Volume 38, Issue 10

Introduction Medical devices for glycaemic control have revolutionised the lives of people with type 1 diabetes (TD1), yet providing children and adolescents with T1D with suitable automated insulin delivery (AID) systems remains challenging, leading to unmet medical needs. Content The conect4children network organised an international multi-stakeholder meeting in conjunction with the Advanced Technologies and Treatment in Diabetes (ATTD) 2023 congress to discuss how to improve access to suitable AID systems for young people with T1D. Summary A total of 125 participants attended the 1-day meeting (academics/clinicians, n=50; advocates for children with T1D, n=21; industry, n=26; regulators, n=28). The attendees discussed treatment options, including available medical devices and their limitations. Carers and adolescents described their experiences related to T1D and accessing the latest technologies. The most advanced appropriate technology is often unavailable to children with T1D in Europe. The challenges and potential solutions for providing AID systems to very young children were discussed in the context of understanding the differences in European and United States medical device regulations. The main issues highlighted were a lack of long-term evidence of benefits/clinical effectiveness and safety of AIDs in very young children, lengthy and expensive regulatory approval processes in the European Union, variable market access and reimbursement across countries and even within countries, depending on the proximity of the patient to specialist centres (or their ability to travel). Outlook All stakeholders need to take their responsibility and cooperate to ensure that young people with T1D have access to appropriate technology and therapy regardless of their age and place of living.

Objectives The aim of this research was to assess the psychological problems of pubertal girls who presented with early menarche. To the best of our knowledge, there is no similar prospective cross-sectional research in the medical literature. Methods Group I included patients under 10 years old, who presented with menarche. Peripheral causes of puberty were excluded. Group II included 9–10-year-old prepubertal healthy girls. Four mental tests were employed to both groups. Children in Group I was recalled for re-evaluation after 6 months. Results A total of 49 girls (Group I, n=28; Group II, n=21) were included. Median ages of the groups were similar (9.7 (0.4) years vs. 9.3 (0.6) years, p=0.06, respectively). Median bone age and the time between first signs of puberty and menarche in girls in Group I were 11.4 (1) years and 12 (0.1) months, respectively. Height age, height, weight, and BMI SD scores were significantly higher in Group 1 (p<0.01). Mental test scores and the frequency of mood disorders were similar among the groups (Group I, n=2, 7 % vs. Group II, n=2 (9 %), p=0.76)). Re-evaluation of 17 patients (60.7 %) in Group 1 revealed no significant differences in test scores and no new cases of psychiatric conditions. Conclusions There was no significant difference in psychological and behavioral problem scores between the early menarche and control groups. Gonadotropin releasing hormone (GnRH) analogue therapy should not be based on the assumption that premature pubertal development will cause psychosocial effects and should only be considered after a thorough psychiatric evaluation.

Objectives Testosterone therapy is recommended for management of puberty from the age of 12 years in boys with Duchenne muscular dystrophy (DMD). Height measurement is problematic in these adolescent boys as lower limb contracture can be common and estimated height from segmental body part measurements may over-estimate height. Methods Bone growth was assessed using metacarpal and phalangeal measurements from hand radiographs. Raw length measurements were converted to Z-scores based on published normative data and compared by calculating the mean of each patient as ‘composite bone length Z-score’. Biochemical data was also collected to monitor the safety of testosterone therapy. Results A total of 22 boys with DMD on daily glucocorticoid were included in the study. Mean age at commencement of testosterone therapy was 14.05 (SD 1.20). 13 boys were commenced on intramuscular testosterone therapy and nine were commenced on topical testosterone therapy. At baseline, 20/22 (91 %) were pre-pubertal (G1). At follow-up, 16/22 (77.3 %) were at early stages of puberty (G2 or G3) and 6/22 (22.7 %) were at late stages of puberty (G4 or G5). At baseline and follow up, composite bone length Z-scores for chronological age were significantly lower than zero, −2.7 (SD 1.07) (p<0.001 vs. zero) and −3.3 (SD 1.17), (p<0.001 vs. zero), respectively. There were no statistically significant differences between the topical and IM group at baseline (p=0.61) or 1 year (p=0.40). Conclusions Measurements of metacarpophalangeal bone length confirms that testosterone therapy enhanced long bone growth in boys with DMD but does not achieve full catch-up growth. Both IM and topical testosterone effectively promote secondary sexual characteristics with no significant side effects.

