Top

International Journal of Pediatric Endocrinology

Published in:

Open Access 01-12-2016 | Case report

46,XY disorder of sex development due to 17-beta hydroxysteroid dehydrogenase type 3 deficiency: a plea for timely genetic testing

Authors: Chelsey Grimbly, Oana Caluseriu, Peter Metcalfe, Mary M. Jetha, Elizabeth T. Rosolowsky

Published in: International Journal of Pediatric Endocrinology | Issue 1/2016

Abstract

Background

17β-hydroxysteroid dehydrogenase type 3 (17βHSD3) deficiency is a rare cause of disorder of sex development (DSD) due to impaired conversion of androstenedione to testosterone. Traditionally, the diagnosis was determined by βHCG-stimulated ratios of testosterone:androstenedione < 0.8.

Case presentation

An otherwise phenotypically female infant presented with bilateral inguinal masses and a 46,XY karyotype. βHCG stimulation (1500 IU IM for 2 days) suggested 17βHSD3 deficiency although androstenedione was only minimally stimulated (4.5 nmol/L to 5.4 nmol/L). Expedient genetic testing for the HSD17B3 gene provided the unequivocal diagnosis.

Conclusion

We advocate for urgent genetic testing in rare causes of DSD as indeterminate hormone results can delay diagnosis and prolong intervention.

Moghrabi N, Hughes IA, Dunaif A, Andersson S. Deleterious missense mutations and silent polymoprhisms in the human 17beta-hydroxysteroid dehydrogenase 3 Gene (HSD17B3). J Clin Endocrinol Metab. 1998;83:2855–60.PubMed

Ahmed SF, Hughes IA. The genetics of male undermasculinization. Clin Endocrinol. 2002;56:1–18.CrossRef

Morel Y, Rey R, Teinturier C, Nicolino M, Michel-Calemard L, Mowszowicz I, Jaubert F, Fellous M, Chaussain JL, Chatelain P, David M, Nihoul-Fékété C, Forest MG, Josso N. Aetiological diagnosis of male sex ambiguity: a collaborative study. Eur J Pediatr. 2002;161:49–59.CrossRefPubMed

Boehmer AL, Brinkmann AO, Sandkuijl LA, Halley DJ, Niermeijer MF, Andersson S, de Jong FH, Kayserili H, de Vroede MA, Otten BJ, Rouwé CW, Mendonça BB, Rodrigues C, Bode HH, de Ruiter PE, Delemarre-van de Waal HA, Drop SL. 17ß-hydroxysteroid dehydrogenase-3 deficiency: diagnosis, phenotypic variability, population genetics, and worldwide distribution of ancient and de novo mutations. J Clin Endocrinol Metab. 1999;84:4713–21.PubMed

Ahmed SF, Iqbal A, Hughes IA. The testosterone:androstenedione ratio in male undermasculinization. Clin Endocrinol. 2000;53:697–702.CrossRef

Moeller G, Adamski J. Integrated view on 17beta-hydroxysteroid dehydrogenases. Mol Cell Endocrinol. 2009;301:7–19.CrossRefPubMed

George MM, New MI, Ten S, Sultan C, Bhangoo A. The clinical and molecular heterogeneity of 17βHSD-3 enzyme deficiency. Horm Res Paediatr. 2010;74:229–40.CrossRefPubMed

Maimoun L, Philibert P, Cammas B, Audran F, Bouchard P, Fenichel P, Cartigny M, Pienkowski C, Polak M, Skordis N, Mazen I, Ocal G, Berberoglu M, Reynaud R, Baumann C, Cabrol S, Simon D, Kayemba-Kay’s K, De Kerdanet M, Kurtz F, Leheup B, Heinrichs C, Tenoutasse S, Van Vliet G, Grüters A, Eunice M, Ammini AC, Hafez M, Hochberg Z, Einaudi S, Al Mawlawi H, Nuñez CJ, Servant N, Lumbroso S, Paris F, Sultan C Phenotypical, biological, and molecular heterogeneity of 5α-reductase deficiency: an extensive international experience of 55 patients. J Clin Endocrinol Metab. 2011;96:296–307.CrossRefPubMed

Khattab A, Yuen T, Yau M, Domenice S, Frade Costa EM, Diya K, Muhuri D, Pina CE, Nishi MY, Yang AC, de Medonça BB, New MI. Pitfalls in hormonal diagnosis of 17β-hydroxysteroid dehydrogenase III deficiency. J Pediatr Endocrinol Metab. 2014;28:623–8.

10.

Lee YS, Kirk JM, Stanhope RG, Johnston DI, Harland S, Auchus RJ, Andersson S, Hughes IA. Phenotypic variability in 17β-hydroxysteroid dehydrogenase-3 deficiency and diagnostic pitfalls. Clin Endocrinol. 2007;67:20–8.CrossRef

11.

