Kanshi Minamitani

Difference in height associated with a translation start site polymorphism in the vitamin D receptor gene

The function of 1,25-dihydroxyvitamin D3 in bone development is to regulate the differentiation or proliferation of osteoblastic, osteoclastic, and chondrocytic lineage, affecting bone mineralization and linear bone growth. An A(T/C)G substitution exists in the first of the two putative translation initiation sites in exon 2 of the vitamin D receptor (VDR) gene. We studied the relationship between exon 2 polymorphism and height in 90 healthy Japanese female subjects aged 18-20 y, who had attained final height, in 159 healthy Japanese aged 13 y, and 24 children with constitutional short stature aged 6-10 y less than -1.5 SD in height, mostly with parents of normal height. Exon 2 polymorphism was analyzed by PCR-single strand conformation polymorphism, PCR-direct sequencing, and PCR-restriction fragment length polymorphism. The frequency of the exon 2 polymorphism was genotype CC (ACG/ACG), 0.37; genotype CT (ACG/ATG), 0.51; and genotype TT (ATG/ATG), 0.12 in 249 normal subjects. The mean height of female subjects aged 18-20 y with the genotype CT was 160.3 ± 4.3 cm (mean ± SD), whereas that with CC was 4.4 cm lower (p < 0.0001), and that with TT was 2.7 cm lower (p = 0.0302). At age 13 y, this trend was observed, and the mean height SD score of subjects with the genotype CT was taller than homozygotes (CC/CT; p = 0.0363 and CT/TT; p = 0.0208) in 159 subjects. Genotype CT in 24 children with constitutional short stature was less frequent than other genotypes (CC, 0.62; CT, 0.21; TT. 0.17) (χ2 p value, 0.0171). In conclusion, the exon 2 polymorphism affecting the VDR mRNA and protein is one of the major determinants of adult height at least in female Japanese, which was noted at the age of 13 y examined in both sexes.

Association of HLA-DR, DQ genotype with different beta-cell functions at IDDM diagnosis in Japanese children.

Japanese IDDM patients have been demonstrated to have unique and different HLA associations from white patients. To elucidate the effect of HLA-associated genetic factors on the clinical heterogeneity of IDDM in Japanese people, HLA-DRB1, DQA1, and DQB1 genotypes in 88 childhood-onset Japanese IDDM patients were examined by polymerase chain reaction-sequence-specific oligonucleotide (PCR-SSO) or sequence-specific primers (SSP). Of the 88 IDDM patients, 26 (29.5%) had DRB1*0405-DQA1*0302-DQB1*0401/X (DR4-DQ4/X), 38 (43.2%) had DRB1*0901-DQA1*0302-DQB1*0303/X (DR9-DQ9/X), and 9 (10.2%) were DR4/9-DQ4/9 heterozygous in the present study (X does not contain protective alleles). Clinical heterogeneity such as age distribution at onset, prevalence and serum level of anti-GAD antibodies (GADAb), and residual pancreatic β-cell function after diagnosis were compared between patients with HLA-DR4-DQ4 and DR9-DQ9. The frequency of DR9-DQ9 genotype was significantly higher in the younger (0–10 years) than in the older (11–16 years) age-group of onset, but the frequency of DR4-DQ4 was higher in the older (11–16 years) age-group. Although no association of DR-DQ genotypes with the prevalence and serum level of GADAb was found among newly diagnosed patients, long-standing DR9-DQ9 patients had significantly higher levels of GADAb than those with DR4-DQ4. While no difference in time course of serum C-peptide (CPR) levels was detected between GADAb+ and GADAb− patients, a remarkable difference was demonstrated between DR9-DQ9 and DR4-DQ4 patients. The residual pancreatic β-cell function was retained more in patients with DR4-DQ4 than in those with DR9-DQ9 at diagnosis through 12–18 months after diagnosis. These results suggest that the DR9-DQ9 genotype may induce stronger autoimmune destructive response (T-helper 1 function) against target β-cells than the DR4-DQ4 genotype does. Our findings may warrant further studies on the association of diabetogenic autoimmune response with HLA class II molecules and contribute to a clarification of interracial differences in HLA-encoded susceptibility to IDDM.

