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A 5-year-old XY pseudohermaphrodite was found to have a defect of steroid biosynthesis consistent with a partial deficiency of the enzyme 3β-hydroxysteroid dehydrogenase (3β-HSD). Circulating concentrations of ⁵ steroids and ⁵ urinary steroid metabolites were elevated and remained elevated after orchidectomy. There was no evidence of salt loss, plasma renin being within normal limits, and no detectable glucocorticoid abnormality. The coding sequences of the genes for 3β-HSD types I and II were amplified by PCR and screened for mutations by denaturing gradient gel electrophoresis (DGGE) and manual and automatic DNA sequencing. A mutation in the gene for 3β-HSD type II was observed at codon 173 (CTACGA), leading in the affected patient to a homozygous substitution in which the leucine at residue 173 was altered to an arginine (L173R). The propositus's 2-year-old XX sister was also homozygous for L173R and showed the biochemical characteristics of partial 3β-HSD deficiency without clinical symptoms or signs. The mutation segregated as an autosomal recessive. Three related heterozygous adult females showed evidence of a small over-production of ⁵ steroids and steroid metabolites and a variable reduction in ovarian function. Concentrations of ⁵ steroids and steroid metabolites in the heterozygous father of the propositus were within the normal range.

These data are discussed in relation to the endocrine causes of pseudohermaphroditism and hirsutism. Evidence for tight linkage between the genes for 3β-HSD types I and II was obtained using a microsatellite polymorphism in the third intron of the gene for 3β-HSD type II and synonymous and non-synonymous mutations and polymorphisms in the gene for 3β-HSD type I. The latter polymorphisms were located 88 bp apart at the 3' end of the type I coding sequence and could be physically resolved as haplotypes using DGGE. The application of DGGE to the analysis of mutations in members of a multigene family is discussed.

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