Embryology 

During the third week of development, mesenchymal cells, deriving from the primitive line, migrate to around the cloacal membrane and determine the formation of a pair of slightly elevated plicae, the cloacal folds.  
Cranially to the cloacal membrane, these folds join together to form the genital tubercle, which is completed at the sixth week of intrauterine life, when the cloacal membrane comes to be subdivided by the urorectal septum into the urogenital membrane and the anal membrane. The cloacal folds are in their turn subdivided into two regions: 
- urethral folds, anteriorly; 
- urethral folds, posteriorly. 
Meanwhile another pair of elevations, the genital folds or intumescences, become visible on each side of the urethral folds: in the male these will lead to the scrotum. 
The genital tubercle will then be made up of: 
a) a urogenital conduit 
b) two symmetrical urethral plicae 
c) two genital folds 
d) a distal portion (destined to form the glans). 
The aspect as described will remain so until the third month. 
There are multiple factors that intervene to differentiate the genital tubercle into the male orientation. In the 7 week-old fetus the H-Y antigen determines the transformation of the undifferentiated gonad into a testicle where, at the beginning of the eighth week, the Leydig cells appear.  
Under the control of HCG, these cells start up testosterone production (beginning from the twelfth week, this control will be assumed by the LH of the fetal hypophysis).  
In order for the testosterone to be active in the masculizing sense, it is converted in the genitals into 5alpha dihydrotestosterone, the work of the enzyme alpha5-reductase. The Sertoli cells secrete MIH, a hormone that inhibits müllerian-derived structures until their disappearance. 
These hormonal messages cause: the closure of the urogenital conduit in a proximodistal direction, through the fusion of the urethral plicae.  
The process finishes at the fourteenth week with the formation of the penile urethra, whose meatus is found at the base of the glans.  
Fusion of the genital folds takes place with the formation of the scrotum, which will accommodate the testicles that descend during the last month of the pregnancy.  
The canalization of the glans occurs at the fourth month of intrauterine life and is realized in a distal-proximal direction; thus will be formed the navicular fossa and the glans portion of the urethra that will be anastomosed with the penile urethra.  
All of this is brought about contemporaneously with the rapid lengthening of the genital tubercle that thus forms the phallus. 
Making a comparison of the succession of events as  described with the hypospadias genitals aspect, hypospadias is intuitively considered as an interruption in the closure of the urethra in its various phases. 

Etiology 

Until now, no single cause for the developmental fault that leads to genital malformation has been identified.  
As often happens when the etiology of congenital disorders is investigated, called into question from time to time are: genetic anomalies, maternal or fetal endocrinal imbalances, the taking of drugs during pregnancy and many other factors.  
From the epidemiological point of view, these may be defined as risk factors without being able to establish an actual relationship with the malformation.  
This also counts for hypospadias: several studies have been conducted to try to define the way in which an endocrinopathy determines such a disorder, that cannot be regarded as a local dysmorphic problem but, rather, as a local manifestation of a systemic endocrinopathy or, better still, as an aspecific consequence of a wide variety of endocrinal disorders.  
The results arrived at by these studies, carried out on groups of patients affected by hypospadias as well as on control groups, are often in discordance.  
In the complex and delicate hormonal system concerned with the organogenesis of the male genitals, a leading role has been attributed to the conversion of testosterone by alpha5-reductase. The studies dedicated to demonstrating a diminution of the enzyme in genital skin, have actually detected values close to normal, in most cases. In other cases, on the other hand, especially the serious ones with a genital ambiguity, it was possible to document a production or utilization deficiency of androgens (because of the scarcity of, or anomaly in, the receptor sites).  
Allen and Griffen, evaluating 15 patients with grave hypospadias, found an endocrinal disorder in 11 cases; the most frequent alteration detected was diminished or absent testosterone secretion following stimulation with HCG. This investigation also reported no less than 6 types of endocrinal defect in the hormone/target organ chain. 
As far as genetic factors are concerned, most authors agree in holding these to be an important element in determining hypospadias.  
Bauer carried out a retrospective study on the family histories of 307 children affected by hypospadias, extrapolating the following data: in 21% of cases, a second family member was affected; in 14% of these cases, this was a brother and in the remaining 7% the father presented with the same anomaly. In a family nucleus in which there is already one  hypospadias child, the risk of having a second affected child is around 12%; if another family member has hypospadias, this risk increases to 19%, and reaches 26% if the father has the disorder. 
Thorough studies have been conducted to identify substances which, when assumed during the pregnancy, may cause a hypospadias in the unborn baby. The after-effects deriving from the use of progestagens, because of oral contraception or threatened abortion, were particularly looked at.  
Initially, great responsibility was attributed to these substances but more recent investigations agree, on the contrary, in excluding an increased incidence of hypospadias due to the use of progestagens. 
The increased incidence in the neonates of mothers who were treated with anticonvulsants and in the children of chronic alcoholics appears to be statistically significant. 
In conclusion, the etiology of hypospadias still leaves many problems unresolved, in the sense that one or more teratogenic factors, responsible for such malformations, have not yet been identified.  
It is not to be excluded, however, that hypospadias might be the phenotypic expression of various pathogenic mechanisms that act in a similar way.

