In contrast to the glucocorticoid maintenance therapy employed in patients with 21 hydroxylase deficiency (21OHD), the initial therapy remains to be optimized. The Japanese Society for Pediatric Endocrinology recommends a hydrocortisone (HC) dose of 25–100 mg/m², which is higher than that employed in Western countries. Herein, we aimed to retrospectively verify the impact of initial HC treatment during infancy and early childhood. Between 2010 and 2018, 15 classical patients with 21OHD were enrolled and divided into the following groups based on initial HC therapy: high dose group (HDG, n = 6), medium dose group (MDG, n = 5), and low dose group (LDG, n = 4). In the HDG and MDG, HC was initiated at 100 mg/m² and reduced to maintenance doses over 4–6 mo and 2–3 wk, respectively. In the LDG, HC was initiated with a maintenance dose of 7 mg/d, accompanied by fludrocortisone and oral NaCl. During the second year, 17α-hydroxyprogesterone was sufficiently suppressed in all three groups. At two years of age, no significant differences in anthropometric data were observed. Our retrospective study did not reveal any apparent advantages or disadvantages of high-dose initial HC therapy for 21OHD, and a lower dose would be preferable for the initial 21OHD treatment.

Gain-of-function variants in SAMD9, which resides on chromosome 7, cause MIRAGE syndrome that is associated with congenital adrenal insufficiency and gonadal dysgenesis. We previously reported a Japanese patient with MIRAGE syndrome carrying a de novo heterozygous SAMD9 variant (p.Ala1479Ser). In this study, we confirmed the pathogenicity of Ala1479Ser-SAMD9 in vitro. Genetic study results revealed an atypically low variant allele frequency (26%) and we suspected of genomic rearrangement(s) involving chromosome 7. Single nucleotide polymorphism (SNP) array and short tandem repeat analysis showed presence of mosaic maternal isodisomic uniparental disomy 7 (UPD7). Deep sequencing using DNA samples obtained at 0, 6, 10, and 25 mo of age revealed that the percentage of cells with UPD7 increased constantly from 6% to 82% over 25 mo, and this increase coincided with a decrease in the percentage of cells with p.Ala1479Ser from 94% to nearly undetectable levels. We further screened for low-allele-frequency and rare SAMD9 variants in eight patients with Silver-Russel syndrome and maternal UPD7; however, none of the patients harbored such a variant. In conclusion, our case demonstrates that genetic findings can vary considerably in patients with MIRAGE syndrome and that a comprehensive diagnostic approach, including SNP array and deep sequencing, is important in such cases.

This retrospective study aimed to clarify the characteristics of bone maturation using longitudinal data in short-stature prepubertal children. Children with chronological ages (CAs) of 4.5–10.5 yr with nonfamilial idiopathic short stature (ISS, n = 95), familial ISS (FSS, n = 21), and short-stature children born small for gestational age (SGA, n = 23) were selected, of which 435 left-hand plain radiographic images were evaluated. Bone age (BA) delay was defined as BA minus CA. In the ISS group, there was a statistically significant difference in median BA delay among the CA groups (P < 0.001), as median BA delay gradually increased from 5- to 9-yr-old groups (−1.06 [range, −2.17 to 0.27] and −2.45 [range, −4.35 to −0.32] yr, respectively). In the FSS group, median BA delays were approximately −1 yr in all CA groups. In the SGA group, median BA delay gradually decreased from 7- to 10-yr-old groups (−1.96 [range, −2.99 to 0.56] and −0.04 [range, −2.44 to 0.92] yr, respectively), but with no significant difference (P = 0.647). The heavier weight of children with FSS and the probable earlier onset of adrenarche in children born SGA compared to those with ISS could have affected bone maturation.

We previously performed next-generation sequencing-based genetic screening in patients with autoantibody-negative type 1 diabetes, and identified the p.Leu168Pro mutation in HNF1B. Here,we report the clinical course of the patient and the results of functional characterization of this mutation. The proband had bilateral renal hypodysplasia and developed insulin-dependent diabetes during childhood. The pathogenicity of Leu168Pro-HNF1B was evaluated with three-dimensional structure modeling, Western blotting, immunofluorescence analysis and luciferase reporter assays using human embryonic kidney 293 cells. Three-dimensional structure modeling predicted that the Leu168 residue is buried in the DNA-binding Pit-Oct-Unc-specific (POU_S) domain and forms a hydrophobic core. Western blotting showed that the protein expression level of Leu168Pro-HNF1B was lower than that of wild-type (WT) HNF1B. Immunofluorescence staining showed that both WT- and Leu168Pro-HNF1B were normally localized in the nucleus. The cells transfected with WT-HNF1B exhibited 5-fold higher luciferase reporter activity than cells transfected with an empty vector. The luciferase activities were comparable between WT-HNF1B/Leu168Pro-HNF1B and WT-HNF1B/empty vector co-transfection. In conclusion, Leu168Pro is a protein-destabilizing HNF1B mutation, and the destabilization is likely due to the structural changes involving the hydrophobic core of POU_S. The disease-causing Leu168Pro HNF1B mutation is a loss-of-function mutation without a dominant-negative effect.

21-hydroxylase deficiency (21-OHD) is the most common type of congenital adrenal hyperplasia. Phenotypically, 21-OHD can be divided into classical and non-classical (NC) forms. The genotype-phenotype correlation in 21-OHD is well established. The P30L mutation is usually associated with the NC form and common among Japanese patients with the NC form of 21-OHD. Herein, we report the clinical course of four patients with 21-OHD with the P30L mutation on one allele and loss-of-function variants on the other allele. Contrary to the findings of most previous studies, all patients were treated with hydrocortisone, and two required fludrocortisone therapy in early childhood. The management strategies for patients with 21-OHD, especially those with the P30L mutation on at least one allele, should be determined based on the clinical phenotype predicted by the CYP21A2 genotype and individual clinical symptoms and biochemical data.

Multiple endocrine neoplasia type 2B (MEN2B) is an extremely rare disease, most often caused by a de novo p.Met918Thr RET mutation. Medullary thyroid carcinoma of MEN2B has a good prognosis if diagnosed by one year of age. However, diagnosis of MEN2B within the first year of life is markedly challenging owing to its high de novo occurrence and lack of clarity in terms of extra-endocrine symptoms that could aid early diagnosis. Herein, we present six cases of Japanese children with MEN2B harboring the p.Met918Thr RET variant. Exploratory data extraction was conducted using a questionnaire. The patients underwent thyroidectomy at a median age of 11 yr (range, 6–19 yr). Four of the six patients underwent neonatal hospitalization at birth without complications, and three tested positive for neuroblastoma screening at infancy. The patients presented at least one MEN2B-associated symptom before one year of age, including ganglioneuromas, pseudo-Hirschsprung disease, alacrima, bumpy lips, sucking disability, or decreased muscle tone, along with other suspected comorbidities, such as Williams or Prader–Willi syndrome. This case series demonstrates that MEN2B manifests through several extra-endocrine symptoms by the age of one year.