Post-operative complications following masculinizing genitoplasty in moderate to severe genital atypia: results from a multicenter, observational prospective cohort study

Summary

Introduction

Differences of sex development (DSD) are congenital conditions in which there is atypical chromosomal, gonadal and/or phenotypic sex. A phenotype of severe genital atypia in patients raised as male is a relatively rare occurrence and standards for management are lacking. Decision making for early surgical planning in these rare cases includes, but is not limited to, degree of atypia, location of testes, and presence of Müllerian remnants. In this study we describe surgical approaches and short-term outcomes for masculinizing genitoplasty in moderate to severe genital atypia in young patients raised male, for whom parents opted for early surgery.

Methods

This NIH-sponsored study is an ongoing, observational, multicenter investigation assessing medical, surgical and psychological outcomes in children and their parents affected by atypical genitalia due to DSD. Participants were prospectively enrolled from 12 children’s hospitals across the United States that specialize in DSD care. Criteria for child enrollment were a Quigley score of 3–6 in those with a 46, XY or 45,X/46, XY chromosome complement, age <3 years with no previous genitoplasty; patients were included independent of whether genitoplasty was performed. Cosmesis was graded according to a 4-point Likert scale and complications per the Clavian-Dindo classification.

Results

Of the 31 participants, 30 underwent hypospadias repair and 1 patient did not undergo a genitoplasty procedure. The majority of participants (22) received a staged hypospadias repair. Seventeen complications were identified in 12 of the 31 children (41%) at 12 months of follow up. Glans dehiscence and urethrocutaneous fistula were the most common complications. Orchiopexy was performed in 14 (44%) and streak gonads were removed in 4 (13%) participants. Both parents and surgeons reported improved cosmesis after surgery when compared to baseline.

Conclusion

Genitoplasty was chosen by parents for the majority of children eligible for study. No single surgical approach for masculinizing moderate to severe genital ambiguity in young patients with 46, XY or 45,X/46, XY DSD was adopted by all surgeons. Complications occurred in 41% of those who underwent genitoplasty for severe hypospadias. Overall, appearance of the genitals, as determined by parents and surgeons, improved following genitoplasty. Outcomes of early genitoplasty are needed to guide families when making decisions about such procedures for their young children.

Summary Figure

River plot comparing Likert cosmesis score over time for mothers, fathers, and surgeons. Panel A includes all patients in the cohort.

Introduction

Disorders of sex development (DSD, intersex) are congenital conditions in which there is atypical chromosomal, gonadal and/or phenotypic sex. The exact incidence of DSD is difficult to determine because of the variable inclusion criteria utilized in the literature but is estimated to range from 1 in 1000 to 1 in 5000 [1]. Genital atypia in patients with DSD varies depending on the underlying diagnosis. Genital phenotype is an important component, along with genetic and gonadal sex, to inform sex of rearing. The newborn sex of rearing is ideally based on a shared-decision making model between families and multidisciplinary care teams composed of endocrinologists, geneticists, surgeons and mental health providers. The paucity of well-designed studies with appropriate follow-up of DSD patients has led to a lack of consensus on best practice principles, and a lack of understanding about the complications and outcomes after following interventions [2].

In particular, there are a lack of quality data on the management of masculinizing genitoplasty in the setting of moderate to severe genital atypia in DSD individuals reared male. Surgical decision making for masculinizing genitoplasty in patients with moderate to severe genital atypia is dependent upon several factors, including the location of the urethral meatus, the degree of penile curvature or chordee, the size of the phallus, the quality of the skin tissue, the development of the scrotum, and the position of the gonads. The goals of masculinizing genitoplasty, when performed, are orthoplasty, urethroplasty, and phalloplasty, with orchiopexy to allow for more typical long-term urinary, sexual, and reproductive function. Additionally, patient and parent reported outcomes and/or satisfaction has become an important measurement to document success beyond surgeon reported outcomes in hypospadias surgery [3].

