Objective: Childhood onset Graves’ disease (GD) has been documented to be clinically distinct from adult onset GD, and an association with the genes encoding HLA and CTLA-4 (cytotoxic T lymphocyte antigen-4) has been reported in both Caucasian and Japanese adult GD patients. The aim of this study was to determine whether HLA-DR, -DQ and CTLA-4 are associated with childhood onset GD in Japanese individuals. Methods: We investigated the genotype of HLA class II (DRB1, DQB1) and the A/G transition polymorphism of CTLA-4 exon 1 position 49 in 43 GD patients and in healthy controls for comparison. The CTLA-4 alleles were identified by the polymerase chain reaction (PCR) of genomic DNA and restriction fragment-length polymorphism analysis (PCR-RFLP) with Ita1. Results: The frequency of both HLA-DRB1*0405 and DQB1*0401 was increased in the patient group (DRB1*0405: 26.7%, p < 0.001; DQB1*0401: 25.6%, p < 0.005) compared with the controls. Patients with GD had a significantly lower frequency of the AA genotype of CTLA-4 than the controls, but there was no difference in allele frequency between the G and A allele. Conclusions: the association of HLA-DRB1 and DQB1 genotype with susceptibility to childhood onset GD differs from that in adult onset GD, whereas the association between CTLA-4 gene polymorphism and childhood onset GD is similar to that in adult onset GD in Japanese individuals, but the association is weak.

The CTLA4 gene might confer a susceptibility to childhood-onset Type 1 diabetes in the Japanese population. The association between this CTLA4 polymorphism and the HLA genotype was similar for both major groups with HLA high-risk alleles. CTLA4 might contribute to the humoral immune response to GAD in newly diagnosed subjects.

Acanthosis nigricans (AN) is a skin lesion characterized by thickening and obvious darkening of the keratin layer of the skin. It has been demonstrated to be associated with hyperinsulinemia, and is used as an empirical marker for elevated risk of type 2 diabetes. The prevalence of school children with simple obesity in Japan has recently increased to over 10%. We investigated the clinical characteristics of AN-positive and AN-negative subjects, and compared 105 obese children (64 males and 41 females) with regard to sex, percentage overweight, age distribution, duration of obesity, standard deviation score (SDS) of height, liver function, birth weight, and family history of diabetes mellitus. Forty-one (27 males, 14 females) (39.0%) of the 105 subjects had AN on the neck and/or in the axilla. There was a significant difference between the AN-positive and AN-negative groups in age (p<0.05), percentage overweight (p <0.0005), duration of obesity (p<0.03), and serum ALT level as a marker of fatty liver (p<0.01). The prevalence of AN was significantly higher in older subjects (≥8 years) and in subjects with higher levels of percentage overweight (≥50%). There was no significant difference in birth weight or family history of diabetes mellitus between the AN-positive and AN-negative groups. It is a very important to determine the frequency with which AN-positive obese subjects develop overt diabetes later in life.

Leptin levels are similar in girls and boys and increase with age in both sexes before the onset of puberty. During sexual maturation, leptin levels continue to rise in girls. However, in boys, leptin rises from the prepubertal to the early pubertal stage and then declines in the late pubertal stage. The sexual dimorphism in leptin levels is strongly related to pubertal stage. 1 In adults, males have lower leptin levels than females at any level of adiposity; for example, leptin messenger ribonucleic acid expression is lower in obese boys than in obese girls. 2 These gender differences in serum leptin concentrations are well established 3,4 and in vitro results suggest that testosterone may be an important regulator of leptin secretion. 2 A strong inverse association between serum levels of leptin and testosterone is reported in untreated and testosterone-treated hypogonadal men. 5 Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder of steroid metabolism. The most frequent and best known form is due to deficient activity of 21hydroxylase, causing increases 17α-hydroxyprogesterone (17-OHP) and androstenedione and a reduction in cortisol. Clinical symptoms include virilization, most notable in females, and salt wasting in many affected individuals. A markedly elevated testosterone level in the serum is a feature of CAH. The aim of the present investigation was to assess whether manipulation of testosterone in a girl with CAH would alter serum leptin concentrations independently of changes in body fat mass. Case ReportA 7.6-year-old girl was referred to our hospital because of over stature and severe clitoromegaly (Prader stage I). 6 There was no history of consanguinity. She was born to a mother at full-term after an uncomplicated pregnancy with a birth weight of 3382 g. Her mother was completely healthy and received no glucocorticoid preparation in any form during pregnancy. Neonatal screening for whole blood 17-OHP was reported to be normal (6.7 ng/mL; cut-off value 7.0) and no endocrine studies were performed. Her neonatal course was uneventful. At the age of 7.6 years, the mother noticed accelerated linear growth and Tanner stage 3 appearance of pubic hair. The patient's height was 141.3 cm (+3.74 SD) with a previous annual growth rate of 8.0 cm. The patient was well nourished and her blood pressure was 134/64 mmHg. Her bone age was 11.8 years according to the Tanner-Whitehouse Radius : Ulna and Short bones (RUS) method for the Japanese population. 7 The patient manifested Tanner stage 1 breast development, but had not menstruated at that time. The karyotype obtained at that time was 46,XX. Endocrinologic examinationsPelvic ultrasonography identified normal-sized ovaries and uterus for age; however, abdominal computed tomography (CT) revealed enlargement of both adrenal glands. Serum electrolyte levels were normal (Table 1). Hormonal examination revealed elevated plasma 17-OHP and testosterone levels, but serum leptin levels were lower than those of normal children. A leuteinizing hormone-re...