Shohei Harada

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: Newborn screening and its relationship to the diagnosis and treatment of the disorder

Abstract Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency can be detected by newborn screening. The screening alone in 29 programs from 13 countries resulted in the diagnosis of CAH in 1 2 of affected newborns and expedited the diagnosis in 1 3 of affected newborns clinically suspected to have CAH. The benefits of newborn screening for CAH were prevention of severe adrenal crisis, its sequela, incorrect male sex assignment of severely virilized female newborns, and progressive signs of androgen excess. Screening revealed a higher incidence of CAH worldwide (1:15000 live births) compared with the case survey incidence (1:32000 live births) The false-positive rate (usually found in low birth weight and premature infants) was acceptably low (0.01–0.5%) except for three programs (0.7–2.5%). The false-negative rate of CAH screening was negligible. Prenatal diagnosis of CAH is possible by HLA typing or 21-hydroxylase B gene analysis of cultured fetal cells from chorionic villus biopsy sampling in the first trimester and from amniotic cells or hormonal analysis of amniotic fluid in the second trimester. Prenatal treatment of CAH is possible via maternal dexamethasone therapy beginning early pregnancy. However, efficacy and side effects of maternal dexamethasone therapy require further investigation.

Descriptive Epidemiology of IDDM in Hokkaido, Japan: The Childhood IDDM Hokkaido Registry

OBJECTIVE To identify the incidence of IDDM with regard to sex, age, family history of diabetes, season, and 5-year period of childhood IDDM among children ages 0–14 years from a population-based epidemiological study in Hokkaido, Japan, from 1973 to 1992. RESEARCH DESIGN AND METHODS Registration of all new IDDM cases in Hokkaido was conducted by the Childhood IDDM Hokkaido Registry Study Group from 1973 to 1992. The cases were selected from among 1) patients who were admitted to the member hospitals of the study group, 2) patients who answered a questionnaire distributed to hospitals and diabetic clinics throughout Hokkaido, and 3) patients whose cases were recorded in free-treatment medical records of urban and rural districts. The case ascertainment rate was estimated to be 100%. Differences in incidence with regard to sex, age, family history of diabetes, season, and year period were analyzed by the Poisson regression analysis by GENMOD. RESULTS During the 20-year period studied, 396 cases (181 boys, 215 girls) of abruptonset IDDM were registered. Statistically significant differences in annual incidence were found according to sex (female), age (8–14 years), history (having no diabetes in family), season (spring), and 5-year period. CONCLUSIONS This is the first population-based, long-term epidemiological study of childhood IDDM from Japan. We observed a significantly higher annual incidence (per 100,000/year) of IDDM in female subjects (1.81), older age-groups (2.25 for 8–14 years), subjects with no family history of diabetes (1.26), diabetes onset in the spring (2.20), and an increased trend over the 20 years. In addition, the heterogeneity of IDDM among Japanese children needs to be elucidated.

Partial iodide organification defect caused by a novel mutation of the thyroid peroxidase gene in three siblings

background Three siblings with goitre and latent to mild hypothyroidism were suspected of having thyroid peroxidase (TPO) abnormality. Direct sequencing of their genomic DNAs showed two novel mutations of the TPO gene, one of which was G1687T (Gly533Cys; exon 9) and the other 1808–13del (Asp574/Leu575del; exon 10). The two mutations were compound heterozygous, as the former was found in their fathers DNA as heterozygous, and the latter was found in DNA from their mother, also as heterozygous. As Gly533 and Asp574/Leu575 were well‐conserved amino acids in the peroxidase superfamily, Gly533Cys‐ and Asp574/Leu575del‐TPOs were thought to be affected structurally or functionally. In expression studies using CHO‐Kl cells and mRNAs introduced with individual mutations, both mutated TPO proteins were expressed at the same molecular size as wild‐type TPO and had enzyme activity, although Gly533Cys‐TPO was slightly lower in efficiency of expression and more degenerative than wild‐type TPO.

Influence of iodine excess due to iodine-containing antiseptics on neonatal screening for congenital hypothyroidism in Hokkaido prefecture, Japan

