ABNORMALITIES OF GONADAL DIFFERENTIATION

Gonadal differentiation involves a complex interplay of developmental pathways. The sex determining region Y (SRY) gene plays a key role in testis determination, but its interaction with other genes is less wel l understood. Abnormalities of gonadal differentiation result in a ran ge of clinical problems. 46,XY complete gonadal dysgenesis is defined by an absence of testis determination. Subjects have female external g enitalia and come to clinical attention because of delayed puberty. in dividuals with 46,XY partial gonadal. dysgenesis usually present in th e newborn period for the valuation of ambiguous genitalia. Gonadal his tology always shows an abnormality of seminiferous tubule formation. A diagnosis of 46,XY true hermaphroditism is made if the gonads contain well-formed testicular and ovarian elements. Despite the pivotal role of the SRY gene in testis development, mutations of SRY are unusual i n subjects with a 46,XY karyotype and abnormal gonadal development, 46 ,XX maleness is defined by testis determination in an individual with a 46,XX karyotype. Most affected individuals have a phenotype similar to that of Klinefelter syndrome. In contrast, subjects with 46,XX true hermaphroditism usually present with ambiguous genitalia. The majorit y of subjects with 46,XX maleness have Y sequences including SRY in ge nomic DNA. However, only rare subjects with 46,XX true hermaphroditism have translocated sequences encoding SRY. Mosaicism and chimaerism in volving the Y chromosome can also be associated with abnormal gonadal; development. However, the vast majority of subjects with 45,X/46,XY mo saicism have normal testes and normal male external genitalia.