46, XY complete gonadal dysgenesis (CGD) is marked by lack of testicular development, streak gonads, the presence of well-developed Mullerian structures (a uterus and fallopian tubes), underdeveloped breasts, and female external genitalia. Individuals with 46,XY CGD are typically raised female and present at puberty with amenorrhea and the absence of secondary sexual characteristics. However, the diagnosis may be suspected in utero due to an inconsistency between karyotype (46,XY) and ultrasound findings (female). In rare cases, SRY mutations have been associated with 46,XY partial gonadal dysgenesis (also called 46,XY disorder of sex development or 46,XY DSD). 46,XY DSD is characterized by the presence of ambiguous genitalia, dysgenetic testes, and absent to fully developed Mullerian structures. Both 46,XY CGD and 46,XY DSD are associated with an increased incidence of gonadoblastoma and germinoma.
46,XY gonadal dysgenesis is a genetically heterogeneous disorder with autosomal, X-, and Y-linked forms (Sarafoglou et al., 2000). The Y-linked form is caused by mutations or deletions of the SRY gene (also known as TDF or testis determining factor), which is located on chromosome Yp11.3. Typically, the Y-linked form of XY complete gonadal dysgenesis is sporadic, although approximately 30% of all identified SRY mutations are inherited (Hawkins et al., 1995). GeneDx also offers sequencing of the NR5A1 (SF-1) gene, which causes autosomal dominant 46,XY gonadal dysgenesis with or without adrenal insufficiency.
GeneDx also offers SRY FISH to determine the presence or absence of the SRY gene in individuals with 46,XX testicular DSD who have a 46,XX karyotype and ambiguous or normal male external genitalia with two testicles, azoospermia, and absent Mullerian structures.