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Lipoid Adrenal Hyperplasia

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 in the cytoplasm. The adrenals become grossly engorged with lipid, hence the name "lipoid adrenal hyperplasia."

Treatment with glucocorticoid, mineralocorticoid, and salt corrects the metabolic abnormality. Estrogen replacement therapy is given to induce puberty (combined with cyclical progestogen in 46,XX cases).

Androgen insensitivity syndrome is the most studied of the disorders of sexual differentiation. 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, and no uterus.

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) but can be much shorter. Women with CAIS may be relatively tall. In adult patients, serum testosterone levels.

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.

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%.