Monographs on Endocrinology Volume 26 Edited by F. Gross, Heidelberg' M. M. Grumbach, San Francisco A. Labhart, Zurich . M. B. Lipsett, Bethesda T. Mann, Cambridge' L. T. Samuels (t), Salt Lake City J. Zander, Munchen M. I. New L. S. Levine Congenital Adrenal Hyperplasia With 35 Figures and 6 Tables Springer-Verlag Berlin Heidelberg New York Tokyo 1984 Maria I. New, M. D. Lenore S. Levine, M.D. Division of Pediatric Endocrinology Department of Pediatrics The New York Hospital-Cornell Medical Center 525 East 68th Street New York, NY 10021jU.S.A. ISBN-13 :978-3-642-820 13-7 e-ISBN- 13 :978-3-642-82011-3 DOl: 10.1007/978-3-642-82011-3 Library of Congress Cataloging in Publication Data New. Maria L Congenital adrenal hyperplasia. (Monographs on endocrinology; v. 26) Includes bibliographical references and index. 1. Adrenogenital syndrome. 2. Pediatric endocrinology. L Levine, L. S. (Lenore S.), 1933~ . II. Title. III. Series. RJ420.A3N48 1984 618.92'45 84-1234 ISBN-13 :978-3-642-82013-7 (US.) This work is subject to copyright. All rights are reserved, whether the whole or part of the ma terial is concerned, specifically those of translation, reprinting, fe-use of illustrations, broad casting, reproduction by photocopying machine or similar means, and storage in data banks. Under §54 of the German Copyright Law where copies are made for other than private use. a fee is payable to 'Verwertungsgesellschaft Wort'. Munich. 1[. Springer-Verlag Berlin. Heidelberg 1984 Softcover reprint of the hardcover 1s t edition 1984 The use of registered names, trademarks, etc. in this publication does not imply. even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product Liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. 2127/3020-543210 Acknowledgements Much of the work described in this monograph was supported by NIH grants HD 00072, HD 15084 and HL 17749, and by a grant (RR 47) from the General Clinical Research Centers Program of the Division of Research Resources, NIH. This manuscript could not have been completed without the tireless efforts and extremely knowledgeable assistance of Mrs. Vita Amendolagine and Ms. Robin Grimm. Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IX 1 Steroidogenesis and Enzymatic Conversions of Adrenal Steroid Hormones. . ... ... . . ...... . ..... . . . . .. . .. .. .. .... ......... 1 A. Steroidogenesis............................................ 1 I. Mineralocorticoids (17-Deoxy Pathway). . . . . . . . . . . . . . . . . . 1 II. Glucocorticoids (17-Hydroxy Pathway) .................. 1 III. Sex Steroids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 B. Mechanism of Adrenal Steroid Regulation . . . . . . . . . . . . . . . . . . . 4 2 Fetal Sexual Development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 3 Enzyme Defects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 A. 21-Hydroxylase Deficiency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 I. Simple Virilizing 21-Hydroxylase Deficiency. . . . . . . . . . . . . . . 9 II. Salt-Wasting 21-Hydroxylase Deficiency................... 11 B. 11[)-Hydroxylase Deficiency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 C. 3[)-Hydroxysteroid Dehydrogenase Deficiency. . . . . . . . . . . . . . . . 13 D. 17et-Hydroxylase Deficiency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 E. Cholesterol Desmolase Deficiency. . . . . . . . . . . . . . . . . . . . . . . . . . . 15 F. Corticosterone Methyloxidase Deficiency .................... 18 I. Type I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 II. Type II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 G. 17[)-Hydroxysteroid Dehydrogenase Deficiency. . . . . . . . . . . . . . . 20 H. 17,20-Lyase Deficiency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 4 Recent Advances: The Fasciculata and Glomerulosa as Two Distinct Glands .. ...................... " . . .. . .... . . .. .. ..... . .. . 22 A. 11 [)-Hydroxylase Deficiency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 B. 21-Hydroxylase Deficiency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 C. 17et-Hydroxylase Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 D. 3[)-Hydroxysteroid Dehydrogenase Deficiency. . . . . . . . . . . . . . . . 30 5 Treatment................................................ 