ECEESPE2025 Poster Presentations Fetal and Neonatal Endocrinology (15 abstracts)
Hypospadias and fetal growth restriction: a shared genetic origin?
Silvia Pecorelli 1 , 2 , Anne Bergougnoux 3 , 4 , Yannis Bonnin 1 , Safa Aouinti 5 , Nadège Servant Fauconnet 4 , Aurélie Cazals 3 , Charles Sultan 3 , Alice Faure 6 , Jean Breaud 7 , Nicolas Molinari 8 , Francoise Paris 3 4 5 & Nicolas Kalfa 1 3 9
1Département de Chirurgie Viscérale et Urologique pédiatrique, Hôpital Lapeyronie, CHU Montpellier, Université Montpellier, Montpellier, France; 2Departement of Pediatric Surgery, Spedali Civil Children’s Hospital, Brescia, Italy; 3Centre de Référence Maladies Rares du Développement Génital DEVGEN, Constitutif Sud, Hôpital Lapeyronie, CHU Montpellier, Université Montpellier, Montpellier, France; 4Laboratoire de Génétique Moléculaire, PhyMedExp, INSERM, CNRS UMR, CHU Montpellier, Université Montpellier, Montpellier, France; 5Unité d’endocrinologie pédiatrique, Hôpital Arnaud de Villeneuve, CHU Montpellier, Montpellier, France; 6Service de Chirurgie Viscérale et Urologie Pédiatrique, Hôpital Timone, AP-HM, Marseille, France; 7Service Chirurgie Viscérale et Urologie Pédiatrique, CHU Lenval, Nice, France; 8Département de l’Information Médicale, Unité de Recherche Clinique et Épidémiologie, Hôpital la Colombière, Montpellier, France; 9UMR 1302 Institute Desbrest of Epidemiology and Public Health, INSERM, Univ Montpellier, Montpellier, France
JOINT2785
Background: Placental dysfunction is suspected to be linked to hypospadias since placental HCG stimulates fetal testis and subsequently support urethral development in the male fetus. Preterm births and intra-uterine growth restriction are thus associated with an increased risk of hypospadias but a shared molecular mechanism has not been elucidated yet. We aim to identify a JOINT genetic basis for hypospadias, preterm birth and fetal growth restriction using next generation sequencing (NGS).
Method: Prospective comparative multicenter study including 276 children with hypospadias. Phenotype ranged from glandular to penoscrotal hypospadias, without abnormal karyotype or pathogenic variants of candidate genes for XY-DSD. Genes included in the NGS panel were genes implicated in hypospadias or gonadal/genital development and that are expressed in the placenta. Frequency of variants was compared between preterm vs full-term patients, and between small for gestation age (SGA) vs normal growth patients. Univariate analysis and multivariate logistic regression analysis with stepwise backward selection were used.
Results: 57 Hypospadiac boys were preterm (20. 6% of cases). Among these children, the variant rs4986873 on CYP11A1 (a gene implicated in testicular steroidogenesis and trophoblastic development) was more frequently found than in full-term babies (8. 8% vs 1. 8%, OR=5. 239, P = 0. 015). 44 hypospadiac boys were SGA (15. 9% of cases). Among these children, 4 variants in RSPO1, ARID1A, CITED2 and CUL7 were more frequent than in hypospadiac patients without growth restriction. The identified variants are rs45577433 in RSPO1 (OR=7. 35, P < 0. 01), rs35428899 in ARID1A (OR=4. 14, P = 0. 01), rs1131400 in CITED2 (OR=6. 73, P < 0. 01) and rs9394939 in CUL7 (OR=4. 1, P = 0. 02). This group of SGA patients had more severe hypospadias (40. 9% vs 24. 5% of mid-penile or posterior hypospadias, P < 0. 01), more frequent chordee (53. 5 vs 35. 5%, P = 0. 03), more frequent undescended testis (11. 9% vs 3. 15%, P = 0. 03) and more frequent bifid scrotum (9. 3% vs 1. 3%, P = 0. 01) than hypospadiac boys with normal growth.
Conclusions: We identified 5 variants that are more frequent in hypospadiac patients with prematurity (in CYP11A1) or SGA (in RSPO1, ARID1A, CITED2 and CUL7) than in full-term hypospadiac boys with normal growth. These findings are in accordance with previous findings since besides being implicated in gonadal function and genitalia differentiation, CYP11A1 regulates trophoblastic proliferation and RSPO1, ARID1A, CITED2 and CUL7 regulate placental angiogenesis and have been associated with fetal growth retardation. These 5 genes may be at the crossroads of sex development and placental function. This finding makes a little further the connection between hypospadias and placental insufficiency at the molecular level.
Volume 110
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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