Medical management with methimazole (MMI), an antithyroid drug, is the first-line treatment for pediatric Graves’ disease. However, if severe side effects develop, MMI should be stopped immediately, inorganic iodine administered to prevent worsening thyrotoxicosis, and surgical intervention performed without delay. We report a case of thyroid storm induced by inorganic iodine escape phenomenon in a 13-yr-old girl diagnosed with probable Graves’ disease who was initially treated with MMI. She presented with a severe rash and dyspnea, which were considered side effects of MMI. After MMI was discontinued and inorganic iodine monotherapy was initiated, she was transferred to our hospital. Although her thyroid function had generally improved at that time and a total thyroidectomy was recommended, her family declined surgical intervention. Subsequently, she developed thyroid storm and, after receiving treatment with steroids and high-dose iodine, underwent a total thyroidectomy once her condition had stabilized. In this case, the escape phenomenon occurred during the same treatment period as that reported in a previous study on iodine monotherapy. Furthermore, this case indicates that high-dose iodine administration may be effective even during a thyroid storm following iodine escape.

The endocrine behavior of residual ovarian tissue following testis‑preserving surgery in ovotesticular disorders of sex development (DSD) during adolescence remains poorly characterized. We report an adolescent male who presented with Tanner stage B4 gynecomastia despite male‑typical external genitalia. Baseline evaluation revealed elevated gonadotropins, relative hyperestrogenism (estradiol 58.7 pg/mL), and SRY‑negative chromosome mosaicism (47,XX,+der(8)/46,XX). Pelvic imaging demonstrated a small prostate and bilateral intratesticular cysts, and laparoscopy and cystoscopy confirmed a male internal phenotype without Müllerian structures. Because firm intratesticular foci suggested the presence of ovarian tissue, testis‑preserving partial gonadectomy was performed. Histopathological examination revealed bilateral ovotestes, with ovarian follicles adjacent to seminiferous tubules and no OCT3/4‑positive germ cells. Postoperatively, estradiol levels initially decreased but later showed intermittent fluctuations in parallel with testosterone, suggesting hormonal activity from a small residual ovarian remnant. Gynecomastia gradually regressed, bone mineral density remained normal, and serial testicular MRI findings were stable. This case demonstrates that even minimal residual ovarian tissue can remain hormonally active after testis‑preserving surgery in ovotesticular DSD and influence pubertal hormonal dynamics, highlighting the importance of careful long‑term postoperative surveillance with hormonal evaluation and targeted imaging.

Graves’ disease (GD) is the most common cause of hyperthyroidism in children and adolescents. When remission is not achieved with antithyroid drugs, definitive treatment with radioiodine therapy (RAI) or thyroidectomy is recommended. We conducted a structured literature review of studies indexed in PubMed/MEDLINE to evaluate the efficacy and safety of these approaches in the paediatric population. Twenty-one studies including 9,490 patients were analysed. RAI achieved high remission rates (85–96%), with hypothyroidism representing the expected therapeutic outcome. Thyroidectomy provided definitive disease control in the vast majority of patients, with recurrence mainly associated with subtotal procedures. The most frequent surgical complication was transient hypocalcaemia (16.9%), while permanent hypoparathyroidism was rare (0.79%). RAI was generally associated with infrequent reported adverse events, such as transient sialadenitis, and long-term data did not show increased risks of malignancy or reproductive complications. Overall, available observational evidence suggests that both RAI and total thyroidectomy are effective definitive treatments for paediatric GD. In the absence of randomized comparative studies, treatment choice should be individualized according to patient age, thyroid characteristics, institutional expertise, and patient and family preferences.

Congenital hyperinsulinism (CHI) is a rare disorder resulting in hypoglycemia due to increased insulin secretion and is subdivided into focal and diffuse forms. CHI is associated with neurological damage due to hypoglycemia, making adequate blood glucose management crucial. Although subcutaneous octreotide injection can effectively treat CHI, frequent octreotide administration may be burdensome for patients. Here, we describe a boy with early neonatal-onset persistent CHI treated with octreotide long-acting release (LAR). At first, he received treatment with continuous glucose infusion, diazoxide, and glucagon. Genetic analysis revealed the patient was a compound heterozygote for ABCC8, with diffuse form predicted. Although the focal form can be treated by surgery, the diffuse form requires long-term drug therapy. Therefore, he was treated with octreotide subcutaneous injections and subsequently transitioned to octreotide LAR to avoid the inconvenience of frequent injections. He has been receiving octreotide LAR for four years and has not experienced developmental delays or any apparent side effects, such as necrotizing enterocolitis. The dosing interval can be extended without increasing hypoglycemia. Octreotide LAR reduced the burden on the patient and his family. Octreotide LAR can be an effective long-term treatment for CHI. However, further cases are needed for verification.