Comparison of methimazole and propylthiouracil in the management of children and adolescents with Graves’ disease: efficacy and adverse reactions during initial treatment and long-term outcome

Abstract Objective: The aim of this study was to compare the efficacy and adverse reactions during initial treatment and long-term outcome between children and adolescents with Graves’ disease (GD) treated with propylthiouracil (PTU) and those treated with methimazole (MMI). Design, setting and participants: Retrospective and collaborative study. Children and adolescents with GD were divided into group M (MMI: n=64) and group P (PTU: n=69) and into four subgroups by initial dose: group M1 (<0.75 mg/kg of MMI, n=34), group M2 (≥0.75 mg/kg, n=30), group P1 (<7.5 mg/kg of PTU, n=24) and group P2 (≥7.5 mg/kg, n=45). Main outcome measures: The duration for normalization of serum T4 on initial treatment, the incidence of adverse effects for one year and outcomes at 10 years after were compared. Results: Mean durations for normalization of T4 (±SD) were 1.7±1.0 months in group M and 2.3±2.4 in group P [not significant (NS)], while the mean duration in group P1 (3.1±3.3) was significantly longer than those in the other subgroups (M1: 1.9±1.2; M2: 1.4±0.7; P2; 1.7±1.3). No major adverse reaction was observed. Minor adverse effects occurred in 25.0% of cases in group M and 31.9% in group P (NS). The incidence in group P2 (44.4%) was significantly higher than those in group M1 (20.6%) and group P1 (8.3%). Remission rates did not differ between the MMI-treated group (35.0%, n=20) and PTU-treated group (50.0%, n=40). Conclusions: PTU may not be suitable for initial use in children and adolescents with GD, even with the risk of major adverse reactions such as liver failure excluded.

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.

Higher dose of methimazole causes frequent adverse effects in the management of Graves' disease in children and adolescents.

Abstract Objective: Methimazole (MMI) is used as a first-line antithyroid drug in children and adolescents with Graves’ disease (GD). The aim of this study was to evaluate the correlation between the initial dose of MMI and the clinical course of GD after treatment. Design: Retrospective and collaborative study. Setting: Nine facilities in Chiba prefecture, Japan. Patients: Sixty-four children and adolescents with GD were analyzed. The subjects were divided into three groups by the initial daily dose of MMI: group A, 0.4±0.1 mg/kg (mean±SD, n=11); group B, 0.7±0.2 (n=37); group C, 0.9±0.2 (n=16). Main outcome measures: The duration of time required for normalization of serum free T4 on initial treatment and the incidence of adverse effects for 1 year after the start of MMI were compared. Outcomes were compared among patients who were followed more than 3 years (group A, n=7; group B, n=24; group C, n=12). Results: Mean duration of times for normalization of T4 was 1.9±1.5 months in group A, 1.6±0.9 in group B and 1.9±1.5 in group C (NS). No major adverse reactions were observed. Minor adverse effects occurred in 9.1% of cases in group A, 13.5% in group B and 62.0% in group C (p<0.01). Remission rates did not differ among the three groups. Conclusions: Higher doses of MMI are harmful for initial use in children and adolescents with GD.

Guidelines for diagnosis and treatment of 21-hydroxylase deficiency (2014 revision).

Purpose of developing the guidelines: The first guidelines for diagnosis and treatment of 21-hydroxylase deficiency (21-OHD) were published as a diagnostic handbook in Japan in 1989, with a focus on patients with severe disease. The “Guidelines for Treatment of Congenital Adrenal Hyperplasia (21-Hydroxylase Deficiency) Found in Neonatal Mass Screening (1999 revision)” published in 1999 were revised to include 21-OHD patients with very mild or no clinical symptoms. Accumulation of cases and experience has subsequently improved diagnosis and treatment of the disease. Based on these findings, the Mass Screening Committee of the Japanese Society for Pediatric Endocrinology further revised the guidelines for diagnosis and treatment. Target disease/conditions: 21-hydroxylase deficiency. Users of the guidelines: Physician specialists in pediatric endocrinology, pediatric specialists, referring pediatric practitioners, general physicians; and patients.

Guidelines for the treatment of childhood-onset Graves' disease in Japan, 2016

Abstract. Purpose behind developing these guidelines: Over one decade ago, the “Guidelines for the Treatment of Graves’ Disease with Antithyroid Drug, 2006” (Japan Thyroid Association (JTA)) were published as the standard drug therapy protocol for Graves’ disease. The “Guidelines for the Treatment of Childhood-Onset Graves’ Disease with Antithyroid Drug in Japan, 2008” were published to provide guidance on the treatment of pediatric patients. Based on new evidence, a revised version of the “Guidelines for the Treatment of Graves’ Disease with Antithyroid Drug, 2006” (JTA) was published in 2011, combined with the “Handbook of Radioiodine Therapy for Graves’ Disease 2007” (JTA). Subsequently, newer findings on pediatric Graves’ disease have been reported. Propylthiouracil (PTU)-induced serious hepatopathy is an important problem in pediatric patients. The American Thyroid Association’s guidelines suggest that, in principle, physicians must not administer PTU to children. On the other hand, the “Guidelines for the Treatment of Graves’ Disease with Antithyroid Drug, 2011” (JTA) state that radioiodine therapy is no longer considered a “fundamental contraindication” in children. Therefore, the “Guidelines for the Treatment of Childhood-Onset Graves’ Disease with Antithyroid Drug in Japan, 2008” required revision.