The aims  
of hypospadias surgery 

The clinical problem of hypospadias varies greatly according to the degree of genital malformation: it ranges from small esthetic problems to very serious esthetic and functional problems. In this particular field the esthetics assume remarkable importance, equivalent to the functional significance.  
Today, the indication for corrective surgery is laid down for all cases of hypospadias, being absolute in the grave, proximal and intermediate forms and only facultative though strongly recommended in the distal forms, account taken of the psychological repercussions that may possibly ensue from making comparisons with others of the same age group at kindergarten, school or the gymnasium.  
This is an aspect that has only been taken into consideration recently; indeed, up until 20-30 years ago, any patients presenting with a glans or coronal meatus were regarded as normal on the functional plane and therefore not in need of a corrective operation. 
But let us now see what the most important moments have been in the development of this field of surgery, that is still probably the only one in which an extraordinarily high number of reparative techniques have been put forward. 
The history of surgery in the treatment of hypospadias goes back about 150 years, in the course of which, more than 300 different procedures have been proposed for the correction of urethral malformation and the bowing curve of the shaft that is associated with it in 35% of cases.  
It is precisely the resolution of the curvature first, and the construction of the neo-urethra after, that has characterized various operation types in two or more sessions that, initially applied to most cases, is today increasingly less employed and reserved for particular cases of perineal hypospadias associated with penoscrotal transposition and severe cases of bowing.  
Between 1837 and 1845, Dieffenbach followed up the first session of penile curvature correction with a second session in which the tubularized ventral penile skin went to make up the neo-urethra.  
Duplay and Thiersch, in 1847 and 1869 respectively, introduced some modifications to this procedure in order to avoid the overlapping of suture lines. Rochet in 1899 and Bucknall in 1907 made use of the scrotal skin, but this technique was very quickly abandoned since it involved the inclusion of pilonidal elements that predisposed to later complications such as stone formations and infections. In 1911, Ombredanne first introduced employing an obtained pedicle flap on the ventral surface of the shaft.  
A step forward was then made by using some of the dorsal foreskin to construct the neo-urethra and to re-cover the ventral cutaneous defect. The first free grafts were carried out in 1897 by Novè-Josserand and they foresaw the use of the epidermis only, sampled from zones that were theoretically hairless such as the upper arms.  
Failure due to stenosis or flap retraction was constant and this technique was very soon set aside, only to be then resumed several times this century by various authors (Young, Benjamin and others) who reported major successes with the transplantation of full-thickness skin, less subject to retraction compared to the flaps made from epidermis alone. It was in 1961, with Devine and Horton who made use of full-thickness preputial skin, that this technique saw the fullness of its development.  
More recently still, in 1981, Hendren re-proposed using, alongside the preputial skin, also some extragenital skin collected with a dermatome from the internal facies of the upper arms.  
A high success rate was reported.  
Many of the procedures mentioned up to now did not allow for the positioning of the meatus in the glans site and foresaw a later repair where anastomosis between the hypospadias meatus and the neo-urethra would be performed only after having checked out the integrity and patency of the newly formed urethra. 
Whatever type the hypospadias happens to be, an appropriate treatment cannot leave out of consideration a careful evaluation, in the erection, of the presence and degree of chordee. The correction of this bowing can represent the first phase of a two-stage repair or, more modernly, the initial move in a single-stage repair. 
The fundamental progress for hypospadias surgery in the last 10-15 years has in fact been the introduction of techniques that foresee one single operative session.  
These days, therefore, most surgeons look on all those procedures that provide for the reconstruction of the external genitals over two, three or more stages, as having been surpassed. 
The choice of which technique to adopt in order to achieve satisfactory esthetic and functional results is conditioned by the position of the meatus, by the glans aspect and depth of the urethral conduit, by the presence and extent of chordee and, principally, by the surgeon's individual inclination and experience. 

