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.

To manage of 21-hydroxylase deficiency (21-OHD), transition medicine from pediatric to adult health care is an important process and requires individually optimized approaches. We sent cross-sectional questionnaire surveys on the current status of transition from pediatric to adult health care in 21-OHD patients to all councillors of the Japanese Society for Pediatric Endocrinology. Many pediatric departments (42.2%) experienced adult 21-OHD patients, and 115 patients (53 males, mean age of 26) in 46 institutions were identified. Whereas almost two-thirds of pediatric endocrinologists regarded the problems of counterparts and cooperation as hindrance of transition medicine, the major reason for continuing to be treated in pediatrics was the patient's own request. The prevalence of long-term complications including obesity, osteoporosis, infertility, menstrual disorder, gender dysphoria, and testicular adrenal rest tumor were 27.5%, 8.8%, 11.1%, 26.3%, 7.1%, 12.5%, respectively, which is comparable to those of other cohorts previously reported. However, several items, especially infertility and osteoporosis were not checked well enough in adult 21-OHD patients treated in pediatrics. Though 44 of 62 female patients had genital reconstructive surgery, more than half of them were not followed up by gynecologists or pediatric urologists. Quite a few adult 21-OHD patients had been followed up in pediatrics even after coming of age; however, surveillance by pediatric endocrinologists of gynecological, reproductive, and mental problems may be insufficient. Therefore, multidisciplinary approaches should be required in transition medicine for 21-OHD and prerequisite for graduation of pediatrics. Pediatric endocrinologists will need to play a leading role in the development of transition systems.

BACKGROUND: One of the major purposes of newborn screening for 21-hydroxylase deficiency (21OHD) is preventing life-threatening adrenal crisis. However, the details of adrenal crisis in newborns are not precisely documented. AIM: We aimed to clarify the clinical details of salt-wasting in newborn 21OHD patients. METHODS: Based on the follow-up survey of the screening in Tokyo from 1989 to 2017, we retrospectively analysed the conditions of classical 21OHD neonates before the initiation of therapy. RESULTS: One hundred classical 21OHD patients (55 male, 45 female) were analysed. The age at the first hospital visit was 0-20 days with sex difference (male: 9.0 ± 3.5 days; female: 6.2 ± 3.9 days). Thirty-seven (37.4%) patients exhibited severe salt-wasting (SSW), that is, Na < 130 mEq/L, K > 7 mEq/L or Na/K ratio < 20; except for one case, SSW developed in or after the second week of life. The serum concentrations of Na, K and Na/K were linearly correlated with age in days (R2  = .38, .25, and .34 respectively), suggesting that the risk of SSW increases linearly without a threshold. The age at which the regression lines reached Na < 130 mEq/L, K > 7 mEq/L and Na/K < 20 was approximately coincided, 11.1, 12.3 and 11.2 days, respectively. All SSW patients exhibited decreased body weight from birth in their second week of life. CONCLUSION: Our data revealed that the risk of developing SSW increases during the second week of life without a threshold, and for preventing SSW, early intervention, ideally during first week of life, is desirable. An increased body weight in the second week of life indicates the absence of SSW.

In the Original publication of the article, there are two minor errors in Fig. 2 and these include one missing arrow in Fig. 2d and appears as an incorrectly drawn solid lines as dashed line in Fig. 2d.

副腎ホルモン産生異常症全国疫学調査(2003〜2007年の症例対象)において、先天性副腎酵素欠損症に占める21水酸化酵素欠損症(21OHD)の割合は90.4%で、21OHD例のうち二次調査に回答が得られたのは642例であった。今回、この642例を対象として2018年度に予後調査を行った結果を報告した。調査項目は「現在の診療科」「同胞の有無」「同胞に対する出生前診断・治療の有無」「副腎クリーゼの経験の有無」「成人期の体格」「成人期の合併症」などとした。有効回答数は403例で、男女比は1:1.3であった。現在の診療科は小児科が66%、内科が29%、その他3%、無回答3%であった。小児科から内科へ移行していたものが130例(32%)あり、移行時年齢は25.4±7.5歳であった。調査時年齢25歳以上例のうち39%は小児科通院を継続中であった。同胞に対して出生前診断・治療が行われていたのは14%であった。副腎クリーゼは22%が経験しており、クリーゼの発症時期は乳幼児期が多かった。成人期(17歳7ヵ月以上)の体格は、男性が身長162.7±5.1cm、BMI 24±4.0、女性が身長151.2±7.0cm、BMI 24.6±6.3であった。成人期の合併症は、月経異常が22%、耐糖能異常、高血圧、脂肪肝、肝機能異常、骨塩量低下がそれぞれ約5%などであった。

