany; ^b Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany; ^c Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany, Institute of Systems Neuroscience, Medical Faculty, Düsseldorf, Germany; ^d Section of Molecular Genetics in Mental Disorders, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; ^e Helios University Hospital Wuppertal, Witten/Herdecke University, Wuppertal, Germany, Center for Child and Adolescent Medicine, Wuppertal, Germany; ^f University Hospital Essen, University of Duisburg-Essen, Essen, Germany, Department of Pediatrics II, Essen, Germany

Introduction and Objectives

Adolescence is a vulnerable period for the onset of mental health problems, yet the underlying biological mechanisms remain poorly understood. Adrenarche, marked by rising adrenal androgens, particularly dehydroepiandrosterone (DHEA), and gonadarche, marked by rising testosterone and estradiol levels, have been proposed to influence emotional and behavioral outcomes, potentially through early neurodevelopmental effects. However, longitudinal evidence linking preadolescent hormonal profiles to later psychopathology remains limited and mixed, especially regarding sex-specific effects.

Methods

Using Adolescent Brain Cognitive Development (ABCD) Study data (N_max=10,562), we tested whether preadolescent salivary DHEA, testosterone, and estradiol (females only) predicted later CBCL internalizing/externalizing symptoms. Hormone concentrations from baseline (9.91±0.62 years) and 1-year follow-up (10.92±0.64 years) were averaged to capture overall preadolescent levels and reduce temporal noise. CBCL was assessed at 2–4 year follow-ups (up to 14.08±0.68 years). Sex-stratified linear mixed models were calculated, adjusting for age, race/ethnicity, BMI, puberty stage, and physical activity.

Results

In boys, higher DHEA levels at baseline/1-year follow-up were linked to fewer externalizing symptoms at 2-year (B=–0.47, reflecting score change in CBCL per log-unit increase in DHEA, 95% CI [–0.71, –0.23]), 3-year (B=–-0.56, 95% CI [–0.81, –0.30]) and 4-year follow-ups (B=–0.70, 95% CI [–1.06, –0.34]). For internalizing symptoms, DHEA levels were negatively associated with symptom severity at the 3-year (B=–0.27, 95% CI [–0.51, –0.04]) and 4-year follow-ups (B=–0.36, 95% CI [–0.70, –0.03]). Testosterone mirrored DHEA effects, possibly due to its shared adrenal origin in preadolescent boys. By contrast, DHEA, testosterone, and estradiol levels were not associated with psychopathology in girls. DHEA × sex interaction effects increased with age for both symptom domains.

Conclusions

Higher DHEA levels in preadolescence were consistently linked to fewer mental health problems in adolescent boys, especially externalizing symptoms. No similar associations were found in girls. Interestingly, the sex-specific effects of preadolescent DHEA became stronger with increasing age. These findings suggest that endocrine influences during preadolescence may contribute to the subsequent emergence of sex differences in mental health vulnerability during adolescence. Future studies should consider adrenarche as a potentially sensitive period for hormonal effects on mental health.

WHEN TO SUSPECT MONOGENIC OBESITY IN CHILDREN – PRELIMINARY RESULTS FROM THE INDICATOR STUDY

Eric Wenzel ^a,b , Robert Stein ^a,b , Ruth Gausche ^d,a , Christoph Beger ^d,a , Antje Körner ^a,b , Roland Pfäffle ^a,d

^a University of Leipzig, Medical Faculty, University Hospital for Children & Adolescents, Center for Pediatric Research Leipzig, Leipzig, Germany; ^b Helmholtz Zentrum Munich, Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany; ^c German Center for Child and Adolescent Health (DZKJ), partner sitemLeipzig/Dresden, Germany, Leipzig, Germany; ^d Medical Faculty, University of Leipzig, CrescNet, Leipzig, Germany

Introduction and Objectives

The prevalence of monogenic obesity is estimated to be approximately 7% among children with severe obesity. Diagnosing these traits is crucial for families, in part because targeted treatment options, such as Setmelanotide, are available for some cases. Therefore, clinical guidance on when to suspect a genetic cause is important.

The INDICATOR study aimed to determine the prevalence of genetic obesity in children with early-onset extreme obesity, identify typical patterns in weight development, and evaluate the role of hyperphagia in detecting monogenic obesity.

Methods

The study utilized data from the CrescNet registry, containing anthropometric data from children throughout germany. The inclusion criterion of early-onset extreme obesity (combination of BMI > P97 at ages 0-5 and BMI > P99.5 at ages 5-18) was fulfilled by 7,484 patients. All eligible families were offered study participation in cooperation with their treating physician. Genetic testing was performed via exome analysis using a panel of 88 obesity-related genes.

Results

Currently, invitations were sent to 4,004 families, of whom 447 registered for the study. Genetic results are currently available for 292 children. The prevalence of monogenic obesity was found to be 5.1% (N=15/292), which is comparable to a separate outpatient clinic screening that found a 4.4% prevalence. Pooled BMI trajectories showed no significant difference, with the exception of one patient with a homozygous LEP variant. Children with monogenic obesity tended to have a higher BMI SDS (3.3 vs 2.9) and an earlier obesity onset (0.8 vs 1.6 years) than those without a finding, but the groups overlapped substantially. The Dykens hyperphagia score also showed no significant difference.

