Ancient literature and art have recorded a variety of genital anomalies. The Greeks deified Hermaphrodite and numerous Greek artists depicted hypospadiac genitalia in their drawings and sculptures.
The term hypospadias derives its origin from the Greek word "hypo" meaning under and "spadon" which denotes a rent or fissure. Hypospadias is a congenital anomaly of the penis resulting from a deficiency or incomplete development of the anterior urethra. The urethral meatus is found at any location along the undersurface of the glans or penile shaft and in severe cases may even open onto the scrotum or perineum.
The first widely accepted anatomic classification of hypospadias was that of Smith in 1938. 1 First degree hypospadias is defined as a meatus located in the distal third of the penis, second degree from this point to the penoscrotal junction, and third degree denoted a meatus located proximal to the penoscrotal junction. Schaeffer and Erbes2 simplified the classification in 1950 by simply labeling the hypospadias according to its position at the time of initial presentation: glanular if it was located on the glans, penile when it was somewhere along the shaft of the phallus, and perineal when its location was proximal to the penoscrotal junction. In 1973 Barcat, 3 a French surgeon, using the simplified Schaeffer- Erbes terminology, made an important and clinically very significant modification to the classification. The meatal position was classified not by its site at the time of initial presentation, but rather by its new location after correction of the associated chordee (ventral bend of the glans and penile shaft) and correction of torsion if present. This improved nomenclature denotes glanular as a meatus situated on the inferior surface of the glans; coronal when the meatus is in a balanopenile location; distal, mid, and posterior penile for different locations along the penile shaft; penoscrotal for a penoscrotal junction location; scrotal when the meatus is situated in the scrotum; and perineal when the meatus is posterior to the scrotum. This last classification not only depicts the anatomic site more precisely but also defines for the surgeon the degree of complexity of the reconstructive procedure.
Anterior locations of the hypospadiac meatus on the glans, corona, or distal shaft after correction of chordee account for approximately 70% of all cases, mid penile locations for 10% to 15%, and proximal penile, penoscrotal, scrotal, and perineal locations account for the remaining 10% to 15% of cases.
External genital development is identical in both sexes until the eighth week of fetal life. In the male, androgenic stimulation from the fetal testis, under the influence of maternal chorionic gonadotropin, results in elongation of the genital tubercle at this time. The ventral urethral groove is continuous with the urogenital sinus and extends distally with growth of the genital tubercle. The urogenital folds on either side of the urethral groove fuse progressively, from proximal to distal, thereby forming a normal tubularized urethra.
Some authors believe that the glanular urethra is formed by an ingrowth of ectoderm that subsequently tunnelizes and joins the fused penile urethra at the coronal level. Mesodermal differentiation of the dartos fascia, Buck's fascia, and corpus spongiosum, and ventral migration of the heaped up redundant prepuce dorsally completes normal penile development by the 14th to 16th week.
Hypospadias, chordee, and penile torsion are the consequence of an arrest or anomaly in this sequence of events. Chordee appears to be a normal stage of embryogenesis. It is most prominent in the 16th through 20th weeks of gestation but can persist into the third trimester, disappearing in most male fetuses before birth. Consequently, some premature infants, with or without hypospadias, may have spontaneous resolution of their chordee during the early months of extrauterine life.4 This observation explains those cases of chordee due to arrested rather than anomalous development where no abnormal fibrous bands are present at the time of surgical correction. Failure of the redundant prepuce to migrate inferiorly accounts for the lack of ventral preputial tissue in most hypospadiac children.
Hypospadias is one of the more common urogenital anomalies, with a reported incidence ranging from 0.8 to 8.2 per 1,000 live male births. Some geographic variation may exist but the differences in reported rates are probably more a reflection of differing methods of case ascertainment and underreporting of mild cases rather than a true geographic variation. The unique medical surveillance system of the Rochester, Minnesota population allowed Sweet et al5 to publish an accurate case control study of hypospadiacs and their families. The incidence was found to be 8.2 per 1,000 live male births for the period 1940 through 1970 inclusive, ie, 1 in 125 live births. Nearly all in this population study were whites. There may be a racial difference in the incidence of hypospadias. Blacks seem to be less prone to hypospadias than whites.
Prematurity occurred four times more frequently in index cases than the control groups in the Minnesota population. This is consistent with the 1953 Denmark study reported by S0rensen.6 The severity of the hypospadias in premature infants, however, did not differ from the rest of the group.
Maternal age of hypospadiac patients was similar to that of mothers in the control group, and there were no significant differences with respect to number of previous pregnancies, deliveries, abortions, stillbirths, incidence of preeclampsia, frequency of cesarean sections, twinning, Rhesus incompatibility, and blood types. Similarly, no specific differences were detected in index mothers with respect to exposure to drugs or radiation during the pregnancy.
