Tokuo Mukai

This nationwide study analyzed glucocorticoid treatment regimens and auxological outcomes in 349 Japanese patients with 21-hydroxylase deficiency (21-OHD) (145 males, 204 females; median (IQR) age 20.3 (14.7–30.8) years, of whom 98% had the classical form), using data from a 2017 follow-up survey. Hydrocortisone was used in all patients under 10 years (mean dose: 16.4 ± 3.6 mg/m2). In adults (≥21 years), 56/171 (33%) received hydrocortisone monotherapy, while others received synthetic glucocorticoids or combination therapies. The mean hydrocortisone-equivalent dose in adults was 18.5 ± 7.6 mg/m2, exceeding the 2014 Japanese guideline recommendations. Adult height (AH) standard deviation score (SDS) was –1.40 ± 1.05 for males and –1.32 ± 1.29 for females, with a significant negative correlation with age. The proportion of obesity in adults was notably high (30.2% in males, 40.0% in females). In adult females, a unique negative correlation was observed between hydrocortisone-equivalent dose and body mass index (BMI), possibly reflecting muscle wasting effects of high-dose glucocorticoids. Comparisons among three birth cohorts (post-newborn screening [NBS], pre-NBS, and pre-secular trend plateau) revealed significant improvements in the younger generation: the post-NBS group achieved significantly better AH SDS (males: –1.17 vs. –1.97, p = 0.033 for trend; females: –1.05 vs. –2.27, p = 0.001 for trend) and lower BMI (males: 23.0 vs. 27.5 kg/m2, p = 0.005 for trend; females: 23.0 vs. 28.2 kg/m2, p = 0.002 for trend) compared to the oldest generation. In conclusion, although glucocorticoid doses in this Japanese cohort remained relatively high, AH and BMI have significantly improved in younger generations. Continued optimization of glucocorticoid therapy is crucial to further enhance long-term health outcomes in patients with 21-OHD.

Aldosterone synthase deficiency (ASD), which is caused by a genetic defect in CYP11B2, involves a deficiency in aldosterone alone. Newborn and early childhood ASD patients can present with salt-wasting symptoms. In severe cases, this can lead to shock and be life-threatening. ASD must also be differentiated from another disease, pseudohypoaldosteronism type 1 (PHA1), which involves resistance to aldosterone. PHA1 can be classified into PHA1a, PHA1b, and secondary PHA1. PHA1a is caused by a heterozygous defect in NR3C2, which encodes the mineralocorticoid receptor. PHA1b is an autosomal recessive disorder caused by defects in the 3 epithelial sodium channel subunits α, β, and γ, encoded by SCNN1A, SCNN1B, and SCNN1G. Since ASD is a very rare disorder, the “The Intractable Adrenal Disorders Research by the Ministry of Health, Labour, and Welfare” developed the “Diagnostic criteria and severity classification for aldosterone synthase deficiency” to better understand the disorder. The criteria are as follows: Clinical symptoms: patient meets criteria 1 and 2. 1) Presents with salt-wasting symptoms (poor feeding, vomiting, dehydration, poor weight gain). 2) No skin pigmentation. Laboratory findings: patient meets criteria 1 through 3. 1) Low serum sodium and high serum potassium. 2) Low to normal plasma aldosterone and high plasma renin activity or high plasma active renin concentration. 3) No low blood cortisol level. Diagnoses of exclusion include PHA1, 21-hydroxylase deficiency, congenital lipoid adrenal hyperplasia, and congenital adrenal hypoplasia. We believe that the diagnostic criteria of ASD will enable clinicians and researchers to better understand congenital aldosterone deficiency.

Wolfram syndrome (WS) is a monogenic diabetes caused by variants of the WFS1 gene. It is characterized by diabetes mellitus (DM) and optic atrophy. Individuals with WS initially present with autoantibody-negative type 1 DM (type 1B DM; T1BDM). The diagnosis is often delayed or misdiagnosed, even after visual impairment becomes apparent. We report a case of WS diagnosed by ophthalmologic screening before the appearance of visual impairment. A 7 -year -old male patient developed T1BDM at the age of 3 years. At 6 years of age, his endogenous insulin secretion decreased but was not completely absent, and glycemic control was good with insulin treatment. Fundus examination at that time revealed optic nerve head pallor, and WFS1 gene analysis confirmed a compound heterozygous variant (c.2483delinsGGA/c.1247T>A). Ophthalmological screening can help in early diagnosis of WS in T1BDM, especially when endogenous insulin secretion is preserved, which would facilitate effective treatment.