To provide more robust information on how to optimize care for young children with DSD including moderate to severe genital ambiguity, an NIH-sponsored collaboration between 12 leading children’s hospitals across the United States was started in 2013 to prospectively follow patients [4–6]. We have previously published the baseline characteristics of this cohort with particular focus on the phenotype, diagnoses, and sex of rearing decisions made, as well as on parent psychosocial factors related to well-being, adjustment and stress [6]. More recently, we have reported the early post-operative complications and both parent and surgeon reported satisfaction after feminizing genitoplasty in DSD individuals reared female with moderate to severe genital atypia [7]. While that paper focused on patients reared female, the aim of this study is to describe early post-operative complications and outcomes of young DSD patients with moderate to severe genital atypia reared male undergoing current approaches to masculinizing genitoplasty. We hypothesize that boys with severe genital atypia will have a higher surgical complication rate with a single stage vs 2-stage repair, with similar improvements in cosmetic outcomes following genitoplasty.

Materials and methods

Participants

This NIH-sponsored research is part of an ongoing, observational, multicenter study assessing medical, surgical and psychological outcomes in children and families affected by moderate to severe genital atypia in the child due to DSD. Institutional review board approval was obtained at each participating center prior to participant enrollment. Criteria for child enrollment were a Quigley score of 3–6 in those with a 46, XY or 45,X/46, XY chromosome complement, age <3 years with no previous genitoplasty. Children were excluded if they presented with malformations of organ systems in addition to urogenital. Criteria for parent enrollment were comprehension of English or Spanish as a primary language and ≥18 years of age. Children and parents were eligible to participate whether or not genitoplasty was elected. Data reported here include 6–12 month outcomes following masculinizing genitoplasty in children reared male, or 6–12 month follow-up since enrollment in boys whose parents elected not to proceed with genitoplasty for their sons. Preliminary results from a subsample of the current, complete cohort have previously been reported [8].

Data collection and statistical analyses

Data were collected into a REDCap database. Variables collected include karyotype, DSD etiology, type of masculinizing surgery when genitoplasty was elected, post-operative complications and subjective evaluation of children’s’ genital appearance (cosmesis score) provided by parent(s) and surgeons prior to and post-surgery. Cosmesis score was based on a 4-point Likert scale and was graded as: 1 = good, 2 = satisfied, 3 = dissatisfied and 4 = very dissatisfied; cosmesis was scored by each parent, as well as the surgeon. To standardize the cosmesis assessment across all repair types, the time point of 6 months after surgery was defined as 6 months after the repair for single stage procedures and 6 months after the urethroplasty/glansplasty procedure for planned 2-stage operations. Post-operative complications were scored with the Clavian-Dindo grading system. A complication after hypospadias repair was defined as an occurrence that would result in an additional surgical procedure, such as urethrocutaneous fistula, glans dehiscence, recurrent penile curvature, or urethral diverticulum. Recurrent penile curvature was identified by surgeon and/or parental assessment. Urinary tract infection (UTI) and wound infections were also considered complications and were captured. Surgical approach for primary repair and complication repair were noted as well as indications for and the administration of preoperative testosterone was determined by surgeon preference and differed across sites. Patient follow-up was standardized across institutions and consisted of 6–12 month office visits.

Statistical methods:

Cosmesis scores are presented as either counts and percentages or medians and interquartile range (IQR), as appropriate. Comparisons of mean cosmesis scores between matched groups, for example, mother vs. father or mother at baseline vs. at 6 months post-surgery, were analyzed using Student t-test for paired data. Results were analyzed using R (version 3.6.1 (2019-07-05)). Results corresponding to p-values < 0.05 are described as significant.

Results

A total of 31 child participants from 7 centers met inclusion criteria, all of whom underwent a surgical procedure (1 did not undergo genitoplasty). All participants presented with severe proximal hypospadias. The median age at first surgery was 9.5 months (range 4.1–29.3 months). The median age at surgery for a planned one stage procedure was 11.5 months (range 6.0–20.5 months). For patients undergoing a 2-stage repair, the median age at the first procedure was 9.4 months and 17.0 months for the second stage.

