Among a group of patients with abnormal sexual differentiation, we have identified two subjects who had a 46,XY karyotype, ambiguous genitalia, and well-developed Mullerian structures, but normal appearing testes. The presence of ambiguous genitalia and persistent Mullerian structures implied both Leydig cell and Sertoli cell dysfunction, hence, gonadal dysgenesis. However, the normal testicular histology suggested that the underlying abnormality was not a defect in testis determination itself but an abnormality in timing of gonadal ridge and testis development. In one of the two subjects genomic DNA was available. The sequence of the SRY gene was normal. Because rare patients with partial androgen insensitivity may have a similar phenotype, the AR gene was evaluated by denaturing gradient gel electrophoresis (DGGE) and was normal. Some subjects with mutation of the WT1 gene or with deletion of the distal short arm of chromosome 9 may have similar phenotypes. The WT1 gene was studied by single-strand conformation polymorphism (SSCP) analysis and was normal. In addition, there was no loss of heterozygosity of polymorphic markers in distal 9p. The gene for Mullerian inhibiting substance (MIS) was also studied by SSCP and was normal. Although the exact mechanism for the defect in the two subjects is unknown, it may be due to an abnormality in a gene or genes involved in the timing of gonadal ridge development.
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