Objectives Glycogen storage diseases (GSDs) are inherited metabolic disorders caused by deficiencies in the enzymes responsible for glycogen synthesis and breakdown. GSD subtypes involving the liver are commonly associated with symptoms such as fasting hypoglycemia and hepatomegaly, and medical nutrition therapy remains the gold standard of treatment. Fibroblast growth factor 21 (FGF21), a hormone primarily secreted by the liver, plays a key role in regulating lipid, glucose, and energy metabolism. This study measured FGF21 levels in patients with hepatic forms of GSD at Çukurova University, evaluating differences among GSD subtypes and their correlations with biochemical parameters. Methods The study included 50 patients with hepatic GSD who were categorized by subtypes: 10 with type Ia, 2 with type Ib, 16 with type III, 3 with type VI, 8 with type IXa, 4 with type IXb, and 7 with type IXc. Serum FGF21 levels were measured, and their associations with biochemical findings, abdominal imaging results, and growth parameters were evaluated. Results Of the 50 patients, 52 % were female and 48 % male. The mean age at admission was 142.26 ± 76.19 months (range: 23–360 months). Common reasons for admission included abdominal distension, hepatomegaly, hypoglycemia, and growth retardation. The average FGF21 level across all patients was 318.3 ± 126.9 pg/mL, with the highest levels observed in patients with GSD type IXc (464.31 ± 112.88 pg/mL), followed by those with type IXa (343.35 ± 137.18 pg/mL) and type III (323.80 ± 116.04 pg/mL). Patients with GSD type IXc had significantly higher FGF21 levels than those with other subtypes (p=0.001). Conclusions This is the first study to evaluate FGF21 levels in patients with GSD. FGF21 levels in this cohort were comparable to those observed in patients with acute fatty liver disease and hepatosteatosis. Although no statistically significant differences were observed across most GSD subtypes, patients with GSD type IXc exhibited notably higher FGF21 levels, indicating that FGF21 may serve as a biomarker for identifying more severe phenotypes of GSD.

Objectives Remote physical activity programs have emerged as a promising strategy to improve adherence to exercise guidelines, specifically among pediatric patients with obesity. This study investigated the effectiveness of in-person vs. virtual supervised training in improving cardiometabolic health in children and adolescents with obesity. Methods Forty-six children and adolescents (BMI z-score ≥ 2SD; aged 8–16) were enrolled and assigned to either in-person or virtual supervised combined training. All participants underwent a 12-week, thrice-weekly exercise program (36 sessions total), and the metabolic syndrome (MetS) z-score was used to assess metabolic risk. Results Both virtual and in-person supervised training programs resulted in improvements in the primary outcome, the MetS z-score, within each group. The virtual group showed a mean reduction of −0.26 (p=0.014), while the in-person group showed a greater reduction of −0.44 (p<0.001). Both interventions also improved waist-to-height ratio and blood pressure (p<0.01). Only the in-person group showed significant reductions in fasting glucose (p<0.001), triglycerides (p<0.001), and BMI z-score (p=0.004). The virtual group showed a greater improvement in diastolic blood pressure (p<0.01). Conclusions Both in-person and virtual exercise programs positively impact cardiometabolic health in children with obesity. The research supports the potential of remote exercise programs to enhance adherence to physical activity.

Objectives We aimed to determine the effect of high-dose cholecalciferol supplementation starting soon after diagnosis on residual β-cell function (RBCF) and partial remission (PR) rates in children with type 1 diabetes (T1D). Methods A prospective, randomized, open-label study was conducted in children aged 2–12 years with newly-diagnosed T1D. Cases received additional cholecalciferol (60,000 IU every fortnight) for six months, while age-matched controls received standard care. Primary outcome variables included change in RBCF (measured by stimulated C-peptide, SCP) and the proportion of patients with PR (insulin dose-adjusted HbA 1c , IDAA1c ≤9.0 %) at study endpoint. Secondary outcomes included change in mean daily insulin dose (DID) and mean HbA 1c levels. Results The mean serum vitamin D concentrations achieved in cases (n=32, mean age 7.2 ± 2.8 years) were higher at 6 months (44.91 ± 5.36 vs. 24.87 ± 4.10 ng/mL, p<0.001). Compared to controls (n=31, mean age 6.6 ± 2.5 years), children receiving vitamin D exhibited a slower decline in SCP levels (mean decrease −0.28 ± 0.10 vs. −0.50 ± 0.10 ng/mL, p<0.001). The mean decrease in IDAA1c was higher in cases (−11.1 ± 0.56 %) compared to controls (−10.1 ± 0.52 %), but the difference in mean decrease (−1.1 ± 0.61) did not attain statistical significance (p=0.08). At 6 months, PR rates were significantly higher in cases compared to controls (19, 59.4 % vs. 6, 19.4 %, p<0.001). Regression analysis revealed baseline SCP as strong predictor of SCP at the study endpoint (r=0.92, p<0.001). Conclusions High-dose vitamin D supplementation may preserve RBCF and prolong PR in children with newly diagnosed T1D. Large-scale randomized controlled trials are warranted.

