46,XY complete gonadal dysgenesis

46,XY complete gonadal dysgenesis, also known as Swyer syndrome or 46,XY pure gonadal dysgenesis, is a rare disorder of sex development in which individuals have a 46,XY karyotype (typically associated with male development) but develop as phenotypically female due to complete failure of testicular development during embryonic life. The gonads remain as non-functional fibrous tissue called streak gonads, which do not produce testosterone or anti-Müllerian hormone. As a result, the internal reproductive structures develop along the female pathway, with a uterus and fallopian tubes present, and the external genitalia appear typically female. Affected individuals are usually raised as girls and come to medical attention during adolescence when they fail to undergo spontaneous puberty and present with primary amenorrhea (absence of menstruation). They are typically of normal or tall female stature, as the Y chromosome's growth-promoting effects are partially retained. The streak gonads carry a significant risk (estimated 15–35%) of developing gonadal tumors, particularly gonadoblastoma and dysgerminoma, which necessitates prophylactic gonadectomy (surgical removal of the streak gonads) once the diagnosis is made. The condition can be caused by mutations in several genes, most notably SRY (the sex-determining region on the Y chromosome), but also NR5A1 (SF1), DHH, MAP3K1, and others. In many cases, the underlying genetic cause remains unidentified. Treatment involves hormone replacement therapy with estrogen and progesterone to induce puberty and maintain secondary sexual characteristics and bone health. Fertility is not possible through natural conception, but pregnancy via donor oocytes and in vitro fertilization has been achieved in some individuals, as the uterus is present and functional when hormonally supported.

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