Published 2018-01-11
Nura Eky Vikawati Ardy Santosa Achmad Zulfa Juniarto Sultana MH Faradz


Objective: Hypospadias is a malformation in urethra which has many range of severity. A patient with Isolated hypospadias (IH), a mild disorder of sex development (DSD) has a hypospadias phenotype only. Hypospadias is considered as multifactorial disease in which genetic factors contribute to its development. Chromosome analysis in DSD including hypospadias is conducted for gender assignment and other possible genetic contributions. This analysis solely could not elucidate all genetic causes of hypospadias. Polymorphism of V89L in SRD5A2 is suggested as one of genetic risk factors of hypospadias. To determine the genetic risk factor and pattern of inheritance, a good pedigree construction is required. Material & methods: 35 eligible subjects with IH admitted to Center for Biomedical Research (CEBIOR) during 2012-2015 were randomly selected. 35 normal male as control were included in this study. Data on three generation pedigrees were collected from medical records in 35 affected subjects. Chromosome analyses were done by using G-banding technique. Polymorphism analysis of V89L in SRD5A2 gene was done using PCR-RFLP technique in all samples. Results: From the 35 affected subjects, the most frequent phenotype was penile hypospadias (47%), a pair of twins were monozygotic and one had a cousin diagnosed with urogenital abnormalities (i.e micropenis and chordae). All subjects had 46,XY chromosome. No chromosomal aberration was found. No positive correlation between polymorphism of V89L in SRD5A2 and risk of hypospadias (PR of CC+CG vs GG=1.0, 95% CI: 0.342−2.921, p value=1.0). Conclusion: The pedigree data from our study implies tendency of genetic involvement in hypospadias cases. There were no chromosomal aberrations in hypospadias cases. The finding on polymorphism of V89L in SRD5A2 gene does not support that of previous studies.



Pedigree, hypospadias, risk factor, SRD5A2


Wang MH, Baskin LS. Endocrine disruptors, genital development, and hypospadia. Journal of Andrology. 2008; 29(5): 499-505.

Hadidi AT (n.d.). In Hypospadia Surgery ― Art and Science. Retrieved from:

El-Sherbiny M. Disorders of sexual differentiation: I. Genetics and pathology. Arab Journal of Urology. 2013; 11(1): 8.

El-Sherbiny M. Disorders of sexual differentiation: II. Diagnosis and treatment. Arab Journal of Urology. 2013; 11(1): 6.

Kojima Y, Kohri K, Hayashi Y. Genetic pathway of external genitalia formation and molecular etiology of hypospadias. Journal of Pediatric Urology. 2010; 6: 346-54.

Van der Zanden LFM, van Rooij IALM, Feitz WFJ, Franke B, Knoers NVAM, Roeleveld N. Aetiology of hypospadias: A systematic review of genes and environment. Human Reproduction Update. 2012; 18(3): 24.

Fredell L, Lichtenstein P, Pedersen NL, Svensson J, Nordenskjold A. Hypospadias is related to birth weight in discordant monozygotic twins. The Journal of Urology. 1998; 160: 3.

Van der Zanden LFM, van Rooij IALM, Feitz WFJ, Vermeulen SHHM, Kiemeney LALM, Knoers NVAM, et al. Genetics of hypospadias: Are single-nucleotide polymorphisms in SRD5A2, ESR1, ESR2, ATF3 really associated with the malformation? J Clin Endocrinol Metab. 2010; 95: 2384-90.

Samtani R, Bajpai M, Vashisht K, Ghosh PK, Saraswathy KN. Hypospadias risk and polymorphism in SRD5A2 and CYP17 genes: Case control study among Indian children. The Journal of urology. 2011; 185: 2334-9.

Sata F, Kurahashi N, Ban S, Moriya K, Tanaka KD, Ishizuka M, et al. Genetic polymorphisms of 17β-hydroxysteroid dehydrogenase 3 and the risk of hypospadias. J Sex Med. 2010; 7: 2729-38.

Makridakis N, Ross RK, Pike MC, Chang L, Stanczyk FZ, Kolonel LN, et al. A prevalent missense substitution that modulates activity of prostatic steroid 5α-reductase. Cancer Research. 1997; 57: 1020-2.

Wang R, Dong Z, Wang W, Xiao Y, Ni J, Wang D. Mutation analysis of the SRD5A2, AR and SF-1 genes in 52 Chinese boys with hypospadias. J Pediatr Endocr Met. 2013; 7.

Wang Y, Li Q, Xu J, Liu Q, Wang W, Lin Y, et al. Mutation analysis of five candidate genes in Chinese patients with hypospadias. European Journal of Human Genetics. 2004; 12: 706-12.

Marzuki NS, Suciati LP, Dewi M, Tridjaja B. Two novel mutation of SRD5A2 gene in Indonesian siblings with clinical 5-apha reductase deficiency [Abstract]. Journal of Pediactric Endocrinology and Metabolism. 2010; 23(12): 1329-33.

Manson JM, Carr MC. Moleculer epidemiology of hypospadias: Review of genetic and environmental risk factors. Birth Defects Research (Part.A). 2003; 67(10): 825-36.

Brouwers MM, Feitz WFJ, Roelofs L, Kiemeney L, De Gier R, Roeleveld N. Risk factor for hypospadia. Eur J Pediatr. 2006; 166: 671-8.

Gatti JM. Hypospadia. [serial online]. Update 2009 September 25 [cited 2010 January 14]; Available from: Medscape.

Wattendorf DJ, Hadley DW. Family history: The three-generation pedigree. American Family Physician. 2005; 72(3): 8.

Vokwana CKJ. Mapping gene variation in Sub-Saharan African populations. [Dissertation].2008. Retrieved from:

Juberg RC, Jewson DV, Taylor MB, Moore VL. Chromosome studies in patients with hypospadias. Pediatrics. 1969; 43(4): 7.

deCalais FL, Soardi FC, Petroli RJ, Gori Lusa AL, de Paiva e Silva RB, Maciel-Guerra AT, et al. Molecular diagnosis of 5α-Reductase type II deficiency in Brazilian sibling with 46,XY disorder of sex development. International Journal of Molecular Science. 2011; 12: 9471-80.

Thai hanh TT. Hypospadia: Gene mapping and candidate gene studies [thesis]. Stockholm, Sweden: Karolinska Institutet; 2009.

Visser R, Burger NCM, van Zwet EW, Hilhorst-Hofstee Y, Haak MC, van den Hoek J, et al. Higher incidence of hypospadias in monochorionic twins. Twin Research and Human Genetics. 2015; 18(5): 5.

Fujimoto T, Suwa T, Kabe K, Adachi T, Nakabayashi M, Amamiya T. Placental insufficiency in early gestation is associated with hypospadias. Journal of Pediatric Surgery. 2008; 43: 425.

Copyright Information
Department of Urology, Faculty of Medicine/Airlangga University