Conclusions

The findings suggest that restricting genetic screening to only extreme phenotypes does not significantly increase the yield of positive findings. Furthermore, it is not possible to distinguish most monogenic traits using BMI trajectories or the Dykens hyperphagia questionnaire within this already selective patient group, aside from classical cases like homozygous LEP variants. Therefore, genetic screening for monogenic obesity should not be limited to extreme phenotypes. The study also suggests that hyperphagia screening tools may need to be improved for better detection.

References

Malhotra S et al. J Pediatr Genet. 2021

INDUCTION OF PUBERTY AND ACHIEVEMENT OF NORMOZOOSPERMIA WITH HUMAN CHORIONIC GONADOTROPIN (HCG) AND FSH IN PROP1-ASSOCIATED PANHYPOPITUITARISM

Miriam Wilhelm ^a,b , Kay Winner ^a,b , Melanie Schirmer ^a,b , Christian Denzer ^a,b , Martin Wabitsch ^a,b

^a Ulm University Medical Center, Department of Pediatrics and Adolescent Medicine / Division of Pediatric Endocrinology and Diabetes, Ulm, Germany; ^b German Reference Center for Disorders of Sex Development (DRN-DSD), Ulm, Germany

Introduction and Objectives

First-line therapy in congenital hypogonadotropic hypogonadism (CHH) are gonadotropins to induce puberty through induced testosterone production and to promote testicular growth and spermatogenesis. CHH can be a part of multiple pituitary hormone deficiency (MPHD).

We report a 15-year-old boy with absent puberty at the age of 15 years with PROP1-associated panhypopituitarism with the following findings: history of cryptorchidism, short stature at 4 years. At the age of 11 years he received substitution of thyroxine due to low fT4 levels as well as growth hormone therapy due to GH deficiency.

Methods

A GnRH agonist (GnRHa) stimulation test (100 µg buserelin) was done. Gonadotropin replacement therapy according to treatment protocol Group A [1], was used to induce puberty and spermatogenesis. Testicular volumes were measured using a Prader orchidometer and ultrasonography. Routine laboratory tests were conducted.

Results

The GnRHa stimulation test showed low stimulated gonadotropins (max. LH with 0,85 and FSH 0.82 IU/l). Gonadotropin replacement therapy included hCG (2x250-1000 IU/week) and rFSH (3x150 IU/week) with a treatment duration of 3 years. After 3 years pubertal development and virilization was observed with a significant increase in testicular volume (20 ml). During the treatment, we measured high testosterone levels (max. 13 µg/l after 21 months) and saw a normalization of inhibin B levels (from 43 to max. 265 ng/l after 25 mo). First semen analysis was obtained after a treatment duration of 27 month (asthenoteratozoospermia) controlled after two months showing normozoospermia with a sperm count of 76 millions per milliliter (reference value > 16 MPM).

Conclusions

In clinical practice, the protocol combining gonadotropin therapy with hCG and rFSH is applicable to induce pubertal development with significant increase in testicular volume, normalization of testosterone levels and promoting spermatogenesis. Red flags such as eyebrow hair loss before puberty in combination with cryptorchidism should indeed prompt consideration of CHH.

References

1. Rohayem J, Hauffa BP, Zacharin M, Kliesch S, Zitzmann M; “German Adolescent Hypogonadotropic Hypogonadism Study Group”. Testicular growth and spermatogenesis: new goals for pubertal hormone replacement in boys with hypogonadotropic hypogonadism? -a multicentre prospective study of hCG/rFSH treatment outcomes during adolescence. Clin Endocrinol (Oxf). 2017 Jan;86(1):75-87. doi: 10.1111/cen.13164. Epub 2016 Sep 7. PMID: 27467188.

ADDISON’S CRISIS LEADS TO A DSD DIAGNOSIS DUE TO CYP11A1 DEFICIENCY: A DIAGNOSIS QUICKLY OVERLOOKED

Miriam Wilhelm ^a,c , Kay Winner ^a,c , Agnes Bauer ^a,c , Melanie Kapapa ^b,c , Martin Wabitsch ^a,c

^a Ulm University Medical Centre, Department of Pediatrics and Adolescent Medicine / Division of Pediatric Endocrinology and Diabetes, Ulm, Germany; ^b Ulm University Medical Centre, Department of Surgery / Division of Paediatric Surgery, Ulm, Germany; ^c German Reference Center for Disorders of Sex Development (DRN-DSD), Ulm, Germany

Introduction and Objectives

CYP11A1 plays an important role in steroidogenesis as it catalyses the first step in the synthesis of steroid hormones: the conversion of cholesterol to pregnenolone. CYP11A1 deficiency is a rare disorder and is characterized by early-onset adrenal insufficiency and XY-DSD. Genital phenotype in 46,XY karyotype may range from normal male to female. We present the case of an 18-month-old girl with sudden unconsciousness, hypoglycaemia and hyponatremia. History revealed hyperpigmentation and inguinal hernia.

