Taylor_Speroff's Clinical Gynecologic Endocrinology and Infe

Chapter 8 • Normal and Abnormal Sexual Development 269

deficiency, incidence varies with ethnicity. In Israel, the incidence of 11 β -hydroxylase deficiency is as high as 1 in 5,000 births among Jews of Moroccan ancestry. 197 The enzyme deficiency is an autosomal recessive disorder caused by mutations in the CYP11B1 gene, which is located on the long arm of chromosome 8 (8q21–q22). The known muta tions include missense mutations that result in production of an inactive enzyme, 165,198–200 frameshift and nonsense mutations that prevent enzyme synthesis, 201–203 and oth ers resulting from unequal recombination between the CYP11B1 and CYP11B2 genes. 204,205 The CYP11B2 gene is located in the same region on chromosome 8 and encodes an enzyme having both 11 β -hydroxylase and 18-hydroxylase (also designated P450c18 or P450aldo) activity, mediating the conversion of corticosterone to 18-hydroxycorticoste rone and, subsequently, aldosterone. There are no specific correlations between genotype and phenotype in patients with 11 β -hydroxylase deficiency. 206 Although the late-onset form of 11 β -hydroxylase deficiency may be caused by muta tions yielding an enzyme with reduced but still significant activity, none has yet been identified. Diagnosis of 11 β -hydroxylase deficiency is based on demonstrating high serum concentrations of 11-deoxy cortisol and 11-deoxycorticosterone, as well as testoster one; both basal and ACTH-stimulated levels generally are elevated in affected neonates. 189,207,208 In adolescents and young adults, basal 11-deoxycortisol and 11-deoxycorti costerone levels may be normal and ACTH stimulation often is required to make the diagnosis ; results must be compared to established age and sex-specific normal values. 3 β -Hydroxysteroid Dehydrogenase Deficiency

In the late-onset nonclassical form of 21-hydroxylase deficiency, serum 17-OHP concentrations often are only slightly elevated, especially late in the day, and the serum dehydroepiandrosterone sulfate (DHEA-S) concentration usually is normal. In children, morning values greater than 82 ng/dL suggest the diagnosis, which can be confirmed by performing an ACTH stimulation test. In adult women, morning values less than 200 ng/dL (obtained during the early follicular phase of the cycle) exclude the diagnosis, levels over 800 ng/dL are virtually diagnostic, and inter mediate results require additional evaluation with an ACTH stimulation test; in most patients with nonclas sical 21-hydroxylase deficiency, the stimulated 17-OHP level will exceed 1,500 ng/dL. 139,181,188 A 21-hydroxylase deficiency can be distinguished from 11 β -hydroxylase and 3 β -HSD deficiencies by also measuring 11-deoxycortisol and 17 α -hydroxypregnenolone, but the distinction in patients with late-onset CAH has little or no clinical relevance and generally is unnecessary. 11 β -Hydroxylase (P450c11) Deficiency The enzyme 11 β -hydroxylase (also designated P450c11 and CYP11B1) mediates the conversion of 11-deoxycortisol to cortisol and of 11-deoxycorticosterone to corticosterone (an intermediate steroid in aldosterone synthesis). The clinical features of 11 β -hydroxylase deficiency result from the excess production of adrenal androgens and the mineralocorticoid action of 11-deoxycorticosterone; 11-deoxycortisol has no significant biologic activity. Although 11 β -hydroxylase deficiency is the second most common cause of CAH, it accounts for only about 5–8% of adrenal steroid enzyme defects. 168,169,189 Like 21-hydroxy lase deficiency, 11 β -hydroxylase deficiency has severe salt wasting and simple virilizing forms and a milder late-onset form. In females, 11 β -hydroxylase deficiency can result in virilization of the external genitalia, but also may pres ent later, in children with sexual precocity or in adolescent or young women with hirsutism and menstrual irregu larity. 190–192 In most affected individuals, the disorder has unique clinical features that help to distinguish it from 21-hydroxylase deficiency. Whereas both 21-hydroxylase deficiency and 11 β -hydroxylase deficiency may result in salt wasting, approximately two-thirds of patients with 11 β -hydroxylase deficiency exhibit hypertension due to an increased production of mineralocorticoids. 189,193–195 Hypokalemia also may be observed and plasma rennin activ ity often is low. These effects generally have been attributed to excess production of 11-deoxycorticosterone, which has significant mineralocorticoid activity, although blood pres sure and serum 11-deoxycorticosterone concentrations do not correlate closely. 190,196 The explanation for the wide varia tion in the clinical manifestations of 11 β -hydroxylase defi ciency is not clear. The overall incidence of 11 β -hydroxylase deficiency is approximately 1 in 100,000 live births, but like 21-hydroxylase

II

The enzyme 3 β -hydroxysteroid dehydrogenase/D 5 -D 4 isom erase (3 β -HSD) catalyzes the oxidation and isomerization of D 5 -3 β -hydroxysteroid precursors into D 4 -ketosteroids, an essential step in the formation of all classes of steroid hor mones (glucocorticoids, mineralocorticoids, progestogens, androgens, and estrogens). There are two 3 β -HSD isoen zymes, designated type I and type II. The type I 3 β -HSD gene ( HSD3B1 ) mediates 3 β -HSD activity in the placenta and peripheral tissues (skin, breasts, prostate) and the type II 3 β -HSD gene ( HSD3B2 ) is active in the adrenal, ovary, and testis. Deficiency of type II 3 β -HSD causes an uncommon form of CAH, accounting for less than 5% of cases. 209 The type I isoenzyme is normal in patients with 3 β -HSD defi ciency. Consequently, serum concentrations of D 4 steroids, such as 17-OHP and androstenedione, can be normal or even sometimes modestly elevated in affected patients. Serum lev els of the substrates for the type I enzyme (pregnenolone, 17 α -hydroxypregnenolone, DHEA) are increased due to the defect in the type II enzyme in the adrenals and gonads. The clinical presentation of patients with 3 β -HSD defi ciency varies significantly, but can be divided into salt-­ wasting and non–salt-wasting forms. The salt-wasting form has been associated with nonsense mutations introducing Copyright © 2019 Wolters Kluwer, Inc. Unauthorized reproduction of the content is prohibited.