32 A. Endocrine Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 B. Sex Assignment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 VIII Contents 6 Pubertal Development ..................................... 37 A. 21-Hydroxylase Deficiency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 I. Menstrual Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 II. Male Reproductive Function ............................ 39 B. 11f3-Hydroxylase Deficiency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 C. 3f3-Hydroxysteroid Dehydrogenase Deficiency. . . . . . . . . . . . . . . . 41 D. 17~-Hydroxylase Deficiency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 E. Cholesterol Desmolase Deficiency. . . . . . . . . . . . . . . . . . . . . . . . . . . 42 F. Corticosterone Methyloxidase Deficiency: Types I and II ...... 42 G. 1713-Hydroxysteroid Dehydrogenase Deficiency . . . . . . . . . . . . . . . 43 H. 17,20-Lyase Deficiency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 7 Genetics................................................. 44 A. Population Studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 B. HLA Linkage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 C. Heterozygote Detection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 D. Genetic Linkage Disequilibrium. . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 E. Nonclassical 21-Hydroxylase Deficiency ..................... 49 F. Hormonal Standards for Genotyping 21-Hydroxylase Deficiency 60 G. Allelic Variants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 H. Clinical Spectrum of 21-Hydroxylase Deficiency: Phenotypic Variability. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 I. HLA Linkage to Other Enzyme Defects of Steroidogenesis. . . . . 64 J. Screening and Future Population Studies .................... 64 8 Prenatal Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 A. 21-Hydroxylase Deficiency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 B. 11f3-Hydroxylase Deficiency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 C. Cholesterol Desmolase Deficiency. . . . . . . . . . . . . . . . . . . . . . . . . . . 68 Summary................................................... 69 References .................................................. 71 Subject Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 Introduction Congenital adrenal hyperplasia (CAH) consists of a group of disorders of adrenal steroidogenesis. Each disorder results from an inherited deficiency of one of the several enzymes necessary for normal steroid synthesis. The different enzyme deficiencies produce characteristic patterns of hormonal abnormalities; the clinical symptoms of the different forms of CAH depend on the particular hormones that are deficient or that are produced in excess. The earliest documented description of CAH was by DeCrecchio in 1865 (DeCrecchio 1865). This Neapolitan anatomist described a cadaver having a penis with first degree hypospadias but no externally palpable gonads. Dis section revealed a vagina, uterus, fallopian tubes, ovaries, and markedly enlarged adrenals. It is interesting that the subject suffered a confusion of sex assignment, being declared a female at birth and a male 4 years later. He conducted himself as a male sexually and socially. Since the original descrip tion of this case, investigators have unravelled the pathophysiology of the inborn errors of steroidogenesis. 1 Steroidogenesis and Enzymatic Conversions of Adrenal Steroid Hormones A. Steroidogenesis The adrenal synthesizes three main classes of hormones: mineralocorticoids (17-deoxy pathway), glucocorticoids (17-hydroxy pathway), and sex steroids. A simplified scheme of adrenal steroidogenesis appears in Fig. 1. Each hydro xylation step is indicated and the newly added hydroxyl group is circled. The adrenocorticotropic hormone (ACTH) acts on the adrenals to increase the conversion of cholesterol to pregnenolone, the principal substrate for all these pathways. ACTH binds to receptors on the external membranes of adrenal cortical cells, stimulating increased synthesis of adenosine-3',5' monophosphate (cyclic AMP). Cyclic AMP activates adrenal cellular phos phoprotein kinases, which catalyze the side-chain cleavage, converting cho lesterol to pregnenolone (Garren et al. 1971; Harding 1979). I. Mineralocorticoids (17-Deoxy Pathway) Pregnenolone, a L\ 5 -steroid, is converted to a biologically active L\ 4 -steroid, progesterone, by the enzymes 3,B-hydroxysteroid