Methods

Emergency Room diagnostics included clinical assessment, blood gas analysis, inflammation parameters and adrenal hormones. After referral to our centre steroid metabolome diagnostics were added. Ultrasound was performed to determine internal sex organs, karyotyping to confirm suspected DSD and an NGS panel was evaluated for candidate genes.

Results

The lab results showed hypoglycemia (17 mg/dl), hyponatremia (117 mmol/l), and hyperkalemia (5.13 mmol/l). An emergency treatment with i.v. hydrocortisone was initiated and the patient stabilized. A primary adrenal insufficiency was diagnosed presenting as acute Addison’s crisis. Diagnosis of 46,XY DSD was determined with bilateral undescended testes and undervirilization. External genitalia were female with mild clitoromegaly. Molecular genetics revealed compound-heterozygous pathogenic mutations in CYP11A1. Mild clitoral hypertrophy and inguinal hernia with gonadal prolapse were previously known, as well as hyperpigmentation of the skin for 8 months. Currently (age 5 4/12), the patient is doing well without another Addison’s crisis under treatment with hydrocortisone and fludrocortisone.

Conclusions

This case highlights the diverse and acute presentations of DSD. In cases of CYP11A1 variants adrenocortical failure can lead to life-threatening situations if not diagnosed. Red flags such as clitoral hypertrophy in a term-born child combined with an inguinal hernia, a prolapsed gonad and hyperpigmentation of the skin should have prompted consideration of further diagnostics and referral to a specialized center.

FERTILITY INFORMATION NEEDS IN ADULT SURVIVORS OF CHILDHOOD CANCER – FIRST RESULTS OF THE FEPROCAYA STUDY

Miriam Wilhelm ^a , Karamdeep Khinda ^b , Tana Dornbrach ^b , Klaus Hönig ^b , Katharina Hancke ^c , Karin Bundschu ^c , Martin Wabitsch ^a , Christian Denzer ^a

^a University Medical Center Ulm, Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, Ulm, Germany; ^b University Medical Center Ulm, Department of Psychosomatic Medicine and Psychotherapy, Ulm, Germany; ^c University Medical Center Ulm, Department of Gynaecology and Obstetrics, Ulm, Germany

Introduction and Objectives

Endocrine late effects impacting reproductive function are a major concern for childhood cancer survivors. FeProCAYA, a cohort study within the FePro-Ulm research center at the University Medical Center Ulm (funded by the Federal Ministry of Research, Technology and Space, BMFTR), examines fertility risks, quality of life (QoL) and information needs in individuals treated for childhood and adolescent conditions associated with impaired adult fertility.

Methods

This analysis assessed self-reported endocrine late effects, QoL (WHOQOL-BREF), and fertility-related QoL with reproductive concerns (RCAC, RCS) in long-term childhood cancer survivors (≥20 years post-diagnosis) via an online questionnaire. From clinical records, n=225 eligible survivors (diagnosed <18 years) who received potentially gonadotoxic treatment at the University Medical Center Ulm between 1999 and 2004 were identified. Of these, n=168 with valid postal addresses were invited to participate, and n=55 (total response rate 32.7%) completed the survey.

Results

The median age of study participants was 28.0 years (range 20.0–40.0), with a median follow-up period since cancer diagnosis of 23.0 years (range 20.0–26.0). Endocrine conditions were self-reported by 61.8% (n=34), most commonly hypothyroidism (n=13), bone metabolism disorders (n=15), sex hormone replacement (n=5), growth hormone deficiency (n=5) and puberty induction (n=3). Self-reported QoL (WHOQOL-BREF) was unimpaired with a global mean score of 75.7 ±15.5 comparable to the general population. While 20% (n=11) had children, 50.9% (n=28) expressed significant fertility concerns, and 68.5% (n=37) reported unmet information needs regarding fertility after cancer. Notably, only 40% (n=20) recalled receiving fertility counseling before treatment or during follow-up care.

Conclusions

Long-term childhood cancer survivors face a substantial burden of disease, including a particularly high prevalence of endocrine late effects that may further exacerbate fertility concerns. While overall QoL in our cohort appears to be largely preserved, there remains a significant, persistent gap in meeting patients’ information needs regarding fertility-related issues. Structured and repeated reproductive health counseling during long-term follow-up may help address unmet information needs and improve fertility-related QoL.

