Molecular and clinical studies of three cases of female pseudohermaphroditism with caudal dysplasia suggest multiple etiologies

Female pseudohermaphroditism with caudal dysplasia is a clinical entity in which normal-appearing male genitalia may occur in the apparent absence of testosterone or the sex-determining gene (SRY). We have extended observations of two previously reported cases, and report a third case, which strongly suggests multiple etiologies. The first case was one of identical twins. The other identical twin did not show female pseudohermaphroditism with caudal dysplasia, but both patients had the rare birth defect of neonatal cataracts. We have explored skewed X-inactivation as a possible difference between the two twins, with a negative result. The second case had a deletion at 10q25.3→ter. This is near the location of PAX2, and we searched for mutations in PAX2 in both this and the first case, with negative results. Neither patient had a scrotal raphe, suggesting that a failure of division of the cloacal membrane was an important step in their development of female pseudohermaphroditism. The final case is newly described and differed from the above two in the presence of a scrotal raphe and an elevated testosterone level. Although no source for the testosterone was found, this case suggests that the etiology in this patient was different and that the presence of a scrotal raphe can be used to distinguish between at least two etiologies.