Background: Monogenic obesity comprises a group of rare genetic disorders characterized by severe early-onset obesity and hyperphagia. Pharmacological treatment options for severe early-onset obesity remain limited, particularly in young children. Case Presentation: We report two children younger than 6 years of age with severe early-onset obesity, including one with genetically confirmed monogenic obesity, who showed reductions in BMI-SDS during semaglutide treatment. Case-1: A 4.5-year-old girl with a homozygous ADCY3 (c.1102G>A) variant presented with severe obesity, hyperphagia, hypertension, hepatosteatosis and Blount’s disease. Baseline BMI was 48.0 kg/m2 (+5.5 SDS). Semaglutide was initiated at 0.125 mg/week and titrated to 1.5 mg/week. After 18 months, BMI-SDS decreased from +5.5 to +4.1 (-25.5%), accompanied by improved in hyperphagia and resolution of left ventricular hypertrophy. No significant adverse effects were observed, and linear growth remained age appropriate. Case-2: A 3.3-year-old boy with hyperphagia, severe obesity and dyslipidaemia was diagnosed with Klinefelter syndrome (47,XXY). Clinical Exome Sequencing identified no causative variant for obesity. Baseline BMI was 32.6 kg/m2 (+5.7 SDS). Semaglutide was initiated at 0.0625 mg/week and gradually titrated to 2.0 mg/week. After 21 months, BMI-SDS decreased from +5.7 to +4.4 (-22%). Treatment was generally well tolerated, with normal linear growth. Conclusion: This two cases describe reductions BMI-SDS during semaglutide treatment in very young children with severe early-onset obesity, including one child with genetically confirmed ADCY3-related monogenic obesity. These findings suggest a potential clinical benefit of semaglutide in this young population, warranting evaluation in larger studies.
Introduction: Thyroid nodules are less common and more likely to be malignant in children than in adults. Data on pediatric autonomous thyroid nodules (ATN) are scarce. Methods: Retrospective descriptive study. Twelve-year single-center case series of 12 patients (8 females) diagnosed with ATN at median age 15.7 years (3.6-17.3). A thirteenth patient with papillary thyroid carcinoma and hyperthyroidism was reported and described in the study but their data were not included in the descriptive statistics due to uncertainty regarding the autonomous nature of their nodule. Results: Over half the patients presented with a goiter and/or palpable nodule (72.7%). Symptoms of hyperthyroidism were present in 75%. Laboratory findings included suppressed serum TSH (100%). Free T4 was either normal (92.7%) or elevated (8.3%) with elevated total T3 (33.3%). Positive thyroperoxidase or thyroglobulin auto-antibodies were reported in three (25%) and one (8.3%) patients respectively. Two patients (16.7%) had TSH receptor antibodies at baseline. On ultrasound, thyroid nodule sizes were 2-4 cm (75%) or above 4 cm (25%). TIRADS scores were: 1 (8.3%), 2 (33.3%), 3 (8.3%), 4 (25%) or 5 (25%). Findings typical of ATN were detected in 10 of 11 patients (90.9%) on scintigraphy. Cytopathology was available on 8 nodules from 5 patients. Bethesda classifications were: II (n=2), III (n=3), IV (n=1), and V (n=1). Molecular analysis showed activating TSH receptor mutation in three of five tested patients. Ten patients completed surgery: total thyroidectomy (n=1) or lobectomy (n=9). Pathology was consistent with benign nodules in 9 cases. In one, the ATN was benign, but pathology detected incidental thyroid microcarcinoma in the same lobe. Conclusions: The presentation of children with ATN is highly variable. Clinical signs of hyperthyroidism may not be present initially and the interpretation of laboratory and imaging data could be complicated by confounding factors . Multicenter studies are needed to establish the frequency of malignancy in pediatric ATN and better understand its pathophysiology.
