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Introduction: Precocious puberty (PP), which is sometimes divided into gonadotropin-dependent or gonadotropin-independent PP, is a pathological condition characterized by premature secretion of gonadal steroids resulting in the early development of secondary sexual characteristics. Girls younger than 6 years with idiopathic gonadotropin-dependent PP (referred to as central PP or CPP) who receive gonadotropin-releasing hormone analog (GnRHa) therapy experience an increase in their adult height (AH) in contrast to girls who are aged 6 years or more, who show no consistent pattern of increase even with GnRHa therapy., Methods: In total, 133 girls aged 6 years or more who visited any one of the seven study centers between April 2000 and March 2020 and who met the diagnostic criteria for PP in Japan were retrospectively examined. The participants were divided into a treatment (n = 56) and no-treatment group (n = 77). The AH and target height (TH) were compared between the groups, and the factors influencing the AH were examined., Results: The patients receiving GnRHa therapy achieved significantly greater increase in their AH, AH - TH, and predicted AH at the age of 6, 7, and 8 years (6 ≤ years < 9) than those without the treatment. The TH and height at the start and end of treatment influenced the AH of the former group., Conclusion: GnRHa therapy was effective in improving the AH in girls with CPP onset at the age of 6, 7, or 8 years. The TH was a strong determinant of the AH., (© 2024 S. Karger AG, Basel.)

Case: Burosumab is a novel drug developed to treat hereditary fibroblast growth factor 23 (FGF23)-related disorders. We report the case of an 11-year-old girl with McCune-Albright syndrome (MAS) who sustained hypophosphatemia due to excess FGF23 and multiple bone lesions of fibrous dysplasia (FD). Burosumab therapy markedly improved not only the biochemical parameters but also the radiographic appearance of the FD lesions and clinical symptoms., Conclusion: This is the first report to demonstrate that burosumab is effective in improving FD lesions in a patient with MAS., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSCC/C440)., (Copyright © 2024 by The Journal of Bone and Joint Surgery, Incorporated.)

