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Molecular genetics and phenotype/genotype correlation of 5-α reductase deficiency in a highly consanguineous population

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Abstract

Context and objectives

5-α reductase deficiency is a rare 46,XY disorder of sex development. We present detailed phenotypic and genotypic features of a cohort of 24 subjects from a highly consanguineous population of Saudi Arabia

Subjects and Methods

We studied the clinical presentation and hormonal profiles of 24 subjects diagnosed with 5-α reductase deficiency and performed genetic testing on DNA isolated from their peripheral blood using polymerase chain reaction and direct sequencing of the SRD5A2.

Results

All subjects had 46,XY karyotype and presented with atypical appearance of external genitalia ranging from clitoromegaly, micophallus with hypospadias, undescended testes to completely normally looking female genitalia. Thirteen (54%) of them had severe under virilization and were assigned female sex at birth. The other 11 subjects were raised as males. Stimulated Testosterone:Dihydrotestosterone ratio was high in all 16 subjects in whom it was measured. The genetic testing revealed 2 nonsense mutations (p.R103X and p.R227X) in 2 unrelated subjects, 3 missense mutations (p.P181L, p.A228T, p.R246Q) in 11 subjects and a splice site mutation (IVS1-2A > G) in 11 other subjects. There was significant phenotypic variability even in subjects with the same mutation and also within the same family.

Conclusion

This is the first and largest report of the clinical and molecular genetics of 5-α reductase deficiency from the Middle East. It shows weak genotype/phenotype correlation and significant phenotypic heterogeneity. IVS1-2A > G mutation is the most common mutation and is likely to be a founder mutation in this part of the world.

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References

  1. J. Imperato-McGinley, L. Guerrero, T. Gautier, R.E. Peterson, Steroid 5alpha-reductase deficiency in man: an inherited form of male pseudohermaphroditism. Science 186(4170), 1213–1215 (1974)

    Article  CAS  Google Scholar 

  2. P.C. Walsh, J.D. Madden, M.J. Harrod, J.L. Goldstein, P.C. MacDonald, J.D. Wilson, Familial incomplete male pseudohermaphroditism, type 2. Decreased dihydrotestosterone formation in pseudovaginal perineoscrotal hypospadias. N. Eng. J. Med. 291(18), 944–949 (1974). https://doi.org/10.1056/NEJM197410312911806

    Article  CAS  Google Scholar 

  3. L. Maimoun, P. Philibert, B. Cammas, F. Audran, P. Bouchard, P. Fenichel, M. Cartigny, C. Pienkowski, M. Polak, N. Skordis, I. Mazen, G. Ocal, M. Berberoglu, R. Reynaud, C. Baumann, S. Cabrol, D. Simon, K. Kayemba-Kay’s, M. De Kerdanet, F. Kurtz, B. Leheup, C. Heinrichs, S. Tenoutasse, G. Van Vliet, A. Gruters, M. Eunice, A.C. Ammini, M. Hafez, Z. Hochberg, S. Einaudi, H. Al Mawlawi, C.J. Nunez, N. Servant, S. Lumbroso, F. Paris, C. Sultan, Phenotypical, biological, and molecular heterogeneity of 5alpha-reductase deficiency: an extensive international experience of 55 patients. J. Clin. Endocrinol. Metab. 96(2), 296–307 (2011). https://doi.org/10.1210/jc.2010-1024

    Article  CAS  PubMed  Google Scholar 

  4. J.D. Wilson, J.E. Griffin, D.W. Russell, Steroid 5 alpha-reductase 2 deficiency. Endocr. Rev. 14(5), 577–593 (1993). https://doi.org/10.1210/edrv-14-5-577

    Article  CAS  PubMed  Google Scholar 

  5. E.P. Jenkins, S. Andersson, J. Imperato-McGinley, J.D. Wilson, D.W. Russell, Genetic and pharmacological evidence for more than one human steroid 5 alpha-reductase. J. Clin. Invest. 89(1), 293–300 (1992). https://doi.org/10.1172/JCI115574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. A.E. Thigpen, R.I. Silver, J.M. Guileyardo, M.L. Casey, J.D. McConnell, D.W. Russell, Tissue distribution and ontogeny of steroid 5 alpha-reductase isozyme expression. J. Clin. Invest. 92(2), 903–910 (1993). https://doi.org/10.1172/JCI116665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. F. Labrie, Y. Sugimoto, V. Luu-The, J. Simard, Y. Lachance, D. Bachvarov, G. Leblanc, F. Durocher, N. Paquet, Structure of human type II 5 alpha-reductase gene. Endocrinology 131(3), 1571–1573 (1992). https://doi.org/10.1210/endo.131.3.1505484

