Purpose Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder; however, its molecular etiology remains poorly understood. Methods We performed genetic analysis of 24 causative genes using next-generation sequencing in 167 CH cases, comprising 57 dyshormonogenesis (DH), 32 dysgenesis (TD) and 78 undiagnosed. The pathogenicity of variants was assessed by the American College of Medical Genetics guidelines, inheritance pattern, and published evidence. Furthermore, we compared the oligogenic groups and monogenic groups to examine the correlation between variant dosage and severity. Results We identified variants in 66.5% cases (111/167) and 15 genes, DUOX2, TSHR, PAX8, TG, TPO, DUOXA2, JAG1, GLIS3, DUOX1, IYD, SLC26A4, SLC5A5, SECISBP2, DIO1, and DIO3. Biallelic variants were identified in 12.6% (21/167), oligogenic in 18.0% (30/167), and monogenic in 35.9% (60/167); however, 68.5% of variants were classified as variant of unknown significance (VUS). Further examinations showed that 3 out of 32 cases with TD (9.4%) had pathogenic variants (2 of TSHR and 1 of TPO), and 8 out of 57 cases with DH (14.0%) (7 of DUOX2, 1 of TG) had pathogenic variants. In addition, TSH levels at the first visit were significantly higher in the oligogenic group than in the monogenic group. Conclusions The detection rate of pathogenic variants in Japanese CH was similar to that previously reported. Moreover, oligogenic cases were likely to be more severe than monogenic cases, suggesting that CH may exhibit a gene dosage effect. Further analysis of VUS pathogenicity is required to clarify the molecular basis of CH.

Key Clinical MessageWe report two Japanese patients with Schinzel–Giedion syndrome. When polyhydramnios is observed, additional fetal findings such as overlapping fingers, hydrocephalus, hydronephrosis, and very characteristic facial appearance comprising high, prominent forehead, hypertelorism, and depressed nasal root may suggest Schinzel–Giedion syndrome.

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Background More than 40 years have passed since the introduction of newborn screening programs (NBS) for congenital hypothyroidism (CH), and there have been many reports on the long-term outcome of CH identified by NBS. There are some reports that CH is associated with early adiposity rebound and adult obesity. On the other hand, the association between AR and CH has not been revealed in Japan. Objective The aim of this study was to evaluate the timing of AR in individuals with CH detected by NBS in our institution, furthermore, to find out the risk factors of early AR in CH individuals. Patients and Methods The study included 212 CH children (105 female/107 males) who were ten years of age or older as of September 2021. We retrospectively collected height and weight data from one to ten years of age, and the timing of AR was visually determined. We examined the association between the AR age and the severity of hypothyroidism at NBS and at the first visit. Results The median AR age was 5.6 years for boys and 6.2 years for girls, which was unexpectedly not unexpectedly younger than that of the general Japanese population reported by Koyama (4.8 ± 1.4 years for boys, 4.7 ± 1.5 years for girls). Data from 115 patients (107 males, 105 females) whose physique data between the age of 15 and 18 were available showed that body mass index (BMI) was 21.1±3.2 kg/m2 for males and 20.6±2.7 kg/m2 for females, positively correlated with AR age, and not significantly different from BMI at 15-19 years of age (21.1±3.6 for males and 20.2±2.2 for females) in the 2019 National Nutrition and Health Survey (p=0.790, p=0.619). NBS-FT4 was slightly positively correlated to AR age (r=0.234, p=0. 0315). We found that the AR age may be earlier and adult BMI may be higher in CH patients without ossification of the distal femoral epiphyseal nucleus at first evaluation. Discussion Severe fetal hypothyroidism may cause an absence of mineralization of the distal femoral epiphyses in the neonatal period. Our results indicate that severe fetal hypothyroidism, even if diagnosed and treated at neonatal, contributes to the development of adult obesity. Conclusion The AR age and BMI at 15-18 years of CH are not significantly different from the general population. However, severe fetal hypothyroidism could result in adult obesity. Presentation: No date and time listed

Some patients with developmental and epileptic encephalopathy (DEE) respond to adrenocorticotropic hormone (ACTH) therapy but relapse soon after. While long-term ACTH therapy (LT-ACTH) has been attempted for these patients, no previous studies have carefully assessed adrenal function during LT-ACTH.We evaluated the effectiveness of LT-ACTH, as well as adverse effects (AE), including their adrenal function in three DEE patients. Patients underwent a corticotropin-releasing hormone (CRH) stimulation test during LT-ACTH, and those with peak serum cortisol below 15 μg/dL were considered to be at high risk of adrenal insufficiency (AI). Two of three responded, and their life-threatening seizures with postgeneralized electroencephalogram (EEG) suppression decreased. Although no individuals had serious AE, CRH stimulation test revealed relatively weak responses, without reaching normal cortisol peak level (18 μg/ dL). Hydrocortisone replacement during stress was prepared in a case with lower cortisol peak than our cutoff level. LT-ACTH could be a promising treatment option for cases of DEE that relapse soon after effective ACTH treatment. The longer duration and larger cumulative dosage in LT-ACTH than in conventional ACTH could increase the relative risk of AI. Careful evaluation with pediatric endocrinologists, including hormonal stimulation tests, might be useful for continuing this treatment safely.