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Swyer syndrome

Swyer syndrome, or XY gonadal dysgenesis, is a type of female hypogonadism in which no functional gonads are present to induce puberty in an otherwise normal girl whose karyotype is then found to be XY. Her gonads are found to be nonfunctional streaks. Oestrogen and progesterone therapy is usually then commenced. The gonads are normally removed surgically because they do not function and may develop cancer.

Pathogenesis

The first known step of sexual differentiation of a normal XY fetus is the development of testes. The early stages of testicular formation in the second month of gestation require the action of several genes, of which one of the earliest and most important is SRY, the “sex-determining region of the Y chromosome”.

Mutations of SRY account for most cases of Swyer syndrome. When this gene is defective, testes fail to develop in an XY (genetically male) fetus. Without testes, no testosterone or antimullerian hormone are produced. Without testosterone the external genitalia fail to virilize, resulting in female genitalia. Without testosterone, the wolffian ducts fail to develop, so no internal male organs are formed. Without AMH the mullerian ducts develop into normal internal female organs (uterus, fallopian tubes, cervix, vagina).

A baby girl is born who is normal in all anatomic respects except that she has nonfunctional streak gonads instead of ovaries or testes. As girls’ ovaries produce no important body changes before puberty, there is usually no suspicion of a defect of the reproductive system until puberty fails to occur.

Diagnosis

Because of the inability of the streak gonads to produce sex hormones (both oestrogens and androgens), most of the secondary sex characteristics do not develop. This is especially true of estrogenic changes such as breast development, widening of the pelvis and hips, and menstrual periods. Because the adrenal glands can make limited amounts of androgens and are not affected by this syndrome, most of these girls will develop pubic hair, though it often remains sparse.

Evaluation of delayed puberty usually reveals the presence of pubic hair, but elevation of gonadotropins, indicating that the pituitary is providing the signal for puberty but the gonads are failing to respond. The next steps of the evaluation usually include checking a karyotype and imaging of the pelvis. The karyotype reveals XY chromosomes and the imaging demonstrates the presence of a uterus but no ovaries (the streak gonads are not usually seen by most imaging). At this point it is usually possible for a physician to make a diagnosis of Swyer syndrome.

Treatment

The consequences to the girl with Swyer syndrome of her streak gonads:

  1. Her gonads cannot make oestrogen, so her breasts will not develop and her uterus will not grow and menstruate until she is given oestrogen. This is often given through the skin now.
  2. Her gonads cannot make progesterone, so her menstrual periods will not be predictable until she is given a progestin, still usually as a pill.
  3. Her gonads cannot produce eggs so she will not be able to conceive children naturally. A woman with a uterus but no ovaries may be able to become pregnant by implantation of another woman’s fertilised egg (embryo transfer).
  4. Streak gonads with Y chromosome-containing cells have a high likelihood of developing cancer, especially gonadoblastoma. Rarely, this can begin as early as a few years of age, so the streak gonads are usually removed by surgery within a year or so after discovery of the diagnosis.

Similar conditions

Swyer syndrome results from a failure of one of the earliest stages of differentiation of a genetic male: translation of the SRY gene to initiate testicular development. In a minority of cases of apparent Swyer syndrome, some other very early defect of testicular development (testicular dysgenesis) occurs. Since estrogens are made from androgens, any severe defect of androgen production (e.g., congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency) will also produce estrogen deficiency and result in a failure of pubertal development in a girl with an XY karyotype. On the other hand, a defect of androgen action (e.g., androgen insensitivity syndrome) is readily distinguished because the breasts begin to develop normally without much delay, though pubic hair may be minimal.

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