A CASE OF A PHENOTYPICALLY MALE PATIENT WITH A VARIANT OF TURNER’S SYNDROME (KARYOTYPE 45X/46XI(Y)(P10))

Kay Winner ^a , Miriam Wilhelm ^a , Agnes Bauer ^a , Christian Denzer ^a , Martin Wabitsch ^a

^a Universitätsklinik für Kinder- und Jugendmedizin, Universitätsklinikum Ulm, Sektion Pädiatrische Endokrinologie und Diabetologie, Ulm, Germany

Introduction and Objectives

Turner’s syndrome (TS) is associated with phenotypical females. 45,X/46,XY mosaicism often presents as mixed gonadal dysgenesis and rarely as male ² . We present the case of a boy with 45,X/46,Xi(Y)(p10) karyotype, male genital phenotype and clinical features of TS. The patient was born prematurely at 25 weeks gestation with IUGR, failure to thrive and developmental delay. He had surgery for undescended testes at 2 years. First presentation to a pediatric endocrinologist was delayed until the age of 8 when he was diagnosed with severe hypothyroidism due to autoimmune thyroiditis (Hashimoto).

Methods

Diagnosis of 45,X mosaicism was confirmed at the age of 4 months by cytogenetic and molecular genetic testing. His development was regularly assessed by a pediatric neurologist and his local pediatrician. At first presentation to our clinic (age 8 10/12), we performed additional clinical, imaging and laboratory tests including growth analysis, screening for autoimmune disorders and other comorbidities, as well as imaging and clinical assessment of gonadal function and genital phenotype.

Results

The patient has a mosaic of 2 cell lines: 45,X and 46,X with Isochromosome Yp. Further assessment revealed: severe hypothyroidism due to autoimmune thyroiditis (fT4 minimal 0.5pmol/l, elevated anti-TPO and -Tg antibodies), delayed psychomotor development with autistic features, short stature with height development near median of TS percentiles ¹ , horseshoe kidneys, epicanthal folds, low set ears, high arched palate, retrognathia, cubitus valgus and wide intermamillary distance. Echocardiography results were normal. Genital phenotype (internal and external) was completely male with no sign of DSD or gonadal dysgenesis. In total the diagnostic process revealed a combination of several typical TS symptoms with a male phenotype.

Conclusions

Boys with 45,X/46,XY mosaicism, complete male genital phenotype and significant TS features are very rare and therefore easily overlooked. The patient was never presented to a TS/DSD-centre until first complications arose. A higher degree of virilization is often correlated with a mild phenotype in other organs ² . In this case however, we postulate a higher 46,XY cell content in the gonads leading to typical male sex development while other tissues were more affected by 45,X with more severe TS features and problems. L-thyroxine and growth hormone treatment have now been commenced.

References

1: Ranke et al, Eur J. Pediatr. 141:81-88 (1983)2: Colindres et al. Evidence-Based Management of Patients with 45,X/46,XY Gonadal Dysgenesis and Male Sex Assignment: from Infancy to Adulthood. Pediatr Endocrinol Rev. 2016

BIALLELIC VARIANTS OF UNKNOWN SIGNIFICANCE (VUS) IN DHX37 IN A 46,XY DSD PATIENT

Kay Winner ^a,d , Miriam Wilhelm ^a,d , Agnes Bauer ^a,d , Martin Wabitsch ^a,d , Margit Klehr-Martinelli ^b , Anne-Karoline Ebert ^c

^a University Medical Center Ulm, Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics, Ulm, Germany; ^b University Medical Center Ulm and Ulm University, Institute of Human Genetics, Ulm, Germany; ^c University Medical Center Ulm, Clinic for Urology and Paediatric Urology, Ulm, Germany; ^d Ulm University, Center for Rare Endocrine Diseases, Ulm, Germany

Introduction and Objectives

Heterozygous gain-of-function variants in DHX37 (DEAH-box helicase 37) have been associated with 46,XY-DSD^1,2. Biallelic loss-of-function variants, however, are associated with a severe neurodevelopmental disorder (NEDBAVC, OMIM 618731)^1,2. Here, we present a case of DSD with compound-heterozygous VUS in DHX37. The patient was born with micropenis (0.5cm), bifid scrotum and penoscrotal transposition and presented for a follow-up to our DSD clinic at the age of 9 years.

Methods

We performed clinical assessment of genital phenotype, ultrasound of both gonads and pelvic organs, karyotyping, hormonal assessment and molecular genetic testing (NGS, 70 gene panel) to identify the cause of DSD in this patient. He had previously been assessed at age 1.5 years without discovering the cause of undervirilization.

Results

Scrotoplasty had been previously performed at the age of 1.5 years. Stretched penile length was 2.5 cm at age 9. Ultrasound showed typical testes and no muellerian remnants. Karyotype was 46,XY. Inhibin B and AMH were in the lower normal range. NGS revealed 2 VUS in DHX37: #1: c.985G>A; p.(Val329Ile) and #2: c.71C>T; p.(Pro24Leu). No other gene variant was found. Examination of parental DNA confirmed variant #1 to be maternal and variant #2 paternal. No family history of DSD was present. In-silico prediction tools show probable benign effects for both variants, MutationTaster, however, predicts the maternal variant to be disease causing. Population frequency for the maternal variant is 0.01% while the paternal variant has not yet been described.

