Swyer syndrome: XY chromosomes, a female body and a uterus
People with Swyer syndrome carry a 46,XY karyotype yet develop a typically female body, complete with a uterus. Their gonads never become working testes or ovaries, so puberty usually fails to start. Most learn of the condition as teenagers, when doctors investigate why nothing is happening.
The condition takes its name from Gerald Swyer, an endocrinologist at University College Hospital in London. Its formal name is XY complete gonadal dysgenesis, and it is classed as pure gonadal dysgenesis because the sex chromosomes themselves are a normal set; the fault usually lies in a particular gene. That sets it apart from Turner syndrome, where part or all of the second sex chromosome is missing.
The mechanism starts early in pregnancy. In a typical XY fetus, testes begin forming in the second month, driven by several genes, among the earliest of which is SRY on the Y chromosome. When SRY or a related gene fails, the gonads stay undifferentiated. No testosterone means no internal male structures and no virilised genitals; no anti-Müllerian hormone means the Müllerian ducts go on to form a uterus, fallopian tubes, cervix and vagina. The gonads end up as fibrous streaks. Researchers note that over 60 percent of 46,XY gonadal dysgenesis cases still lack a genetic explanation, and one exome study reported new variants in genes including GATA4 and NR5A1.
Diagnosis typically follows a teenager's delayed puberty. Blood tests show high gonadotropins, meaning the pituitary is sending its signal but the gonads are not answering. A karyotype reveals XY chromosomes, and imaging finds a uterus without ovaries. Complete androgen insensitivity can also produce an XY karyotype, but the uterus and the absence of breast development rule it out. Because the adrenal glands still make some androgens, pubic hair usually appears, though often sparsely.
Streak gonads containing Y-chromosome cells carry a high risk of cancer, especially gonadoblastoma, which can begin even in infancy, so they are usually removed within about a year of diagnosis. Estrogen and progestogen therapy then brings on female development and helps protect bones. The gonads make no eggs, but pregnancy has sometimes been achieved with assisted reproduction, and in at least one case without it. A 2017 study estimated about 1 in 100,000 females are affected.
Source: XY gonadal dysgenesis