Achondroplasia (ACH) is a rare, autosomal dominant skeletal dysplasia characterized by short stature, characteristic facial configuration, and trident hands. Before vosoritide approval in Japan, patients with ACH could start growth hormone (GH) treatment at age 3 years. However, ACH and its treatment in young Japanese children have not been studied. This retrospective, longitudinal, medical records-based cohort study (before vosoritide approval) summarized symptoms, complications, monitoring, surgery/interventions, and height with/without GH in Japanese patients with ACH <5 years. Complications were observed in 89.2% of all 37 patients; 75.7% required surgery or intervention. All patients were monitored by magnetic resonance imaging; 73.0% had foramen magnum stenosis, while 54.1% had Achondroplasia Foramen Magnum Score 3 or 4. Of 28 GH-treated patients, 22 initiating at age 3 years were generally taller after 12 months versus 9 non-GH-treated patients. Mean annual growth velocity significantly increased from age 2 to 3 versus 3 to 4 years in GH-treated patients (4.37 vs. 7.23 cm/year; p = 0.0014), but not in non-GH-treated patients (4.94 vs. 4.20 cm/year). The mean height at age 4 years with/without GH was 83.6/79.8 cm. These results improve our understanding of young patients with ACH in Japan and confirm that early diagnosis of ACH and monitoring of complications help facilitate appropriate interventions., (© 2024 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Context: Adrenal crisis (AC) is a life-threatening complication that occurs during follow-up of patients with adrenal insufficiency (AI). No prospective study has thoroughly investigated AC in children with primary and secondary AI., Objective: This work aimed to determine the incidence and risk factors for AC in patients with pediatric-onset AI., Methods: This multicenter, prospective cohort study conducted in Japan enrolled patients diagnosed with AI at age ≤15 years. The incidence of AC was calculated as events per person-year (PY), and risk factors for AC were assessed using Poisson regression multivariable analysis., Results: The study population comprised 349 patients (164 male, 185 female) with a total follow-up of 961 PY. The median age at enrollment was 14.3 years (interquartile range [IQR] 8.5-21.2 years), and the median follow-up was 2.8 years (IQR 2.2-3.3 years). Of these patients, 213 (61%) had primary AI and 136 (39%) had secondary AI. Forty-one AC events occurred in 31 patients during the study period. The calculated incidence of AC was 4.27 per 100 PY (95% CI, 3.15-5.75). Poisson regression analysis identified younger age at enrollment (relative risk [RR] 0.93; 95% CI, 0.89-0.97) and increased number of infections (RR 1.17; 95% CI, 1.07-1.27) as significant risk factors. Female sex (RR 0.99; 95% CI, 0.53-1.86), primary AI (RR 0.65; 95% CI, 0.30-1.41), or equivalent dosage of hydrocortisone per square meter of body area (RR 1.02; 95% CI, 0.96-1.08) was not a significant risk factor., Conclusion: A substantial proportion of patients with pediatric-onset AI experience AC. Younger age and an increased number of infections are independent risk factors for developing AC in these patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Central congenital hypothyroidism (CH) can occur as an isolated deficiency or as part of combined pituitary hormone deficiency. Unlike primary CH, central CH cannot be detected by newborn screening (NBS) using dry filter paper blood TSH levels, and early diagnosis remains challenging. In this study, the clinical and genetic backgrounds of patients with isolated central CH were determined through a questionnaire-based survey among members of the Japanese Society for Pediatric Endocrinology. The known causes of isolated central CH were studied in 14 patients, including six with previously reported patient data. The results revealed IGSF1 and TBL1X pathogenic variants in nine and one patient, respectively. All six patients with low free thyroxine (FT4) levels detected in NBS carried IGSF1 pathogenic variants. Five patients with isolated central CH diagnosed after 3 months of age were variant-negative, except for one female patient with a heterozygous IGSF1 variant. Two of the four variant-negative patients and a variant-positive patient were diagnosed with pituitary hypoplasia. One and two patients with IGSF1 variant had obesity and intellectual disability, respectively. Left amblyopia was identified in the patient with a TBL1X variant. The study revalidated that IGSF1 variants comprise the most frequent pathogenic variant in patients with isolated central CH in Japan. The neonatal period is the optimal time for the diagnosis of central CH, particularly IGSF1 abnormalities, and the introduction of T4 screening should be considered in the future, taking cost-effectiveness into consideration.

Introduction: The testicular regression syndrome (TRS) is a form of differences of sex development (DSD) in which the testes differentiate and function during early embryonic development, but subsequently regress. The clinical phenotype of TRS often overlaps with that of partial gonadal dysgenesis (PGD). Previous studies have demonstrated a causal association between TRS/PGD and heterozygous missense variants of DHX37., Methods: We enrolled 11 Japanese 46,XY individuals (from 10 families) with TRS/PGD who exhibited undetected or hypoplastic testes, Müllerian duct regression, and low serum testosterone or anti-Müllerian hormone levels. The subjects underwent targeted sequencing of 36 known causative genes for DSD, PCR-based Sanger sequencing of DHX37, or whole exome sequencing., Results: Previously described pathogenic variants or novel nonsense variants (SRY, NR5A1, and DMRT1) were observed in four out of 10 families. Additionally, we identified two heterozygous rare variants of DHX37 in four families: a previously reported pathogenic variant (c.923G>A, p.Arg308Gln) in three and a novel likely pathogenic variant (c.1882A>C, p.Thr628Pro) in one. The external genitalia of patients with the DHX37 variants varied from female-type to male-type without micropenis. Eighty percent of Japanese patients with TRS/PGD had monogenic disorders including DHX37 variant being the most commonly identified (40%). The external or internal genital phenotype of TRS/PGD overlaps between DHX37 variant carriers and others., Conclusions: DHX37 variant is one of common genetic causes in Japanese patients with TRS/PGD without Müllerian derivatives. Genetic test is helpful in detecting DHX37-related TRS/PGD, because of the phenotypic diversity of the external genitalia in this disorder., (S. Karger AG, Basel.)

