MAMLD1 (mastermind-like domain containing 1), previously known as CXorf6 (chromosome X open reading frame 6), has been shown to be a causative gene for hypospadias. This is primarily based on the identification of nonsense mutations (E124X, Q197X, and R653X), which undergo nonsense mediated mRNA decay, in patients with penoscrotal hypospadias. Subsequent molecular studies have shown that the mouse homolog is transiently expressed in fetal Sertoli and Leydig cells around the critical period for sex development, and that transient knockdown of Mamld1 results in significantly reduced testosterone production in murine Leydig tumor cells. These findings suggest that the MAMLD1 mutations cause hypospadias primarily because of compromised testosterone production around the critical period for sex development.

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Steroid 21-hydroxylase deficiency (21-OHD) accounts for 90-95% of congenital adrenal hyperplasia (CAH) cases. It is classified into three distinct clinical phenotypes: the salt-wasting (SW), simple virilizing (SV) and nonclassical forms (NC). As girls with the SW and SV forms of 21-OHD are exposed to high systemic levels of adrenal androgens during fetal life, they show genital ambiguity. To ameliorate the degree of genital virilization, prenatal dexamethasone treatment has been performed for more than two decades, although mainly in the USA and Europe. This treatment has proven to be effective in preventing or reducing genital virilization. Some data also show that prenatal diagnosis and treatment are safe for the mother and fetus. However, prenatal treatment is still controversial for the following reasons. First, the risk of having an affected female fetus is only one in eight when both parents are known carriers of the autosomal recessive trait. Therefore, seven of eight fetuses will receive dexamethasone unnecessarily, and this raises ethical questions. Furthermore, maternal side effects such as excessive weight gain and hypertension have been observed. Finally, the long-term safety and outcome for dexamethasone-exposed children have not been established. In Japan, prenatal diagnosis and treatment has rarely been reported because of these reasons. Therefore, we must be cautious, and this treatment should be carried out in special centers with the approval of their ethical committees, that are capable of performing chorionic villus sampling (CVS) and subsequently determining the karyotype and genotype of 21-OHD.

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Human chromosome 14q32.2 carries a cluster of imprinted genes. They include paternally expressed genes (PEGs) such as DLK1 and RTL1, and maternally expressed genes (MEGs) such as GTL2 (alias, MEG3), RTL1as (RTL1 antisense), and MEG8. Consistent with this, paternal and maternal uniparental disomies for chromosome 14 (upd(14)pat and upd(14)mat) cause distinct phenotypes. In this review, we summarize the current knowledge about the underlying factors for the development of upd(14)pat and upd(14)mat phenotypes. The data available suggest that the DLK1-GTL2 intergenic differentially methylated region (IG-DMR) plays an important role in the maternal to paternal epigenotypic switch, and that excessive RTL1 expression and decreased DLK1 and RTL1 expression play a major role in the development of upd(14)pat-like and upd(14)mat-like phenotypes, respectively.

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We examined pathogenic characteristics in Japanese children with type 1 diabetes presenting before 5 years of age. The subjects were 23 Japanese children, 9 males and 14 females, 1.1-4.8 yr of age at diagnosis. The majority had severe metabolic decompensation accompanied by complete absence of β-cell function at diagnosis. We found a high frequency of preceding viral illness (41.7%) among them. The prevalence of antibodies to GAD and IA-2 at diagnosis in young children were significantly lower than those in older cases diagnosed after 5 yr of age (31.6% vs. 86.3%, 47.1% vs. 82.5%, respectively). These findings suggest that non-autoimmune mechanisms or age-related differences in autoimmunity could be involved in the pathogenesis of diabetes in young children. In regard to diabetes-related HLA-DRB1 and DQB1 alleles, all subjects had high-risk genotypes in both alleles. On the other hand, none of the patients had any of the protective genotypes in either allele. In regard to haplotypes, the frequencies of DRB1*0405-DQB1*0401 and DRB1*0901/ DQB1*0303 were 60.9% and 52.2%, respectively, and both these haplotypes are associated with strong susceptibility to type 1 diabetes. Patients with early-childhood onset may have diabetes-related autoimmunity and genetic backgrounds different from those of patients diagnosed at a later age.

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