Abstract Introduction: Iodine excess in newborn infants due to the use of iodine-containing antiseptics (povidone-iodine, PVP-I) has been a substantial cause of transient hypothyroidism, particularly in iodine-deficient areas of the world. However, Japan is an iodine-sufficient area. To evaluate the influence of iodine excess due to PVP-I during the perinatal period on neonatal screening for congenital hypothyroidism (CH) in an iodine-sufficient country such as Japan, we determined the iodide status and thyrotropin (TSH) levels in neonates during exposure and without exposure to perinatal PVP-I. Methods: Dried blood on filter paper was collected for neonatal screening at ages 4–7 days before PVP-I exposure (phase I) and after withdrawal of PVP-I from umbilical cord care (phase II). Voided urine samples from the infants and maternal breast milk samples were collected at the time of neonatal blood collection. Iodide was measured in urine and breast milk using an iodide-specific electrode. TSH was measured in the dried blood specimens by enzyme linked immunosorbent assay (ELISA). Results: Urinary iodide and TSH levels were highest in breast-fed infants on PVP-I for umbilical cord care and born to iodine-overloaded mothers who received PVP-I by vaginal application. During phase II, urinary iodide and TSH decreased in infants born in the same clinics where PVP-I had been used. Good correlation was noted between iodide concentrations in breast Witk and the degree of iodine overload in the mother. Discussion: The direct application of PVP-I to infants and iodide in breast milk are essential pathways of iodine overload to infants. Withdrawal of PVP-I significantly decreased the false-positive rate of neonatal screening for CH. Consequently, PVP-I should not be used in delivery or perinatally, even in iodine-sufficient areas such as Japan.

Comparison of atrophic and goitrous auto-immune thyroiditis in children: Clinical, laboratory and TSH-receptor antibody studies

We studied the clinical features, laboratory and thyroid functions and thyrotropin (TSH)-receptor and thyroid-stimulation antibodies in 21 patients with atrophic auto-immune thyroiditis (AAT) and 48 patients with goitrous auto-immune thyroiditis (GAT) of childhood onset. The clinical features of patient with AAT were cessation of growth and obesity, while asymptomatic enlargement of the thyroid gland was the sole symptom in most patients with GAT. Although the ages at diagnosis were comparable in both groups, the estimated ages at onset were much lower in patients with AAT than in those with GAT. Patients with AAT exhibited more severe hypothyroidism when evaluated by serum thyroxine (T4), tri-iodothyronine (T3), TSH, cholesterol levels and basal metabolic rates. The 24h123I-thyroidal uptake was significantly lower in patients with AAT than in those with GAT. None of the 19 patients with AAT possessed TSH-binding inhibitor immunoglobulins (TBII). On the other hand, 3 of the 32 GAT patients tested, possessed weak to potent TBII activities. Three TBII-positive patients with GAT also possessed thyroid-stimulation blocking antibodies. These findings suggest that: 1. Pathogenesis of AAT in children whose onset of hypothyroidism was before puberty is not due to TSH-receptor blocking antibodies, which are often found in patients with AAT of postpubertal onset. 2. AAT in children is considered not to be due to the later stage of GAT. 3. Some patients with GAT possessed TSH-receptor blocking antibodies. The aetiology and pathogenesis of AAT in children have yet to be elucidated.

Increased Incidence of Extrathyroidal Congenital Malformations in Japanese Patients with Congenital Hypothyroidism and Their Relationship with Down Syndrome and Other Factors

BACKGROUND Much remains unknown regarding extrathyroidal congenital malformations (ECMs) in patients with primary congenital hypothyroidism (PCH) and Down syndrome (DS). Here, we investigated the frequency of ECMs in patients with PCH, particularly among patients with or without DS. METHODS In a retrospective review of questionnaires based on medical records, ECMs were identified in 1520 patients with PCH and were compared with congenital malformations among nationwide live births or liveborn infants with DS. The ECMs in PCH patients with or without DS were then analyzed. The statistical analysis was based on the Poisson distribution. Ethnicity, sex, and familial and seasonal factors were also observed in relation to the ECMs. RESULTS The incidences of ECMs (222/1520, 14.6%) and DS (86/1520, 5.7%) were significantly higher among the PCH patients than among the general population. Among the 127 PCH patients without chromosomal abnormalities, 101 had a single ECM and 26 had multiple ECMs. Unlike previously reported American and Egyptian patients with PCH, a significantly higher incidence of cardiovascular malformations was observed in the Japanese PCH patients, and a female predominance was also observed, except in patients with multiple ECMs. Regarding the PCH patients with DS, a significantly higher, male-predominant incidence of duodenal atresia was observed, compared with data for liveborn infants with DS, whereas a male-predominant, significantly higher incidence of gastrointestinal malformations and a female-predominant, significantly higher incidence of cardiovascular malformations were found compared with data among PCH patients without DS. Moreover, urogenital and orofacial ECMs were absent among the PCH patients with DS. Regarding PCH patients without DS, a male-predominant, significantly higher incidence of urogenital malformations and a female-predominant, significantly higher incidence of cardiovascular and nervous malformations were found, compared with data for nationwide live births. In PCH patients with DS and in PCH patients with a single ECM, both familial and seasonal factors existed, while in PCH patients with multiple ECMs, only familial factors were observed. CONCLUSION The incidence of ECMs in PCH patients was significantly higher than in the normal population, and ethnic-, sex-, and DS-related differences were observed. Genetic and environmental factors were also identified in PCH patients with ECMs.

