Band 38, Heft 11

Objectives The incidence of type 1 diabetes (T1D) in children increased during the first two years of the COVID-19 pandemic and declined thereafter. It is not known whether the decline is associated with COVID-19 vaccination rates in children. This study investigates whether COVID-19 vaccination rates are associated with T1D incidence in children. Methods Population-based ecological study of children with new-onset T1D in the years 2022 and 2023 from the German Prospective Diabetes Registry. COVID-19 vaccination rates (VR) for 2022 were obtained from the Digital Vaccination Rate Monitoring-Project of the Robert-Koch-Institute. Spatial Spearman correlation analysis between period-averaged COVID-19 VR and T1D standardized incidence ratios (SIR) per county were used for the year 2022. Bayesian conditional autoregressive (CAR) Poisson models, including a time lag of 0–12 months between COVID-19 VR and T1D SIR, were used to assess their association. Results Data of 6,736 children and adolescents with new-onset T1D in the years 2022 and 2023 and of 4,208,377 vaccinated children aged 5–17 years across 336 German counties were analyzed. Neither the month-averaged spatial analysis (5–11 years: r=−0.029 [95%CI −0.136; 0.079]; 12–17 years: r=0.031 [95%CI −0.077; 0.138]) nor the spatiotemporal CAR models including time shifts of 0–12 months showed significant correlations between T1D SIR and COVID-19 VR. Conclusions This study found no significant associations between childhood COVID-19 vaccination rates and the subsequent incidence of type 1 diabetes over the next 12 months. Further research is needed to investigate the relationship in younger children.

Objectives Quantitative glycemic metrics are needed to identify undiagnosed celiac disease in type 1 diabetes and reduce delays in celiac diagnosis. Celiac enteropathy drives malabsorption that increases the risk of prandial insulin-glucose mismatch and hypoglycemia. We assessed if children with type 1 diabetes and celiac disease have lower post-prandial glucose levels preceding celiac diagnosis vs. those without celiac disease, leveraging continuous glucose monitoring (CGM) data and a computational meal annotation algorithm. Methods In this retrospective cohort study, children with type 1 diabetes <12 months duration using CGM, positive celiac serologies and biopsy confirmed celiac disease (n=16) were matched 1-to-4 to those with negative celiac serologies (n=60). Meals were computationally annotated in the 30-day window before serologies. Differences in post-prandial trough glucose and other prandial glycemic outcomes were assessed via mixed models. Results Undiagnosed celiac disease was associated with a lower glucose rise from meal start to peak vs. no celiac disease (−8.9 %, 95 % CI, −14.9–−2.5 %, p=0.009) and, during the first meal of the day, a lower fall from peak to trough (−9.3 %, 95 % CI, −16.5 %–−1.5 %, p=0.02). There was no significant association between celiac disease and trough glucose, meal hypoglycemia or time hypoglycemic. Conclusions Computational analysis revealed that blunted prandial glycemic trajectories, not hypoglycemia, are associated with undiagnosed celiac disease in children with type 1 diabetes using CGM. These findings challenge current guidelines, and future studies should validate and integrate these glycemic biomarkers into a CGM-based model for real-time prediction of celiac disease in type 1 diabetes.

Objectives Continuous glucose monitors (CGM) are the mainstay of glucose monitoring in type 1 diabetes (T1D). However, the impact of race/ethnicity and the timing of CGM adoption following T1D diagnosis is unclear. We examined the effect of race/ethnicity and CGM adoption on glycemia and partial remission (PR) in T1D. Methods A 24-month longitudinal retrospective cohort study of youth with T1D who used Dexcom CGM G5/G6 between 2018 and 2022 was conducted. Subjects were classified as non-Hispanic White (NHW) or Other (Asian, Black/African American, Hispanic/Latino, or other). Glycemia was measured as %change in hemoglobin A 1c (A 1c ) and time in range (TIR) from baseline to 24 months. PR was denoted as an insulin-dose-adjusted A 1c (IDAA 1c ) value of ≤9. The statistical approach included the paired t-test, the Wilcoxon signed-rank test, and mixed effects models for repeated measures. Results Early CGM adoption occurred in 90 % (61/68) of NHW subjects vs. 63 % (43/68) of the Other, p=0.0003. Early CGM adoption was associated with improved glycemia and PR as marked by a significantly greater %decrease in A 1c , p=0.0008, and IDAA1c, p=0.0003, at 24 months following CGM adoption. Temporal trends in A1c and IDAA1c were significantly lower among NHW subjects, p<0.0001, and the probability of PR was significantly greater, p<0.0001. Early CGM adoption conferred a greater probability of PR than late CGM adoption, p<0.0001. Conclusions Early adoption of diabetes technology should be accelerated in all children with T1D, particularly minority children, to reduce hyperglycemia, promote PR, and close the gap in diabetes care and complications in the United States.

