Chapter 14

Hypospadias
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Definition Penoscrotal hypospadias: The abnormal opening is

at the base of the penis, which is at the level of the scro-
An abnormal opening of the urethra on the underside tum (Figure 14-1).
(ventral surface) of the penis. Perineal hypospadias: The lowest abnormal opening
in the urethra, located below the scrotum and on the
perineum (Figure 14-1).
ICD-9: 752.605 (hypospadias, first degree Chordee: This term refers to a congenital curvature
[1°], glandular, coronal) or chordee of the penis, which is associated with a
752.606 (hypospadias, second shortened ventral raphe. Chordee is usually present
degree [2°], penile) with hypospadias, but can occur without hypospadias.
752.607 (hypospadias, third degree Foreskin: Boys with hypospadias typically have a
[3°], perineal, scrotal) redundancy or excess of prepuce on the top of the penis
752.620 (congenital chordee with (dorsally) and a deficiency of foreskin on the ventral side
hypospadias) of the foreskin. The morphology of the foreskin affects
752.621 (congenital chordee alone) the usefulness of this tissue in the surgical repair of hypos-
padias. In the examination of 174 affected males, the
ICD-10: Q54.0 (hypospadias, glandular)
most common types or shapes of the foreskin were clas-
Q54.1 (hypospadias, penile)
sified as: “monk’s hood or one humped” in 25%, “cobra
Q54.2 (hypospadias, penoscrotal)
eyes or 2 humped” in 46% and “flat” in 14% (3).
Q54.3 (hypospadias, perineal)
Mendelian #146450 (hypospadias)
Inheritance
in Man:
241750 (hypospadias)

Appearance A
Glandular hypospadias: In this mildest type of hypos-
padias, there is a long, slit-like urethral orifice that B
extends to the ventral surface of the glans (1) [Figures
14-1 to 14-3]. Sometimes there is, at birth, a membrane
Copyright 2011. Oxford University Press.

over the anterior end of the slit.

C
Penile Hypospadias
D
Typically there is a small (1 to 2 mm) opening along the FIGURE 14.1 Diagram of location of ectopic opening of urethra in
urethra in the midline and on the underside (ventral the different types of hypospadias: glandular (A), penile (B), penos-
surface) of the penis (2) [Figures 14-1 and 14-4). crotal (C) and perineal (D).

139
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 140 COMMON MALFORMATIONS

In the analysis of 5,481 boys with hypospadias born

in California (1983–1997), 70% had hypospadias as an
“isolated” abnormality (6). 30% of the affected boys
did have associated abnormalities. This analysis con-
firmed, also, the strong association of spina bifida with
hypospadias. The observed/expected ratio (O/E) was
9.2 for the affected boys in California in comparisons
to the O/E ratio of 18.3 in a similar study in Spain (7).

FIGURE 14.2 Shows ventral side of penis in newborn

infant with glandular hypospadias (arrow) and defect in
foreskin.

Associated Malformations

Hypospadias is an anomaly associated with deficient

structure of the penis (2). There are two types of associ-
ated malformations, those in other genital structures,
and those in nongenital structures.
In a review of 625 boys who had had surgical
treatment for hypospadias (1952–1972), Svensson (4)
identified the common associated genitourinary abnor-
malities: “hypoplasia” of the penis in 8%; cryptorchid-
FIGURE 14.3 Shows ventral side of penis with glandular
ism, 6%; and bifid scrotum, 4%. By using voiding hypospadias (arrow) and foreskin defect.
cystourethrography, additional abnormalities were
identified: vesicoureteral reflux in 6 (7%) of 84 studied
obstructive and nonobstructive urethral folds in 32%
and urethral recesses on the posterior wall in 13%. The
frequency of other genitourinary anomalies was higher
among children with more severe types of hypospadias
in comparison to those with the milder forms (4).
The British Columbia Health Surveillance registry (5)
identified among 295,656 male infants (1966–1981)
additional anomalies in 20% of the affected boys: 60%
had one other malformation, 18% had two, and 21%
had three or more. In this registry, cryptorchidism
and inguinal hernia were the most common other
malformations (101/264: 38%). Heart defects
(14%), gastrointestinal anomalies (9%), and club
foot deformity (9%) were other common associated
abnormalities. FIGURE 14.4 More severe penile hypospadias.

