We aimed to determine insulin levels and the homeostasis model assessment of insulin resistance (HOMA–IR) index in a cohort of children with isolated premature pubarche, to analyze the potential influence of adiposity, and to compare these parameters with those of a reference population. This study included 50 prepubertal patients with isolated premature pubarche between the ages of 5 and 8 yr (girls) and up to 9 yr (boys). Anthropometric parameters, abdominal circumference, body composition assessed by bioelectrical impedance analysis, and bone age were evaluated. Blood glucose, lipid profile, insulin, IGF-1, and androgen levels were measured. Standard deviation scores for insulin and the HOMA–IR index were calculated using age- and sex-specific reference values for our population.Among the participants, 76% were girls, and 20% had obesity. Insulin levels and the HOMA–IR index in normal-weight patients were similar to the population mean, whereas they were significantly increased in patients with excess adiposity. Higher levels were also observed in children who were formula-fed at birth compared with those who were breastfed, and in those with advanced bone age compared with those with bone age appropriate for chronological age; in both cases, this association was mediated by adiposity. The increase in insulin levels and the HOMA–IR index in patients with isolated premature pubarche appears to be influenced by adiposity.

Pathogenic variants in the insulin receptor gene (INSR) cause a broad spectrum of metabolic disorders, from severe insulin resistance to milder phenotypes such as hyperinsulinemic hypoglycemia. We describe a preterm female neonate with persistent, asymptomatic hyperinsulinemic hypoglycemia, characterized by markedly elevated insulin and C-peptide levels with suppressed ketones. Genetic testing revealed two novel, maternally inherited heterozygous INSR variants in cis, c.3541A>C p.(Thr1181Pro) and c.3566A>C p.(Tyr1189Ser), located in the tyrosine kinase domain. The infant remains clinically stable without pharmacological treatment and demonstrates normal growth and development. Her 7-yr-old brother, carrying the same variants, is asymptomatic but shows relatively increased insulin responses during oral glucose tolerance testing, while the mother developed insulin-resistant diabetes in early adulthood. This family highlights the age-dependent phenotypic variability associated with the same INSR variants, ranging from neonatal hyperinsulinemic hypoglycemia to childhood hyperinsulinemia with euglycemia and adult insulin resistance. These observations expand the clinical spectrum of heterozygous INSR variants and underscore the influence of residual receptor activity, age, and metabolic demands on disease expression. Early genetic testing in infants with even mild hyperinsulinemic hypoglycemia is important for prognosis, family screening, and long-term follow-up to detect evolving insulin resistance.

Noonan syndrome (NS) is a multisystem RASopathy marked by characteristic facies, congenital heart disease, short stature, and variable neurodevelopmental and systemic complications. Although molecular and clinical knowledge has advanced, evidence-based clinical guidance in Japan has been limited. A multidisciplinary committee in pediatric endocrinology, clinical genetics, and pediatric cardiology developed consensus guidelines on diagnosis, comorbidity assessment, treatment, and transitional care. Clinical questions were defined, and the literature published through March 2024 was systematically reviewed. Evidence was graded in partial accordance with the Minds Clinical Practice Guideline Development Manual 2020 and the GRADE framework, with expert consensus supplementing areas of limited evidence. External review included patient groups and academic societies, and the guideline was approved in 2025. The guideline recommends expanding diagnostic panels to include LZTR1, SOS2, MRAS, RRAS, and RRAS2 in addition to established genes. It advises comprehensive childhood assessment for tumor predisposition, coagulation abnormalities, hearing and ophthalmologic problems, neurodevelopmental features, and endocrine and cardiovascular complications, with strong emphasis on cardiac evaluation. Growth hormone therapy is recommended for short stature with careful monitoring for malignancy risk. MEK inhibitors may help selected patients with refractory hypertrophic cardiomyopathy or lymphatic abnormalities. Lifelong multidisciplinary surveillance and structured transition to adult care are strongly emphasized.