    Article  CAS  PubMed  Google Scholar 

  8. A. Nicoletti, L. Baldazzi, A. Balsamo, L. Barp, P. Pirazzoli, M. Gennari, G. Radetti, E. Cacciari, A. Cicognani, SRD5A2 gene analysis in an Italian population of under-masculinized 46,XY subjects. Clin. Endocrinol. (Oxf.). 63(4), 375–380 (2005). https://doi.org/10.1111/j.1365-2265.2005.02348.x

    Article  CAS  PubMed  Google Scholar 

  9. A.E. Thigpen, D.L. Davis, A. Milatovich, B.B. Mendonca, J. Imperato-McGinley, J.E. Griffin, U. Francke, J.D. Wilson, D.W. Russell, Molecular genetics of steroid 5 alpha-reductase 2 deficiency. J. Clin. Invest. 90(3), 799–809 (1992). https://doi.org/10.1172/jci115954

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. N.A. Al-Jurayyan, Ambiguous genitalia: two decades of experience. Ann. Saudi. Med. 31(3), 284–288 (2011). https://doi.org/10.4103/0256-4947.81544

    Article  PubMed  PubMed Central  Google Scholar 

  11. N.A. Al-Jurayyan, S.D. Al Issa, A.M. Al Nemri, H.M. Al Otaibi, A.M. Babiker, The spectrum of 46XY disorders of sex development in a University centre in Saudi Arabia. J. Pediatr. Endocrinol. & Metab.: JPEM 28(9-10), 1123–1127 (2015). https://doi.org/10.1515/jpem-2014-0503

    Article  Google Scholar 

  12. J.A. Kari, D. Bockenhauer, H. Stanescu, M. Gari, R. Kleta, A.K. Singh, Consanguinity in Saudi Arabia: a unique opportunity for pediatric kidney research. Am. J. Kidney Dis. 63(2), 304–310 (2014). https://doi.org/10.1053/j.ajkd.2013.08.033

    Article  PubMed  Google Scholar 

  13. M.I. El-Mouzan, A.A. Al-Salloum, A.S. Al-Herbish, M.M. Qurachi, A.A. Al-Omar, Regional variations in the prevalence of consanguinity in Saudi Arabia. Saudi. Med. J. 28(12), 1881–1884 (2007)

    PubMed  Google Scholar 

  14. O. Hiort, G.H. Sinnecker, H. Willenbring, A. Lehners, A. Zöllner, D. Struve, Nonisotopic single strand conformation analysis of the 5 alpha-reductase type 2 gene for the diagnosis of 5 alpha-reductase deficiency. J. Clin. Endocrinol. & Metab. 81(9), 3415–3418 (1996). https://doi.org/10.1210/jcem.81.9.8784107

    Article  CAS  Google Scholar 

  15. N. Skordis, P.C. Patsalis, I. Bacopoulou, C. Sismani, C. Sultan, S. Lumbroso, 5alpha-reductase 2 gene mutations in three unrelated patients of Greek Cypriot origin: identification of an ancestral founder effect. J. Pediatr. Endocrinol. & Metab.: JPEM 18(3), 241–246 (2005)

    CAS  Google Scholar 

  16. G. Ocal, P. Adiyaman, M. Berberoglu, E. Cetinkaya, N. Akar, A. Uysal, T. Duman, O. Evliyaoglu, Z. Aycan, S. Lumbroso, C. Sultan, Mutations of the 5alpha-steroid reductase type 2 gene in six Turkish patients from unrelated families and a large pedigree of an isolated Turkish village. J. Pediatr. Endocrinol. & Metab.: JPEM 15(4), 411–421 (2002)

    Article  CAS  Google Scholar 

  17. C. Shammas, V. Neocleous, M. Toumba, C. Costi, A.A. Phedonos, E. Efstathiou, A. Kyriakou, L.A. Phylactou, N. Skordis, Overview of genetic defects in endocrinopathies in the island of Cyprus; evidence of a founder effect. Genet. Test. Mol. Biomark. 16(9), 1073–1079 (2012). https://doi.org/10.1089/gtmb.2011.0381