Objectives This study aims to characterize the clinical spectrum of pediatric adrenocortical tumors (P-ACTs) in individuals aged <20 years and to compare the distinguishing features of pediatric adrenocortical adenomas (P-ACAs) and carcinomas (P-ACCs). Methods This retrospective study consisted of P-ACT patients who presented to our institute over the past 24 years (2001–2024). They were categorized as P-ACC or P-ACA based on Wieneke score. Data on clinical presentation, hormonal evaluation, imaging, management, and outcomes were recorded. Results A total of 30 (22 females) P-ACT patients (7 P-ACA and 23 P-ACC) were identified. The median age at presentation was 7 (range, 1.0–20) years, with a median symptom duration of 6.0 months (range 0.6–42 months). All patients, except one 16-year-old having P-ACC, had hormonal hypersecretion. Cortisol and androgen co-secretion was most common (56.6 %), followed by isolated cortisol (26.6 %) and androgen hypersecretion (13.3 %). On steroid profiling by LCMS/MS, P-ACC patients had raised levels of multiple steroid metabolites (6–9) as compared to P-ACA (2–5). P-ACA patients were relatively older (17.0 vs. 6.0 years, p=0.045), more often had isolated cortisol secretion (57.1 vs. 17.3 %, p=0.060), had smaller tumors (2.8 vs. 8.5 cm, p=0.002), a lower incidence of calcification (0 vs. 80 %) and a lower percentage venous enhancement (PVE 109.6 vs. 187.8 %, p=0.008) and achieved higher disease remission rates (100 vs. 21.4 %, p=0.005). Conclusions CECT features, particularly PVE, may aid in differentiating P-ACT from P-ACC. Serum steroid panels may have a role in preoperative assessment, but their utility remains to be validated.

Objectives To investigate the association between free and total 25(OH)D levels and fetal growth during pregnancy, and to evaluate whether free 25(OH)D is a better indicator of vitamin D status compared to total 25(OH)D. Methods A total of 160 pregnant women and their newborns were consecutively recruited from a Jiangsu hospital (March–May 2019). Maternal blood was collected before delivery, and cord blood was collected after umbilical cord disconnection. Serum free and total 25(OH)D were measured by ELISA. Clinical data, including pregnancy records, neonatal assessments, and 6-month follow-ups, were extracted from electronic medical records. Associations between vitamin D levels and developmental outcomes were analyzed using univariate correlation analysis and multivariable linear regression in SPSS 20.0 (p<0.05). Results Maternal-umbilical free 25(OH)D correlation was stronger than total (rho=0.699 vs. 0.475; both p<0.001). Maternal free 25(OH)D showed stronger associations with early pregnancy femur length (11.37 ± 3.39 mm; β=2.053), late pregnancy biparietal diameter (82.65 ± 4.60 mm; β=−0.273), and femur length growth efficiency (0.89 ± 0.15 mm/week; β=−0.289) than total 25(OH)D (all p<0.05). Umbilical free 25(OH)D correlated with mid-pregnancy transverse cerebellar diameter (22.0[21.0–23.0] mm; β=−0.231) and femur length growth efficiency (0.92[0.78–1.05] mm/week; β=−0.224) (p<0.05 and p<0.01). Maternal free 25(OH)D negatively associated with late pregnancy head circumference (330.11 ± 7.89 mm; β=−9.050, p<0.01). Conclusions Compared to total 25(OH)D, free 25(OH)D in maternal and umbilical blood may be more strongly associated with early-life physical growth parameters.

Objectives This study retrospectively evaluated long-term clinical and biochemical findings in children and adolescents diagnosed with Hashimoto’s thyroiditis (HT). Methods A total of 233 patients aged 2–18 years, diagnosed with HT and followed for at least three years, were included. Patients were classified into five subgroups based on thyroid stimulating hormone (TSH) and free thyroxine (fT4) levels at diagnosis. Clinical, laboratory, and radiological findings at baseline and during follow-up were analyzed. Results The most common initial thyroid status was subclinical hypothyroidism (SCH) (39.5 %), followed by euthyroidism (36.5 %), overt hypothyroidism (OH) (18.5 %), subclinical hyperthyroidism (3.9 %), and overt hyperthyroidism (1.7 %). Data from 173 patients were available at the third and fifth years. Total of 48.4 % of patients were monitored without treatment, 47.6 % were initiated on levothyroxine and 3 % were initiated on methimazole. Among OH patients, 9 % became euthyroid over time and discontinued treatment. Levothyroxine was initiated in 73.6 % of SCH patients, but only one discontinued treatment due to normalization. Among 63 untreated patients following for five years, no functional deterioration was observed. While autoantibody levels remained stable across all groups at year three, both TPO-Ab and TG-Ab levels significantly decreased by year five (p=0.000). Conclusions Given its dynamic nature, HT requires continuous monitoring through regular clinical assessments and thyroid function testing.