Objectives To comprehensively investigate the association between HLA class II alleles and haplotypes with type 1 diabetes mellitus (T1DM) susceptibility in a Jordanian population. Methods In this case-control study, 205 patients with clinically confirmed T1DM and 99 ethnically matched healthy controls were genotyped for HLA-DRB1 , DQA1 , and DQB1 loci. Autoantibodies and thyroid function were evaluated. Haplotype frequencies were compared using the BIGDAWG R package, with odds ratios (ORs), 95 % confidence intervals (CIs), and false discovery rate (FDR) correction. Results HLA-DRB1*03 : 01 (OR=4.94, p<0.001), DRB1*04 : 02 (OR=3.87, p=0.003), and DRB1*04 : 05 (case-only; p=0.002) were associated with T1DM. Strong associations were also observed for DQA1*05 : 01 (OR=6.61, p<0.001) and DQB1*02 : 01 (OR=5.70, p<0.001). Protective effects were identified for DRB1*07 : 01 , DRB1*15 : 02 , DQA1*05 : 05 , and DQB1*03 : 01 (all FDR<0.05). Among haplotypes, DR3∼DQ2 conferred the greatest risk (OR=5.40, p<0.001), while DRB1*11 : 04∼DQA1*05 : 05∼DQB1*03 : 01 was protective (OR=0.25, p=0.004). DRB1*03 : 01 was associated with GAD65 autoantibodies and celiac serology. DQA1*03 : 01 and DQA1*05 : 01 were linked to thyroid autoantibodies. No significant differences in age or HbA 1c at diagnosis were observed across HLA alleles. Conclusions HLA class II variation was strongly associated with T1DM in Jordan, with DR3∼DQ2 and DR4 haplotypes driving susceptibility and DRB1*07 , DRB1*15 : 02 , and DQB1*03 : 01 conferring protection, reflecting global patterns while highlighting region-specific features. These findings support incorporating HLA genotyping into T1DM risk assessment and suggest shared genetic links with other autoimmune diseases.

Objectives There is little data on prevalence, incidence rate and clinical characteristics on diabetes amongst the pediatric and adolescent group in sub-Saharan Africa. Therefore, this study aimed to document annual case counts, describe clinical characteristics, and assess loss to follow-up among pediatric and adolescent patients with diabetes at Kenyatta National Hospital. Methods This was a hospital-based retrospective, descriptive study carried out at Kenyatta National Hospital, Pediatric Endocrinology Unit, between January 2008 and December 2021 amongst diabetic patients aged 25 years and below. Data was analyzed using Statistical Package for Social Science (SPSS) version 23.0. Results Type 1 diabetes was the leading form of diabetes at 99.3 % (n=288). Most, 56.3 %, of cases of type 1 diabetes got diagnosed within the ages of 6–18 years, majority being 6–11 years. Most patients, 90.2 % presented in diabetic ketoacidosis (DKA) at initial diagnosis. There was a sustained increasing trend in type 1 diabetes with a notable dip in hospital visitations during covid time, the year 2020. Patients with type 1 diabetes took an average of 2.5 months and a median interval of 18 days from symptom onset to diagnosis. A third of the cases of type 1 diabetes, 31.25 %, were lost to follow up. Conclusions The increasing cases of type 1 diabetes with delayed diagnosis require allocation of more resources and increased awareness creation. Measures need to be put in place to manage chronic conditions during pandemics. Hospital-based tracking system is required to prevent loss to follow up cases.