dehydrogenase (3,B-HSD) and an isomerase. Progesterone is then hydroxylated at the C position to 21 form deoxycorticosterone (DOC), which has a salt-retaining ability. When DOC is hydroxylated at the C position, corticosterone (compound B) is ll formed. Corticosterone is a weak mineralocorticoid and is the precursor of aldosterone, the most potent salt-retaining hormone (Gaunt 1971). Synthesis of aldosterone, which is unique because of the aldehyde group at C is 18, restricted to the outer zone of the adrenal cortex, the zona glomerulosa (Ulick and Vetter 1965; Ulick 1976a). The mechanism of synthesis of aldosterone from corticosterone has not been entirely elucidated (Ulick 1976a). II. Glucocorticoids (17-Hydroxy Pathway) Glucocorticoid synthesis requires hydroxylation at the C position. In 17 studies of bovine adrenal cortex, negligible 17 -hydroxylase activity has been found in the cells of the zona glomerulosa, in contrast to the active 17- hydroxylation occurring in the inner adrenal zona fasciculata (Harkins et al. 1974). A similar pattern of 17-hydroxylase activity is believed to exist in the human adrenal cortex, and it is generally accepted that glucocorticoids and adrenal androgens, both of which depend on 17-hydroxylation for their synthesis, originate predominantly in the zona fasciculata and the zona reticularis. Pregnenolone and progesterone yield 17-hydroxypregnenolone and 17-hydroxyprogesterone (17-0HP), respectively, when hydroxylated at the C17 position. The L\ 5-steroid 17-hydroxypregnenolone is converted to 17- 2 Steroidogenesis and Enzymatic Conversions of Adrenal Steroid Hormones MINERALOCORTICOID GLUCOCORTICOID SEX HORMONES . rt5; D.~::3\ fH3 ~rt5~ "~ ! HO~ HOaY1 170H 17,20 lyase Preg.e.olo.e • 110H preg.e.olo.ei • OHEA 3~HSO 3~HSO rH3 D~: _,m~ ~ O~ ",20 Pragester.ne 1 170H • 110H pro.estero.e! -lyase "'4 A.dros0te .e4io.e 210H CH,@ 210H CH,@ ,O:?I I 17{3 HSJ ,~~ 1 1 DOC II OH rH,OH S llOH Testosterone rH,OH ~JtS0 (@~~OH o~ o~ 1 B lSOH ~H,OH i6@Hb,C c=o lBOHB : lSOH dehydro,gecnase &1 HbO fH',O H Fig. 1. Simplified scheme for adrenal steroidogenesis. Each hydroxylation step is indicated, and the newly added hydro Aldostero.e xyl group is circled. (After New and Levine 1973) OHP, a ~4-steroid, by enzymatic steps similar to those that convert pregnenolone to progesterone in the 17-deoxy pathway. When 17-0HP under goes 21-hydroxylation, 11-deoxycortisol (compound S) is formed. 11- Deoxycortisol is further hydroxylated at C to form cortisol (compound F), II the most potent glucocorticoid in humans. Thus it can be seen from Fig. 1 that parallel hydroxylation steps at C and C of progesterone and 17-0HP ZI ll result in the formation of corticosterone and cortisol, respectively. Although these steps are parallel, it has not been proven that the enzymes for the 17- hydroxylated substrates are identical to those for the 17-deoxy substrates. III. Sex Steroids The main unconjugated C steroid secreted by the adrenal cortex is de l9 hydroepiandrosterone (DHEA).1t results from the side-chain cleavage of the C steroid, 17 -hydroxypregnenolone, by the action of a desmolase enzyme. ZI Steroidogenesis 3 NORMAL A DRENOGEN I TAl I HYPOTHAlAMUSr-NeUral. sllmull ! : Fig. 2. The regulation of cortisol - secretion in normal subjects and in Cortisol patients with congenital adrenal hy II i perplasia. (After New and Levine I 1973) Peripheral receptors t Depletion body Na+ I , Loss fluid, ~ ACTH /'/ ..... electrolytes ~-----I I~~~II~( ~ ----- ........ Aldo" Adrrena l K+ ........ Decreased ~k."" ____ ----renal arterial Fig. 3. Regulation of aldosterone Kidney - pressure secretion. (Adapted from New and """'" Peterson 1966) Angiotensin <E(,----Renin "--"-_ Depletion body Na+ RENIN_ + T e •• . ANGtlO II • • • • • • t • . P P 170HP • DHEA t · t t t DOC •• DOC S •• 64 t • t ~OH +.. . t l8C:: DOC B Na+ RETENTION B DOC F T t PLASMA VOLUME t EXPANSION l80HB B l8r / ALDO Fig. 4. Regulation of adrenocortical steroidogenesis considering the fasciculata and glomerulosa as two separate glands. Dotted arrows indicate negative feedback. P, progesterone; DOC, deoxycorticosterone; B, corticosterone; 170HP, 17-hydroxyprogesterone; S, 11-deoxycortisol; F, cortisol; ,14, L~.4-androstenedione; DHEA, dehydroepiandrosterone; T, testosterone; 180HDOC, 18-hydroxydeoxycortiosterone; 180HB, 18-hydroxycorticosterone; ALDO, aldos terone. (After New et al. 1982)