Paternal factors were also analyzed in the Minnesota study. The fathers of index patients had a significantly higher proportion of testicular anomalies. These included postpubertal unilateral cryptorchidism, varicocele, and atrophic testes secondary to previous inguinal hernia repair or following mumps orchitis. All of these conditions are known to affect spermatogenesis and semen quality. However, very few semen analyses were actually performed among the fathers of index patients and therefore a definite relationship between semen quality and hypospadias must remain speculative.
Experimental studies have shown that progestins given to animals can cause hypospadias, and Aarskog7 has implicated progestin administration in the first trimester of pregnancy as a possible causative factor in humans. He documented progestin ingestion in five of 80 mothers whose children were born with hypospadias. In two cases the progestational agents were administered to prevent threatened abortions, and in three cases the progestin was used for the purpose of a pregnancy test. Moreover, earlier progestin administration seemed to result in more severe forms of hypospadias in the affected children.
A number of authors have questioned the concept of hypospadias being simply a local dysmorphic problem. Allen and Griffin8 contend that "theoretical considerations alone mandate that hypospadias must be the local manifestation of some underlying systemic endocrinopathy even when this is not evident superficially. " They reported finding six different endocrine-related abnormalities among 11 of 15 boys less than 4 years old with penoscrotal to perineal hypospadias who were extensively evaluated endocrinologically. The most striking finding was a poor testosterone response to human chorionic gonadotropin (HCG) stimulation in seven boys and a poor genital response to exogenous testosterone in three patients despite theit normal androgen binding receptor levels. Of particular interest were those patients whose testosterone response to HCG stimulation improved with time; in two the response actually normalized. They postulate that one major cause of hypospadias may be a delay in maturation of the hypothalamic-pituitary-testicular axis. Okuyama9 and Knorr10 have also observed a blunted response to HCG stimulation in their hypospadiac patients. Campo and associates,11 however, were unable to confirm this. Svensson and Snochowski12 as well as Gonzales and Keenan13 reported decreased levels of androgen receptors in the genital tissues of patients with hypospadias compared with controls. Coulan and associates14 reported defective conversion of testosterone to dihydrotestosterone and some qualitative defect in androgen receptor activity. Allen and Griffin8 were unable to confirm Svensson's12 or Gonzales's13 or Coulan's14 observations. These disparate results have confused the picture with respect to the endocrine role in the pathogenesis of hypospadias.
Isolated hypospadias is generally considered to be multifactorial in etiology. The familial mode of inheritance in this condition best fits a polygenic model. In the survey of Bauer et al15 of familial hypospadiacs, 7% of the fathers of index cases were found to have hypospadias. Twelve percent of the siblings of an index child can be expected to be affected when no other family members are affected. When the proband had penile or penoscrotal hypospadias, the risk of hypospadias in a subsequent sibling increased to 14% and 18% respectively. The potential risk increases with the severity of the hypospadias in the index child. If two members of the family are affected, and if the second member is the father, the risk of a subsequent child developing hypospadias increases to 26%. 15 There are also at least six reported instances of isolated hypospadias occurring in three or more generations, suggesting that familial isolated hypospadias can be inherited as a sex-linked autosomal dominant (or Y-linked) gene.16
Hypospadias is also associated with multiple rare syndromes with mendelian inheritance. The SmithLemli-Opitz syndrome of facial dysmorphism, small stature, and hypospadias is inherited as an autosomal recessive. Leap et al17 described a syndrome with multiple phenotypic defects where hypospadias constituted only one of the abnormalities. Partial deletion of the short arm of chromosome 4 appeared to be responsible for the defect.
Associated Genitourinary Findings
Meatal stenosis is a frequent finding in children with hypospadias, particularly in the mild glanular and coronal forms. Inguinal hernias and undescended testes are the most commonly encountered associated anomalies. Khuri et al,18 in their evaluation of 1,076 hypospadiac boys seen over a 16-year period at the Hospital for Sick Children in Toronto, reported a 9.3% incidence of undescended testes and a 9.1% incidence of inguinal hernias. The more severe the hypospadias, the greater was the incidence of these associated conditions. The penoscrotal and more proximal varieties of hypospadias revealed a 32% incidence of cryptorchidism as well as a 17% incidence of inguinal hernias.
The fact that the incidence of genital-related anomalies rises sharply with the increasing severity of the hypospadias supports the concept that developmentally, hypospadias is related to decreased androgenization during a critical phase of embryogenesis. Further evidence in support of this hypothesis is provided by Shima et al,19 who reported the incidence of male vagina or utriculus masculinus as 11.8% in the 272 hypospadiac patients surveyed. Devine et al,20 in a more recent study, found a 14% incidence of an enlarged prostatic utricle in boys with penoscrotal or perineal hypospadias. Although a utriculus masculinus is usually found in the more severe cases, it can be present even in glanular and coronal forms of hypospadias.
