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17ß-Hydroxysteroid Dehydrogenase-3 Deficiency: Diagnosis, Phenotypic Variability, Population Genetics, and Worldwide Distribution of Ancient and de Novo Mutations¹

Division of Endocrinology, Department of Pediatrics, Sophia Children’s Hospital (A.L.M.B., S.L.S.D.), Rotterdam; Wilhelmina Children’s Hospital (M.A.V.), Utrecht; University Hospital Nijmegen (B.J.O.), Nijmegen; University Hospital Groningen (C.W.R.), Groningen; Free University Hospital Amsterdam (H.A.D.W.), Amsterdam; the Department of Endocrinology and Reproduction, Erasmus University (A.L.M.B., A.O.B., F.H.J., P.E.R.), Rotterdam; Department of Clinical Genetics, University Hospital Rotterdam and Erasmus University (A.L.M.B., L.A.S., D.J.J.H., M.F.N.), Rotterdam; the Department of Internal Medicine III, University Hospital Rotterdam (F.H.J.);, Rotterdam, The Netherlands; The Netherlands; Cecil H. and Ida Green Center for Reproductive Biological Sciences, University of Texas Southwestern Medical Center (S.A), Dallas, Texas 75235; the Division of Endocrinology, Department of Pediatrics, Medical Genetics Division, Institute of Child Health, Istanbul Medical Faculty, University of Istanbul (H.K.), Istanbul, Turkey; the Developmental Endocrinology Unit, Division of Endocrinology, Hospital das Clinicas, University of Sao Paulo (B.B.M.), Sao Paulo, Brazil; Hospital Maria Pia (C.R.), Porto, Portugal; and the Department of Pediatric Endocrinology, Sydney Children’s Hospital (H.H.B.), Randwick, Australia

Address all correspondence and requests for reprints to: Dr. Annemie L. M. Boehmer, M.D., Department of Pediatrics, Division of Endocrinology, Sophia Children’s Hospital, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands. E-mail: boehmer{at}ALKG.AZR.NL

17ß-Hydroxysteroid dehydrogenase-3 (17ßHSD3) deficiency is an autosomal recessive form of male pseudohermaphroditism caused by mutations in the HSD17B3 gene. In a nationwide study on male pseudohermaphroditism among all pediatric endocrinologists and clinical geneticists in The Netherlands, 18 17ßHSD3-deficient index cases were identified, 12 of whom initially had received the tentative diagnosis androgen insensitivity syndrome (AIS). The phenotypes and genotypes of these patients were studied. Endocrine diagnostic methods were evaluated in comparison to mutation analysis of the HSD17B3 gene. RT-PCR studies were performed on testicular ribonucleic acid of patients homozygous for two different splice site mutations. The minimal incidence of 17ßHSD3 deficiency in The Netherlands and the corresponding carrier frequency were calculated. Haplotype analysis of the chromosomal region of the HSD17B3 gene in Europeans, North Americans, Latin Americans, Australians, and Arabs was used to establish whether recurrent identical mutations were ancient or had repeatedly occurred de novo.

In genotypically identical cases, phenotypic variation for external sexual development was observed. Gonadotropin-stimulated serum testosterone/androstenedione ratios in 17ßHSD3-deficient patients were discriminative in all cases and did not overlap with ratios in normal controls or with ratios in AIS patients. In all investigated patients both HSD17B3 alleles were mutated. The intronic mutations 325 + 4;AT and 655–1;GA disrupted normal splicing, but a small amount of wild-type messenger ribonucleic acid was still made in patients homozygous for 655–1;GA. The minimal incidence of 17ßHSD3 deficiency in The Netherlands was shown to be 1:147,000, with a heterozygote frequency of 1:135. At least 4 mutations, 325 + 4;AT, N74T, 655–1;GA, and R80Q, found worldwide, appeared to be ancient and originating from genetic founders. Their dispersion could be reconstructed through historical analysis. The HSD17B3 gene mutations 326–1;GC and P282L were de novo mutations.

17ßHSD3 deficiency can be reliably diagnosed by endocrine evaluation and mutation analysis. Phenotypic variation can occur between families with the same homozygous mutations. The incidence of 17ßHSD3 deficiency is 0.65 times the incidence of AIS, which is thought to be the most frequent known cause of male pseudohermaphroditism without dysgenic gonads. A global inventory of affected cases demonstrated the ancient origin of at least four mutations. The mutational history of this genetic locus offers views into human diversity and disease, provided by national and international collaboration.

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