Objectives Clinical trials of sodium-glucose transporter 2 inhibitors (SGLT2i) in youth with type 2 diabetes (T2D) showed significant improvement in HbA1c% and fasting plasma glucose, yet there is limited real-world data on their use. This study sought to assess real-world use and effectiveness of SGLT2i medications in management of T2D in a diverse cohort of youth. Methods This retrospective study analyzed youth newly prescribed a SGLT2i for management of T2D at two academic pediatric diabetes centers. Change in HbA 1c , BMI, and insulin use from baseline to follow-up were evaluated for those taking SGLT2i added to their background diabetes treatment. Wilcoxon signed-rank test and McNemar’s test were used to compare paired continuous and categorical variables, respectively. Results A total of 81 patients with youth-onset T2D (mean age 17.3 years (SD 1.93), 63 % female, 51 % non-Hispanic Black, 13 % Hispanic, 33 % with private insurance) were prescribed SGLT2i. Among the 61 (75 %) reporting adherence or partial adherence at a median follow-up of 98 days, median HbA 1c decreased from 8.4 to 7.1 % (p<0.001). There was a small but significant reduction in mean BMI Z-score from baseline to follow-up (2.66 to 2.57, p=0.0004). The proportion of patients prescribed basal insulin decreased from 44 to 34 % (p=0.03), and prandial insulin from 23 to 13 % (p=0.01). Conclusions Real-world use of SGLT2i in youth with T2D is associated with decreased HbA 1c levels and lower BMI Z-score and may also reduce use of insulin for youth with T2D.

Objectives The present study aimed to investigate whether nitric oxide synthase ( NOS ) enzyme gene variants ( iNOS rs1060826, eNOS rs1799983, eNOS 27-bp VNTR) play a role in the etiopathogenesis of nonalcoholic fatty liver (NAFLD) in adolescents. Methods This cross-sectional study was conducted with obese adolescents [body mass index (BMI) standard deviation score (SDS) ≥2] aged 10–19 years (104 individuals) and age- and sex-matched healthy individuals (64 individuals) whose presence of NAFLD was determined by ultrasound. The iNOS rs1060826 and eNOS rs1799983 variants were performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, and the eNOS 27-bp VNTR variant was analyzed using the PCR method. The genotypes detected were compared between the patient group and the healthy controls and with the clinical parameters of the patients. Results iNOS rs1060826 and eNOS rs1799983 were independent of obesity, whereas eNOS 27-bp VNTR was independent of NAFLD. However, in the obese group, especially in those with NAFLD (+), the iNOS rs1060826 GG genotype was found to be associated with lower diastolic blood pressure (DBP) (p=0.011). Compared with the clinical parameters, insulin resistance (HOMA-IR) was higher in those carrying the eNOS rs1799983 gene variant-TT genotype in the NAFLD (+) group (p=0.051). Conclusions While the three functional gene variants of the NOS enzyme did not show a significant difference in terms of genotype between patients and healthy controls, it was determined that both the iNOS rs1060826 gene variant-GG allele was associated with low DBP and HOMA-IR may be higher in those carrying the eNOS rs1799983 gene variant TT genotype in NAFLD (+) patients. The iNOS rs1060826 polymorphism is a potentially important genetic variant that may influence DBP regulation through its effects on nitric oxide production.

Objectives To evaluate cardiometabolic risk factors in girls with premature adrenarche (PA), with a specific focus on outcomes based on adrenal androgen levels (typical vs. exaggerated adrenarche). Methods Eighty-four girls with PA were followed from diagnosis to mid-puberty. Clinical, biochemical, and hormonal parameters were assessed at both time points. Participants were stratified based on dehydroepiandrosterone sulfate (DHEAS) levels: typical PA (40–130 μg/dL) and exaggerated adrenarche (>130 μg/dL). Age- and sex-matched controls (n=58) were included for pubertal comparisons. Results At baseline, 25 % of PA girls were overweight/obese, and 22 % had elevated HOMA-IR. Exaggerated adrenarche was present in 19 % of subjects. By puberty, overweight/obesity prevalence rose to 33.3 %, with significant increases in fasting insulin, HOMA-IR, and declines in insulin sensitivity indices (QUICKI, FGIR). Comparisons with controls revealed significantly higher BMI, waist circumference, and insulin resistance among PA girls. However, there were no significant metabolic differences between exaggerated and typical PA groups, except for a higher waist circumference in the exaggerated group. Conclusions Elevated mid-childhood DHEAS does not independently predict worsened metabolic outcomes by puberty. Baseline adiposity, not androgen level, is the principal determinant of insulin resistance and cardiometabolic risk in PA. Lifestyle interventions targeting weight management are crucial in mitigating future risk.