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 HYPOSPADIAS
FIGURE 14.5 Penoscrotal hypospadias with small phal-
lus and chordee in a prematurely born infant, diagnosed
as having pseudovaginal perineoscrotal hypospadias.
Developmental Defects (8-10)
The urethral folds and groove are first visible in the
sixth week (8). In the eighth week, in response to andro-
gens, the genital tubercle in the male fetus elongates
and forms the glans penis. The urogenital folds fuse,
beginning proximally, to form the shaft of the penis by
the 14th week. The curvature of the penis is most prom-
inent in the 16th to 20th week, disappearing usually in
the third trimester. The distal glandular urethra arises
by ectodermal ingrowth and subsequently undergoes
lamination, to produce the completed urethra in the
fetus with 76 mm crown-rump length. The prepuce
(foreskin) begins to develop after the formation of the
glandular urethra. These developmental events are pro-
duced by a series of genes that lead to the expression of
several hormones, including corticotrophin, gonado-
tropin and, later, thyrotropin (8, 9).
Significantly higher levels of plasma testosterone have
been measured in male fetuses in comparison to female
fetuses of 12 to 18 weeks gestation. The position of the
urethral meatus, i.e., the degree of closure of the ure-
thral groove, has been correlated with the level of tes-
tosterone (11).
The observed association of hypospadias with low
birth weight or intrauterine growth restriction has led to
hypotheses of the underlying cause. Akre and colleagues
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141
(12) postulated that the occurrence of hypospadias is
associated with early malfunction of the placenta, which
causes decreased secretion of placental and fetal hor-
mones and diminished fetal growth. A significant asso-
ciation with the mother having pre-eclampsia has also
been observed (13). Another hypothesis is that hypospa-
dias is more common when the levels of testosterone are
low during pregnancy. Low levels of maternal testoster-
one at 6 to 14 weeks of gestation were identified in one
study (14) in association with genital abnormalities and
growth restriction in the male infants of these women.
Studies in Denmark (15) showed that boys with hypos-
padias had, at age 3 months, elevated serum levels of the
hormone FSH, but not elevated levels of either testoster-
one or LH. The higher levels of FSH were thought to
reflect an increased gonadotropin drive of testicular
function and a primary testicular dysfunction
Prevalence
The prevalence of hypospadias, including all degrees of
severity, was 0.41% (1:250) in Minnesota (1940–1970)
[16], 0.38% in Latin America (1967–1975) [17], and
0.41% in northern Italy (1978–1983) [18]. In these
three studies the distribution of mild (glandular), mod-
erate (penile), and more severe (perineoscrotal) types
were: 77, 10, and 3%; 72, 18.5, and 9.5%; and 75,
21.4, and 3.6%, respectively.
Over the past 25 years, an increase in the frequency
of hypospadias has been documented in many parts of
the world, including Atlanta (19), Hungary (20), the
Netherlands (21), and Singapore (13). One factor to
consider in evaluating these increases is the impact of
the sources of information. Many examining pediatri-
cians do not record the specific location of the abnor-
mality and simply record “mild” hypospadias. If this is
glandular hypospadias, that is not considered a major
malformation by some malformation surveillance pro-
grams. However, the term “mild” could also be used
for an ectopic opening of the urethra just below the
glans, which is technically “penile” hypospadias. Also,
the precise location cannot be determined until the
foreskin has been retracted, which may not occur until
the infant is older and after the examinations are
reviewed by a surveillance program. Another factor
influencing prevalence rates is the higher frequency in
low birth weight infants (12–14, 22, 23), which have
been more likely to survive with improvements in care.
Race/Ethnicity
No significant differences between racial groups have
been identified. In Singapore (13), the frequencies of
hypospadias in Chinese, Malay, and Indian infants were
very similar and did not differ from those in Caucasian
infants (16–18).
 142
Parental Age
In some (24), but not all (18, 25) studies, an increased
frequency of hypospadias has occurred more often
among the sons of older women. In another study (26),
there was an increased risk for hypospadias among the
extremes of maternal age: less than 20 years and over
40 years.
Birth Status
Infants with hypospadias are more likely to be small for
gestational age (SGA) [defined as weight less than 10th
centile] than unaffected controls (12, 18, 22). Likewise,
hypospadias was ten times more common in SGA
infants than in the general population with no correla-
tion with the severity of the hypospadias (27). An
increased frequency of hypospadias has been observed
with decreasing birth weight, independent of gesta-
tional age (28).
Twinning
One study published in 1973 (29) showed that hypos-
padias was 8.5 times more common in monozygotic
twins than in singletons.
With regard to concordance in twins, 9 twins were
identified in the surveillance of 41,078 male births in
northern Italy (18); three sets were monozygous, and in
one set both twins were affected.
In an analysis of 18 pairs of twins, proven to be
monozygous by microsatellite markers, 16 were discor-
dant and the co-twin with the lowest birth weight had
hypospadias (30).
Genetic Factors
Epidemiologic studies (17, 18, 25, 29, 31) have shown
that the rates of occurrence of hypospadias among the
brothers of an affected boy were 9.1% (18) and 9.7%
(30). The heritabilities among first-degree relatives were
68% (17), 66.9% (18), 65% (25), and 74% (31) in the
different studies.
The examination of 399 first-degree male relatives of
294 index cases showed that 4% also had hypospadias,
a nine-fold increase in comparison to the general popu-
lation (25). The more severe the hypospadias, the higher
the rate of occurrence among the relatives (29, 30, 32).
The careful examinations by Farkas (1) of the 148
fathers and brothers of 122 boys with hypospadias
showed that many (24.6%) had malformations of the
external urethral meatus or prepuce, in comparison to
15.7% of 177 healthy men. Subfertility, due to lower
motility of spermatozoa and a higher frequency of
abnormal sperm morphology, is more common among
the fathers of boys with hypospadias (25, 33).
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COMMON MALFORMATIONS
Mutations in several genes have been associated with
the occurrence of hypospadias (34):
1. Steroid 5-alpha reductase type 2 (SRD 4A2) [MIM
#264600]: (These autosomal recessive mutations
have been found in many 46,XY male pseudoher-
maphrodites, who have ambiguous external geni-
tals, including varying degrees of hypospadias, a
bifid scrotum, and blind vaginal pouch. At puberty
they develop a male habitus with enlargement of the
phallus and production of semen. This phenotype
has been referred to as “pseudovaginal perineoscro-
tal hypospadias” [Figure 14-5].)
2. 17-beta hydroxysteroid dehydrogenase (HSD 17BB)
[MIM #264300]: (The phenotype is similar to that
produced by SRD5A2 deficiency: 46,XY individuals
with undescended testes, normal epididymis, vas
deferens, and seminal vesicles, but female external
genitals. At puberty they develop gynecomastia and
masculinize. Autosomal recessive.)
3. Androgen receptor gene (AR) [MIM ∗313700]: (The
X-linked AR mutations identified in individuals with
hypospadias have had other genitourinary malfor-
mations and signs of partial androgen insensitivity,
not isolated hypospadias. Mutations in AR have
been uncommon in boys and isolated, nonsyndro-
mic hypospadias [35].)
4. Wilms tumor 1 gene (WT1): WT1 gene mutations
are associated with the occurrence of two syndromes
with genitourinary anomalies:
a) Wilms tumor, aniridia, genitourinary anomalies,
and mental retardation: MIM #194072;
b) Denys-Drash Syndrome with nephropathy, Wilms
tumor, and genital anomalies: MIM #194080.
However, heterozygous mutations in WT1 have been
associated with mild effects on differentiation, includ-
ing hypospadias and cryptorchidism (36).
In a systematic search for mutations in SRDSA2, AR,
WT1, SRY and SOX9 among 90 Chinese individuals
with hypospadias, 16 different mutations were identi-
fied in 24 (27%) of these individuals (37). None had
mutations in either SRY or SOX9.
Other potential genetic factors in the occurrence of
“isolated” hypospadias are polymorphisms in these or
related genes involved in development of the genital
structures in male fetuses. The presence of these poly-
morphisms would be supportive of the concept that
nonsyndromic “isolated” hypospadias occurs because
of the multiple genetic and nongenetic interactions of
multifactorial inheritance. Two examples of such poly-
morphisms are: polymorphisms in the ESR1 and ESR2
genes, which enclode the estrogen receptors ERα and
ERβ (38) and the V89L polymorphism in the 5-α-
reductase gene (39). The presence of these two poly-
morphisms in males were associated with a reduced
risk for developing hypospadias.
 HYPOSPADIAS 143