Hypophosphatasia (HPP) is a rare osteometabolic disease. Enzyme replacement therapy (ERT) for HPP was approved in 2015 and has significantly improved the survival and quality of life of patients. Poor responses to ERT have been reported; however, detailed information is limited. We encountered a case of severe perinatal HPP refractory to ERT with neutralizing antibody (NAb) expression that possibly affected bone mineralization. Asfotase alfa (AA) (6 mg/kg/wk) was initiated 2 mo after birth and resulted in complete resolution of rickets by age 7 mo. However, rickets recurred at age 18 mo without any other identifiable cause than NAbs detected. The AA dose was increased to 9 mg/kg/wk based on the United States prescribing guidelines when the patient was age 3 yr. By ages 4 yr and 8 yr, rickets in the upper limbs and lower limbs, respectively, had nearly disappeared. NAbs were not detected at age 6 yr. We reduced the AA dose (6 mg/kg/wk) at age 8 yr. Rickets recurrence was not observed. Changes in bone mineralization corresponded to NAb expression, suggesting that NAbs may have influenced the therapeutic effect. The optimal AA dose may vary based on clinical findings and the NAb status.

Concerns regarding linear growth and dysmorphic features are common in several genetic syndromes. Among these, PTHLH-related brachydactyly type E (BDE), which is inherited in an autosomal dominant manner, is a rare but distinct genetic disorder. This condition is caused by heterozygous variants in the PTHLH gene, which encodes a parathyroid hormone-related protein, a key regulator of endochondral bone development. To date, very few cases of this condition have been reported. Here, we describe a case of a PTHLH gene variant (heterozygous for c.54C>G p.Tyr18Ter) in an Indian boy who presented with linear growth problems, BDE, and subtle dysmorphism. This case underscores the importance of genetic evaluation to clarify ambiguous clinical presentations and guide appropriate management strategies. This detailed phenotypic characterization of the early truncating PTHLH variant p.Tyr18Ter expands the clinical spectrum associated with PTHLH haploinsufficiency.

We have previously published efficacy and safety data up to 24 mo of GH treatment (0.35 mg/kg/wk) for SHOX-related short stature in 19 Japanese pediatric patients before pubertal entry (jRCT2080223889). Here, we report similar efficacy and safety data up to 48 mo obtained by an extension study for the same 19 patients before and after pubertal entry. The height SDS for chronological age (CA) was increased during the study period in 18 of the 19 patients and exceeded –2.0 in 17 of the 19 patients at the latest visit. Height velocity obviously increased in the first year. Bone age (BA) progressed faster than CA, and ΔBA/ΔCA remained above 1.0 throughout the study period. Serum IGF-1 SDS increased during the first 12 mo and remained relatively stable thereafter. GH treatment was generally well-tolerated with no severe adverse events, although one patient showed a markedly high serum IGF-1 value which was coped with the reduction in GH dosage to 0.23 mg/kg/wk, and two patients manifested insulin resistance. While further studies are required to clarify the long-term efficacy and safety and adult height in GH-treated patients, the results argue for the beneficial effects of GH therapy in SHOX-related short stature.

We aimed to examine 25-yr trends in the incidence, age at diagnosis, seasonal variation, and frequency of diabetic ketoacidosis among children and adolescents with newly diagnosed type 1 diabetes mellitus in Serbia, before, during, and after the COVID-19 pandemic. This nationwide, multicentre, study included all individuals aged £ 19 yr diagnosed with T1DM between 2000 and 2024 across 15 paediatric centres in Serbia. Clinical characteristics were compared using parametric and non-parametric tests, as appropriate. A total of 4,335 new T1DM cases were registered. The incidence increased significantly from 9.7 per 100,000 in 2000 to 25.5 per 100,000 in 2021 (annual percent change (APC) 3.12%, p < 0.001). Among children aged 0–14 yr, incidence rose until 2016 (APC 4.14%, p = 0.01), followed by a plateau through 2024, suggesting possible stabilization in younger age groups. Monthly variations in the frequency of newly diagnosed T1DM cases did not reach statistical significance (p = 0.876). Overall, 42.4% of patients presented with DKA, with a marked rise during the COVID-19 pandemic (47.7%) and persistently higher post-pandemic levels compared with pre-pandemic years. Over 25 yr, Serbia experienced a steady increase in paediatric T1DM incidence with recent stabilization among younger children. DKA remains persistently high in post pandemic years.

