Margot Ollivier1, Francoise Paris2, Pascal Philibert3, Sarah Garnier1, Amandine Coffy4, Nadège Fauconnet-Servant3, Mirna Haddad5, Jean Michel Guys5, Rachel Reynaud6, Alice Faure7, Thierry Merrot7, Kathy Wagner8, Jean Bréaud9, Jean Stéphane Valla9, Eric Dobremez10, Laura Gaspari11, Jean-Pierre Daures4, Charles Sultan11, Nicolas Kalfa12. 1. Department of Pediatric Surgery and Urology, Lapeyronie Hospital, CHU Montpellier, Montpellier University, Montpellier, France. 2. National Reference Center of Genital Development (Constitutive South), Arnaud de Villeneuve Hospital, CHU Montpellier, Montpellier University, Montpellier, France; Pediatric Endocrinology and Gynecology Unit, Department of Pediatrics, Arnaud de Villeneuve Hospital, CHU Montpellier, Montpellier University, Montpellier, France; Genetic Genital Development Unit, University Institute of Clinical Research, CHU Montpellier, Montpellier University, Montpellier, France. 3. National Reference Center of Genital Development (Constitutive South), Arnaud de Villeneuve Hospital, CHU Montpellier, Montpellier University, Montpellier, France; Genetic Genital Development Unit, University Institute of Clinical Research, CHU Montpellier, Montpellier University, Montpellier, France. 4. Laboratory of Biostatistics and Epidemiology, University Institute of Clinical Research, Montpellier University, Montpellier, France. 5. Department of Pediatric Surgery and Urology, Timone Hospital, AP-HM, Marseille, France. 6. Pediatric Endocrinology and Diabetology Unit, Timone Hospital, AP-HM, Marseille, France. 7. Department of Pediatric Surgery and Urology, Nord Hospital, AP-HM, Marseille, France. 8. Pediatric Service, Lenval Hospital, CHU de Nice, Nice, France. 9. Department of Pediatric Surgery and Urology, Lenval Hospital, CHU de Nice, Nice, France. 10. Department of Pediatric Surgery, Pellegrin Children's Hospital, Bordeaux, France. 11. Pediatric Endocrinology and Gynecology Unit, Department of Pediatrics, Arnaud de Villeneuve Hospital, CHU Montpellier, Montpellier University, Montpellier, France. 12. Department of Pediatric Surgery and Urology, Lapeyronie Hospital, CHU Montpellier, Montpellier University, Montpellier, France; National Reference Center of Genital Development (Constitutive South), Arnaud de Villeneuve Hospital, CHU Montpellier, Montpellier University, Montpellier, France; Pediatric Endocrinology and Gynecology Unit, Department of Pediatrics, Arnaud de Villeneuve Hospital, CHU Montpellier, Montpellier University, Montpellier, France; Genetic Genital Development Unit, University Institute of Clinical Research, CHU Montpellier, Montpellier University, Montpellier, France. Electronic address: nicolaskalfa@gmail.com.
Abstract
PURPOSE: While familial forms of complex disorders/differences of sex development have been widely reported, data regarding isolated hypospadias are sparse and a family history is thought to be less frequent. We aimed to determine the frequency of hypospadias in families of boys with hypospadias, to establish whether these familial forms exhibit a particular phenotype and to evaluate the prevalence of genetic defects of the main candidate genes. MATERIALS AND METHODS: A total of 395 boys with hypospadias were prospectively screened for a family history with a standardized questionnaire, extensive clinical description, family tree and sequencing of AR, SF1, SRD5A2 and MAMLD1. RESULTS: Family history of hypospadias was more frequent than expected (88 patients, 22.3%). In 17 instances (19.3%) familial hypospadias cases were multiple. Familial hypospadias was related to the paternal side in 59.1% of cases, consisting of the father himself (30.7%) as well as paternal uncles and cousins. Premature birth, assisted reproductive techniques, other congenital abnormalities and growth retardation were not more frequent in familial hypospadias than in sporadic cases. The severity of phenotype was similar in both groups. The results of genetic analysis combined with previous data on androgen receptor sequencing revealed that familial cases more frequently tend to demonstrate genetic defects than sporadic cases (5.68% vs 1.63%, p = 0.048). CONCLUSIONS: Familial forms of hypospadias are far more frequent than previously reported. Even minor and isolated forms justify a full clinical investigation of the family history. Detecting these hereditary forms may help to determine the underlying genetic defects, and may improve followup and counseling of these patients.
PURPOSE: While familial forms of complex disorders/differences of sex development have been widely reported, data regarding isolated hypospadias are sparse and a family history is thought to be less frequent. We aimed to determine the frequency of hypospadias in families of boys with hypospadias, to establish whether these familial forms exhibit a particular phenotype and to evaluate the prevalence of genetic defects of the main candidate genes. MATERIALS AND METHODS: A total of 395 boys with hypospadias were prospectively screened for a family history with a standardized questionnaire, extensive clinical description, family tree and sequencing of AR, SF1, SRD5A2 and MAMLD1. RESULTS: Family history of hypospadias was more frequent than expected (88 patients, 22.3%). In 17 instances (19.3%) familial hypospadias cases were multiple. Familial hypospadias was related to the paternal side in 59.1% of cases, consisting of the father himself (30.7%) as well as paternal uncles and cousins. Premature birth, assisted reproductive techniques, other congenital abnormalities and growth retardation were not more frequent in familial hypospadias than in sporadic cases. The severity of phenotype was similar in both groups. The results of genetic analysis combined with previous data on androgen receptor sequencing revealed that familial cases more frequently tend to demonstrate genetic defects than sporadic cases (5.68% vs 1.63%, p = 0.048). CONCLUSIONS: Familial forms of hypospadias are far more frequent than previously reported. Even minor and isolated forms justify a full clinical investigation of the family history. Detecting these hereditary forms may help to determine the underlying genetic defects, and may improve followup and counseling of these patients.
Authors: Courtney Finlayson; Ilina Rosoklija; Christopher E Aston; Paul Austin; Dana Bakula; Laurence Baskin; Yee-Ming Chan; Alexandria M Delozier; David A Diamond; Allyson Fried; Saul Greenfield; Thomas Kolon; Bradley Kropp; Yegappan Lakshmanan; Sabrina Meyer; Theresa Meyer; Natalie Nokoff; Larry L Mullins; Blake Palmer; Megan N Perez; Dix P Poppas; Pramod Reddy; Kristy J Scott Reyes; Marion Schulte; Christina M Sharkey; Elizabeth Yerkes; Cortney Wolfe-Christensen; Amy B Wisniewski; Earl Y Cheng Journal: J Endocr Soc Date: 2018-12-13