Taylor_Speroff's Clinical Gynecologic Endocrinology and Infe

Chapter 8 • Normal and Abnormal Sexual Development 281

and gonads, but not in the placenta. A wide variety of mutations in the StAR gene (located at 8p11.2) have been described, most resulting in reduced activity of the protein. 414,417–419 The disorder also can result from a heterozygous mutation in the CYP11A1 gene encoding the cholesterol side chain cleavage enzyme, which converts cholesterol to pregnenolone. 420 In either case, all steroidogenic pathways are affected, resulting in a global deficiency of steroid hormones that reflects both the intrinsic defect in steroidogenesis and the progressive cellular damage that results from the accumulation of cholesterol. 417 Serum cortisol and aldosterone concentrations are very low, ACTH and plasma renin activity levels are very high, sex ste roid concentrations are low, and serum gonadotropin levels are elevated, even in young children. 420,421 Patients with congenital lipoid adrenal hyperplasia typi cally present very soon after birth or in early infancy with symptoms of severe adrenal insufficiency (vomiting, diar rhea, volume depletion, hyponatremia, hyperkalemia). 422 Male infants usually have female external genitalia due to the severe androgen deficiency. Females are normally devel oped at birth and even may undergo spontaneous puberty, 423 possibly because the prepubertal ovary, unlike the adrenals and testes, is relatively dormant and thus may escape cellu lar damage from cholesterol accumulation. Although two thirds of reported patients died in infancy, 421 some treated with glucocorticoids and mineralocorticoids have survived to reach puberty. 424

Disorders of Androgen Action Mutations in the gene that encodes the androgen recep tor ( AR ) can produce a variety of phenotypes in males having normal testes and testosterone production; more than 400 different AR mutations have been identified. 425 Collectively, these 46,XY DSD are known as androgen insensitivity syndromes (AISs). The genetics, pathophysi ology and endocrinology of androgen receptor disorders are quite similar. The phenotype depends on whether androgen receptors are absent entirely, 426,427 present but functionally abnormal, 428–430 or normal but decreased in quantity 428,431 (Figure 8.11) . Complete Androgen Insensitivity Syndrome Complete androgen insensitivity was first described in detail by Morris, at Yale, who coined the name “testicular feminization.” 432 However, complete AIS now is the pre ferred term. 433 Complete AIS can result from a wide variety of inactivating mutations in the AR gene, including major gene deletions, premature stop codons, splicing abnormali ties, and missense mutations that result in amino acid sub stitutions in the androgen receptor. The AR gene is located on the X chromosome (Xq12), and complete AIS therefore follows an X-linked recessive pattern of inheritance. One in three phenotypic sisters of an affected individual will have an XY karyotype. Consequently, careful investigation to identify other affected family members is warranted.

II

Androgen receptor defect

Post receptor defect

Circulation

Cytoplasm

Spermatogenesis

T + Receptor

Wolffian development

T T

Nucleus

External virilization

DHT + Receptor

5 α -reductase

Sexual maturation at puberty

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5 α -reductase deficiency

Androgen receptor defect

Post receptor defect

FIGURE 8.11