There is continuing controversy in the literature regarding the incidence of urinary tract anomalies associated with hypospadias and the need for screening for other urologie defects. Older reports suggested a significant increase in their occurrence and implied the need for screening in all children. McArdle and Liebowitz21 in 1975 challenged this contention. They found only six urinary tract abnormalities among 200 boys with isolated hypospadias. None of these anomalies required surgical correction. They concluded, therefore, that screening of the urinary tract in boys with isolated hypospadias was unnecessary.
In 1977 Lutzker, Kogan and Levitt22 collated the published reports of hypospadias and associated urinary tract anomalies and included their own series of cases. Forty cases of obstruction, dilatation of the collecting system, renal dysplasia, hypoplasia, aplasia, and cystic disease of the kidney were recorded among the total of 1,014 hypospadiac males. Included were only clinically important abnormalities, defined as those resulting in a significant loss of renal substance or requiring surgical correction for conservation of renal substance. The incidence of significant congenital anomalies detected on urography using these criteria was 3.9%. Although low, this exceeds the incidence of renal anomalies found in the general population.
Shelton and Noe,23 in a more recent prospective study, screened 102 asymptomatic boys with isolated hypospadias, using intravenous urography and voiding cystourethrography. They confirmed the 3.9% incidence of significant upper urinary tract anomalies reported earlier by Lutzker et al. They also demonstrated a 10% incidence of unsuspected vesicoureteral reflux. Only one of these cases was considered to have potentially significant reflux, and the reflux in that child subsequently ceased spontaneously.
Prudence and reason based upon the available information suggest the need for an adequate history and physical examination as well as a routine urine analysis and culture in all children with hypospadias. Those with a family history of vesicoureteral reflux, urologie symptomatology, covert bacteriuria, or who have ambiguous genitalia or other organ system anomalies (other than cryptorchidism), should be adequately screened with a voiding cystourethrogram and renal ultrasound. Cryptorchidism, when present, does not influence the incidence of upper urinary tract anomalies,18 although utricular pouches are more common.
Asymptomatic, abacteriuric boys with isolated hypospadias should, in our opinion, be evaluated with renal and bladder ultrasonography. Ultrasonography is a noninvasive technique that is free from the allergenic and possible radiation hazards of urography and is capable of accurately detecting anomalies of renal size and position as well as hydronephrosis. It will detect the low, although apparently increased incidence of significant renal anomalies in hypospadiac children, thereby allowing for early surgical intervention in the occasional case of obstructive hydronephrosis. Dilatation of the collecting system, even when mild, should alert the physician to the possibility of vesicoureteral reflux and, therefore, the need for voiding cystourethrography. Moreover, the information provided by such screening is important in planning long-term management, including followup and advice regarding contact sports in children with solitary kidneys. An abnormal ultrasound mandates the need for voiding cystourethrography.
Boys with hypospadias, regardless of the degree, when found to have associated cryptorchidism or small testes or ambiguous genitalia must be evaluated for intersexuality. Retrograde urethrography, sometimes combined with voiding cystourethrography, is important to exclude a utricular pouch or other müllerian remnants. Pelvic ultrasonography may detect an unsuspected uterus. Karyotyping and an endocrinologie evaluation, including measurements of 17-hydroxyprogesterone, a baseline androgen profile with testosterone and dihydrotestosterone ratios, and an HCG stimulation test may all be required to elucidate the nature of the problem. Cystoscopy and laparoscopy as well as gonadal biopsy may be necessary in some cases to complete the evaluation.
Boys with isolated penile shaft or more distal forms of hypospadias who have descended normal testes do not require karyotyping.
EFFECTS OF HYPOSPADIAS
The abnormal location of the meatus when accompanied by chordee (ventral bend of the glans and penile shaft) or a prominent dorsal bridge of meatal epithelium or meatal stenosis results in ventral deflection of the urinary stream on micturition. The child experiences difficulty directing his stream into the toilet bowl in a standing position unless he contorts his penis in one or other direction. This, together with the cosmetic deformity, causes major embarrassment to the boy during his impressionable formative years and can result in significant long-term psychologic sequelae. In mild cases without chordee or meatal stenosis there is no functional disability. Esthetics is the only consideration.
Significant obstruction from a stenosed meatus is uncommon in newborns. Paradoxically, when it does occur it is more frequently encountered in the more minor glanular and coronal forms of hypospadias.