The median number of total surgeries (planned plus procedures to address complications) per participant was 2 (IQR 1.5–3.5). Hypospadias surgical management is outlined in Table 1. Eighteen (60%) of 30 participants with hypospadias had their chordee corrected with plication alone. Seven (24%) underwent a ventral lengthening procedure with a single corporotomy, 3 of whom received a simultaneous dorsal plication. Twenty-two (73%) participants had a staged hypospadias repair while 8 (27%) received a single-stage proximal tubularized incised plate (TIP) repair (Table 1). The baseline characteristics of penile length, degree of chordee, and location of meatus did not differ between single-stage and 2-stage groups. One patient did not undergo hypospadias repair.

Table 1.

Surgical management of hypospadias for included patients. Additional procedures included those patients with streak gonads and undescended testes.

Anatomic descriptors	N = 30
Glans width (Median, IQR)	12 mm (10, 14)
Penile length (Median, IQR)	3 cm (1–3.5)
Degree of Chordee
Moderate	9/30
Severe	21/30
Location of urethral meatus
Penoscrotal	17/30
Scrotal	11/30
Perineal	2/30
Chordee management	N = 30 (% overall cohort)
Degloving only	3 (10%)
Ventral Fairy cuts	2 (7%)
Dorsal plication	18 (60%)a
Plication + Corporotomy	3 (10%)
Corporotomy	4 (13%)
Hypospadias repair	N = 30 (% overall cohort)
Single stage (proximal TIP)	8/30 (27%)
Staged Repair	22/30 (73%)
Byars Flaps	14
Ventral skin graft	8
Additional procedures	N = 20 (% overall cohort)
Gonadectomy (Streak gonad)	4 (13%)
Unilateral orchiopexy	5 (16%)
Bilateral orchiopexy	6 (19%)
Laparoscopic orchiopexy	3 (10%)
Re-do orchiopexy	2 (6%)

^a2 patients that underwent dorsal plication alone developed recurrent penile curvature.

A streak gonad was identified and removed in 4 (13%) participants, 3 of whom were removed laparoscopically and 1 via an open approach. Orchiopexy was performed in 14 (47%) subjects, 11 of which were performed at the time of hypospadias repair. Gonads were palpable in 11 of these participants and non-palpable in 3. A laparoscopic orchiopexy for intra-abdominal testis was required for 3 children. 2 children required a subsequent orchiopexy due to an ascending testicle.

Underlying conditions were identified in 7 (23%) participants and included 5-α reductase deficiency (3), SRY gene mutation, 45XO/46 XY mosaicism (2), and 17-β Hydroxylase deficiency.

There were 17 surgical complications identified in 12 (40%) children (Fig. 1), with the most common being glans dehiscence in 4 (13%) and urethrocutaneous fistula in 6 (20%).

Fig. 1.

Surgical complications after hypospadias repair. A total of 17 complications occurred in 12 participants.

Urethrocutaneous fistulas were more common in the 2-stage repair group while urethral diverticulum and ventral skin contracture occurred in the single stage repair group. Recurrent penile curvature was noted in 2 participants (both in the 2-stage repair group) after a dorsal plication, both of whom subsequently underwent a ventral lengthening procedure. Complications were more common in those undergoing a single-stage repair (4/8, 50%) than in planned 2-stage repairs (8/22, 36%), although this was not sufficiently powered to reach statistical significance. Secondary complications included one patient in the 2-stage group that developed ventral skin scarring and required a subsequent Buccal mucosa graft. In the 1-stage group one patient developed meatal stenosis.

Cosmesis assessment of the genitalia were obtained at baseline and at 6 months after surgery (Table 2). Surgeons initially reported greater dissatisfaction with participants’ cosmesis compared to parents; however, this discrepancy resolved by 6-month follow-up. Cosmesis scores improved throughout the evaluation period for all evaluators regardless of surgical type (Fig. 2). Subgroup analysis of planned 2-stage masculinizing surgery showed that the majority of improvement in cosmesis occurred after the first stage repair (Table 3, Fig. 2C).

Table 2.

Comparison of Likert scores for mother, father and surgeon before surgery and 6 months after urethroplasty and glans closure.