Treatment situation of male hypogonadotropic hypogonadism in pediatrics and proposal of testosterone and gonadotropins replacement therapy protocols.

Abstract Male hypogonadotropic hypogonadism (MHH), a disorder associated with infertility, is treated with testosterone replacement therapy (TRT) and/or gonadotropins replacement therapy (GRT) (TRT and GRT, together with HRT hormone replacement therapy). In Japan, guidelines have been set for treatment during adolescence. Due to the risk of rapid maturation of bone age, low doses of testosterone or gonadotropins have been used. However, the optimal timing and methods of therapeutic intervention have not yet been established. The objective of this study was to investigate the current situation of treatment for children with MHH in Japan and to review a primary survey involving councilors of the Japanese Society for Pediatric Endocrinology and a secondary survey obtained from 26 facilities conducting HRT. The subjects were 55 patients with MHH who reached their adult height after HRT. The breakdown of the patients is as follows: 7 patients with Kallmann syndrome, 6 patients with isolated gonadotropin deficiency, 18 patients with acquired hypopituitarism due to intracranial and pituitary tumor, 22 patients with classical idiopathic hypopituitarism due to breech delivery, and 2 patients with CHARGE syndrome. The mean age at the start of HRT was 15.7 yrs and mean height was 157.2 cm. The mean age at reaching adult height was 19.4 yrs, and the mean adult height was 171.0 cm. The starting age of HRT was later than the normal pubertal age and showed a significant negative correlation with pubertal height gain, but it showed no correlation with adult height. As for spermatogenesis, 76% of the above patients treated with hCG-rFSH combined therapy showed positive results, though ranging in levels; impaired spermatogenesis was observed in some with congenital MHH, and favorable spermatogenesis was observed in all with acquired MHH. From the above, we propose the establishment of a treatment protocol for the start low-dose testosterone or low-dose gonadotropins by dividing subjects into two groups to determine different treatment protocols, acquired and congenital MHH, and to conduct them at a timing closer to the onset of puberty, namely, at a timing near entrance to junior high school. We also propose a new HRT protocol using preemptive FSH therapy prior to GRT aimed at achieving future fertility in patients with congenital MHH.

Time trend and geographic distribution of treated patients with congenital hypothyroidism relative to the number of available endocrinologists in Japan.

OBJECTIVE To investigate the time trend and geographic distribution of treated patients with congenital hypothyroidism (CH) and explore their possible relationship to the availability of endocrinologists in Japan. STUDY DESIGN The 2-source capture-recapture method was used to estimate the total number of patients. The ratio of the total estimated number of patients with CH to the number of endocrinologists and Spearman correlation coefficients were calculated. Curve fitting for changes in incidence or prevalence was estimated. RESULTS The incidence and prevalence of CH exhibited upward trends, with linear slopes of increase during the period 1994-2002. A statistically significant positive correlation was observed between the prevalence of CH and the ratio of the number of patients with CH to the number of endocrinologists in the 10 regions studied. The prevalence of CH was significantly higher in the regions with a higher ratio of patients with CH to endocrinologists, and also in younger patients. CONCLUSIONS A shortage of endocrinologists may be one reason for the upward trend in the incidence and prevalence of treated patients with CH.

Guidelines for Mass Screening of Congenital Hypothyroidism (2014 revision)

Purpose of developing the guidelines: Mass screening for congenital hypothyroidism started in 1979 in Japan, and the prognosis for intelligence has been improved by early diagnosis and treatment. The incidence was about 1/4000 of the birth population, but it has increased due to diagnosis of subclinical congenital hypothyroidism. The disease requires continuous treatment, and specialized medical facilities should make a differential diagnosis and treat subjects who are positive in mass screening 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, new findings on prognosis and problems in the adult phase have emerged. Based on these new findings, the 1998 guidelines were revised in the current document (hereinafter referred to as the Guidelines). Target disease/conditions: Primary congenital hypothyroidism. Users of the Guidelines: Physician specialists in pediatric endocrinology, pediatric specialists, physicians referring patients to pediatric practitioners, general physicians, laboratory technicians in charge of mass screening, and patients.

Attitude to extended use and long-term storage of newborn screening blood spots in Japan.

Background:  Residual dried blood spots (DBS) remaining after routine newborn screening (NBS) tests are candidate specimens for extended uses such as quality assurance and the development of new technology. A trial of NBS using tandem mass‐spectrometry was launched in 2004 in Japan. The aim of the present study was to analyze the attitudes of the public, patient families, and medical professionals toward the extended use and long‐term storage of residual DBS, and to construct a standardized informational brochure.