Objectives McArdle disease (also known as glycogen storage disease type V) is a rare metabolic myopathy that is caused by myophosphorylase deficiency, leading to impaired glycogenolysis in skeletal muscles. This study explored the clinical, histopathological, and genetic landscape of McArdle disease in a regional cohort from Turkey, emphasizing diagnostic and management challenges. Methods A retrospective analysis was conducted on 350 muscle biopsies performed between 2013 and 2024 in a tertiary care center. Results Seven patients (2.1 %) were diagnosed with McArdle disease. The clinical features included exercise intolerance (100 %), muscle pain (75 %), and the second wind phenomenon (62.5 %). Two patients presented with acute renal failure due to rhabdomyolysis with myoglobinuria, leading to metabolic acidosis. Histopathological findings revealed glycogen accumulation in subsarcolemmal vacuoles and absent myophosphorylase activity in all cases. Genetic analysis identified five distinct PYGM pathogenic variants, including c.808C>T (p.Arg270Ter) and c.2262del (p.Lys754fs). These findings highlight the phenotypic and genetic heterogeneity of McArdle disease. Conclusions McArdle disease remains underdiagnosed due to its variable clinical presentation and limited access to advanced diagnostic tools. This study underscores the importance of a multidisciplinary approach that integrates clinical assessment, muscle biopsy, and molecular analysis. Increased awareness and training among healthcare providers are critical for early recognition and intervention. Future research should focus on expanding genetic databases and exploring targeted therapies to improve outcomes in this challenging condition.

Objectives Precocious puberty in girls is a condition marked by the early onset of secondary sexual characteristics, with vascular factors like uterine artery pulsatility index having been suggested as potential indicators. Methods We performed Mendelian randomization (MR) analysis using genetic instruments from large-scale genome-wide association studies (GWAS) datasets, including ebi-a-GCST008403, ukb-a-250, and ukb-b-11971, to evaluate the relationship between arterial stiffness and precocious puberty. Exposure and outcome data were sourced from the GWAS Catalog, eQTLGen, and the R11_E4_PREPUB dataset. The TwoSampleMR package was employed to assess causal relationships, with several MR methods applied, including inverse variance weighted, MR Egger, weighted median, and mode-based methods. Results Our analysis of arterial stiffness using ebi-a-GCST008403, ukb-a-250, and ukb-b-11971 datasets did not show a statistically significant causal relationship with precocious puberty. The IVW method showed an OR of 0.707 (p=0.885) for arterial stiffness, indicating no reliable association. The investigation into MMP2 also yielded non-significant results across all methods, with an OR of 0.778 (p=0.330) from the IVW method. However, the analysis of MMP9 revealed a significant association with precocious puberty, showing an OR of 3.89 (p=0.004) using the IVW method, and an OR of 3.96 (p=0.027) from the Weighted Median method, indicating a strong positive effect of MMP9 on precocious puberty risk. Conclusions Our findings suggest that while arterial stiffness and other MMPs do not have a significant causal role, MMP9 may significantly increase the risk of precocious puberty in girls.

Objectives Osteopetrorickets is a rare autosomal recessive disease that affects many systems and is characterized by dense bone mass and paradoxical rickets due to insufficient resorption of calcified cartilage. Its rarity and presentation with nonspecific symptoms may cause delays in diagnosis. Early diagnosis and improvement of rickets accompanying bone marrow transplantation as a curative treatment option before the development of any irreversible complications are essential for prognosis. However, the etiopathogenesis and management of rickets treatment strategies are still controversial. Case presentation A 4-month-old female patient, whose loss of vision had been followed for 1.5 months, was admitted to our clinic with the request for a disability report. Clinical and laboratory findings were consistent with osteopetrorickets. Molecular analysis revealed a homozygous variant in the TCIRG1 gene. She was normocalcemic and hypophosphatemic, and the 25-OH vitamin D level was normal, while 1.25-dihydroxyvitamin D levels were quite high. Treatment was started with low-dose calcium replacement and calcitriol. The dose of calcitriol was gradually increased to 300 ng/kg/d, and a significant clinical response was achieved. Bone marrow transplantation was conducted at 8 months postnatally from an HLA-compatible non-related donor; nonetheless, the patient succumbed to respiratory problems on the 71st day following the procedure. Conclusions Nonspecific symptoms of osteopetrorickets should be considered for early diagnosis, as a timely intervention in the first months of life can be life-saving. The pathophysiology of rickets remains unclear, but low calcium-phosphorus product and resistance to 1.25-dihydroxyvitamin D appear to play key roles. High-dose calcitriol and cautious calcium supplementation may improve outcomes, though further research is needed to optimize treatment strategies.

