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Testicular feminization syndrome (androgen insensitivity syndrome)

Androgen insensitivity syndrome is the most studied of the disorders of sexual differentiation testicular feminization syndrome, androgen insensitivity syndrome. Women with complete androgen insensitivity syndrome (CAIS) have a normal Y chromosome and fully functioning testes. The androgen receptor in this condition is either absent or unable to bind androgen or transduce the androgenic signal to target genes. XY women with androgen insensitivity syndrome are phenotypically female, with female external genitalia, a short blind-ending vagina.

The diagnosis frequently is made in infancy or childhood because most girls with CAIS have bilateral inguinal hernias containing testes. Alternatively, the girl may seek help in adolescence when menstruation does not occur despite normal breast development. Pubic hair is either completely absent or very sparse. The vagina is usually about 6 cm in length (two-thirds of normal).

Women with CAIS may be relatively tall. In adult patients, serum testosterone levels are in the male range or higher, serum LH is normal or elevated, and serum estradiol levels are between the normal male and female ranges. In 80% of cases, assays of androgen binding show this to be absent or very low (these patients are called "receptor-negative").

Because of the fact that the androgen receptor is on the X chromosome, CAIS is an X-linked disorder. In most cases, a mutation in the coding region of the gene for the AR can be demonstrated, and extensive structure-function studies have been carried out. Similar to all steroid receptors, the AR is a ligand-dependent transcription factor. Mutations in the gene encoding AR may consist of complete absence, large deletions, or point mutations introducing premature stop codons that cause complete disruption of the protein sequence. Point mutations affecting hormone binding, DNA binding, and dimerization of the receptor have enabled the construction of a detailed map of the functional domains.

In this rare condition, the phenotype resembles Klinefelter's syndrome (XXY) in that the testes are small (pealike) and dysgenetic, such that infertility is inevitable. Patients can be normal males or somewhat eunuchoid with gynecomastia. Mullerian structures are absent. The hypothesis that testes develop because of a small Y-to-X translocation bearing the testis-determining gene is borne out in 90% of cases. Y chromosome-derived DNA is apparently absent in the remaining 10% (although DNA of gonadal origin has not always been studied). It remains possible that, in some cases, testis determination can occur.

If an infant has a phallus that is intermediate in size between a normal penis and a normal clitoris, an aberrantly located urethral opening, and at least one impalpable gonad, the term ambiguous genitalia.

The two most likely diagnoses are congenital adrenal hyperplasia (21-hydroxylase deficiency) and gonadal dysgenesis (including true hermaphroditism). Partial androgen insensitivity syndrome (PAIS) and 17beta-hydroxysteroid dehydrogenase deficiency (a defect in testosterone biosynthesis) are next in order of prevalence, followed by a group of very rare conditions (11beta-hydroxylase deficiency, 3beta-hydroxysteroid dehydrogenase deficiency, 5alpha-reductase deficiency, 17alpha-hydroxylase deficiency, placental aromatase deficiency, and LH receptor mutations). In at least one third of cases, even the most thorough investigation fails to reveal the underlying cause. There is no clear distinction between what one clinician might call "a disorder of sexual differentiation" and what another might refer to as "perineal hypospadias." In patients with hypospadias, the following additional features should prompt further investigation: a family history of hypospadias, height below the third percentile, associated dysmorphic features, one or more impalpable testes, any evidence of retained mullerian structures.

Questions that should be asked on history taking are as follows: Was the mother taking any medications during pregnancy that could affect fetal genital development? Does she have any symptoms or signs of a virilizing disorder? Is there a family history of ambiguous genitalia or of perinatal death? Because genital appearances in such cases are highly variable, a staging system is extremely useful . According to the Prader classification, external genital appearances are given one of six grades from O (female) to V (male) according to the relative size of the phallus, the number of orifices, and the degree of midline fusion. Having defined the Prader grade by inspection of the genitalia, the examiner looks for other clues to the diagnosis. Careful inspection under daylight or a white light source may reveal a brownish-yellow hyperpigmentation of the genital skin if ACTH secretion is increased (e.g., an infant with congenital adrenal hyperplasia). Asymmetry of the labioscrotal folds is seen more often in cases of mixed gonadal dysgenesis and true hermaphroditism than in partial androgen insensitivity or testosterone biosynthetic defects. On a more general inspection, the infant may be found.