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Swyer's Syndrome (Complete 46,XY Gonadal Dysgenesis)

If the gonad fails to progress beyond the indifferent stage, it may produce no testosterone. Complete XY gonadal dysgenesis usually is diagnosed when a healthy girl of normal stature becomes concerned in her midteens about lack of pubertal development. Eunuchoid skeletal proportions may be found, and the bone age will be delayed Swyer's Syndrome. Primary gonadal failure is indicated by elevated levels of serum follicle-stimulating (FSH) and luteinizing hormone (LH) and a low plasma estradiol level. Pelvic ultrasound shows the presence of a small uterus.

Chromosomal mosaicism is the cause in most cases; however, in the last 8 years, several genes that regulate gonadal differentiation and testis determination have been discovered, and mutations in several of them have been found in association with gonadal dysgenesis. In 10% to 15% of cases, complete 46,XY gonadal dysgenesis is caused either by a mutation in the SRY gene or by a Yp deletion of the pseudoautosomal junction region.

All patients with CYP17 (also called P450 c17 or 17alpha-hydroxylase) deficiency are female regardless of whether they are XX or XY, because there is a complete block in the biosynthesis of androgens and estrogens both prenatally and postnatally. Adrenal hyperplasia results from impairment of cortisol biosynthesis and a secondary elevation in ACTH secretion. Consequently, the secretion of both desoxycorticosterone and corticosterone is greatly elevated, causing hypertension and hypokalemia.

Treatment with dexamethasone reduces ACTH secretion and therefore the levels of desoxycorticosterone and corticosterone, and blood pressure returns to normal. Estrogen is given from age 11 years to 46,XY patients who have no uterus and in combination with cyclical progestogen to 46,XX patients who do have a uterus. Low-dose testosterone is given to induce pubic hair development. The ovaries of 46,XX patients contain numerous follicles. In one case in which testosterone was provided as an aromatizable substrate, follicular maturation could be induced, but fertilization proved impossible. Numerous mutations in the gene for CYP17 have been demonstrated in patients with deficiency. Several have been expressed in COS cells.

In this rare disorder, affected XX and XY infants are phenotypic females who lack the ability to secrete any adrenal or gonadal steroids owing to a complete block in cholesterol side-chain cleavage. Salt loss becomes clinically evident within a week of birth, and severe hypoglycemia may also occur. The lips and genitalia are often deeply pigmented.

Because of the apparent absence of cholesterol side-chain cleavage enzyme activity, it was assumed that the defect would reside in the gene encoding P450 scc (CYP11A); however, when this gene was cloned, it was found to be structurally normal in all cases of lipoid adrenal hyperplasia. Subsequently, mutations were found in the gene encoding the steroidogenic acute regulatory protein (StAR). This protein regulates the transport of cholesterol into the mitochondrion where it can be acted upon by P450 scc (CYP11A). A mutation in the gene encoding StAR results in the accumulation of cholesterol.