Studies of the mothers of affected boys have also TABLE 14-1 Hypospadias: recognized etiologies and
identified genetic polymorphisms which decreased the associations (excluding coronal hypospadias)∗
risk. In Japan (40), the mothers with the CYP1A1 MSP1 Isolated Multiple Total (n=118)
variant had a decreased risk of having affected sons. (n=91) Anomalies
(n=23)
Families in which many men have had hypospadias
have been reported (41, 42). Autosomal dominant (41) Apparent etiologies
and autosomal recessive (42) inheritance have been 1. Mendelian disorders (8; 6.8%)
postulated in different families. No molecular studies a. Opitz-Frias Syndrome 1
were carried out on the affected individuals. b. Smith-Lemli-Opitz 2
Syndrome
Environmental Factors c. Partial androgen 2
resistance
Several exposures during pregnancy have been postu- d. Pseudovaginal 1
perineoscrotal
lated to cause hypospadias: progesterone (43), phytoe- hypospadias
strogens (44), diethylstilbestrol (45), and phthalates e. Alpha-thalassemia, 1
(46, 47). These hypotheses require confirmation by sep- homozygote;
arate independent studies. For example, other analyses 45,X/46,XY
refute the association between exposure to progester- f. Epidermolysis bullosa∗∗ 1
one and the occurrence of hypospadias (48). 2. Chromosome abnormalities (5; 4.2%)
An increased frequency of hypospadias has been a. Trisomy 21 mosaic 1
noted, also, in some studies of the fetal effects of the b. Chromosome 10p+ 1
(de novo unbalanced
anticonvulsant drugs, including carbamazepine (49) translocation)
and valproate (50). c. Chromosome 4p- 1
Male infants conceived by in vitro fertilization (51), d. Chromosome 22q11.2 1
especially with the intracytoplasmic sperm injection deletion
(ICSI) technique (52), have been shown to have an e. Trisomy 13 1
increased risk of developing hypospadias. This associa- 3. Syndromes (1; 0.8%)
tion with ICSI raises the question as to whether the a. anencephaly with 1
sperm used in conception is conveying on the fetus microphthalmia and
genetic factors that had caused the father’s reduced split-hand deformity
fertility. 4. Twinning/multiple (6; 5.1%)
gestations
Questions raised about the association of environ-
a. triplets 2∗∗∗
mental exposures in pregnancy with the occurrence of
b. monozygous twins 1
hypospadias will be answered with more certainty with
c. like-sex twins – 1∗∗∗∗
objective measurements. For example, measuring the unknown zygosity
blood level or urine level of the alleged teratogen in the d. dizygous twins◊ 1 1
mother provides objective confirmation of the exposure 5. Exposures in pregnancy (7; 5.9%)
at the critical time in pregnancy. Careful study exami- a. infants of diabetic 5
nations of the physical features of the exposed fetus in mothers
infancy confirm the presence of the hypospadias and b. carbamazepine and 1
other features. This objectivity has been possible in lithium
some studies of phthalate exposure in pregnancy (47). c. phenytoin 1
The exposed boys had a reduced ano-genital distance 6. Unknown etiology 78 13 (91; 77.1%)
and associated hypoplasia of the penis itself. 93 25
Total 118 (1:1,748)