All masculinizing Surgery	pre-surgery	6 months post-final surgery	p-value pre- vs post-surgery
Mother	2.9 ± 1.0 (28)	1.5 ± 0.6 (26)	<0.0001
Father	2.8 ± 0.9 (26)	1.4 ± 0.5 (20)	<0.0001
Surgeon	3.5 ± 0.6 (30)	1.5 ± 0.6 (26)	<0.0001

Cosmesis scores are: 1 = Good, 2 = Satisfied, 3 = Dissatisfied, 4 = Very Dissatisfied.

P-values obtained from paired t-tests comparing the respective groups.Mean ± SD (N); p-value from paired T-test.

Fig. 2.

River plot comparing Likert cosmesis score over time for mothers, fathers, and surgeons. Panel A includes all patients in the cohort. Panel B includes patients that underwent a planned single stage repair. Panel C includes those patients that underwent a planned 2-stage repair.

Table 3.

Comparison of Likert scores for mother, father and surgeon for patients undergoing a 2-stage masculizing surgery only. Comparison is made for cosmesis scores pre-surgery, 6 months after the first stage repair, and finally after the urethroplasty/glansplasty procedure.

2-stage masculinizing surgery	pre-surgery	6 months post-1st surgery	p-value pre- vs 6 m post-1st surgery	6 months post-final surgery	p-value 6 m post- vs post-final surgery
Mother	3.0 ± 1.1 (20)	1.3 ± 0.6 (17)	<0.0001	1.4 ± 0.7 (20)	0.33
Father	3.0 ± 0.9 (19)	1.6 ± 0.6 (17)	<0.0001	1.4 ± 0.5 (17)	0.33
Surgeon	3.5 ± 0.6 (21)	1.6 ± 0.7 (18)	<0.0001	1.5 ± 0.5 (21)	0.67

Cosmesis scores are: 1 = Good, 2 = Satisfied, 3 = Dissatisfied, 4 = Very Dissatisfied. P-values obtained from paired t-tests comparing the respective groups.

Mean ± SD (N); p-value from paired T-test.

Discussion

Multicenter, prospective data on the management of masculizing genitoplasty in the setting of severe genital atypia are lacking. We present our short-term surgical and non-surgical outcomes with improved cosmesis scores after genitoplasty for both parents and surgeons, with a complication rate consistent with the published literature on proximal hypospadias.

Timing for hypospadias surgery typically occurs before 18 months of age [9]. Earlier age at surgical reconstruction is associated with fewer complications and improved psychosocial outcomes [10] and surgery in adults is associated with a higher complication rate compared to infants [11]. Patient reported outcome measures administered to adults who underwent hypospadias repair in childhood show that, in general, sexual satisfaction and the age at initiation of sexual activity were similar to controls [12]. Decreased satisfaction is associated with surgical complications, emphasizing the need to identify approaches to genitoplasty that minimize both, when patients and families opt for genitoplasty. Fewer surgical complications and improved patient education may improve patient perception of their genitals as DSD care evolves [12,13].

The majority of participants in the current study underwent a staged hypospadias repair and the complication rate was higher for the single stage proximal hypospadias repair, consistent with the established literature [14,15]. The median number of procedures received by our participants undergoing surgery was 2 but ranged as high as 6, although this study is ongoing and future complications will continue to be monitored. Those undergoing a staged urethral repair had a lower complication rate compared to the planned single stage repair (36% vs 50%, respectively), although our study wasn’t sufficiently powered for this difference to reach statistical significance.

Our study includes patients with moderate to severe genital atypia and as such is consistent with the high degree of rater (parents, surgeon) dissatisfaction with the genital appearance prior to surgery. In 2002, assessment of an adult population with a similar grade of genital atypia revealed a high degree of dissatisfaction and increased risk for surgical complications for patients reared male [16]. More contemporary techniques used for reconstruction could lead to better outcomes, but multi-center prospective data are lacking and long term follow up will be required for comparable analysis. The improvement in cosmesis per parental and surgeon assessment in the early recovery period suggests a trend in this direction although further longitudinal study will be imperative in answering this question.

