MOLECULAR-BIOLOGY OF DISORDERS OF SEX-DIFFERENTIATION

Sexual ambiguity can be a difficult and sometimes confusing diagnostic problem in children. Recent developments in molecular biology have pr ovided the opportunity to analyze the gene responsible for testicular determination, SRY, the androgen receptor gene and the gene encoding t he cP450 enzyme specific for 21-hydroxylation, CYP21B, whose defects a re responsible for congenital adrenal hyperplasia. Southern-blotting s tudies and PCR analyses of SRY, androgen receptor and CYP21B genes can be routinely used for the direct diagnosis of gonadal dysgenesis, and rogen insensitivity syndromes and congenital adrenal hyperplasia, resp ectively. In sex-reversed XY females, several de novo mutations or del etions in the SRY gene have been reported. Defects in the human androg en receptor cause a spectrum of defects in male phenotypic sexual deve lopment associated with abnormalities in the receptor protein. Analyse s of the androgen receptor gene structure have identified the causativ e mutation in some families: mutations that result in large-scale alte rations of the structure of the androgen receptor, mRNA or gene mutati ons that alter the primary structure of the androgen receptor protein and mutations that alter the level of mRNA. The diversity of clinical phenotypes, apparent in 21-hydroxylase deficiency, is paralleled by a considerable degree of mutational heterogeneity in the CYP21 gene locu s. Various changes causing severe 21-hydroxylase deficiency have been reported: point mutations, gene conversions and gene deletions. In con clusion, substantial progress has been made elucidating genetic defect s causing sex reversal in XY females, the androgen insensitivity syndr ome and congenital adrenal hyperplasia. Molecular genetics can also be applied for carrier identification and prenatal diagnosis.