Q1 Which of the following is true regarding hypospadias?

A Hypospadias is an uncommon congenital anomaly in boys.

B Caucasian mothers appear to be at a higher risk of having offspring with hypospadias than non-
Caucasian mothers.

C Hypospadias is uncommon in babies whose birthweight is low.

D Hypospadias has not been found to be associated with twin birth.

E Maternal vegetarian diet has not been found to be associated with higher incidence of occurrence of
hypospadias.

A1 B The word ‘ hypospadias’ is derived from Greek ‘hypo’ meaning ‘under’, and ‘spadon’, meaning rent
or fissure. Hypospadias is one of the most common congenital anomalies found in up to 1 : 200 boys.
The urethral meatus in hypospadias is found proximal to its normal glanular position to anywhere along
the penile shaft, scrotum or even perineum. Eighty per cent of hypospadias is minor, involving glanular
and penile hypospadias forms, whereas only 20% are classified as scrotal or perineal. These latter forms
frequently occur in association with other genital anomalies such as micropenis, bifid scrotum,
penoscrotal transposition, cryptorchidism, partial or complete androgen insensitivity syndrome and may
also occur in association with malformations of other organs. Caucasian mothers appear to be at a
higher risk of having offspring with hypospadias than non-Caucasian mothers. Low birthweight, small
head circumference and birth length are also associated with an increased risk of hypospadias. It has
been found that low maternal age, low parity, gravidity and also mothers over 35 years of age with low
parity are associated with a higher risk of hypospadias, and studies have shown that late menarche or
previous stillbirth are also risk factors. Several studies have shown an increased risk of hypospadias after
in vitro fertilisation, particularly when intracytoplasmic sperm injection is used. Hypospadias is nearly 10
times more frequent when the placenta weight is lower than normal. Pre-eclampsia is associated with
an increased risk of hypospadias and this could be the cause of placental growth retardation.
Hypospadias has long been found to be associated with twin birth. The incidence of hypospadias in
male/male pairs is nearly twice that of male/female pairs. Hypospadias is more common in the first born
and inversely related to the maternal parity. Maternal ill health has also been implicated as a cause of
hypospadias, including maternal diabetes, epilepsy, renal failure, asthma and influenza during the first
trimester. Maternal vegetarian diet has also been found to be associated with hypospadias, possibly due
to an increased amount of phyto-oestrogens.

Q2 Which of the following statement is not true about hypospadias?

A Idiopathic hypospadias is not caused by multiple factors.

B Isolated hypospadias of unknown cause accounts for 70% of all cases and chromosomal causes
account for the remaining 30% of cases.

C In approximately10% of cases first- or second-degree relatives are affected.

D The risk of hypospadias in subsequent siblings is about 15%.

E The risk is higher in subsequent siblings if the hypospadias is of severe degree in index patient.

A2 A Isolated hypospadias of unknown cause accounts for 70% of all cases whereas monogenic or
chromosomal causes account for remaining 30% of cases. One or more first-, second- or third-degree
relatives affected with hypospadias, is seen in about 10% of cases. The risk of hypospadias in subsequent
siblings of affected patients is about 15%, whereas 7% of fathers of a child with hypospadias are also
affected. It has also been found that the more severe the malformation of the index patient, the higher
the risk of hypospadias in subsequent male siblings. It is widely accepted that idiopathic hypospadias is
caused by multiple factors whereby the cumulative effects of minor genes and environmental factors
result in the malformation. Genetic factors play an important role in the occurrence of hypospadias in
either non-syndromic or syndromic forms.

Q3 Which of the following is not true about genetics causing hypospadias?

A Autosomal dominant forms of syndromic hypospadias are caused by mutations in genes involved in
early genital development.

B The recessive form is caused by mutation in the genes affecting the actions and metabolism of
androgens.

C Early atrophy of the Leydig cells of the fetal testes does not cause hypospadias.

D Chromosomal anomalies are found in about 7% of children with hypospadias.

E Mutations in androgen receptor (AR) gene can cause severe forms of hypospadias.

A3 C Gender is genetically determined at conception. The urogenital sinus is formed at the sixth week of
gestation and the whole process of sex differentiation, which involves tubularisation of the urogenital
sinus, is completed by week 16. Early genital development is controlled by the genetic programme
operating prior to the production of steroid hormones, whereas the second phase of penile
development requires exposure to an androgen, either testosterone or dihydrotestosterone.
Testosterone is synthesised by Leydig cells of the testes and is first seen just prior to the second phase of
penile development. Hypospadias probably results from factors such as abnormal androgen production
by the fetal testes, altered sensitivity to androgen in the developing genitalia, or secondary to early
atrophy of the Leydig cells of the testes. Autosomal dominant forms of syndromic hypospadias are
caused by mutations in the genes involved in early genital development, whereas the recessive form is
caused by mutations in genes affecting the actions and metabolism of androgens such as mutations of
the 5-alpha reductase gene (SRD5A2). Mutations in the AR gene have also been found in patients with
penoscrotal or perineal hypospadias and hypospadias associated with cryptorchidism, micropenis, and
partial and complete androgen insensitivity syndromes. Nearly 198 syndromes have been identified with
hypospadias, and about 7% of patients with hypospadias have chromosomal anomalies of widely varying
type including Klinefelter’s syndrome and mixed gonadal dysgenesis. Autosomal abnormalities, such as
translocations, deletions (Wilms’s tumour, aniridia, genitourinary anomalies, and mental retardation
(WAGR) syndrome, WT1 gene, chromosome 11p13), or duplications have also been associated with
syndromic hypospadias. Sonic hedgehog gene (Shh) is expressed in the endodermal epithelium of the
developing urethral plate, which is essential for outgrowth and patterning of the genital tubercle. It has
been found that targeted deletion of Shh gene in mice results in penile and clitoral agenesis.