Risk Factors for Hypospadias: A Case Control Study

Despite being one of the most common congenital defects in boys, the etiology of hypospadias remains largely unknown. In this study we evaluated a spectrum of potential risk factors for hypospadias in which we focused on both paternal and maternal factors and chromosomal aberrations. Cases were selected from the Genetic Clinic, Medical Research Institute, University of Alexandria. A total of 176 cases with hypospadias were included in this study, and a matching control group of normal 300 boys for the association study. All cases were subjected to detailed family, pregnancy, genetic histories, clinical examination, and pedigree study. Chromosome analysis was performed using peripheral blood lymphocyte cultures by trypsin G-banding technique. Hormonal assays, abdominal and pelvic ultrasound were carried out according to case presentation. Both parents of cases and the control group completed written questionnaires. Abnormal karyotyes were detected in 23 cases (13.07%) associated with other anomalies, sex chromosome abnormalities were present in 69.56% and autosomal aberrations in 30.43%. Patients with chromosomal abnormalities were excluded from the association study. Logistic regression analysis was used to assess the independent contribution of different factors to the risk of hypospadias. Our data did not support an association with increased parental age. The most profound result was the increased risk of hypospadias for boys with positive family history (n=23; OR=26.36; 95% CI: 5.90-164.23). Strong indications for an increased risk of hypospadias were also found with low birth weight (n=45; OR=13.47; 95% CI=6.09-30.70), preterm birth (n=6; OR=12.20; 95% CI=1.45-271.47), twin or triplet pregnancy (n=4; OR=8.03; 95% CI=0.84-190.23), and when mothers had preeclampsia (n=16; OR=11.56; 95% CI=3.11-50.77). Associations with pregnancy achieved with fertility treatment, and mother used iron supplements were also found. In conclusion, routine karyotype screening permits the diagnosis of chromosomal anomalies especially in those with the most severe forms of hypospadias and additional anomalies. Several risk factors have been identified for hypospadias which support the idea that genetic predisposition, placental insufficiency, and substances that interfere with natural hormones before conception or during fetal development play a role in the etiology of hypospadias. INTRODUCTION Hypospadias is one of the most common developmental disorder of the urogenital tract, with an estimated prevalence of 3 to 8 per 1000 male livebirths[1,2]. Defined as an atypical urethral opening anywhere along the shaft of the penis, scrotum, or perineum. Hypospadias is often associated with a deficient prepuce and chordee. The malformation results from incomplete fusion of the urethral folds 261 Bull High Inst Public Health Vol.38 No.2 [2008] which usually occurs between 7th and 14th weeks of gestation[3]. Hypospadias usually occurs as an isolated defect, but can be part of a recognized syndrome or associated with other genital anomalies[4]. Known etiological factors are the same as those of intersex disorders and include complex genetic syndromes, and chromosomal abnormalities Among single etiological factors chromosomal abnormalities are found in 5% to 12% of cases[5,6]. The etiology of nonsyndromic hypospadias is unknown, and is believed to be multifactorial . An etiological role for genetic and environmental factors has been postulated since ethnic as well as geographic differences in incidence exist and the incidence is increasing in many countries [6]. Recent studies have implicated factors such as familial inheritance, low birth weight, advanced maternal age, paternal subfertility, and environmental exposure in the form of endocrine disruption chemicals in the pathogenesis of hypospadias[4,7]. Endocrine disruptors are exogenous substances that behave similarly to biologic hormones and is the most likely explanation for the worldwide increase in incidence in the last three decades. They interfere with the physiologic functions of the endogenous hormones by affecting the release, binding, or metabolism of the endogenous hormones,. , etc. An example of such is the non-steroidal estrogen diethylstilbestrol (DES)[7]. The aim of the present study was to identify a wide range of risk factors for hypospadias in which we focused on both paternal and maternal factors and chromosomal disorders. This may assist in prevention of this congenital malformation, provide genetic counseling for affected families with hypospadias, and minimize or eliminate exposure to environmental agents that may contribute to this problem.