Conclusions

While both variants can currently not be confirmed to be pathogenic and the patient’s phenotype differs from previously described cases^1,2 (mostly gonadal dysgenesis, testicular regression or anorchia) we postulate a potential effect of either the maternal VUS or an interaction of both variants (due to no wildtype allele being present) as the cause of DSD in this patient. Further functional analysis should be performed to test our hypothesis and shed further light into the unclear role of this gene in testis development and DSD.

References

1: de Oliveira FR, Guaragna MS, Maciel-Guerra AT, Barros BA, de Mello MP, Guerra-Junior G, Fabbri-Scallet H. DHX37 and the Implications in Disorders of Sex Development: An Update Review. Horm Res Paediatr. 2024;97(5):433-444. doi: 10.1159/000535969. Epub 2023 Dec 23. PMID: 38142677.2: McElreavey K, Pailhoux E, Bashamboo A. DHX37 and 46,XY DSD: A New Ribosomopathy? Sex Dev. 2022;16(2-3):194-206. doi: 10.1159/000522004. Epub 2022 Jul 14. PMID: 35835064.

OUTCOMES OF HORMONAL TREATMENT FOR TRANSGENDER PATIENTS: COMPARISON OF TREATMENT BEGINNING IN YOUTH VERSUS ADULTHOOD

Bea Céline Wolf ^a , Franka Hodde ^a , Marie Ritter ^a , Jasmin Asberger ^b , Isolde Krug ^c , Johanna Weekes ^a , Olimpia A. Manzardo ^a , Geeske Mühlschlegel ^a , Philipp Wiehle ^b , Clemens Kamrath ^a

^a Universitätsklinikum Freiburg, Klinik für Allgemeine Kinder- und Jugendmedizin, Sektion für Pädiatrische Endokrinologie und Diabetologie, Freiburg, Germany; ^b Universitätsklinikum Freiburg, Klinik für Frauenheilkunde, Gynäkologische Endokrinologie und Reproduktionsmedizin, Freiburg, Germany; ^c Universitätsklinikum Freiburg, Klinik für Allgemeine Kinder- und Jugendmedizin, Pädiatrische Psychologie, Freiburg, Germany

Introduction and Objectives

The hormonal treatment of transgender youth, whether using pubertal development blockers or gender-affirming hormones, remains a controversial. In particular, concerns have been raised about the potential negative impact on mental health. Potential detransitioning, defined as transgender individuals who have already transitioned taking steps to return to their assigned gender at birth, gives rise to further concerns.

This study aimed to explore the effects of starting treatment either before or after reaching adulthood.

Methods

We included adult patients < 30 years who were treated for gender dysphoria (GD) in our clinic since 2015. We used an online questionnaire based on the RedCAP system to obtain a comprehensive overview of individual´s outcomes in terms of mental health (PHQ-9 depression scale), well-being (WHO-5 quality of life), self-esteem (Rosenberg Self Esteem Scale [RSES]), feelings of gender congruence (Transgender Congruence Scale [TCS]) and the desire to detransition (Detransition Score [DTS]).

Data were compared between individuals who started treatment as adolescents (<18 years) and adults (≥18 years).

Results

Out of the 263 contacted patients, 107 (40.7%) responded to the questionnaires. Of these, 41 (38.3%) started treatment before the age of 18 (median age 16 years, range 13-17), while 66 (61.7%) started treatment in adulthood (median age 20 years, range 18-28).

For the DTS (score 0-9), a higher score indicated a greater wish to detransition and for the TCS (score 0-48), a higher score indicated a higher gender congruence.Compared to those who started treatment in adulthood, patients who started in adolescence had a significantly lower desire to detransition (median score 0 [range 0-2] vs 0 [range 0-9], p=0.030), as well as a higher sense of gender congruence (median score 40 [IQR 34-46] vs 37 [IQR 31-42], p=0.028). No significant differences were detected for the WHO-5, the RSES or the PHQ-9.

Conclusions

Our findings indicate that initiating hormonal treatment during adolescence may be associated with more favorable outcome in terms of gender congruence and a lower desire to detransition in individuals with GD. Furthermore, no significant differences in quality of life or mental health were observed among those who began treatment at an earlier stage.

Our results suggest that initiating hormonal treatment for transgender youth under the age of 18 years could be an effective approach that could lead to a better long-term outcome, however, further research is needed to confirm these findings.

THE CLINICAL RELEVANCE OF TWO MUTATIONS OF HITHERTO UNKNOWN SIGNIFICANCE: A CASE REPORT OF A FAMILY WITH PIRMARY CONGENITAL HYPOTHYROIDISM

Felicitas Wolf ^a , Susanne Herbst ^b , Joachim Pohlenz ^c , Platonas Karatsiolis ^a , Hande Rakicioglu ^a , Clemens Kamrath ^a , Stefan A. Wudy ^a

^a Universitätsklinikum Giessen, Abteilung für pädiatrische Endokrinologie, Giessen, Germany; ^b Charité Vivantes Services GmbH, Labor Berlin, Berlin, Germany; ^c Universitätsmedizin Mayence, Abteilung für pädiatrische Endokrinologie, Mayence, Germany

Introduction and Objectives

Case report: the firstborn sister presented with TSH of 223 mU/ml in neonatal screening and with congenital goiter, therapy with L-Thyroxin was initiated and goiter regressed. The second sister presented with congenital goiter and elevated TSH (48 mU/l) in neonatal screening. At day 10 of life TSH increased further (55 mU/ml) while fT3 and fT4 decreased, so she was started on thyroxin. Because of the family history, the youngest sister was tested for hypothyroidism after birth. All thyroid parameters and ultrasound were normal. At the age of 8 TSH rised and so thyroxin was started.

