田島 敏広

Purpose of developing the guidelines: Newborn screening (NBS) for congenital hypothyroidism (CH) was started in 1979 in Japan, and early diagnosis and treatment improved the intelligence prognosis of CH patients. The incidence of CH was once about one in 5,000-8,000 births, but has been increased with diagnosis of subclinical CH. The disease requires continuous treatment and specialized medical facilities should conduct differential diagnosis and treatment in patients who are positive by NBS to avoid unnecessary treatment. The Guidelines for Mass Screening of Congenital Hypothyroidism (1998 version) were developed by the Mass Screening Committee of the Japanese Society for Pediatric Endocrinology in 1998. Subsequently, the guidelines were revised in 2014. Here, we have added minor revisions to the 2014 version to include the most recent findings. Target disease/conditions: Primary congenital hypothyroidism. Users of the Guidelines: Physician specialists in pediatric endocrinology, pediatric specialists, physicians referring pediatric practitioners, general physicians, laboratory technicians in charge of mass screening, and patients.

Paired box transcription factor 8 (PAX8) is essential for thyroid organogenesis and development. Heterozygous pathogenic variants of PAX8 typically cause congenital hypothyroidism (CH) due to thyroid hypoplasia. Additionally, pathogenic PAX8 variants have been identified in patients with gland in situ (GIS). This study was conducted to analyze the in vitro functional consequences of four PAX8 variants (p.D94N, p.E90del, p.V58I, and p.L186Hfs*22) previously identified in patients with CH and GIS. The transcriptional activity of PAX8 variants on the thyroglobulin (TG) promoter was assessed in a luciferase reporter assay. The levels of transcriptional activity on the TG promoter of p.E90del and p.L186Hfs*22 were significantly reduced, whereas p.D94N and p.V58I showed residual activation. In addition, a dominant negative effect on the wild-type (WT) was not detected in any PAX8 variant using a luciferase reporter assay. Two PAX8 variants (p.E90del and p.L186Hfs*22) may be pathogenic causes of CH with GIS.

Congenital adrenal hyperplasia is a category of disorders characterized by impaired adrenocortical steroidogenesis. The most frequent disorder of congenital adrenal hyperplasia is 21-hydroxylase deficiency, which is caused by pathogenic variants of CAY21A2 and is prevalent between 1 in 18,000 and 20,000 in Japan. The clinical guidelines for 21-hydroxylase deficiency in Japan have been revised twice since a diagnostic handbook in Japan was published in 1989. On behalf of the Japanese Society for Pediatric Endocrinology, the Japanese Society for Mass Screening, the Japanese Society for Urology, and the Japan Endocrine Society, the working committee updated the guidelines for the diagnosis and treatment of 21-hydroxylase deficiency published in 2014, based on recent evidence and knowledge related to this disorder. The recommendations in the updated guidelines can be applied in clinical practice considering the risks and benefits to each patient.