Clinical features at diagnosis and responses to antithyroid drugs in younger children with Graves' disease compared with adolescent patients.

Abstract Objective: The aim of this study was to evaluate clinical manifestations, laboratory findings, and effects of antithyroid drugs in younger children with Graves’ disease (GD). Design: A retrospective and collaborative study. Setting: Nine facilities in Chiba prefecture, Japan. Patients: We analyzed 132 children and adolescents with GD. The subjects were divided according to the median age into a group of young children (group I, 4.1–12.4 years, n=66) and an adolescent group (group II, 12.5–15.9 years, n=66). Main outcome measures: Clinical manifestations, laboratory findings, incidence of adverse effects, and remission rates 5 years after initial therapy were assessed. Results: The mean height SD score of group I (1.0) was higher than that of group II (0.3, p<0.001). The mean BMI SD score of group I (–0.7) was lower than that of group II (–0.3, p<0.05). The most common presentations were goiter, sweating, and hyperactivity in group I, whereas the most common presentations were goiter, sweating, and easy fatigability in group II. Hyperactivity was more frequent in group I (56.7%) than in group II (37.9%, p<0.05). Liver dysfunction appeared more often in group I (14.3%) than in group II (1.9%, p<0.05). There was no difference in the appearance of adverse effects between the two groups. The remission rate was slightly lower in group I (23.1%) than in group II (31.3%), but was not significant. Conclusions: Thyrotoxicosis had more influence on the growth and liver function in younger children.

Direct demonstration of humorally mediated inhibition of the transcription of phosphate transporter in XLH patients

AbstractBackground. X-linked hypophosphatemia (XLH) is the most common form of familial hypophosphatemic rickets, which results from impaired renal phosphate (Pi) reabsorption, renal vitamin D metabolism, and skeletal mineralization. PHEX the gene responsible for XLH, is homologous to members of the neutral endopeptidase family. The role that the PHEX gene plays in Pi transport is not yet known. Methods. In the present study, we investigated the molecular mechanisms of the disorder of renal Pi transport in XLH in seven individuals from Japanese XLH families. Also, to characterize the effect of XLH serum from these patients on the expression of a renal phosphate transporter gene, we performed a functional analysis of the human type II Na/Pi cotransporter (NPT2) gene promoter in a kidney cell line, OK cells (named OK-B2400), which had stable expression of the luciferase reporter vector p3P2400 with 2462 base pairs (nucleotides −2409 to +53) of the NPT2 gene. Results. XLH serum significantly decreased the transcriptional activity of the NPT2 promoter. The mutations identified in our patients included three large deletions, frame shift mutations, and a stop mutation in the PHEX gene, which suggest that the gene is nonfunctional in affected individuals. Conclusion. The present study demonstrated that the serum of XLH patients with PHEX mutations contains inhibitory factor(s) for the transcriptional activity of the NPT2 gene. In addition, the transcription assay of the NPT2 promoter may provide a useful tool for the characterization of the putative PHEX protein substrate.

Incidence and Characteristics of Adrenal Crisis in Children Younger than 7 Years with 21-Hydroxylase Deficiency: A Nationwide Survey in Japan

Background/Aims: We aimed to evaluate the incidence and characteristics of adrenal crisis in Japanese children with 21-hydroxylase deficiency (21-OHD). Methods: We conducted a retrospective nationwide survey for the councilors of the Japanese Society for Pediatric Endocrinology (JSPE) regarding adrenal crisis in children under 7 years with 21-OHD, admitted to hospitals from 2011 through 2016. We defined adrenal crisis as the acute impairment of general health due to glucocorticoid deficiency with at least two of symptoms, signs, or biochemical abnormalities. Results: The councilors of the JSPE in 83 institutions responded to this survey (response rate, 60.1%). Data analyses of 378 patients with 1,101.4 person-years (PYs) revealed that 67 patients (17.7%) experienced at least 1 episode of hospital admission for adrenal crisis at the median age of 2 years. The incidence of adrenal crisis was calculated as 10.9 per 100 PYs (95% confidence interval [CI] 9.6–12.2). Infections were the most common precipitating factors, while no factor was observed in 12.5%. Hypoglycemia occurred concomitantly in 27.4%. One patient died from severe hypoglycemia, resulting in a mortality rate of 0.09 per 100 PYs (95% CI 0.0–0.2). Conclusion: Adrenal crisis is not rare and can be accompanied by disastrous hypoglycemia in children with 21-OHD.