This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Alos, N. Articles by Simard, J. Search for Related Content PubMed PubMed Citation Articles by Alos, N. Articles by Simard, J. Pubmed/NCBI databases Gene GEO Profiles HomoloGene OMIM Protein UniGene Substance via MeSH

A Novel A10E Homozygous Mutation in the HSD3B2 Gene Causing Severe Salt-Wasting 3ß-Hydroxysteroid Dehydrogenase Deficiency in 46,XX and 46,XY French-Canadians: Evaluation of Gonadal Function after Puberty¹

Département de Pédiatrie, Université de Montréal (N.A., G.V.V., L.W., L.L., G.L.), Montréal, Canada H3T 1C5; and Medical Research Council Group in Molecular Endocrinology, CHUL Research Center, Laval University Medical Center (A.-M.M., M.D., J.S.), Québec, Québec, Canada G1V 4G2

Address all correspondence and requests for reprints to: Guy Van Vliet, M.D., Centre de Recherche, Hôpital Sainte-Justine, 3175 côte Sainte-Catherine, Montréal, Canada H3T 1C5. E-mail: gvanvliet{at}justine.umontreal.ca

Severe 3ß-hydroxysteroid dehydrogenase (3ßHSD) deficiency is a rare form of congenital adrenal hyperplasia resulting from mutations in the HSD3B2 gene that impair steroidogenesis in both the adrenals and gonads and cause salt-wasting in both sexes and incomplete masculinization of the external genitalia in genetic males. About two thirds of the reported patients are 46,XY. We describe two French-Canadian patients from two families without a known relationship who presented with severe salt-wasting 3ßHSD deficiency in infancy. Although the diagnosis was considered clinically, plasma steroid profiles were confusing. We have thus directly sequenced DNA fragments generated by PCR amplification of the four exons, exon-intron boundaries, and the 5'-flanking regions of the HSD3B2 gene. Sequencing of exon II revealed the presence of a C to A transversion in both alleles of these two cases, thus converting codon 10 (GCA), which codes for Ala, into GAA, encoding Glu. This Ala is highly conserved in the vertebrate 3ßHSD gene family and is located in the putative NAD-binding domain of the enzyme. The mutant type II 3ßHSD enzyme carrying an A10E substitution exhibited no detectable activity in intact transfected Ad293 cells. Both homozygous patients share the same haplotype, spanning approximately 3.3 centimorgans surrounding the HSD3B2 locus, which is consistent with a founder effect for this missense mutation. The 46,XY patient presented with ambiguous genitalia at birth and underwent normal masculinization at puberty, but was azoospermic at 18.5 yr of age. The 46,XX patient presented progressive breast development, menarche, and evidence of progesterone secretion. The only previously reported cases with pubertal follow-up revealed paternity in one male and hypogonadism in one female. These findings demonstrate the complex relationships between the genotype and the gonadal phenotype in severe 3ßHSD deficiency and the difficulty in predicting fertility.

This article has been cited by other articles:

				J. Simard, M.-L. Ricketts, S. Gingras, P. Soucy, F. A. Feltus, and M. H. Melner Molecular Biology of the 3{beta}-Hydroxysteroid Dehydrogenase/{Delta}5-{Delta}4 Isomerase Gene Family Endocr. Rev., June 1, 2005; 26(4): 525 - 582. [Abstract] [Full Text] [PDF]

				R. Perry, O. Kecha, J. Paquette, C. Huot, G. Van Vliet, and C. Deal Primary Adrenal Insufficiency in Children: Twenty Years Experience at the Sainte-Justine Hospital, Montreal J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3243 - 3250. [Abstract] [Full Text] [PDF]

				T. H. Johannsen, D. Mallet, H. Dige-Petersen, J. Muller, K. M. Main, Y. Morel, and M. G. Forest Delayed Diagnosis of Congenital Adrenal Hyperplasia with Salt Wasting Due to Type II 3{beta}-Hydroxysteroid Dehydrogenase Deficiency J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2076 - 2080. [Abstract] [Full Text] [PDF]

				S. Kosel, S. Burggraf, R. Fingerhut, H. G. Dorr, A. A. Roscher, and B. Olgemoller Rapid Second-Tier Molecular Genetic Analysis for Congenital Adrenal Hyperplasia Attributable to Steroid 21-Hydroxylase Deficiency Clin. Chem., February 1, 2005; 51(2): 298 - 304. [Abstract] [Full Text] [PDF]

				E. Codner, C. Okuma, G. Iniguez, M. A. Boric, A. Avila, M. C. Johnson, and F. G. Cassorla Molecular Study of the 3{beta}-Hydroxysteroid Dehydrogenase Gene Type II in Patients with Hypospadias J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 957 - 964. [Abstract] [Full Text] [PDF]

				S. Pang, W. Wang, B. Rich, R. David, Y. T. Chang, G. Carbunaru, S. E. Myers, A. F. Howie, K. J. Smillie, and J. I. Mason A Novel Nonstop Mutation in the Stop Codon and a Novel Missense Mutation in the Type II 3{beta}-Hydroxysteroid Dehydrogenase (3{beta}-HSD) Gene Causing, Respectively, Nonclassic and Classic 3{beta}-HSD Deficiency Congenital Adrenal Hyperplasia J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2556 - 2563. [Abstract] [Full Text] [PDF]

				M. Iitaka, S. Miura, K. Yamanaka, S. Kawasaki, S. Kitahama, Y. Kawakami, S. Kakinuma, I. Oosuga, S. Wada, and S. Katayama Increased Serum Vascular Endothelial Growth Factor Levels and Intrathyroidal Vascular Area in Patients with Graves' Disease and Hashimoto's Thyroiditis J. Clin. Endocrinol. Metab., November 1, 1998; 83(11): 3908 - 3912. [Abstract] [Full Text]