Introduction
Background
Hypospadias is an abnormality of anterior urethral and penile development in which the urethral opening is ectopically located on the ventrum of the penis proximal to the tip of the glans penis, which, in this condition, is splayed open. The urethral opening may be located as far down as in the scrotum or perineum. The penis is more likely to have associated ventral shortening and curvature, called chordee, with more proximal urethral defects.
The earliest medical text describing hypospadias dates back to the second century AD and was the work of Galen, the first to use the term. During the first millennium, the primary treatment for hypospadias was amputation of the penis distal to the meatus. Since that time, many have contributed to development of modern hypospadias repair. Over 300 different types of repairs have been described in the medical literature. Although most reports have been in the last 60 years, most basic techniques were described over a century ago.
Modern anesthetic techniques, fine instrumentation, sutures, dressing materials, and antibiotics have improved clinical outcomes and have, in most cases, allowed surgical treatment with a single-stage repair within the first year of life on an outpatient basis.
Pathophysiology
Hypospadias is a congenital defect that is thought to occur embryologically during urethral development, from 8-20 weeks' gestation. The external genital structures are identical in males and females until 8 weeks' gestation; the genitals develop a masculine phenotype in males primarily under the influence of testosterone. As the phallus grows, the open urethral groove extends from its base to the level of the corona. The classic theory is that the urethral folds coalesce in the midline from base to tip, forming a tubularized penile urethra and median scrotal raphe. This accounts for the posterior and middle urethra. The anterior or glanular urethra is thought to develop in a proximal direction, with an ectodermal core forming at the tip of the glans penis, which canalizes to join with the more proximal urethra at the level of the corona. The higher incidence of subcoronal hypospadias supports the vulnerable final step in this theory of development.
In 2000, Baskin proposed a modification of this theory in which the urethral folds fuse to form a seam of epithelium, which is then transformed into mesenchyme and subsequently canalizes by apoptosis or programmed cell resorption.1 Similarly, this seam theoretically also develops at the glanular level, and the endoderm differentiates to ectoderm with subsequent canalization by apoptosis.
The prepuce normally forms as a ridge of skin from the corona that grows circumferentially, fusing with the glans. Failure of fusion of the urethral folds in hypospadias impedes this process, and a dorsal hooded prepuce results. On rare occasions, a glanular cleft with intact prepuce may occur, which is termed the megameatus intact prepuce (MIP) variant.
Chordee, or ventral curvature of the penis, is often associated with hypospadias, especially more severe forms. This is thought to result from a growth disparity between the normal dorsal tissue of the corporal bodies and the attenuated ventral urethra and associated tissues. Rarely, the abortive spongiosal tissue and fascia distal to the urethral meatus forms a tethering fibrous band that contributes to the chordee.
Severe penile chordee is shown. Note the extreme ventral curvature of the penile shaft.
The location of the abnormal urethral meatus classifies the hypospadias. Although several different classifications have been described, most physicians use the classification that was proposed by Barcat and modified by Duckett, which describes the location of the meatus after correction of any associated chordee.2,3 Descriptive locations include anterior (glanular and subcoronal), middle (distal penile, midshaft, and proximal penile), and posterior (penoscrotal, scrotal, and perineal). The location is anterior in 50% of cases, middle in 20%, and posterior in 30%; the subcoronal position is the most common overall.
Proximal shaft hypospadias is shown. Note the deficient ventral foreskin, blind urethral pit at the glanular level, and lighter pigmented urethral plate extending to the true meatus at the proximal shaft level.
Proximal shaft hypospadias is shown. Note the typical dorsal hood of foreskin and ventral penile skin deficiency.
Penoscrotal hypospadias is shown. Note the associated ventral chordee and true urethral meatus located at the scrotal level.
Frequency
United States
Hypospadias occurs in approximately 1 in every 250 male births in the United States. In several countries, the incidence of hypospadias may be rising. In the United States, the rate of hypospadias doubled from 1970-1993. Although some have suggested that the increased incidence is, in reality, an increase in reporting of minor grades of hypospadias, increases in severe hypospadias have also been noted. Increasing sensitivity of surveillance systems alone cannot explain this two-fold increase. However, recent reports have linked the increased rate of hypospadias in boys born prematurely and small for gestational age and boys with low birth weight.
International
In several countries, the incidence of hypospadias may be rising but seems rather constant, at 0.26 per 1000 live births in Mexico and Scandinavia and 2.11 per 1000 live births in Hungary.4
Mortality/Morbidity
The treatment for hypospadias is surgical repair. Hypospadias is generally repaired for functional and cosmetic reasons. The more proximally ectopic the position of the urethral meatus, the more likely the urinary stream is to be deflected downward, which may necessitate urination in a seated position. Any element of chordee can exacerbate this abnormality. Fertility may be affected. The abnormal deflection of ejaculate may preclude effective insemination, and significant chordee can preclude vaginal insertion of the penis or can be associated with inherently painful erections. Although the most minor forms of hypospadias are physiologically insignificant, they too may merit repair based on the potential psychological stress of having a genital anomaly.