Methods

Neonatal screening has undoubtedly proved its worth in detecting cases of congenital hypothyroidism at an early stage. If there are several affected individuals in a family, this should be a reason to consider a hereditary form and to initiate molecular genetic testing. The finding of three intrafamilial cases of congenital hypothyroidism led us to initiate a molecular genetic analysis. Autoantibodies against TG or TPO have always been negative in all three patients. The parents are consanguine and without problems of the thyroid gland.

Results

Sequencing showed for all three sisters the same pair of mutations (c.3001+6T>Gp.? and c.5402G>Tp.(Ser1801Ile)), homozygous for the two older sisters (severer forms of hypothyroidism) and heterozygous for the youngest one (milder form). The genetic defect affects the gene coding for thyroglobulin and thus concerns the thyroid hormone synthesis pathway. According to the current state of knowledge, these mutations have so far been regarded as of unclear clinical significance. However, our three similarly affected sisters prove that the mutations are clinically relevant, though we can not estimate whether it is the combination or just one of the two mutations which ultimately is decisive.

Conclusions

1) Familial cases of congenital hypothyroidism should be followed by molecular genetic testing.

2) Our three intrafamilial cases provide evidence, that the mutations c.3001+6T>Gp.? and c.5402G>Tp.(Ser1801Ile) which have hitherto been of unclear significance, are of clinical relevance causing congenital hypothyroidism.

PEDIATRIC PATIENTS WITH LONG-ACTING GROWTH HORMONE THERAPY: REAL-WORLD EVALUATION FROM INSIGHTS-GHT REGISTRY

Joachim Wölfle ^a , Christof Land ^b , Alexander Mann ^c , Erwin Lankes ^d , Ilonka Kreitschmann-Andermahr ^e , Christian Strasburger ^f , David Pittrow ^g,h , Christine Pausch ^h , Dirk Schnabel ⁱ

^a University Erlangen, Department of Pediatrics and Adolescent Medicine, Erlangen, Germany; ^b Centre for Paediatric and Adolescent Endocrinology, Gauting, Germany; ^c MVZ Endokrinologikum, Frankfurt (Main), Germany; ^d Charité Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin und Humboldt-Universität zu Berlin, Pediatric Endocrinology / Center for chronic sick children, Berlin, Germany; ^e University of Duisburg-Essen, Department of Neurosurgery and Spine Surgery, Essen, Germany; ^f Charité Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin und Humboldt-Universität zu Berlin, Department of Endocrinology and Metabolism, Berlin, Germany; ^g Technical University, Institute for Clinical Pharmacology, Dresden, Germany; ^h GWT-TUD, Innovation Centre Real-World Evidence, Dresden, Germany; ⁱ Charité Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin und Humboldt-Universität zu Berlin, Pediatric Endocrinology / Center for chronic sick children, Berlin, Germany

Introduction and Objectives

INSIGHTS-GHT is the world’s first cross-product registry study on growth hormone therapy (GH therapy). Patients of all ages and across all approved indications can be included. This allows for the analysis of many relevant questions and the documentation of real-world clinical routine during childhood, transition and adulthood in Germany. In particular, since the end of 2023, patients receiving the newly approved long-acting growth hormone products Ngenla® (Somatrogron), Skytrofa® (Lonapegsomatropin) and Sogroya® (Somapacitan) can be documented.

Methods

Since its launch in February 2022, the INSIGHTS-GHT registry has already included over 2,100 patients from 30 endocrinology institutions in Germany. We report on an interim analysis of paediatric patients with growth hormone deficiency (GHD) receiving therapy with a new long-acting GH preparation (LAGH). These patients receive LAGH subcutaneously once weekly. The database status of the analysis is 7 July 2025.

Results

A total of 97 children and adolescents under the age of 18 with GHD undergoing LAGH therapy from 9 centres were included. Of these, 78% were male. In 72 cases (75%), idiopathic growth hormone deficiency, and, in 24 cases (25%), organic growth hormone deficiency, were the indication for GH replacement. At the initiation of LAGH therapy, the average age was 9.2 (3.6) years. 52 patients (56%) had previously received daily GH therapy for an average of 3.6 (2.7) years (‘switch patients’). At the start of LAGH therapy, body height was -1.8 (1.1) SDS and BMI was -0.3 (1.1) SDS. The majority of patients (78%) were prepubertal at the start of treatment. The starting dose of the LAGH products was below the manufacturer’s recommendation in 79% of cases, with a median of 92% of the recommended dose.