Genetic defects in GNAS on the maternal allele cause pseudohypoparathyroidism type 1A (PHP1A) with PTH resistance. Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome caused by aberrant methylation in the KCNQ1OT1:transcription start site (TSS)-differentially methylated region (DMR). PHP1A and BWS exhibit postnatal overgrowth. Recently, multi-locus imprinting disturbance (MLID) has been observed in cases with BWS. Deleterious variants in genes encoding proteins that maintain CpG methylation at DMRs have been found in MLID cases and/or their mothers, and ZAR1 is supposed to be one of the MLID causative genes. In this study, we identified a patient with a deletion involving Gsα-coding region and MLID including hypomethylation of the KCNQ1OT1:TSS-DMR by genome-wide copy number variation analysis, genome-wide methylation analysis, and whole-exome sequencing. The patient’s mother had a deletion of the same region on the paternal allele and carried a ZAR1 missense variant considered benign. The patient exhibited severe infantile obesity with a body mass index greater than 33 kg/m² and PTH resistance due to the comorbidity of PHP1A and MLID including hypomethylation of the KCNQ1OT1:TSS-DMR. This study highlights the importance of screening for PHP1A and imprinting disorders with overgrowth, in cases with severe infantile obesity, and for MLID causative genes in MLID cases.

Hematopoietic stem cell transplantation (HSCT)-associated partial lipodystrophy (HSCT-PL) is a serious metabolic complication that develops in remote period among childhood cancer survivors treated with HSCT with total body irradiation (TBI). Since the first proposal in 2013, HSCT-PL seems to be increasingly recognized as a distinct disease entity. The patients with HSCT-PL show profound metabolic dysfunction including insulin resistance, diabetes, elevated triglycerides, and hepatic steatosis. Their body mass index is low–normal, although they show visceral fat accumulation and increased waist-to-hip ratio. In addition, HSCT-PL is characterized by Dunnigan phenotype: lipoatrophy in buttock and extremities combined with lipohypertrophy in face and neck. Although the precise pathogenesis is still obscure, radiation-induced damage to adipose progenitor cells, leading to accelerated senescence, seems to be a main pathway. Literature survey identified 17 patients of HSCT-PL with sufficient information from 12 reports. Among them, clear female predominance (15 females) and possible ethnic difference in disease prevalence (11 Japanese) were ascertained. Genetic factors may be involved in those epidemiological traits. There remains much to be clarified, including establishment of reliable diagnostic procedure, elucidation of long-term prognosis, and invention of effective treatment. Metreleptin is one of the promising options, and the accumulation of its therapeutic efficacy are warranted.

In recent years, the use of immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) has increased and has demonstrated excellent antitumor effects. However, immunotherapy in pediatric patients remains limited, and knowledge of endocrine-related adverse effects is scarce. Here, we report a pediatric case of hypothyroidism and adrenal insufficiency following treatment with a combination of ICI and TKI for renal cell carcinoma. Seven weeks after treatment initiation, laboratory tests revealed free thyroxine at the lower limit of the reference range (fT4 0.96 ng/dL) and elevated thyroid-stimulating hormone (TSH 20 µIU/mL), without clinical symptoms, consistent with hypothyroidism. Three months after treatment initiation, abnormally high early morning fasting ACTH levels were observed, and the patient subsequently developed nausea and fatigue. A rapid ACTH stimulation test revealed a peak cortisol level of 12.1 µg/dL, and urinary free cortisol was low (19.2 µg/d; 13.6 µg/m²/d), leading to a diagnosis of primary adrenal insufficiency. Hormone replacement therapy enabled the patient to continue the treatment. Given the limited number of reports on endocrine dysfunction in pediatric patients receiving combination therapy with ICIs and TKIs, this case highlights the importance of endocrine monitoring and management.