Race
The incidence of hypospadias is greater in whites than in blacks, and it is more common in those of Jewish and Italian descent. A genetic component may be present in certain families; the familial rate of hypospadias is about 7%.
Clinical
History
Obtain a thorough history and physical examination, including any history of a familial pattern of hypospadias, any past medical history or comorbidity, and a physical assessment focusing on the meatal location, glans configuration, skin coverage, and chordee.
A history of infertility and treatment should also be documented, as in vitro fertilization (IVF) has been associated with a higher incidence of hypospadias.
Physical
Although the diagnosis of hypospadias has been made using prenatal fetal ultrasonography, the diagnosis is generally made upon examination of the newborn infant.
- A dorsal hood of foreskin and glanular groove are evident, but, upon closer inspection, the prepuce is incomplete ventrally and the urethral meatus is noted in a proximally ectopic position. Rarely, the foreskin may be complete, and the hypospadias is revealed at the time of circumcision. If hypospadias is encountered during neonatal circumcision, after the dorsal slit has been performed, the procedure should be halted, and the patient should be referred for urologic evaluation.
- Chordee may be readily apparent or discernible only during erection. Proximal hypospadias is commonly associated with a bifid scrotum and penoscrotal transposition, in which the rugated scrotal skin begins lateral to the penis rather than in its normal posterior origin.
Penoscrotal transposition is shown. Note the rugated scrotal skin lateral to the penis, cephalad to its normal position.
Causes
Several etiologies for hypospadias have been suggested, including genetic, endocrine, and environmental factors.
- Genetic factors
- A genetic predisposition has been suggested by the 8-fold increase in incidence of hypospadias among monozygotic twins compared with singletons. This finding may relate to the demand of 2 fetuses for human chorionic gonadotropin (HCG) produced by a single placenta, with an inadequate supply during critical periods of urethral development.
- A familial trend has been noted with hypospadias. The prevalence of hypospadias in male children of fathers with hypospadias has been reported as 8%, and 14% of brothers of children with hypospadias are also affected. The inheritance is likely polygenic.
- Endocrine factors
- A decrease in available androgen or an inability to use available androgen appropriately may result in hypospadias. In a 1997 report by Aaronson et al, 66% of boys with mild hypospadias and 40% with severe hypospadias were found to have a defect in testicular testosterone biosynthesis.5 Mutations in the 5-alpha reductase enzyme, which converts testosterone (T) to the more potent dihydrotestosterone (DHT), have been associated with hypospadias. A 1999 report by Silver et al found nearly 10% of boys with isolated hypospadias had at least one affected allele with a 5-alpha reductase mutation.6 Although androgen receptor deficits, quantitative or qualitative, have been shown to result in hypospadias, this is thought to be relatively uncommon, and other factors are more commonly implicated.
- A higher incidence of hypospadias in winter conceptions has also been proposed. Theoretically, this may be related to the effect of daylight on pituitary function, which, in turn, affects the maternal and fetal hormonal milieu; however, other authors have not noticed this association.
- A 5-fold increased risk of hypospadias appears to exist in males born through IVF when compared with a control group. This may reflect maternal exposure to progesterone, which is commonly administered in IVF protocols. Progesterone is a substrate for 5-alpha reductase and acts as a competitive inhibitor of the T-to-DHT conversion.
- Other factors that contribute to infertility, such as underlying endocrinopathies or fetal endocrine abnormalities, may play a role.
- Environmental factors
- Endocrine disruption by environmental agents is gaining popularity as a possible etiology for hypospadias and as an explanation for its increasing incidence.
- Estrogens have been implicated in abnormal penile development in many animal models. Environmental substances with significant estrogenic activity are ubiquitous in industrialized society and are ingested as pesticides on fruits and vegetables, endogenous plant estrogens, in milk from lactating pregnant dairy cows, from plastic linings in metal cans, and in pharmaceuticals.
- A study by Hadziselimovic in 2000 described an increase in estradiol concentration in placental basal syncytiotrophoblasts of boys with undescended testes compared with a control population.7 Undescended testes and hypospadias have been associated, but increased estradiol concentration has not been implicated in hypospadias per se. This may support the association of hypospadias with increasing parity, increasing maternal age, and low birth weight noted in some studies in relation to lifelong exposure to environmental disruptors and a possible cumulative effect.
- Combination theory: A growing body of evidence suggests that the development of hypospadias has a two-hit etiology involving a genetic predisposition coupled with fetal exposure to an environmental disruptor.8
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Further Reading
Keywords
hypospadias, chordee, penile deformity, anterior urethral anomaly, penile development anomaly, subcoronal hypospadias, ventral curvature of the penis, circumcision, human chorionic gonadotropin, undescended testes, inguinal hernias, disorder of sexual development, DSD, penis development