Conclusions

Baseline data from the INSIGHTS-GHT registry demonstrate that LAGH therapy is increasingly being adopted in clinical practice for both rhGH-naïve and switch patients. In consideration of this still new therapy the LAGH doses prescribed at LAGH initiation until now are mostly low relative to the manufacturers recommended range. The analyses are continuously updated and supplemented.

References

Woelfle J, Kreitschmann-Andermahr I, Strasburger CJ, Pittrow DB, Pausch C, Schnabel D (2025). First 100 patients receiving long-acting growth hormone therapy: real-world evaluation from INSIGHTS-GHT registry. Orphanet Journal of Rare Diseases 20:372

CASE REPORT ABOUT A 46, XY DSD-PATIENT WITH ADRENAL INSUFFICIENCY

Janine Wöllner ^a , Ann-Kathrin Dittrich ^a , Clemens Freiberg ^a , Markus Röbl ^a , Silke Kaulfuß ^b , Maria Kuzyakova ^b , Andreas Jenke ^c , Jutta Gärtner ^a

^a UMG Göttingen, Klinik für Kinder- und Jugendmedizin, Göttingen, Germany; ^b UMG Göttingen, Institut für Humangenetik, Göttingen, Germany; ^c Klinikum Kassel, Neonatologie und allgemeine Pädiatrie, Kassel, Germany

Introduction and Objectives

Mutations in CYP11A1 lead to a deficiency of the enzyme P450 side-chain cleavage (P450scc). P450scc is involved in converting cholesterol into pregnenolone at the inner mitochondrial membrane in all steroidogenic tissues. Mutations in CYP11A1 thus cause a 46, XY phenotype with complete sex reversal in extreme premature babies due to failure of placental and testicular androgen synthesis, along with global adrenal cortex insufficiency and absent adrenal hyperplasia.

Methods

We report a single case of a patient with CYP11A1 mutations resulting in P450scc deficiency.The patient presented here is the 2^nd child of a 27-year-old mother. The parents are consanguineous (first degree cousins) and originally come from Syria. Due to heavy vaginal bleeding, an emergency cesarean section was performed at 23+5 weeks of gestation.

Results

Normal female external genitalia were present at birth. In the first 72 hours of life the patient developed hyperkalemia and recurrent lactic acidosis. Due to low thyroid hormone levels, pituitary insufficiency was suspected and L-thyroxine, hydrocortisone, and fludrocortisone were started. ACTH-testing and steroid profiling confirmed primary adrenal insufficiency. At 4 months of age chromosome analysis revealed the karyotype 46, XY. Ultrasound could not detect adrenal glands, but a narrow tubular structure in the typical uterine position, reminiscent of Müllerian duct remnant. No gonads were found at the typical locations, but subcutaneous pockets with tiny tissue structures were present on both sides at the level of the internal inguinal rings, corresponding to highly dysplastic testes.

Conclusions

We add another case of P450scc deficiency caused by a new homozygous, yet undescribed CYP11A mutation, confirmed by genome analysis. The description extends the genetic cause as well as clinical signs and symptoms of this ultra-rare condition.

References

Olaf Hiort, Paul-Martin Holterhus, Ralf Werner, Christine Marschke, Ute Hoppe, Carl-Joachim Partsch, Felix G. Riepe, John C. Achermann, Dagmar Struve, Homozygous Disruption of P450 Side-Chain Cleavage (CYP11A1) Is Associated with Prematurity, Complete 46,XY Sex Reversal, and Severe Adrenal Failure, The Journal of Clinical Endocrinology & Metabolism, Volume 90, Issue 1, 1 January 2005, Pages 538–541, https://doi.org/10.1210/jc.2004-1059

INCIDENCE OF CHILDHOOD T1D BEFORE, DURING AND AFTER THE CORONA PANDEMIC – THIRTY-EIGHT-YEAR ANALYSIS OF THE DIABETES INCIDENCE REGISTER (DIARY) IN SOUTHWEST GERMANY

Julian Ziegler ^a , Andreas Neu ^a , Stefan Ehehalt ^c , Roland Schweizer ^a , Klaus Dietz ^b

^a Universitätsklinikum Tübingen, Abteilung für Kinder- und Jugendmedizin, Tübingen, Germany; ^b Universität Tübingen, Institut für klinische Epidemiologie und angewandte Biometrie, Tübingen, Germany; ^c Gesundheitsamt Stuttgart, Stuttgart, Germany

Introduction and Objectives

The aim of this work was to evaluate the overall incidence of diabetes mellitus type 1 (T1D) in children and adolescents over a period of 38 years in Baden-Württemberg, before, during and after the corona pandemic considering different subgroups.