Objectives To describe the case of a young girl with severe congenital neutropenia caused by a homozygous variant in the Jagunal homolog 1 ( JAGN1 ) gene, who later developed atypical diabetes. Case presentation JAGN1 deficiency disrupts neutrophil maturation, resulting in immunodeficiency and recurrent infections. Our patient also exhibited impaired humoral immunity, requiring immunoglobulin replacement therapy, which reduced infection frequency. Several years after the identification of her JAGN1 mutation, she developed atypical insulin-dependent diabetes mellitus – a condition not previously associated with JAGN1 mutations. This novel finding suggests a potential role for JAGN1 in pancreatic β-cell function. Conclusions This case expands the spectrum of JAGN 1 -related immune dysfunction and introduces a potential link between JAGN1 deficiency and diabetes. We explore possible mechanisms underlying this association, highlighting the need for further research. Clinicians should consider JAGN1 mutations in the differential diagnosis of combined immune and metabolic disorders.

Objectives The majority of congenital hypopituitarism (CH) cases remain genetically unexplained. The transmembrane receptor Roundabout-1 ( ROBO1 ), activated through interaction with SLIT-family proteins, plays crucial role in axonal guidance, branching, targeting, and midline axonal crossing. ROBO1 variants have been associated with pituitary stalk interruption syndrome and highly variable pituitary-phenotypes, ranging from isolated growth hormone deficiency (IGHD) to combined pituitary hormone deficiency (CPHD). This study aimed to investigate the genetic basis of CH in a newborn and to review current evidence linking ROBO1 variants with CH. Case presentation We report the presence of two ROBO1  variants in compound heterozygosity, the NM_002941:c.2914G>A, p.(Ala972Thr) and the novel NM_002941:c.3757G>A, p.(Val1253Met), as well as the identification of the novel NOTCH3 variant NM_000435:c.1505C>T, p.(Ser502Phe) and the novel GPR161 variant NM_001375883.1:c.1117C>T, p.(His373Tyr), in a newborn with CPHD, dysmorphic features and midline abnormalities. Conclusions This case, together with accumulating evidence, supports ROBO1 as a potential causative gene for CH. ROBO1 should be considered during genetic evaluation of patients with CH and midline abnormalities. The co-occurrence of NOTCH3 and GPR161 variants raises the possibility of an oligogenic or multigenic etiology. The cross-talk between ROBO/SLIT and NOTCH signaling pathways may contribute to the complex phenotype observed and warrants further functional investigation.

Objectives To describe four members of a family with DAX1 deficiency caused by a novel NR0B1 variant. Case presentation All family members carried a novel hemizygous NR0B1 variant, p.Gln318Alafs*71. The elder brother, aged 13 years, developed an adrenal crisis at the age of 3 years. The third brother, aged 4 years, showed a relatively low cortisol response to the short Synacthen test, but exhibited no clinical signs of adrenal insufficiency. The youngest brother developed an adrenal crisis at the age of 16 days. Additionally, their 14-year-old cousin was diagnosed with DAX1 deficiency based on skin pigmentation and family history. Conclusions Despite carrying the same NR0B1 variant, the initial symptoms and age of adrenal insufficiency onset varied among the four members of this family. Male members with a family history of DAX1 deficiency should be confirmed genetically as possible.

Objectives MMP13 -related metaphyseal dysplasia Spahr type, is an extremely rare skeletal disorder, and only a dozen patients with a confirmed molecular diagnosis have been reported. It is characterized by mild short stature, genu varum, and metaphyseal irregularities including fraying, splaying, and cupping of the long bones. The disorder is in the differential diagnosis of rickets, a relatively common disorder in childhood that shares similar clinical and radiological features with metaphyseal dysplasia. Case presentation Herein, we present a 39-month-old girl patient who was initially evaluated for rickets due to mild short stature, bowing of the lower extremities, and metaphyseal changes. Biochemical tests including calcium, phosphate, alkaline phosphatase, and vitamin D levels were all within normal ranges. Radiographies revealed advanced bone age, mildly enlarged epiphyses, wide and irregular metaphyses of the long tubular bones, mildly thickened long tubular bones, and coxa vara. Clinical exome sequencing identified a homozygous variant in the MMP13 gene, confirming the diagnosis of metaphyseal dysplasia Spahr type. Conclusions We emphasize that metaphyseal dysplasias mimic the clinical and radiographic features of rickets and play a significant role in the differential diagnoses, particularly in patients presenting with short stature, genu varum, and metaphyseal irregularities, despite the absence of biochemical abnormalities. In accordance with the Nosology of Genetic Skeletal Disorders: 2023 Revision, we reinforce the dyadic naming system for the two groups of MMP13 -related metaphyseal dysplasia, differentiated solely by their inheritance patterns, which also exhibit consistency with the location of the variants.