Review of genetic and environmental factors leading to hypospadias

Abstract

Hypospadias is one of the most common congenital malformations, affecting about 4–6 males per 1000 male births, and ranging in severity from a urethral meatus that is slightly off-center to a meatus in the perineal area. Over the past three decades its prevalence may have increased due to changes in reporting of mild cases and/or increased survival of low birth weight infants due to improved neonatal care. However, despite the increasing numbers of males with hypospadias, the overall etiology remains unclear and likely multifactorial in nature. The purpose of this review article is to provide a comprehensive overview of the various factors implicated in hypospadias etiology, including genetic and environmental factors. In addition, we list syndromes in which hypospadias is a relatively common association and delineate the areas that require further investigation in an effort to understand this condition.

Introduction

Hypospadias is defined by the Elements of Morphology as a ventrally-placed urethral opening [Hennekam et al., 2013] and is one of the most common congenital malformations, affecting 1 in 200–300 male newborns (if mild forms are included) [Paulozzi et al., 1997]. Some data suggest that the incidence of hypospadias may have increased over the past three decades, which may be related to increased genetic susceptibility, environmental exposure, increased survival of low birth weight infants, and changes in reporting [Aho et al., 2000, Paulozzi et al., 1997]. Hypospadias involves the incomplete development of the penis between 8 and 14 weeks gestational age, resulting in an abnormally placed urethral opening on the ventral side of the penis [Holmes, 2012, Manson and Carr, 2003]. Various terminologies exist in the literature for hypospadias classification [Brouwers et al., 2010, Hennekam et al., 2013, Holmes, 2012, van der Zanden et al., 2012] (Fig. 1). Anterior hypospadias, which is also known as distal or 1st-degree hypospadias, can be divided into hypospadias sine (ventral curvature of the penis with a normally-placed urethral meatus, often omitted from research or not considered to be a true form of hypospadias), glandular (mildest form involving extension of the urethral meatus down to the ventral part of the glans), and sub-coronal (urethral meatus next to the coronal sulcus). Middle hypospadias, which is also known as 2nd-degree hypospadias, can be divided into distal penile, mid-shaft, and proximal penile types, all of which involve the midline placement of the urethral meatus in various positions on the ventral surface of the penile shaft. Posterior hypospadias, also known as proximal or 3rd-degree hypospadias, can be divided into penoscrotal (urethral meatus located where the base of the penis and the scrotum meet), scrotal (urethral meatus located in the scrotum), and perineal (urethral meatus positioned below the scrotum and on the perineum) [Holmes, 2012]. Approximately 70% of cases are considered 1st degree (distal), and the remaining 30% are considered 2nd or 3rd degree with the urethral meatus located in the penoscrotal or perineal area. Hypospadias can occur in isolation or can be accompanied by additional abnormalities, most commonly other genitourinary abnormalities including cryptorchidism, bifid scrotum, vesicoureteral reflux, and inguinal hernia [Holmes, 2012]. In addition, hypospadias can be associated with various syndromes as described below.

Some cases of hypospadias can be attributed to underlying genetic causes or syndromes (<10%), but most are idiopathic [Carmichael et al., 2012]. In addition, many of these cases are associated with intrauterine growth restriction (IUGR) and being small for gestational age (SGA). The purpose of this article is to provide a comprehensive review of the multifactorial etiologies of hypospadias, with a focus on various genetic and environmental contributors that may be interacting to cause this disorder.