Introduction: Hyperglycemic hyperosmolar state (HHS) is a severe diabetic emergency, typically seen in adults with type 2 diabetes, but with high morbidity described in the limited pediatric cases available in the literature. Existing estimates of pediatric HHS incidence are primarily derived from administrative datasets and may be affected by diagnostic misclassification. We sought to determine the minimum incidence, clinical characteristics, management, and outcomes of pediatric HHS. Methods: Approximately 2,700 pediatricians and pediatric subspecialists were surveyed monthly from June 2023 through May 2025 to identify cases of pediatric HHS, via the Canadian Paediatric Surveillance Program. Cases were adjudicated using predefined biochemical criteria, including severe hyperglycemia, elevated serum osmolality (>320 mOsm/kg), and absence of significant acidosis. Detailed clinical data were collected for confirmed cases. Results: Twenty-four cases were reported during the 24-month surveillance period. Following case adjudication, seven cases met diagnostic criteria for HHS, corresponding to a minimum annual incidence of 0.059 cases per 100,000 child-years (95% CI 0.024–0.122). Median age at presentation was 14.8 years, and all cases occurred in individuals with newly diagnosed or previously unrecognized diabetes. Common precipitating factors included infection, trauma, and surgery. Most patients required intensive care admission, with a median hospital stay of six days. Frequent complications included acute kidney injury and hypokalemia, and one patient required intervention for suspected cerebral injury, although no deaths were reported. Half of initially reported cases were subsequently reclassified as hyperosmolar diabetic ketoacidosis, highlighting challenges in the recognition and classification of pediatric hyperglycemic emergencies. Conclusion: National surveillance in Canada identified lower incidence of HHS, indicating that prior estimates based on administrative data likely overstate rates due to misclassification of hyperglycemic emergencies.
Congenital generalized lipodystrophies (CGL) are genetic disorders characterized by generalized lipoatrophy and severe metabolic complications. Neonatal diagnosis remains uncommon because the typical phenotype may not yet be fully established. We report a preterm female neonate presenting with rapidly progressive bilateral cervical, axillary, and inguinal masses. Imaging and histopathological examination identified prominent immature brown adipose tissue. Severe hypertriglyceridemia prompted suspicion of CGL, which was subsequently confirmed by identification of a homozygous pathogenic AGPAT2 variant. During follow-up, generalized lipoatrophy, insulin resistance, and hepatic steatosis progressively developed, whereas the brown adipose tissue deposits completely regressed by 8 months of age. Nutritional management with a medium-chain triglyceride-enriched formula resulted in marked metabolic improvement. This case highlights that prominent immature brown adipose tissue associated with severe neonatal hypertriglyceridemia may represent an early manifestation of CGL1 and should prompt early genetic investigation.
Introduction: NR5A1 encodes steroidogenic factor 1 (SF-1), a key regulator of adrenal and gonadal development, steroidogenesis, AMH transcription, and the balance between pro-testicular and pro-ovarian pathways. The recurrent NR5A1 c.274C>T (p.Arg92Trp) variant is associated with SRY-negative 46,XX testicular and ovotesticular differences in sex development (DSD), but intrafamilial expression remains difficult to predict. Case Presentation We report a rare multigenerational familial presentation of SRY-negative 46,XX ovotesticular DSD associated with the heterozygous NR5A1 p.Arg92Trp variant. The proband was noted antenatally to have atypical genital development. Antenatal karyotyping confirmed a 46,XX, SRY-negative result. At birth, the proband had clitoromegaly, posterior labioscrotal fusion, a perineal urethral opening, absent vaginal opening, and palpable labioscrotal gonads. Testosterone, anti mullerian hormone (AMH), and inhibin B were elevated, consistent with functioning testicular tissue, while adrenal investigations were normal. Imaging and laparoscopy showed mixed Müllerian and Wolffian structures, and gonadal histology confirmed ovarian primordial follicles. The family history was notable for DSD in the mother’s sister, who had undergone childhood genital surgery and gonadectomy, with histology showing intratubular germ cell neoplasia. She was the first family member found to carry the NR5A1 p.Arg92Trp variant, prompting targeted testing in the proband and her mother, both of whom were positive. The variant was subsequently identified in the maternal grandmother and in the proband’s older 46,XX, SRY-negative brother, who was raised male and had typical male external genitalia with bilateral scrotal gonads; the mother’s brother tested negative. The mother had previously been treated for a unilateral ovarian germ cell tumour. These findings demonstrate marked intrafamilial variability and highlight the importance of family-history-led genetic testing, tumour-risk assessment, and long-term multidisciplinary follow-up. Conclusion: This family captures the striking phenotypic breadth of NR5A1 p.Arg92Trp within a single pedigree and illustrates the role of NR5A1 as a developmental regulator of gonadal fate and AMH-mediated ductal differentiation. It emphasises the need for cautious individualised management, tumour surveillance, long-term follow-up, genetic counselling, and psychological support.