SURGICAL TECHNIQUES 

Curvature correction  
The precise extent of this anomaly is especially appreciable during erection so that, before passing on to its correction under general anesthetic, the “artificial erection” technique is proceeded with, as refined by Gittes and McLaughlin in 1974.  
This procedure involves the infusion of physiological solution into the corpora cavernosa, after having prevented any outflow by applying a vascular tourniquet at the root of the penis. 
In cases where it is the skin that impedes a normal erection, the Allen-Spence technique can correct this. This provides for the complete freeing of the virga, achievable by detaching the prepuce and penile skin.  
A lengthwise incision is then made on the dorsal surface in such a way as to obtain two pedicle flaps which, when made to rotate in a helicoid way, reconstitutes its cutaneous integrity. If the chordee derives from a retracting spissitude of the ventral surface of Buck's fascia, then the symmetrical removal of tissue “pickings” on the dorsal side of the penis may be useful.  
This method is known as a plasty according to Nesbit. Possible residual skin imperfections can be corrected with a common “Z-plasty”. 
In other cases, the bowing is sustained by the presence of fibrous tissue immediately underneath the glans corona. This can be incised in such a way as to mobilize the glans' ventral surface; a plicate on the dorsal side will be sufficient to get the glans in axis with the penis. More complicated is the correction of cases where there is a urethral shortness or hypoplasia present, that exercises an action like that of a string subtended to a bow.  
In these conditions it is preferable to carry out a urethral transection that would allow the achievement of a perfectly rectilinear penis. In a second session the reconstruction of urethral continuity would be proceeded with. If, on the other hand, the urethra shows a good trophism and its shortness is of little account, the urethral advancement technique may be indicated. This is more extensively employed in the correction of anterior hypospadias.

MAGPI (Meatal advancement and granuloplasty) 

This is a technique introduced by Duckett in 1981 for the treatment of some kinds of glans and coronal hypospadias without significant curvature.  
The procedure foresees a vertical meatotomy in the glans sulcus, exsecting the fibrous septum that separates the meatus from the navicular fossa.  
The dorsal border of the urethral mucosa is made to advance into the glans and sutured to the sulcus with 2-3 stitches of re-absorbable ligature (6-0); in this way, a modest advancement of the meatus is able to be achieved, as well as its extension.  
This is followed by a cutaneous incision along the glans corona and a dissection of the skin in a proximal direction on the ventral surface of the shaft.  
But the fundamental moment for a good outcome is represented by an adequate freeing of the glans from the underlying urethral plane and by the drawing together again on the median line of the two wings of the glans that are solidarized with horizontal mattress stitches; this confers a more distal aspect to the meatus.  
If the ventral skin is scanty, the preputial skin may be sectioned on the dorsum and transposed ventrally to cover the defect or, in the opposite case, to reconstitute the foreskin (Fig. 7). 
This technique is not indicated where there is a flat, broad and fixed meatus that cannot be mobilized into the glans sulcus. 

