Short Communication Ambiguous external genitalia due to defect of 5-α-reductase in seven Iraqi patients: Prevalence of a novel mutation Chiara Di Marco a, b , Anna Lavinia Bulotta c , Concetta Varetti c , Laura Dosa a, b , Angela Michelucci d , Fulvia Baldinotti d , Daniela Meucci c , Cinzia Castagnini a , Caterina Lo Rizzo a, b , Giovanni Di Maggio c , Paolo Simi d , Francesca Mari a, b , Silvano Bertelloni e , Alessandra Renieri a, b, ⁎, Mario Messina c a Medical Genetics, University of Siena, Siena, Italy b Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy c Section of Pediatric Surgery, Department of Pediatrics, Obstetrics and Reproductive Medicine, University of Siena, Italy d Laboratory of Medical Genetics, Department of Laboratory Medicine, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy e Adolescent Medicine, Department of Obstetrics, Gynecology and Pediatrics, Santa Chiara University Hospital, Pisa, Italy abstract article info Article history: Accepted 24 April 2013 Available online 8 May 2013 Keywords: 46,XY DSD Founder effect Phenotypic variability SRD5A2 gene Steroid 5-α-reductase-2 deficiency We report on seven Iraqi patients with 46,XY karyotype and ambiguous genitalia characterized by perineo-scrotal hypospadias, bifid scrotum, clitoris like phallus, palpable testes in inguinal canal and pseudovagina. Patients were raised five as females and two as males. They are all unrelated with the exception of two couples of brothers. The diagnosis of 5-α-reductase-2 deficiency syndrome was first hypothesized on clinical grounds and then confirmed by molecular analysis. Direct sequencing analysis of the SRD5A2 gene revealed in five patients a novel homozygous frame-shift mutation (c.453delC) and in two related patients a previous reported missense mutation. The presence of the same mutation in unrelated patients of the same population suggests a possible founder effect. This report brings the 5-α-reductase-2 deficiency syndrome to the attention of clinical geneticists and child surgeons and dis- cusses the appropriate clinical and surgical strategies for treating these patients. © 2013 Elsevier B.V. All rights reserved. 1. Introduction Sex development disorders (DSD) are conditions characterized by genetic, hormonal and phenotypic alterations. Patients with 46,XY DSD are characterized by ambiguous or female external genitalia due to incomplete intrauterine masculinization. Steroid 5-α-reductase deficiency (OMIM number #264600) is a rare autosomal recessive form of 46,XY DSD, first described in 1974 by Imperato-McGinley in pa- tients with pseudovaginal perineoscrotal hypospadias, microphallus, and cryptorchid testes (Imperato-McGinley et al., 1974). This under- virilization is due to an alteration in the 5-α-reductase type 2 gene (SRD5A2), which encodes for 5 α reductase activity that catalyzes the conversion of testosterone (T) to its more active metabolite, dihydrotes- tosterone (DHT). Presently, two 5-α-reductase isoenzymes, designed as type 1 and 2, have been identified in humans (Jenkins et al., 1992), but only type 2 is expressed in urogenital sinus and urogenital tubercle during ges- tation and in prostate, seminal vesicle and liver in adulthood and it has higher affinity for steroid substrates, especially T, than type 1. The 5-α-reductase isozyme 2 consists of 254 amino acids, a reduced (NADPH)-dependent isoenzyme, encoded by SRD5A2 gene. The gene is located in the short arm of chromosome 2 and it has five exons (Labrie et al., 1992). Many studies showed that point mutations or the complete deletion of SRD5A2 result in a variable entity of phenotypic expression, depending on the type of mutation and its effect on enzyme activity. In spite of male karyotype, patients with SRD5A2 mutations present pseudovagina and characteristics of dihydrotestosterone deficiency, like perineoscrotal hypospadias, micropenis, rudimentary prostate, clitoris-like phallus, bifid scrotum and cryptorchid testes. Since testos- terone production is normal, Wolffian duct differentiation and regres- sion of Müllerian structures are regular (Imperato-McGinley and Zhu, 2002). The extent of ambiguity of the genitalia has been reported to be quite variable and heterogeneous, varying from a female to a fully male phenotype with hypospadias or only microphallus (Hiort et al., 1996). The resulting phenotype is classified by Sinnecker et al. in 5 dif- ferent categories: type 1 are completely male patients without overt signs of under-masculinization, type 2 are predominantly male with micropenis and hypospadias, type 3 are patients with ambiguous geni- talia, type 4 with predominantly female phenotype and type 5 are completely female (Sinnecker et al., 1996). The percentage of patients raised as male is variable from 20% to 50% (Maimoun et al., 2011; Sinnecker et al., 1996; Wilson et al., 1993). Gene 526 (2013) 490–493 Abbreviation: AR, androgen receptor; DHT, dihydrotestosterone; DSD, sex develop- ment disorder; hCG, human chorionic gonadotropin; MRI, magnetic resonance imaging; SRD, steroid 5-α-reductase deficiency; SRD5A2, 5-α-reductase type 2; T, testosterone. ⁎ Corresponding author at: Medical Genetics, University of Siena, Viale Bracci, 2, 53100 Siena, Italy. Tel.: +39 0577 233303; fax: +39 0577 233325. E-mail address: alessandra.renieri@unisi.it (A. Renieri). 0378-1119/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.gene.2013.04.070 Contents lists available at SciVerse ScienceDirect Gene journal homepage: www.elsevier.com/locate/gene