Objectives 45, X/46, XY mosaicism is a complex chromosomal difference of sexual development, commonly associated with 45, X/46, XY karyotype. It presents a broad phenotypic spectrum, creating challenges in gender assignment. This report examines the management of a child with 45, X/46, XY mosaicism diagnosed in middle childhood, assigned female at birth but later exhibiting gender incongruence, highlighting dilemmas in pubertal induction after prophylactic gonadectomy. Case presentation An 8-year-old female presented with differences in sexual development (DSD) following maternal concerns regarding genital appearance. Genetic investigations confirmed a 45, X/46, XY karyotype, leading to bilateral gonadectomy due to malignancy risk. By age 11, the child expressed alignment with being a boy while reluctantly being perceived as a girl. The absence of endogenous sex hormones following gonadectomy will complicate pubertal induction as there is incongruency between the child’s gender preference and the sex of rearing. Conclusions Limited guidance exists on managing gender incongruence in DSD, particularly regarding pubertal induction. In the UK, while sex assignment at birth is mandated, there is no specific guidance regarding the revision of sex assignment in childhood. A non-coercive environment is essential to support gender exploration whilst balancing medical, psychological, and ethical considerations in decision-making regarding pubertal induction.

Objectives Steroid cell tumors are very rare in children. During the past 25 years, only 3 cases have been reported in Germany. Symptoms may vary from virilization to signs of precocious puberty and increased growth velocity, making it diagnostically challenging. Due to rarity and the wide morphologic as well as differential diagnostic spectrum, initial clinical features may be misleading. Case presentation We report on a 2-year-old girl, who initially presented with symptoms of virilization and precocious puberty, i.e., pubertal hair growth equivalent to Tanner stage P3. Basal hormone profile yielded 10-fold increased testosterone and androstenedione as well as markedly increased estradiol levels in serum. Diagnostic imaging procedures (ultrasound, MRI of the abdomen) revealed a solid tumor in the left ovary, without any signs of peritoneal dissemination or metastases. After salpingo-oophrectomy of the left ovary (en bloc via laparoscopic surgery, without spillage), the diagnosis of an ovarian steroid cell tumor sized 40 × 25 × 22 mm producing both testosterone and estradiol was confirmed. The increased serum levels of androgens as well as estradiol decreased toward prepubertal values within 1 week after surgery. Conclusions Hormone-active steroid cell tumors of the ovary are extremely rare in infancy. In our patient, the tumor was classified as clinical stage Ia. We thus opted for clinical, biochemical, and sonographical controls without chemotherapy. We herein present follow-up data until 18 months after surgery and discuss them within the context of international literature.

Objectives Traditional daily recombinant human growth hormone injections can be burdensome for patients and caregivers, leading to compliance issues. Long-acting growth hormone formulations have been developed to overcome these challenges. Case presentation We report a 7-year-old girl who developed severe lipoatrophy secondary to repeated somatrogon injections at the same anatomical site during the third month of therapy, with complete resolution after 10 weeks of treatment discontinuation. Conclusions To our knowledge, this is only the second reported case of somatrogon-induced lipoatrophy in the literature. This case also showed that lipoatrophy developing as a result of somatogron treatment is a reversible side effect.

Objectives Somatotropinomas are extremely rare in children and frequently associated with genetic causes. Among pituitary gigantism, approximately 30 % are attributed to the aryl hydrocarbon receptor-interacting protein ( AIP ) gene mutations, whereas other genetic causes are less common. These mutations cause more aggressive tumors that are challenging to control with a single intervention and often exhibit resistance to somatostatin analogs (SSAs). Our aim is to present a pediatric patient with a somatotropinoma due to a novel AIP variant who responded positively to SSA therapy following a single surgical intervention. Case presentation A 15-year and 8-month-old male patient presented with complaints of excessive height and enlargement of the hands and feet over the past 2 years. Laboratory investigations revealed a random growth hormone level of 50 μg/L (normal range [NR]: 0.077–10.8) and insulin-like growth factor-1(IGF-1) level of 1,107 ng/mL (age-adjusted NR: 224–978/>+2 standardised deviation scores). Magnetic resonance imaging demonstrated a pituitary macroadenoma extending into the suprasellar region. A craniotomy was performed, and the majority of the tumor was resected. Due to the presence of residual tumor, SSA therapy (octreotide-LAR) was initiated. After 1 year of follow-up, IGF-1 levels returned to the normal range, and tumor growth was controlled. Genetic analysis identified a heterozygous frameshift novel variant (c.25delC, p.(Arg9Glyfs*9)) in the AIP  gene. Conclusions Although AIP mutation-positive cases are typically resistant to SSAs, our patient carrying a novel AIP variant demonstrated a favorable response to SSA treatment.