Urethroplasty according to Mattieu 

This technique figures among the various kinds of repair involving a perimeatal flap and was described by the author in 1932.  
It is still largely employed today for the correction of distal and midshaft hypospadias that present with a broad urethral conduit, a good amount of ventral skin and the absence of significant curvature.  
A skin flap whose length equals the distance between the urethral meatus and the navicular fossa is carved out on the ventral surface of the penis and freed, preserving as much of its vascularization as possible.  
The incision is extended into the glans, from each side, penetrating Buck's fascia and so creating two wings that are then sutured on the median line to cover the neo-urethra; this is achieved by turning over the flap upwards and suturing it to the underlying conduit, with continuous suturing on both sides, as far as the glans tip.  
In order to minimize the risk of fistulas, attention is paid to introflex the flaps during the suturing and recourse can also be made to the denuded internal lamina of the half of the dorsal prepuce that, transposed anteriorly, will cover the entire distal urethra.  
As mentioned above, the glans is re-approximated medially onto the neo-urethra with mattress suture stitches, while isolated subtile stitches will fix the ventral flap of the neo-meatus to the glans. This procedure is not recommended in cases where it is necessary to obtain a long flap because of the major risk of devascularization and thus urethral stenosis as well as a higher possibility of getting skin containing polinidal elements.

Urethroplasty according  
to Thiersch-Duplay  

In Duplay's original (1847) description, this procedure consisted in shaping the edges of the urethral plate, from the hypospadic meatus to the balanopreputial sulcus, then tubularizing the urethral conduit with continuous suturing on the median line. The neo-channel is re-covered by direct suturing of the penile skin. This often involves the producing of sutures under tension, with edema and fistulas. The technique was subsequently refined by Thiersch (1869) and foresaw two surgical sessions: for the purpose of bringing the meatus to the tip, he recommended extending the incision, from both sides, into the glans while, in order to reduce the number of fistulas, he recoated the neo-urethra with two staggered planes, a first subcutaneous one and a second cutaneous one formed from the foreskin cut dorsally and basculated ventrally during the first operation session to straighten the shaft. 
This kind of procedure is still made use of nowadays in re-operations and also in deferred urethroplasties for midshaft or proximal hypospadias with a pronounced curvature. 

Urethroplasty with island preputial flap, tubularized  
 

In 1980, Duckett introduced a modification to the island flap technique that had been put forward by Hodgson in 1970 and by Asopa in 1971. This method, theoretically applicable to all hypospadias forms, is most frequently employed for the one-stage correction of midshaft and proximal hypospadias with curvature.  
The first step is a skin incision along the coronal sulcus right around the shaft's circumference.  
Anteriorly, the fibrous bands present on the ventral surface are excised, at the same time isolating the hypospadic urethral meatus and the distal portion of the urethra from the corpora cavernosa. The skin is dissected from the entire corpus penis, being careful to preserve as much of the preputial vascularization as possible, posteriorly. A transversal flap is created on the internal surface of the foreskin, with a length equal to the distance between the hypospadic meatus and the glans tip and sufficiently broad so as to obtain a satisfactory urethral caliber. Particular attention is paid to retaining vascularization in the separation, at subcutis level, of the two preputial laminas. The dissection should be sufficient to be sure that the peduncle, rotated anteriorly, would not also rotate the penis. The hypospadic meatus, suitably remodeled, is fixed to the ventral penile fascia to avoid its retraction.  
The flap is tubularized on a catheter and then rotated and sutured to the hypospadic meatus in such a way that the suture line of the neo-urethra lies over the corpora cavernosa. Scissors inserted in the plane between the glans and corpora cavernosa create a tunnel while, at the glans tip, a buttonhole is formed by removing a small portion of the spongiose tissue. The passage thus prepared will accommodate the neo-urethra. The urethral meatus is fixed to the glans with unhooked stitches and the tubularized flap anchored with few stitches along the corpus penis so as to avoid plication of the anastomosis.  
The flap's vascular stem is also fixed to the shaft's ventral surface to provide further coating for the urethra. The external lamina of the prepuce incised dorsally and transposed ventrally will finish off the operation (Fig. 8). 
A variant on this procedure, known as “double-faced Duckett” was conceived for cases where a “difficult” cutaneous repair is foreseen for ventrally recoating the neo-urethra.  
This variant provides for the retaining of the dorsal preputial skin together with the corresponding tubularized mucosa part. In this way, joined by the vascular stem, the mucosa and skin are transposed ventrally.  
Should there be an appreciable distance between the hypospadic meatus and the glans tip, following the resolution of the bowing of the corpora cavernosa, a further variant on Duckett's classic procedure may be applied. With this maneuver, known as “augmented Duckett”, the long neo-urethra needed is 60-70% realized with the tubularized translateral preputial flap technique (the same method described for the proximal forms of hypospadias). The remaining 30-40% is accounted for by tubularization of a scrotal or perineoscrotal cutaneous flap (glabrous skin, interscrotal or ventral of the penis). 