    Article  CAS  Google Scholar 

  18. O. Hiort, S.M. Schutt, M. Bals-Pratsch, P.M. Holterhus, C. Marschke, D. Struve, A novel homozygous disruptive mutation in the SRD5A2-gene in a partially virilized patient with 5alpha-reductase deficiency. Int. J. Androl. 25(1), 55–58 (2002)

    Article  CAS  Google Scholar 

  19. E. Simsek, C. Binay, S. Ceylaner, The earlier described mutation (c.307c>T [p.R103X]) in the SRD5A2 gene causing a 46,XY female phenotype. J. Pediatr. Endocrinol. & Metab.: JPEM 25(5-6), 543–545 (2012)

    Article  CAS  Google Scholar 

  20. S.F. Ahmed, O. Khwaja, I.A. Hughes, The role of a clinical score in the assessment of ambiguous genitalia. BJU Int. 85(1), 120–124 (2000)

    Article  CAS  Google Scholar 

  21. S. Eggers, S. Sadedin, J.A. van den Bergen, G. Robevska, T. Ohnesorg, J. Hewitt, L. Lambeth, A. Bouty, I.M. Knarston, T.Y. Tan, F. Cameron, G. Werther, J. Hutson, M. O’Connell, S.R. Grover, Y. Heloury, M. Zacharin, P. Bergman, C. Kimber, J. Brown, N. Webb, M.F. Hunter, S. Srinivasan, A. Titmuss, C.F. Verge, D. Mowat, G. Smith, J. Smith, L. Ewans, C. Shalhoub, P. Crock, C. Cowell, G.M. Leong, M. Ono, A.R. Lafferty, T. Huynh, U. Visser, C.S. Choong, F. McKenzie, N. Pachter, E.M. Thompson, J. Couper, A. Baxendale, J. Gecz, B.J. Wheeler, C. Jefferies, K. MacKenzie, P. Hofman, P. Carter, R.I. King, C. Krausz, C.M. van Ravenswaaij-Arts, L. Looijenga, S. Drop, S. Riedl, M. Cools, A. Dawson, A.Z. Juniarto, V. Khadilkar, A. Khadilkar, V. Bhatia, V.C. Dung, I. Atta, J. Raza, N. Thi Diem Chi, T.K. Hao, V. Harley, P. Koopman, G. Warne, S. Faradz, A. Oshlack, K.L. Ayers, A.H. Sinclair, Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort. Genome Biol. 17(1), 243 (2016). https://doi.org/10.1186/s13059-016-1105-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. L. Johnson, F.W. George, W.B. Neaves, I.M. Rosenthal, R.A. Christensen, A. Decristoforo, H.-U. Schweikert, M.V. Sauer, M. Leshin, J.E. Griffin, J.D. Wilson, Characterization of the Testicular Abnormality in 5a-Reductase Deficiency*. J. Clin. Endocrinol. & Metab. 63(5), 1091–1099 (1986). https://doi.org/10.1210/jcem-63-5-1091

    Article  CAS  Google Scholar 

  23. Y. Dong, Y. Yi, H. Yao, Z. Yang, H. Hu, J. Liu, C. Gao, M. Zhang, L. Zhou, Asan, X. Yi, Z. Liang, Targeted next-generation sequencing identification of mutations in patients with disorders of sex development. BMC Med. Genet. 17, 23 (2016). https://doi.org/10.1186/s12881-016-0286-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. M. Eunice, P. Philibert, B. Kulshreshtha, F. Audran, F. Paris, M.L. Khurana, P.E. Pulikkanath, K. Kucheria, C. Sultan, A.C. Ammini, Molecular diagnosis of 5alpha-reductase-2 gene mutation in two Indian families with male pseudohermaphroditism. Asian J. Androl. 10(5), 815–818 (2008). https://doi.org/10.1111/j.1745-7262.2008.00350.x

    Article  CAS  PubMed  Google Scholar 

  25. J.M. Ko, C.K. Cheon, G.H. Kim, S.H. Kim, K.S. Kim, H.W. Yoo, Clinical characterization and analysis of the SRD5A2 gene in six Korean patients with 5alpha-reductase type 2 deficiency. Horm. Res. Paediatr. 73(1), 41–48 (2010). https://doi.org/10.1159/000271915

