Central precocious puberty (CPP) results from the premature activation of the hypothalamic-pituitary-gonadal (HPG) axis. Although the GnRH stimulation test remains the gold standard for diagnosis, the uterine artery pulsatility index (PI) has been proposed as a functional indicator of pubertal activation. The aim of this review, which included 11 studies and 1,151 patients, was to summarize the current evidence regarding the diagnostic role of uterine artery PI in CPP evaluation. A consistent inverse relationship was observed between the PI and pubertal progression. The reported PI sensitivity for detecting pubertal onset ranges from 77% to 100%, while the specificity varies between 48% and 100%, depending on the cutoff values and study populations. Diagnostic accuracy improved when the PI was combined with uterine morphometric parameters. In girls with CPP undergoing GnRH agonist therapy, the PI increased significantly during treatment, suggesting its potential role as a marker of therapeutic response. Thus, uterine artery PI represents a physiologically plausible and clinically informative adjunctive tool that suggests HPG axis activation. Although not suitable as a stand-alone diagnostic test, its integration into a multimodal diagnostic framework may enhance the non invasive evaluation and monitoring of CPP.
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.
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.
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.
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.
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.
Vitamin D deficiency and rickets are important pediatric health concerns, particularly in high-latitude regions. This study investigated the incidence and clinical characteristics of pediatric vitamin D deficiency in Hokkaido, Japan, between 2015 and 2019. A cross-sectional survey was distributed to the pediatric departments of 88 major hospitals across the region, achieving a response rate of 97.7%. Clinical data were collected from 262 children with vitamin D deficiency (25(OH)D < 20 ng/mL), including 153 with rickets. In 2019, the incidence of vitamin D deficiency rickets was 25.4 per 100,000 live births, approximately threefold higher than 15 yr earlier and eightfold greater than the national average. Most cases (median age 1.4-1.5 yr) occurred in children younger than four years. Patients with rickets exhibited considerably lower Ca/P and higher ALP/iPTH levels than those without rickets, despite having similar 25(OH)D levels. Exclusive breastfeeding was significantly more common in the rickets group. Approximately 90% of patients received alfacalcidol. The incidence of pediatric vitamin D deficiency and rickets in Hokkaido has increased. These findings underscore the need for continued public health education on vitamin D intake, expanded access to native vitamin D supplementation, and attention to maternal vitamin D status.
Fetal alcohol syndrome (FAS) is associated with persistent growth retardation, but the long-term efficacy of GH therapy for FAS-related short stature remains unclear. A Japanese girl born at 37 wk with birth weight 2,064 g (-2.1 SD) and birth height 41.5 cm (-2.7 SD) was diagnosed with FAS based on characteristic facial features, growth failure, developmental delay, and documented maternal alcohol consumption (120 g/d during pregnancy). She scored 4434 on the FASD 4-Digit Diagnostic Code. At 3 yr of age, her height was 78 cm (-4.18 SD) with poor growth velocity. GH therapy was initiated at 0.19 mg/kg/wk, increased to 0.23 mg/kg/wk, and gradually increased to 0.43 mg/kg/wk. After 7 yr of treatment, serum IGF-1 levels increased significantly from 59 ng/mL (-2.5 SD) at baseline to 306 ng/ mL (+2.0 SD) at 8 yr, but height SD scores remained around -4 SD with growth velocity fluctuating between -3 and 0 SD. No adverse effects were observed. While GH therapy appears safe in FAS patients, its efficacy for improving linear growth is limited, suggesting that growth impairment in FAS involves mechanisms beyond GH deficiency, including growth plate dysfunction and peripheral GH resistance.
Diabetic ketoacidosis (DKA) may be complicated by acute kidney injury (AKI). While the pharmacokinetics of insulin degludec were previously suggested to be stable even in chronic kidney disease, its safety profile in acute or dynamic renal dysfunction remains unclear. We herein report a 13-yr-old boy with severe DKA complicated by AKI, who developed prolonged hypoglycemia after switching from continuous intravenous regular insulin to subcutaneous insulin aspart and insulin degludec. Insulin degludec was initiated, although the patient was no longer acidotic, during a period when his serum creatinine level was still rising. The patient repeatedly became hypoglycemic, which required the interruption of basal insulin for 8 d. In retrospect, the decision to initiate long-acting insulin during AKI was made in accordance with standard DKA protocols, without sufficient consideration of the deteriorated clearance of insulin degludec under impaired renal function. This case highlights the need for caution when initiating long-acting insulin analogues in patients with AKI, even in the post-DKA phase. Further studies are needed to elucidate insulin pharmacokinetics during non-steady-state renal impairment.