Urethroplasty with onlay island preputial flap  
 

This technique is particularly indicated for those cases of distal hypospadias with an insufficient availability of ventral skin or even for the mid-shaft or proximal forms that do not have any significant curvature.  
This technique consists in employing the urethral plate as the basis for the neo-urethra, while a pedunculated flap, obtained transversally from the internal lamina of the foreskin, forms its floor. Hodgson was the first to apply this principle utilizing, however, a longitudinal flap obtained at full thickness from the preputial dorsal surface and transposed ventrally. The main advantage of this technique is the reduced overlaying of suture lines and so, theoretically, reduced fistula formation.  
On the other hand, the possibility of re-shaping the flap lessens but this is made feasible instead with the “onlay island” flap.  
This is performed by making an incision along the lateral borders of the urethral plate, from the hypospadic meatus to the glans. The next step is the preparation of the pedunculated flap, created on the internal preputial lamina. If necessary, this is remodeled in such a way as to obtain the desired length and breadth and then transposed ventrally and sutured to the urethral conduit, prepared beforehand, with two continuous sutures. The external lamina of the prepuce, incised on the median line, is used for ventrally recoating the neo-urethra (Fig. 9). 

Urethroplasty with vesical mucosa flap  

In 1947, Memmelaar was the first to describe the use of a mucosal flap from the bladder in urethra repairs. It may be indicated in the more serious cases of hypospadias, or with very unfortunate patients who have been operated on repeatedly with unsuccessful results and who therefore require a total urethral reconstruction, in the absence of available penile or preputial cutaneous tissue. 
The fundamental step in this procedure is the treatment of the chordeic penis: in the more severe forms where it is necessary to resort to using a cavernosum patch, two surgery sessions may need to be considered. But even in this situation, Hendren and Keating have reported successes with the maneuver in a single session.  
Some authors prefer to use a tubularized and pedunculated cutaneous flap for reconstructing the glans tract of the urethra.  
The vesica phase involves a transversal abdominal incision according to Pfannenstiel and, with the recti retracted, the bladder which was previously filled with saline solution or air is exposed. The exposed portion of the bladder's anterior surface is incised just as far as the underlying mucosa.  
Cleaned away from the fasciae musculares until a suitably sized area for sampling is exposed, the margins of the sampling zone are marked out, defining a perimeter that is 10% longer and 20% wider than the required dimensions. This is to provide adequate material for the sutures and to prevent regressions and possible free graft complications.  
The re-shaped graft is then tubularized with continuous sutures inverting it around a siliconed catheter of appropriate size (this will be kept as an intraurethral, extravesical stent), taking care to ensuring that this is maintained in a wet state throughout the maneuver.  
An anastomosis is prepared proximally and distally over the already prepared glans neo-urethra.  
Should it be made necessary or if it is preferred to make use of the same vesical flap to also construct the urethra's distal tract, it is very important to re-shape the flap at the meatus in order to avoid an excess of the tissue that might tend towards exstrophy in this location.  
The taking root of the free flap is usually satisfactory due to neo-angiogenesis from the well-vascularized neighboring tissues.  
There is a high rate of complications, some 40%, that are mainly fistulas; the final outcome, however, is excellent.  
Let us also bear in mind that the mucosal flap may, other than the bladder, be obtained from the internal surfaces of the cheek or lips.  
The sampling is performed following submucosal infiltration to facilitate the dissection.  
The site is chosen on the basis of the dimensions necessary to construct neo-urethras of adequate caliber and length. It is in any case preferable to have at our disposal a graft that is 10% wider than the urethral defect.  
The advantage of the vesical mucosal flap is a greater ease of sampling and a lesser tendency to ectropion in the meatal location which means there is no need to resort to a cutaneous flap to reconstruct this portion.  
A further alternative to the vesical mucosa flap, still in the experimental stage, has been suggested by Shaul who, in his paper published in 1996, proposed the use of a tubularized peritoneum flap. The application of this procedure to some cases of hypospadias in rabbits has produced encouraging results. The transplant is easy to carry out, the number of observed complications has been minimal, flap fibrosis negligible and, furthermore, the peritoneal mesothelium is very quickly replaced by polyptychial epithelium similar to that of the transition.

