Summary
Introduction
Little data exist about the surgical interventions taking place for children with disorders of sex development (DSD). Most studies that have evaluated cosmetic outcomes after genitoplasty have included retrospective ratings by a physician at a single center.
Objective
The present study aimed to: 1) describe frequency of sex assignment, and types of surgery performed in a cohort of patients with moderate-to-severe genital ambiguity; and 2) prospectively determine cosmesis ratings by parents and surgeons before and after genital surgery.
Study design
This prospective, observational study included children aged <2 years of age, with no prior genitoplasty at the time of enrollment, moderate-to-severe genital atypia, and being treated at one of 11 children’s hospitals in the United States of America (USA). Clinical information was collected, including type of surgery performed. Parents and the local pediatric urologist rated the cosmetic appearance of the child’s genitalia prior to and 6 months after genitoplasty.
Results
Of the 37 children meeting eligibility criteria, 20 (54%) had a 46,XX karyotype, 15 (40%) had a 46,XY karyotype, and two (5%) had sex chromosome mosaicism. The most common diagnosis overall was congenital adrenal hyperplasia (54%). Thirty-five children had surgery; 21 received feminizing genitoplasty, and 14 had masculinizing genitoplasty. Two families decided against surgery. At baseline, 22 mothers (63%), 14 fathers (48%), and 35 surgeons (100%) stated that they were dissatisfied or very dissatisfied with the appearance of the child’s genitalia. Surgeons rated the appearance of the genitalia significantly worse than mothers (P < 0.001) and fathers (P ≤ 0.001) at baseline. At the 6-month postoperative visit, cosmesis ratings improved significantly for all groups (P < 0.001 for all groups). Thirty-two mothers (94%), 26 fathers (92%), and 31 surgeons (88%) reported either a good outcome, or they were satisfied (see Summary Figure); there were no significant between-group differences in ratings.
Discussion
This multicenter, observational study showed surgical interventions being performed at DSD centers in the USA. While parent and surgeon ratings were discordant pre-operatively, they were generally concordant post-operatively. Satisfaction with postoperative cosmesis does not necessarily equate with satisfaction with the functional outcome later in life.
Conclusion
In this cohort of children with genital atypia, the majority had surgery. Parents and surgeons all rated the appearance of the genitalia unfavorably before surgery, with surgeons giving worse ratings than parents. Cosmesis ratings improved significantly after surgery, with no between-group differences.
Keywords: Disorder of sex development, Cosmesis, Genitoplasty
Graphical abstract
Summary Fig postoperative cosmesis ratings at baseline and 6 months.
Introduction
Disorders or differences of sex development (DSD) are conditions in which the chromosomal, gonadal or phenotypic sex is atypical [1]; atypical external genitalia are often the presenting feature. The incidence is reported to be 2 per 10, 000 births [2]. It is recommended that genital surgery for a child raised as a female only be considered in cases of severe virilization (Prader 3–5) and that surgery of the clitoris not be performed for reasons of cosmetic appearance alone [1]. For patients with congenital adrenal hyperplasia (CAH) with severe virilization raised as a female, it is recommended that ‘clitoral and perineal reconstruction be considered in infancy’ and those with a low vaginal confluence undergo vaginoplasty at an ‘early age’; the appropriate timing is less certain for those with a higher vaginal confluence [3]. Whether or not to perform clitoroplasty for children with a large clitoris raised as a female is controversial, and the rates of and rationale for clitoroplasty across institutions are unknown. Recommendations for masculinizing genitoplasty are vague [4]. Hypospadias repair is more successful if performed in pediatric rather than adult patients [5]. The current rates of surgery in the United States of America (USA) among children with atypical genitalia are unknown, as there have been no multicenter, prospective studies on this topic. The frequency of surgery and types of procedures performed may differ from prior eras; this is due to changes in attitudes regarding surgery and sex assignment, and because preferences for different procedures and advances in surgical techniques also change over time.
Cosmetic outcomes after genitoplasty are variable [6–12]. Most studies have included only cosmetic and functional outcomes rated by a physician [7,8,10–12], and satisfaction ratings may differ between patients and physicians. Studies that include cosmetic ratings by affected adults are scarce [9,12], and fewer exist among adolescents [7] or children [11], with most being small, retrospective and single center [7,9,10,12].