The prepuce is usually deficient ventrally and the ventral penile skin tends to be thin and poorly developed proximal to the hypospadiac meatus. A midline groove or sulcus distal to the hypospadiac meatus extends dorsally onto the incompletely developed glans, which is frequently tilted ventrally. This, together with the redundant dorsal and lateral preputial hood, gives the penis a cobra head appearance. The degree of ventral curvature (chordee) is variable, and becomes more apparent during erections. The chordee can be so severe that it can preclude penetration during sexual intercourse.
Psychologic Implications and Timing of Surgery
The hypospadias anomaly itself and the reconstructive surgery required for its correction can cause serious behavioral problems in the developing child, and in adulthood. Emotional, cognitive, and body image development as well as sexual identity can be profoundly disturbed. This may manifest in childhood as anxiety, aggressive behavior, regression, negativism, night terrors, and withdrawal. Parental anxiety initiated by an incomplete understanding of the condition, fear about their son's maleness, and concern about family and friends' attitudes to a genital anomaly, and the natural tendency to hide the anomaly, all contribute to this phenomenon. Farkas and Hynie24 reported a feeling of sexual inadequacy in adulthood even when the hypospadias anomaly had been successfully corrected in childhood and when penile development was satisfactory. This manifested in abstention from sexual intercourse in more than 50% of the men questioned, presumably as a result of their retained feelings of inadequacy and inferiority. Others have reported hypospadiac adults to be less competitive and to enter less responsible professions and occupations.
Most of the reported studies of psychologic implications of hypospadias correction at different ages predate the now common practice in most pediatric centers of parental rooming-in as well as the tendency to correct the anomaly at an early age. Hospitalization, with its attendant separation anxiety during the critical phases of emotional development, and prolongation of the "defective" interval before surgical correction and acquisition of a normal body image and sexual identity appear to be the major factors responsible for this vicious cycle of events. A better understanding of these factors, a more informed parent, the avoidance of separation by providing adequate rooming-in facilities for the parent, early surgery (preferably before age Vh years), single stage operations and shorter hospitalizations, and more desirable cosmetic results, should all contribute to a better long-term prognosis.
Two Alexandrian surgeons, Heliodorus and Antyllus, 3 in the first and second centuries AD, are credited with the first attempts at surgical correction of severe male hypospadias. They amputated the distal glans and reshaped it with a glowing cautery. Lusitanus,3 during the Renaissance, fashioned a glanular urethra with the use of a silver cannula. Ambro ise Pare3 was the first surgeon to describe a procedure for correcting chordee without sacrificing the distal ventrally tilted penile shaft. Mettauer,3 a backwoods Virginian surgeon, is credited with the first successful reconstructive operative repair of hypospadias in 1842. There have been well over 150 original operative techniques and modifications described to correct the wide spectrum of hypospadiac anomalies.
The past 25 years have witnessed major advances in reconstructive hypospadiac surgery. Experienced pediatric urologie surgeons, using modern techniques, are now capable of attaining consistently outstanding functional and cosmetic results, even in the most severe forms of hypospadias, with a much lower morbidity than was heretofore the case. Most surgeons prefer single stage reconstructions whenever feasible. Aside from the obvious desirability of achieving a satisfactory result with a single operation, one stage reconstructive procedures have the additional advantage of using unscarred tissue where the normal blood supply has not been disrupted by previous surgery. Technical advances, optical magnification, improvements in suture material, as well as the development of an intraoperative technique that reliably predicts chordee correction, have all contributed to this progress.
Surgical reconstruction of hypospadias requires chordee correction when present, urethral advancement or urethral reconstruction with an adequate caliber lumen, meatus placement on the glans, a normal conical appearance of the glans, and adequate resurfacing of the penile shaft with non-hairbearing skin. Techniques that use the available penile skin or prepuce, either in situ or as a rotational or vascularized pedicle graft to form the neourethra, are preferred by most surgeons. Enthusiasts of free graft urethroplasty also prefer preputial mucosa or skin rather than extragenital skin or mucosa. The pediatrician plays a vital role in preserving this preputial tissue for later reconstructive surgery by preventing overzealous circumcisors from removing this tissue in the neonatal period. When extragenital tissue is required for formation of the neourethra, bladder mucosa appears to be the preferred tissue.
Fistulas and strictures continue to be the major complications of this operation. They occur relatively infrequently in distal forms of hypospadias repair when the repair is done by an experienced pediatric urologist. Moreover, the number of hypospadiac "cripples" requiring multiple operative procedures can be kept to a minimum when experienced pediatric urologists see these children early on and have the opportunity to plan the type and timing of the reconstructive procedure from the outset, rather than seeing the child after a complication has already occurred.
There is no single operative technique that can be applied to the broad spectrum of this condition. There is also no substitute for judgment and experience in the choice of the most suitable operation for the particular hypospadiac child. It requires many years of experience to qualify the surgeon for making this choice and to develop the fine surgical technique necessary to correct this anomaly with consistently good results.
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