Background: 3β-hydroxysteroid dehydrogenase (3βHSD) type 2 (encoded by HSD3B2) is expressed in the adrenals and gonads. HSD3B2 mutations cause the rare form of congenital adrenal hyperplasia ‘3βHSD deficiency’. In its classic form, affected individuals have salt wasting early in infancy and may have ambiguous genitalia in both sexes. The presence of peripheral type 1 3βHSD often complicates the hormonal diagnosis of this disorder, in that very high 17α-hydroxypregnenolone levels can be converted extra-adrenally to 17α-hydroxyprogesterone (17OHP). Patient and Methods: A 46,XX female newborn with no signs of virilization was referred for evaluation of positive 17OHP newborn screening, and developed a salt-wasting crisis at 13 days of age. The confirmatory test revealing highly elevated 17OHP suggested a 21-hydroxylase deficiency, but sequencing of the CYP21A2 gene was not consistent. Further family history suggested a 3βHSD deficiency. The HSD3B2 gene was then sequenced. Results: The patient was homozygous for the novel nonsense mutation Q334X in the HSD3B2 gene, inherited from both parents. Conclusions: We report a novel mutation of the HSD3B2 gene, Q334X, responsible for a classic 3βHSD deficiency. The clinical and hormonal phenotypes can be complicated in this disorder, and this supports the benefits of 17OHP newborn screening to detect various forms of congenital adrenal hyperplasia.

Keywords:
3β-hydroxysteroid dehydrogenase deficiency, Mutation, Sex steroids, Congenital adrenal hyperplasia
1.
Lorence MC, Murry BA, Trant JM, Mason JI: Human 3β-hydroxysteroid dehydrogenase/ δ5 → 4 isomerase from placenta: expression in nonsteroidogenic cells of a protein that catalyzes the dehydrogenation/isomerization of C21 and C19 steroids. Endocrinology 1990;126:2493–2498.
2.
Luu-The V, Lachance Y, Labrie C, Leblanc G, Thomas JL, Strickler RC, Labrie F: Full length cDNA structure and deduced amino acid sequence of human 3β-hydroxy-5-ene steroid dehydrogenase. Mol Endocrinol 1989;3:1310–1312.
3.
Lorence MC, Corbin CJ, Kamimura N, Mahendroo MS, Mason JI: Structural analysis of the gene encoding human 3β-hydroxysteroid dehydrogenase/δ5 → 4-isomerase. Mol Endocrinol 1990;4:1850–1855.
4.
Lachance Y, Luu-The V, Labrie C, Simard J, Dumont M, de Launoit Y, Guerin S, Leblanc G, Labrie F: Characterization of human 3β-hydroxysteroid dehydrogenase/Δ5–Δ4-isomerase gene and its expression in mammalian cells. J Biol Chem 1990;265:20469–20475.
5.
Rheaume E, Lachance Y, Zhao HF, Breton N, Dumont M, de Launoit Y, Trudel C, Luu-The V, Simard J, Labrie F: Structure and expression of a new complementary DNA encoding the almost exclusive 3β-hydroxysteroid dehydrogenase/Δ5–Δ4-isomerase in human adrenals and gonads. Mol Endocrinol 1991;5:1147–1157.
6.
Bongiovanni AM: The adrenogenital syndrome with deficiency of 3β-hydroxysteroid dehydrogenase. J Clin Invest 1962;41:2086–2092.
7.
Simard J, Ricketts ML, Gingras S, Soucy P, Feltus FA, Melner MH: Molecular biology of the 3β-hydroxysteroid dehydrogenase/Δ5–Δ4-isomerase gene family. Endocr Rev 2005;26:525–582.
8.
Miller WL, Auchus RJ: The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev 2011;32:81–151.
9.
Tusie-Luna MT, Traktman P, White PC: Determination of functional effects of mutations in the steroid 21-hydroxylase gene (CYP21) using recombinant vaccinia virus. J Biol Chem 1990;265:20916–20922.
10.
Scott RR, Miller WL: Genetic and clinical features of P450 oxidoreductase deficiency. Horm Res 2008;69:266–275.
11.
Krone N, Dhir V, Ivison HE, Arlt W: Congenital adrenal hyperplasia and P450 oxidoreductase deficiency. Clin Endocrinol (Oxf) 2007;66:162–172.
12.
Byrns MC, Steckelbroeck S, Penning TM: An indomethacin analogue, N-(4-chlorobenzoyl)-melatonin, is a selective inhibitor of aldo-keto reductase 1C3 (type 2 3α-HSD, type 5 17β-HSD, and prostaglandin F synthase), a potential target for the treatment of hormone dependent and hormone independent malignancies. Biochem Pharmacol 2008;75:484–493.
13.
Auchus RJ, Lee TC, Miller WL: Cytochrome b5 augments the 17,20 lyase activity of human P450c17 without direct electron transfer. J Biol Chem 1998;273:3158–3165.
14.
Moisan AM, Ricketts ML, Tardy V, Desrochers M, Mebarki F, Chaussain JL, Cabrol S, Raux-Demay MC, Forest MG, Sippell WG, Peter M, Morel Y, Simard J: New insight into the molecular basis of 3β-hydroxysteroid dehydrogenase deficiency: identification of eight mutations in the HSD3B2 gene eleven patients from seven new families and comparison of the functional properties of twenty-five mutant enzymes. J Clin Endocrinol Metab 1999;84:4410–4425.
15.
Chang YT, Kulin HE, Garibaldi L, Suriano MJ, Bracki K, Pang S: Hypothalamic-pituitary-gonadal axis function in pubertal male and female siblings with glucocorticoid-treated nonsalt-wasting 3β-hydroxysteroid dehydrogenase deficiency congenital adrenal hyperplasia. J Clin Endocrinol Metab 1993;77:1251–1257.
16.
Sanchez R, Rheaume E, Laflamme N, Rosenfield RL, Labrie F, Simard J: Detection and functional characterization of the novel missense mutation Y254D in type II 3β-hydroxysteroid dehydrogenase (3βHSD) gene of a female patient with nonsalt-losing 3βHSD deficiency. J Clin Endocrinol Metab 1994;78:561–567.
17.
Lutfallah C, Wang W, Mason JI, Chang YT, Haider A, Rich B, Castro-Magana M, Copeland KC, David R, Pang S: Newly proposed hormonal criteria via genotypic proof for type II 3β-hydroxysteroid dehydrogenase deficiency. J Clin Endocrinol Metab 2002;87:2611–2622.
18.
Mermejo LM, Elias LL, Marui S, Moreira AC, Mendonca BB, de Castro M: Refining hormonal diagnosis of type II 3β-hydroxysteroid dehydrogenase deficiency in patients with premature pubarche and hirsutism based on HSD3B2 genotyping. J Clin Endocrinol Metab 2005;90:1287–1293.
19.
Welzel M, Wustemann N, Simic-Schleicher G, Dorr HG, Schulze E, Shaikh G, Clayton P, Grotzinger J, Holterhus PM, Riepe FG: Carboxyl-terminal mutations in 3β-hydroxysteroid dehydrogenase type II cause severe salt-wasting congenital adrenal hyperplasia. J Clin Endocrinol Metab 2008;93:1418–1425.
20.
Tajima T, Fujieda K, Nakae J, Shinohara N, Yoshimoto M, Baba T, Kinoshita E, Igarashi Y, Oomura T: Molecular analysis of type II 3β-hydroxysteroid dehydrogenase gene in Japanese patients with classical 3β-hydroxysteroid dehydrogenase deficiency. Hum Mol Genet 1995;4:969–971.
© 2012 S. Karger AG, Basel
2012
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.