Ahmed SF, Cheng A, Dovey L, Hawkins JR, Martin H, Rowland J, Shimura N, Tait AD, Hughes IA. Phenotypic features, androgen receptor binding, and mutational analysis in 278 clinical cases reported as androgen insensitivity syndrome. J Clin Endocrinol Metab. 2000;85:658–65.PubMed

12.

Ahmed SF, Achermann JC, Arlt W, Balen AH, Conway G, Edwards ZL, Elford S, Hughes IA, Izatt L, Krone N, Miles HL, O’Toole S, Perry L, Sanders C, Simmonds M, Wallace AM, Watt A, Willis D. UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development. Clin Endocrinol. 2011;75:12–26.CrossRef

13.

Douglas G, Axelrad ME, Brandt ML, Crabtree E, Dietrich JE, French S, Gunn S, Karaviti L, Lopez ME, Macias CG, McCullough LB, Suresh D, Sutton VR. Consensus in guidelines for evaluation of DSD by the Texas Children’s Hospital Multidisciplinary Gender Medicine Team. Int J Pediatr Endocrinol. 2010;2010:1–17.CrossRef

14.

Paris F, Gaspari L, Philibert P, Maimoun L, Kalfa N, Sultan C. Disorders of sex development: neonatal diagnosis and management. Endocr Dev. 2012;22:56–71.CrossRefPubMed

15.

Chan AO, But BW, Lee CY, Lam YY, Ng KL, Tung JY, Kwan EY, Chan YK, Tsui TK, Lam AL, Tse WY, Cheung PT, Shek CC. Diagnosis of 5α-reductase 2 deficiency: is measurement of dihydrotestosterone essential? Clin Chem. 2013;59:798–806.CrossRefPubMed

16.

Chuang J, Vallerie A, Breech L, Saal HM, Alam S, Crawford P, Rutter MM. Complexities of gender assignment in 17β-hydroxysteroid dehydrogenase type 3deficiency. Is there a role for early orchiectomy? Int J Pediatr Endocrinol. 2013;2013:15.CrossRefPubMedPubMedCentral

17.

Cohen-Kettenis PT. Gender change in 46, XY persons with 5α-reductase-2 deficiency and 17β-hydroxysteroid dehydrogenase-3 deficiency. Arch Sex Behav. 2005;34:399–410.CrossRefPubMed

18.

Andersson S, Geissler WM, Wu L, Davis DL, Grumbach MM, New MI, Schwarz HP, Blethen SL, Mendonca BB, Bloise W, Witchel SF, Cutler GB Jr, Griffen JE, Wilson JD, Russel DW. Molecular genetics and pathophysiology of 17 beta-hydroxysteroid dehydrogenase 3 deficiency. J Clin Endocrinol Metab. 1996;81:130–6.PubMed

19.

Rosler A, Bélanger A, Labrie F. Mechanisms of androgen production in male pseudohermaphroditism due to 17β-hydroxysteroid dehydrogenase deficiency. J Clin Endocrinol Metab. 1992;75:773–8.PubMed

20.

Lee PA, Houk CP, Ahmed SF, Hughes IA. International consensus conference on intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric endocrinology: consensus statement on management of intersex disorders. Pediatrics. 2006;118:e488–500.CrossRefPubMed

21.

Xue Y, Ankala A, Wicox WR, Hegde MR. Solving the molecular diagnostic testing conundrum for Mendelian disorders in the era of next-generation sequencing: single-gene, gene panel, or exome/genome sequencing. Genet Med. 2015;17(6):444–51.CrossRefPubMed

Title: 46,XY disorder of sex development due to 17-beta hydroxysteroid dehydrogenase type 3 deficiency: a plea for timely genetic testing
Authors: Chelsey Grimbly
Oana Caluseriu
Peter Metcalfe
Mary M. Jetha
Elizabeth T. Rosolowsky
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: International Journal of Pediatric Endocrinology / Issue 1/2016
Electronic ISSN: 1687-9856
DOI: https://doi.org/10.1186/s13633-016-0030-x

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

46,XY disorder of sex development due to 17-beta hydroxysteroid dehydrogenase type 3 deficiency: a plea for timely genetic testing

Abstract

Background

Case presentation

Conclusion

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Case presentation

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2016

Anti-Müllerian hormone as a marker of steroid and gonadotropin action in the testis of children and adolescents with disorders of the gonadal axis

The influence of a long-term growth hormone treatment on lipid and glucose metabolism: a randomized trial in short Japanese children born small for gestational age

Positive fertility outcomes in a female with classic congenital adrenal hyperplasia following bilateral adrenalectomy

International Journal of Pediatric Endocrinology reviewer acknowledgement 2015

Etiological and clinical characteristics of central diabetes insipidus in children: a single center experience

An audit of the management of childhood-onset growth hormone deficiency during young adulthood in Scotland