General Medical Information

Male Pseudohermaphroditism in Multiple Malformation Syndromes

Joe Leigh Simpson

Genital ambiguity may occur in individuals with various multiple malformation syndromes. Coexistence of genital ambiguity with the Meckel-Gruber syndrome, Smith-Lemli-Opitz type I syndrome, brachio-skeletal-genital syndrome, and esophageal-facial-genital syndrome has long been recognized. These disorders are inherited in either autosomal recessive or X-linked recessive fashion.

Drash syndrome is an appellation applied to individuals with Wilms’ tumor, aniridia, and male pseudohermaphroditism. This disorder is associated with deletion of chromosome 11p13, for which reason 11p is implicated as an autosomal region integral for male development. Smith-Lemli-Opitz syndrome is an autosomal recessive syndrome in which 46,XY individuals show genital abnormalities (male pseudohermaphroditism). In type II Smith-Lemli-Opitz syndrome, external genitalia may be female (sex reversal). The molecular explanation is mutation involving the gene responsible for converting 7-hydroxycholesteral cannot be converted to cholesterol. The usual molecular explanation is a defect in exon-intron splicing.

In the genito-palato-cardiac (Gardner-Silengo-Wachtel) syndrome, 46,XY individuals show phenotypic variability, not only in external genitalia but also in gonads. Complete sex reversal can even occur in 46,XY individuals who have ovaries. A recently described sex reversal syndrome is that characterized by 46,XY female siblings having spastic paraplegia, optic atrophy, and normal intelligence despite microcephali. General implications of these syndromes for the autosomal control of sex determination has long been recognized by Simpson.