Chromosomal deletions involving several disease-associated genes exhibit diverse phenotypes. HNF1A is one of the causative genes of maturity-onset diabetes of the young. Furthermore, heterozygous variants in DHX37 and SETD1B, located near HNF1A, cause 46,XY disorders of sex development and syndromic neurodevelopmental disorders, respectively. This study describes a 12-yr-old boy with a 12q24.31–32 chromosomal deletion involving HNF1A, DHX37, and SETD1B. The boy was born small-for-gestational age, and experienced seizures, autism spectrum disorder, hearing loss, short stature, and intellectual disability. At five years of age, an 8.6-Mb chromosomal deletion at 12q24.31–32 was identified by array-based comparative genomic hybridization. At 12 yr of age, he developed islet autoantibody-negative diabetes. As the deletion region identified included HNF1A, this suggested that it is a cause of diabetes. Furthermore, SETD1B was considered to be a cause of intellectual disability and autism spectrum disorder. Owing to his intellectual disability, self-management of hypoglycemia was challenging; thus, nateglinide and insulin therapy were deemed effective for diabetes management rather than sulfonylurea drugs. Furthermore, DHX37 haploinsufficiency was considered a cause of hypogonadism. These findings emphasize the importance of diabetes management tailored to the characteristics of children with intellectual disabilities and the potential for hypogonadism due to DHX37 haploinsufficiency.

Hypochondroplasia is a skeletal dysplasia characterized by disproportional short stature with rhizomelic limb shortening, caused by pathogenic variants of FGFR3, most frequently the p.Asn540Lys variant. However, affected individuals harbor a wide variety of pathogenic variants, accounting for the broad phenotypic spectrum of the disorder. Despite being closely related to achondroplasia, hypochondroplasia is a milder condition that was previously believed to be recognizable only in childhood, but not in infancy. However, the widespread use of prenatal ultrasonography and frequent diagnosis of fetal limb shortening have increased the number of hypochondroplastic neonates identified, thereby clarifying the early radiographic findings of the disorder. Radiological diagnosis of hypochondroplasia in children carrying the p.Asn540Lys variant is currently feasible in the neonatal period or even prenatally, using three-dimensional CT. Conversely, some individuals have a mild phenotype with minimal skeletal abnormalities, which hampers the differential diagnosis of hypochondroplasia and constitutional short stature. For a definitive diagnosis, genetic testing for FGFR3 is recommended. This diagnostic guide aims to assist in the early recognition of hypochondroplasia and to facilitate the management of affected children.

Idiopathic short stature (ISS) is a provisional clinical label rather than a final diagnosis. This narrative review (2000–2026) synthesizes how genomic findings intersect with neuroimaging, IGF-1 biology, and GH responsiveness. Diagnostic yield varies by modality: candidate-gene (4.7%), chromosomal microarray (16.3%), multigene panels (21.6%), and exome sequencing (33.3% overall; 15.1% isolated). These estimates decrease if variants of uncertain significance (VUS) are excluded. Recurrent genes include ACAN, NPR2, SHOX, IHH, FGFR3, IGF1R, and PAPPA2. Study comparisons are limited by heterogeneous definitions and neuroimaging selection bias. While major structural hypothalamic-pituitary lesions are uncommon in ISS, pituitary size overlaps significantly with both controls and GH deficiency. GH response is genotype-dependent; SHOX deficiency typically shows robust gains, while ACAN variants yield more modest, sustained responses. ISS should be managed as a heterogeneous working phenotype. A clinically effective approach integrates careful phenotyping, selective MRI, explicit separation of pathogenic findings from VUS, and genotype-informed counseling regarding prognosis and treatment response

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.