Treatment and Prognosis
Several surgical techniques have been used in the repair
of hypospadias. Follow-up is recommended to identify
physical abnormalities (53).
Genetic Counseling
As is true for all common malformations, the first ques-
tion for the examining clinician to ask is whether it is
an isolated anomaly or not.
Legends: ∗ Infants with more severe hypospadias identified in the
surveillance of 206,244 liveborn and stillborn infants and elective
terminations at Brigham and Women’s Hospital in Boston in
1972–1974, 1979–2000. Excludes infants with coronal or glandular
hypospadias. Excludes infants whose mothers had planned to
deliver at another hospital before the prenatal detection of fetal
anomalies.
∗∗
Father and other relatives had also epidermolysis bullosa
simplex, Werner-Cochrayne type, but not hypospadias.
∗∗∗
Two sets of triplets only one affected. Zygosity not known.
∗∗∗∗
Like-sex twin pair in which only one male had
hypospadias.
◊
In dizygous twin pairs, only one infant had hypospadias.

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 144 COMMON MALFORMATIONS
The isolated type of hypospadias is to be expected. In
the examination the common associated genital abnor-
malities, undescended testes and inguinal hernia should
be looked for. Another option is to evaluate for abnor-
malities of the ureters and kidneys.
If the infant has ambiguous genitals, is dysmorphic,
or has associated nongenital malformations, chromo-
some analysis, and chromosome microarray, should be
considered routine tests. Additional testing options in
the future may include analysis for mutations in genes
associated with hypospadias, such as WT1, SRD 4A2,
HSD17BB and AR.
In addition to the laboratory testing, the infant should
have a diagnostic evaluation for having one of the many
possible malformation syndromes associated with
hypospadias (Table 14-1).
As part of the evaluation of the affected infant, the
pregnancy history should be reviewed to identify poten-
tially relevant exposures. Was the infant growth
restricted? Did the affected infant’s mother have pre-
eclampsia or insulin-dependent diabetes mellitus? Does
the father have hypospadias?
If there is no evidence of an environmental exposure
or associated genetic abnormality, there should be a dis-
cussion of the empiric risk of recurrence in a subsequent
pregnancy. The healthy parents with one affected son
will have an approximate 10% risk that each subse-
quent son will have hypospadias. If the first affected
son has more severe hypospadias, the risk appears to be
greater.
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