Congenital central hypothyroidism (C-CH) is caused by defects in the secretion of thyrotropin-releasing hormone (TRH) and/or TSH, leading to an impairment in the release of hormones from the thyroid. The causes of C-CH include congenital anomalies of the hypothalamic-pituitary regions and several genetic defects. In terms of endocrinology, C-CH is divided into two categories: (1) accompanied by another pituitary hormone deficiency and called combined pituitary hormone deficiency, and (2) isolated C-CH, showing mainly TSH deficiency. For isolated C-CH, a mutation in the TSH gene (TSHB) encoding the β-subunit of the protein was first found in 1990 by Japanese researchers, and thereafter several mutations in TSHB have been reported. Mutations in the thyrotropin-releasing hormone receptor gene (TRHR), as well as genetic defects in immunoglobulin superfamily 1 (IGSF1), have also been identified. It was recently found that isolated C-CH is caused by mutations in transducin β-like 1 X-linked and insulin receptor substrate 4. It is noted that all patients with TSHB deficiency and some with IGSF1 deficiency show severe hypothyroidism soon after birth. Among the causes of C-CH, high frequency of mutations in IGSF1 is the most prevalent. This review focuses on recent findings on isolated C-CH.

Almost 90% of nephrogenic diabetes insipidus (NDI) is caused by mutations in the arginine vasopressin receptor 2 gene (AVPR2) on the X chromosome. Herein, we reported clinical and biochemical parameters in four cases of three unrelated Japanese families and analyzed the status of the AVPR2. Two of the four patients had poor weight gain. However, in the male and female sibling cases, neither had poor weight gain while toddlers, but in the male sibling, episodes of recurrent fever, polyuria, and polydipsia led to the diagnosis of NDI at 4 years of age. Analysis of AVPR2 identified two nonsense mutations (c.299_300insA; p.K100KfsX91 and c.296G > A; p.W99X) and one missense mutation (c.316C > T; p.R106C). These mutations were previously reported. The patient with c.316C > T; p.R106C had milder symptoms consistent with previous reports. Of the familial cases, the sister was diagnosed as having NDI, but a skewed X-inactivation pattern in her peripheral blood lymphocytes was not identified. In conclusion, our study expands the spectrum of phenotypes and characterized mutations in AVPR2 in NDI.

Twenty-one-hydroxylase deficiency (21-OHD) is one of the most common forms of congenital adrenal hyperplasias. Since the disease requires life-long steroid hormone replacement, transition from pediatric clinical care to adolescent and adult care is necessary. Recently, several studies have shown that morbidity and quality of life in adolescent and adult patients with 21-OHD are impaired by obesity, hypertension, diabetes mellitus, impaired glucose tolerance, dyslipidemia, and osteoporosis. In addition, excess adrenal androgen impairs fertility in both females and males. This mini review discusses the current health problems in adolescent and adult patients with 21-OHD and ways to prevent them.

中枢性先天性甲状腺機能低下症患児の白血球を用いてPCR direct sequencing法による遺伝子解析を行い、Immunoglobulin Super Family Gene 1(IGSF1)変異を探索した。その結果、新生児マススクリーニング検査もしくは低身長を契機に発見された男児3例において3つの新規IGSF1変異(p.G1085Wfs39X、c.2335+1G>A、124kb deletion)を同定し、いずれもIGSF1のC末端に存在する変異であった。さらに、ラット下垂体腺腫由来GH3細胞を用いてIGSF1のPRL産生に対する効果およびTGFβ-betaglycanシグナル伝達におけるIGSF1の効果を検討した。その結果、IGSF1がTGFβのシグナル伝達系に関与する可能性が示唆された。

IGSF1(Immunoglobulin superfamily member 1)遺伝子異常による先天性中枢性甲状腺機能低下症(C-CH)が2012年に初めて報告されて以降、本邦においても報告例が増えてきた。今回著者等は、幼少期からの便秘と3年前からの腹痛を主訴に当科受診し、高度な低身長を認めたため精査を行いC-CHの診断に至った14歳男児例を経験した。長期に無治療であった貴重な症例と思われたので報告した。患児は消化器症状のほかに肥満と不登校があり、LT4補充治療によって消化器症状と肥満は速やかに改善した。一方、不登校は続き、その理由として14年間無治療であったために不可逆性の心理社会的不適応を生じ、LT4補充が無効であった可能性が示唆された。