We plan to investigate congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency (21-OHD), a defect of cortisol biosynthesis inherited as an autosomal recessive trait linked to the HLA major histocompatibility complex. A mild variant of this disorder, """"""""non-classical"""""""" (NC) 21-OHD, is among the most common human autosomal recessive diseases, with symptoms including hirsutism and infertility. We propose a screening program in a high risk ethnic population to confirm the present high estimates of the frequency of this disorder, and to provide a suitable patient population in which the natural history of this disorder may be prospectively studied. This is likely to have significant impact on therapeutic decisions regarding individuals with this disorder. Two thirds of patients with the more severe """"""""classical"""""""" form of 21-OHD have an additional defect in aldosterone biosynthesis which can result in salt-wasting, shock and death, especially in thee neonatal period. We will investigate the role of allelism in determining the salt-wasting phenotype. We will also examine epigenetic factors which might influence salt-wasting in individuals who have recovered the capacity to synthesize aldosterone, and in HLA-identical sibs with 21-OHD who are nevertheless discordant for salt-wasting. The normal """"""""21-OHase B"""""""" gene, which encodes a specific cytochrome P450, has previously been isolated and characterized. One-fourth of classical 21-OHD alleles are deletions of this gene. Non-deleted mutant genes responsible for different forms of 21-OHD will be isolated from individuals who carry a heterozygous deletion of the 21-OHase B gene. Each mutation will be identified by DNA sequencing, and, when the effect of a mutation is not apparent from inspection of the sequence, the mutant gene will be expressed by transfection into an adrenocortical cell line. Thus, the functioning of each mutant gene can be correlated with clinical presentation. This will provide a new modality for the evaluation of this common disease, particularly applicable to prenatal diagnosis.
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