Fibroblast growth factor 23 (FGF23)-related hypophosphatemic rickets (HPR) are characterized by excess circulating FGF23 and low concentrations of serum phosphorus, leading to skeletal manifestations of rickets, including lower limb deformities in children. The objective of this study was to prospectively evaluate whether treatment with burosumab, a monoclonal antibody neutralizing FGF23, changes lower limb deformities in HPR. Patients who were 15 years of age or younger with a documented clinical diagnosis of HPR, receiving burosumab treatment, and had a minimum follow-up period of one year were included in the study. Various radiological parameters were measured from anteroposterior and lateral radiographs of the bilateral lower limbs taken before administration of burosumab and at 3, 6, 9, and 12 months after treatment for evaluation of lower limb alignment. Outcome was classified as 'improvement', 'no change', or 'deterioration' after 12 months treatment. Five patients (10 limbs), with a mean age of 7.2 years were included in this study. The outcome was 'improvement' in six limbs and 'no change' in four limbs. There were no limbs of 'deterioration'. The improvement in deformities after treatment was more significant in younger patients who originally showed severe lower limb deformities. Older patients with milder deformities, on the other hand, showed less improvement. Burosumab therapy favorably changed lower-limb malalignment in children with FGF23-related HPR., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Biochemically monitoring 21-hydroxylase deficiency (21-OHD) is challenging. Serum/blood 17-hydroxyprogesterone (17OHP) measurements are normally used for this purpose. Urinary pregnanetriol (PT), a urinary metabolite of 17OHP, may also be used. Based on auxological data, we previously reported that the optimal first morning PT value fell in the range of 2.2-3.3 mg/gCr (95% confidence interval of the mean) and 0.59-6.0 mg/gCr (10 th - 90 th percentile) for monitoring 21-OHD treatment. No report thus far has directly compared the first morning urinary PT value with the 17OHP value at various times during the day., Objective: To explore the correlation between the first morning urinary PT value before glucocorticoid administration and the serum/blood 17OHP value at three time points, namely, before and two and four hours after glucocorticoid administration., Design: This was a prospective study done at two children's hospitals., Methods: In total, 25 patients with 21-OHD aged 3-25 years were recruited. Their urinary PT levels and 17OHP levels were measured for three days within a total period of one week. The first morning PT value was collected on all three days. Dried blood spots and serum were used to measure 17OHP., Results: The range for the first morning PT value for all the samples (n=69) was 0.10-56.1 mg/gCr. A significant, positive correlation was found between the first morning PT and 17OHP values before medication (r=0.87, p<0.01), and weaker correlation was observed between the first morning PT and 17OHP values after medication., Conclusions: The first morning PT correlated more significantly with 17OHP before the morning medication. Measuring the first morning PT value may be more practical and useful for monitoring 21-OHD biochemically., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Itonaga, Izawa, Hamajima and Hasegawa.)

Type 1 insulin-like growth factor receptor (IGF1R) plays an important role in normal fetal and postnatal growth. Over 30 pathogenic variants of IGF1R have been identified in patients with short stature. Yet, 20 years after the first report, a variety of phenotypes remain poorly defined. We analyzed the genetic and clinical data and responses to GH therapy in 11 patients using results from questionnaires. Eight of the 11 patients have already been reported in previous articles, and all of the identified mutations were heterozygous. The patients exhibited various phenotypes. At least two patients did not meet the criteria for GH treatment for small for gestational age (SGA) short stature, and two more patients showed lower serum IGF1 levels. Nine of the 11 patients had thin upper lips. Five patients with heterozygous IGF1R treated with GH exhibited similar height gains to those reported in previous Japanese studies on SGA short stature, which also led to extremely high serum IGF1 levels. Patients with short stature due to IGF1R mutations exhibit various phenotypes. Their presentation at diagnosis may be indistinguishable from common short stature. More specific clinical scoring that considers elevated IGF1 levels after GH treatment is needed to better detect IGF1R mutations., Competing Interests: None of the authors have any potential conflicts of interest associated with this research., (2022©The Japanese Society for Pediatric Endocrinology.)