    Article  CAS  PubMed  Google Scholar 

  26. C.Y. Lee, C.W. Lam, C.C. Shek, Steroid 5alpha-reductase 2 deficiency in two generations of a non-consanguineous Chinese family. J. Pediatr. Endocrinol. Metab. 16(8), 1197–1201 (2003)

    CAS  PubMed  Google Scholar 

  27. K. Matsubara, H. Iwamoto, A. Yoshida, T. Ogata, Semen analysis and successful paternity by intracytoplasmic sperm injection in a man with steroid 5alpha-reductase-2 deficiency. Fertil. Steril. 94(7), 2770 e2777–2710 (2010). https://doi.org/10.1016/j.fertnstert.2010.04.013

    Article  Google Scholar 

  28. F. Vilchis, J.P. Mendez, P. Canto, E. Lieberman, B. Chavez, Identification of missense mutations in the SRD5A2 gene from patients with steroid 5alpha-reductase 2 deficiency. Clin. Endocrinol. (Oxf.). 52(3), 383–387 (2000)

    Article  CAS  Google Scholar 

  29. I. Shabir, M.L. Khurana, E. Marumudi, A.A. Joseph, M. Mehta, J. John, A.C. Ammini, Homozygous p.R246Q mutation and impaired spermatogenesis: long term follow-up of 4 children from one family with 5 alpha reductase 2 deficiency. Indian J. Pediatr. 83(5), 481–482 (2016). https://doi.org/10.1007/s12098-015-1915-z

    Article  PubMed  Google Scholar 

  30. N. Skordis, V. Neocleous, A. Kyriakou, E. Efstathiou, A. Sertedaki, P. Philibert, L.A. Phylactou, S. Lumbroso, C. Sultan, The IVS1-2A>G mutation in the SRD5A2 gene predominates in Cypriot patients with 5alpha reductase deficiency. J. Endocrinol. Invest. 33(11), 810–814 (2010)

    Article  CAS  Google Scholar 

  31. Y. Dong, Y. Yi, H. Yao, Z. Yang, H. Hu, J. Liu, C. Gao, M. Zhang, L. Zhou, Asan, X. Yi, Z. Liang, Targeted next-generation sequencing identification of mutations in patients with disorders of sex development. Bmc. Med. Genet. 17(1), 23 (2016). https://doi.org/10.1186/s12881-016-0286-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. R. Nixon, V. Cerqueira, A. Kyriakou, A. Lucas-Herald, J. McNeilly, M. McMillan, A.I. Purvis, E.S. Tobias, R. McGowan, S.F. Ahmed, Prevalence of endocrine and genetic abnormalities in boys evaluated systematically for a disorder of sex development. Hum. Reprod. 32(10), 2130–2137 (2017). https://doi.org/10.1093/humrep/dex280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank the subjects and their parents who agreed to be involved in this study. This work was supported by King Abdulaziz City for Science and Technology (Grant: 13-MED1154-20) to A.S.A. We also deeply acknowledge the support of the Research Center administration and the staff of the Department of Molecular Oncology for their continued support

Funding

This work was supported by King Abdulaziz City for Science and Technology (Grant: 13-MED1154-20) to A.S.A.

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    Authors and Affiliations

    1. Department of Molecular Oncology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

      Meshael M. Alswailem, Lamyaa Alghofaili, Ebtesam Qasem, Mai Almohanaa & Ali S. Alzahrani

    2. Department of Pediatrics, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

      Ohoud S. Alzahrani, Afaf Alsagheir & Bassam Bin Abbas

    3. Department of Pediatrics, King Abdulaziz Medical City, Jeddah, Saudi Arabia

      Najya A. Attia & Adnan Al Shaikh

    4. Department of Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

      Ali S. Alzahrani

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    1. Meshael M. Alswailem
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    Correspondence to Ali S. Alzahrani.

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    All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study was approved by the Institutional Review Board of the King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.

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    The authors contributed equally: Meshael M. Alswailem, Ohoud S. Alzahrani.

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    Alswailem, M.M., Alzahrani, O.S., Alghofaili, L. et al. Molecular genetics and phenotype/genotype correlation of 5-α reductase deficiency in a highly consanguineous population. Endocrine 63, 361–368 (2019). https://doi.org/10.1007/s12020-018-1767-1

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