Central precocious puberty (CPP) is often treated with gonadotropin-releasing hormone (GnRH) analogs to manage compromised adult height and psychological distress. In Japan, only monthly formulations are available, and the perceived burden and satisfaction associated with long-term treatment have not been well described. We conducted a retrospective questionnaire survey among 78 girls with CPP who received leuprorelin acetate between 2012 and 2018. Patients and caregivers were asked about reasons for treatment initiation, perceived burden, and satisfaction with height-related and psychological outcomes. Thirty-six (46%) participants completed the questionnaire. Although treatment was initiated at a mean age of 8.86 yr, when the height benefit was limited, improving final height was the most common reason for treatment initiation. Despite monthly injections over an average of 3 yr, 63.9% of the respondents reported no treatment burden. Satisfaction was high, with 72% of the participants satisfied with the height-related outcomes and 74% satisfied with the psychological outcomes. A greater absolute height at the time of the questionnaire was correlated with higher satisfaction in both domains. These findings do not imply that GnRH treatment improves final height. Instead, patients and caregivers reported high satisfaction despite the limited objective height benefits, underscoring the importance of thorough counseling, expectation management, and individualized decision making in CPP management.

Breastfeeding is recommended as the ideal nutrient source for infants, with the benefit of reducing future metabolic risk. Rapid catch-up growth in infancy has been associated with increased later adiposity and cardiometabolic risk. Few studies have evaluated growth and feeding patterns in Japanese infants. This study aimed to clarify growth and feeding patterns in Japanese infants. Participants were children enrolled in the Japan Environment and Children’s Study cohort. Height, weight, and body mass index (BMI) at 3–4 and 8–12 mo, and 1, 1.5, 2, 2.5, and 3 yr were compared between three feeding patterns at 6 mo: breast-, formula-, and combination-feeding. The breast-, combination-, and formula-feeding groups comprised 19,987, 8,804, and 5,071 infants, respectively. In the combination-feeding group, measured indices at 3–4 mo were lower than in the breastfeeding group (p < 0.0001), although combination-fed infants showed catch-up growth from 8–12 mo to 1 yr (p < 0.05). Breastfed infants showed rapid growth and high BMI from birth to 3–4 mo, and slow growth and low BMI after 8–12 mo. Combination- and formula-fed infants showed slow growth in early infancy then rapid growth. Catch-up pattern observed in combination- and formula-fed infants warrants growth monitoring and access to individualized feeding support.

Hypophosphatasia (HPP) is a rare inherited metabolic bone disorder caused by pathogenic variants in the ALPL gene, with a wide clinical spectrum ranging from severe pediatric forms to mild adult-onset disease. In contrast, heterozygous variants in ACAN are a recognized cause of autosomal dominant short stature, often associated with advanced bone age and premature growth plate closure. We report a 16-yr-old girl evaluated for severe disproportionate short stature with growth arrest during early adolescence. Her medical history included benign childhood epilepsy, mild intellectual disability, and enamel abnormalities. Biochemical evaluation revealed persistently low serum and bone-specific alkaline phosphatase levels, while calcium–phosphate metabolism was otherwise normal. Genetic testing identified a heterozygous pathogenic ALPL variant (c.1426G>A; p.Glu476Lys), inherited from an asymptomatic father, consistent with autosomal dominant HPP with minimal clinical expression. Additionally, a maternally inherited ACAN variant of uncertain significance (c.511G>C; p.Ala171Pro) was detected. Based on phenotypic correlation and family segregation, the growth phenotype is more plausibly explained by ACAN-related growth plate dysfunction, while the ALPL variant likely represents an incidental or mildly expressed finding. This case highlights the importance of careful genotype–phenotype correlation and cautious interpretation of multiple genetic findings in the evaluation of severe short stature.