A unique finding in our cohort is the degree of improvement in cosmesis scores after the 1st stage vs the 2nd stage of a planned 2-stage repair. Given the poorer baseline appearance of the genitalia in this group as rated by parents and surgeons, it is not surprising that correction of penile curvature and penile concealment significantly improved the perception of the genital appearance for both parents and surgeon. The young age of the patients prior to their second procedure makes it unlikely that the ability to stand to void and the quality of the urinary stream were factors in the cosmetic assessment. We suspect that if these patients were of toilet trained age, the second procedure would have had a greater impact on the cosmetic assessment at this time point.

The complications in our surgical cohort are consistent with previous reports and were most commonly urethrocutaneous fistula and glans dehiscence [14,15]. It is likely that the complication rate will increase with follow-up it has been shown that there is a risk for increased complication development as time passes from the initial repair [17]. In the context of 46 XY DSD, these results are likely better than anticipated given the increased risk of an underlying hormonal abnormality, which is associated with a higher rate of complications following genitoplasty [18]. Our rate of 20% re-ascension of testicles after orchiopexy is consistent with the literature [19].

Previous studies have shown that cryptorchid testes of boys who underwent orchiopexy at 3 years of age demonstrated poorer growth compared to undescended testes of boys who underwent orchiopexy at nine months [20]. Uncorrected undescended testes, in particular those that are nonpalpable, as in the 3 cases in this study, are at an increased risk for continued germ and Leydig cell loss [21]. The fertility index (number of spermatogonia per tubule) decreases in boys with cryptorchid testes after one year of age, making surgical repair very time-sensitive. Longer duration of testis non-descent correlates with higher rates of germ cell loss and adult infertility [22–24]. The specific etiology for this compromised fertility is likely related to germ cell depletion and/or defective germ cell maturation, loss of Leydig cells, and/or an increase in testicular fibrosis [24,25]. These histological changes are thus associated with abnormal semen parameters during adulthood [26,27]. Further suggesting that untreated cryptorchidism is a progressive disease, not a static congenital malformation [28].

Gonadectomy is recommended when the risk for malignancy development is high, which is the case in a genetic Y component is present with a streak gonad [29]. As in 4 of our patients, streak gonads are at risk for gonadoblastoma and subsequent malignant transformation to dysgerminoma; therefore, these were removed after discussion of risks and benefits with parents. No active tumor was noted in any specimen.

Our study included one patient that did not undergo genitoplasty. The child had a complex urologic history and required a ureteral re-implantation and bladder neck reconstruction in addition to orchiopexy and removal of a streak gonad. The family elected to not proceed with repair of his perineal hypospadias at this time.

Limitations of our study include the inherent variability encountered in a multi-institutional effort as surgical management was left to the operative surgeon and no standardized algorithm was used to dictate the approach utilized. Given the relatively low incidence of moderate-to-severe genital atypia due to 46 XY DSD, our study is limited to a small number of subjects despite its multi-institutional design. This limited our ability to make appropriately powered comparisons for some measures of interest. The number of patients with specifically identified underlying conditions was small, limiting our ability to correlate a specific contribution to complication development. Finally, our results do not assess the patient satisfaction in regard to the genital outcome given their age; this will have to be deferred until the participants reach a developmentally appropriate age to self-report. Although we have included one patient that did not undergo a genitoplasty, this low number limits our ability to fully assess the cosmetic outcomes and complications of not performing a genitoplasty. This collaboration is an ongoing effort and will incorporate patient reported outcomes when appropriate.

Conclusions

The approach to surgical reconstruction of moderate to severe genital atypia paralleled the variability seen in the hypospadias literature. Complications occurred in 40% of participants who underwent genitoplasty for severe hypospadias and were higher in those who received a single-stage repair, which is consistent with outcomes for proximal hypospadias. For planned 2-stage repairs, cosmesis scores improved drastically after the first stage procedure. As participants mature, their urethral function, fertility and sexual function will be studied. These findings will help guide providers and families with the decision-making process for male genitoplasty in severe genital atypia.