COMPLICATIONS 

The goal that is set out to be achieved by using the techniques illustrated so far, be they in one or more surgical sessions, is to confer an aspect that is as close to normal as possible to the penile shaft,- a total straightening of the penis, a urethral meatus at the tip of the glans and a good, steady outflow stream.  
An important contribution to this achievement of constantly improving esthetic and functional results has come from using re-absorbable and very thin sutures, the use of optical magnification systems, better hemostasis management and, last but by no means least, the increasingly widespread opinion that this type of surgery should be entrusted not just to any surgeon by chance, but rather to a dedicated and experienced specialist. 
In spite of all this, the complication rate reported till now in the literature continues to be relatively high.  
It varies in relation to the significance of the defect and to the complexity of the technique employed.  
Among the various eventualities that can be found following hypospadias correction, we would mention the fistulas, that are traceable to three different causes: to stenosis of the meatus and/or a transitory obstacle to the outflow at the time of the first urination (e.g. a small scab); to a hematoma followed by a small suppuration; to a localized necrosis because of the partial devascularization of the flap used in the repair. The incidence varies from 5-10% in the techniques with perimeatal based flaps, to 6-30% in the procedures that involve the use of free grafts or transversal island flaps.  
The repairs are carried out after an observation period lasting around 6 months so that the healing process would be finished and in consideration of the fact that a spontaneous healing up is possible for small-sized fistulas and where there is no distal urethral stenosis. 
Another possible complication is represented by a stenosis that can be proximal, at the anastomosis between the neo-urethra and the hypospadic meatus, or distal, at the meatus.  
The former occurrence may come about more frequently in the corrections with free grafts but also in the treatment with a tubularized preputial flap.  
The latter, meatal stenosis, though also reported in the operations with perimeatal-based flaps, occurs more frequently in the urethroplasties that use vesical mucosa grafts.  
Curvature persistence may be traced to an inadequate evaluation of the problem, or to an insufficient correction when the urethroplasty was being carried out, or to an unsatisfactory prolongation, in time, of the neo-urethra in relation to the corpus penis.

CONCLUSION 

The surgery for hypospadias is not easy. There is no room for improvisation; in fact, it calls for dedication and experience.  
The essence of the repair is to adapt available tissue to the needs of the child. The concept that the patient selects his own operation is true enough since the combination of curvature, foreskin development, glans aspect and the position of the meatus sorts out the choices and the possible outcome.  
In recent years, very important progress has been shown in the proposals and affirmation of very effective reconstructive surgical techniques, having ambitious functional and esthetic objectives (Figg. 10 and 11), in the realization of the whole reconstruction program in a single surgical session, and the precocity of the timing of the operation.  
Analyzing the various techniques described, it appears clear that there are always a certain number of complications present. In other words, the perfect operation does not exist.  
A surgical failure may, from time to time, be determined by a lack of attention in planning or preparing the neo-urethra, by technical imprecision, by inadequate materials or superficiality in the post-op period.  

Andrea Franchella 
Docente incaricato di Chirurgia Pediatrica 
Scuola di Specializzazione in Chirurgia Pediatrica 
Università degli Studi - Ferrara