Methods

The study used registry data from the oldest German diabetes incidence registry (Diary) for children and adolescents aged 0-14 years with clinically diagnosed T1D in Baden-Württemberg. Overall incidence rates for the whole cohort, age and/or gender-specific incidence rates, and trends in incidence development from 1987 to 2024 were given as rates per 100,000 person-years and as annual percent changes (APC).

Results

The crude overall incidence for children and adolescents younger than 15 years in 1987 was 10.1 per 100,000 children and year and increased to 20.2 in 2024. The incidence rate increased by 4.0% annually until 2008, followed by a plateau with no change in the incidence rate until 2024. The highest incidence rate was found in boys aged 10-14 years at 25.4. During the Corona years, the incidence rate increased slightly to 31.1 and returned to normal by 2024, most recently to 20.2. The estimated prevalence of T1D in children and adolescents under 15 years of age as of December 31, 2024 was 154 per 100.000.

Conclusions

The increase in the incidence rate for children and adolescents in Baden-Württemberg occurred only until 2008, with the exception of the corona years 2021 and 2022, comparable to high-risk countries such as Norway and Finland.

DIABETES TECHNOLOGY AS A RISK FACTOR FOR WEIGHT GAIN IN FEMALE ADOLESCENTS AND YOUNG WOMEN WITH TYPE 1 DIABETES

Julian Ziegler ^a , Reinhard W. Holl ^b,c , Torben Biester ^d , Martin Tauschmann ^e , Joachim Rosenbauer ^f,c , Andreas Neu ^a , Monika Flury ^g , Jochen Seufert ^h , Marie Auzanneau ^b,c , Beate Karges ^i,j

^a Universitätsklinikum Tübingen, Abteilung für Kinder- und Jugendmedizin, Tübingen, Germany; ^b Universität Ulm, Institut für Epidemiologie und Medizinische Biometrie Ulm, Ulm, Germany; ^c Deutsche Zentrum für Diabetesforschung (DZD) Munich-Neuherberg, Neuherberg, Germany; ^d Kinderkrankenhaus AUF DER BULT, Diabetologie, Endokrinologie, Gastroenterologie und Klinische Forschung, Hanover, Germany; ^e Universitätsklinik für Kinder- und Jugendheilkunde Vienna, Abteilung für Pädiatrische Pulmologie, Allergologie und Endokrinologie, Vienna, Austria; ^f Deutsches Diabetes-Zentrum (DDZ) Düsseldorf, Institut für Epidemiologie und Biometrie, Düsseldorf, Germany; ^g Medizinische Fakultät und Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Klinik und Poliklinik für Kinder- und Jugendmedizin, Dresden, Germany; ^h Universitätsklinikum Freiburg, Klinik für Innere Medizin II, Abteilung Endokrinologie und Diabetologie, Freiburg, Germany; ⁱ Uniklinik RWTH Aachen, Klinik für Kinder- und Jugendmedizin, Aachen, Germany; ^j Bethlehem Gesundheitszentrum Stolberg, Klinik für Kinder- und Jugendmedizin, Stolberg, Germany

Introduction and Objectives

Prevalence of being overweight or obesey is increasing in children and adolescents worldwide. In recent years, along with the increased use of diabetes technology, there have been a raising number of observations which report continuous increase in BMI-SDS in patients with type 1 diabetes. Here, we aim to investigate sex- specific BMI differences in adolescents with type 1 diabetes using different forms of insulin therapy.

Methods

Data from the DPV registry for the years 2022 and 2023 were analyzed for children and adolescents with type 1 diabetes with diabetes duration of more than one year and without treatment with metformin, GLP-1 analogues or SGLT2 inhibitors. Patients who switched treatment regimen during the observation period were excluded. BMI-SDS were calculated based on the KiGGS reference. Multivariable linear regression models were implemented, considering age, sex and duration of diabetes, and least squares means (LSMeans) were estimated. Children older than 12 years were defined as adolescents.

Results

22,592 children and adolescents were evaluated (mean age ± SD 12.7±4.0 years, mean duration of diabetes 5.3±3.7 years, 54% male), 13,975 of them were adolescents (mean age 15.3±1.8 years, mean duration of diabetes 6.5±4.0 years 54% male). 4,862 patients used AID-systems, 4,096 used SAP with or without LGS, 4,594 used MDI with CGM, and 423 used MDI without CGM.Female adolescents using AID or SAP had the highest BMI-SDS (AID: +0.56 [0.52;0.59], SAP: +0.53 [0.49;0.57], while male adolescents had the lowest BMI-SDS (+0.25 [0.23;0.27]), regardless of the type of therapy used (all p<0.05). Young women using MDI had significantly lower BMI-SDS (+0.43 [0.38;0.48]) than female users of AID or SAP (p<0.05).The total group did not significantly differ from the adolescent group in terms of BMI-SDS.

Conclusions

Adolescents did not differ in BMI-SDS compared to the total group of children up to 18 years of age. However, adolescent girls treated with AID or SAP had significantly higher BMI-SDS values than those with MDI and CGM and significantly higher BMI-SDS than boys. This finding should be communicated during diabetes group training sessions as well as during individual outpatient consultations.