The present prospective, observational, multi-center study aimed to: 1) describe the frequency of sex assignment and types of surgery performed in a cohort of patients followed with moderate-to-severe genital ambiguity at DSD centers in the USA; and 2) prospectively determine cosmesis ratings by parents and surgeons before and after genital surgery. It was hypothesized that there would be no difference in baseline ratings between parents and surgeons, but that ratings by surgeons would be more favorable than those by parents at the 6-month postoperative visit.
Materials and methods
Participants
Participants included children from 11 children’s hospitals in the USA with programs that specialize in DSD care, they were: Children’s Hospital, Colorado; University of Oklahoma Health Sciences Center; St. Louis Children’s Hospital; University of California, San Francisco; New York Presbyterian Hospital; Boston Children’s Hospital; Lurie Children’s Hospital of Chicago; Women and Children’s Hospital of Buffalo; Children’s Hospital of Philadelphia; Children’s Hospital of Michigan; and Cincinnati Children’s Hospital Medical Center.
Inclusion criteria were: moderate-to-severe genital atypia, as defined by a Prader rating [13] of 3–5 in a 46,XX child; or a Quigley rating [14] of 3–6 in a child with 46,XY or 45,X/46,XY chromosomal complement (see Supplemental Fig.); age <2 years; and no prior genitoplasty at the time of enrollment. Exclusion criteria were: infants and children with malformations of organ systems other than urogenital, and families with a limited comprehension of either English or Spanish.
If surgery was performed, the baseline visit occurred prior to surgery, and the postoperative visit was 6 months after surgery (or after the initial surgery if multiple or staged procedures were planned). If no cosmetic surgery was performed, the follow-up visit occurred 6 months after the baseline visit. The first baseline visit was performed in 2013, and baseline data on parent psychosocial functioning have previously been reported [15].
The present study reports the results for all children who completed both the baseline visit and 6-month visit. The local institutional review boards at all sites approved this study.
Clinical information
The following data were collected: prenatal and family history, karyotype, genetic diagnosis (if known), type of DSD, sex of rearing, results of imaging studies, and type of surgery or surgeries performed. Whether or not surgery was performed, the type of surgery performed, and the extent of the genetic evaluation varied by center and were not dictated by study procedures. The local pediatric urologist performed a standardized genital exam at each visit, which included: phallic length, presence of hypospadias, presence of chordee, and appearance of labia/scrotum. In general, the local pediatric urologist performed the Prader/Quigley ratings.
Parents/guardians of the participating child and the local pediatric urologist completed the cosmetic appearance rating scale: a single-item, self-reported, Likert-type scale rating satisfaction with the cosmetic appearance of the child’s genitalia prior to and 6 months after genitoplasty. One pediatric urologist evaluated cosmetic outcome at each site. Answers, scored as 1–4, were: 1) good, 2) satisfied, 3) dissatisfied, and 4) very dissatisfied. Surgeons rated cosmesis blind to the parents’ ratings, and parents were blinded to the surgeons’ ratings. Whenever possible, separate ratings were obtained from each parent. Parents were also asked to report number of UTIs, which were confirmed with the medical record.
Statistical methods
Grouped data were described either by count and percentage, or by mean standard deviation (SD), as appropriate. Comparisons of Likert ratings between, for example, mother and father, were analyzed as continuous data using Student’s t-tests for paired data. Comparisons of Likert ratings between patients raised as female and those raised as male were analyzed using Student’s t-tests for independent samples. Data were analyzed using SPSS for Windows (IBM SPSS Statistics for Windows, Version 20, released 2011. IBM Corp.: Armonk, NY). Results corresponding to P < 0.05 were described as significant and discussed.
Results
Diagnosis and sex of rearing
Thirty-seven subjects (93% of eligible) completed both the baseline and 6-month visit (Fig. 1). The mean age at the baseline visit was 9.8 months (range: 0.5–28.5); mean age at the 6-month visit was 19.6 months (range: 10.4–36.0). Twenty children (54%) had a 46,XX karyotype, 15 (40%) had a 46,XY karyotype, and two (5%) had sex chromosome mosaicism (Table 1). The most common diagnosis overall was CAH (54%), which accounted for all subjects with a 46,XX chromosomal complement. Eleven children (30%) had an unknown/unclassified genetic diagnosis, which accounted for 73% of those with a 46,XY karyotype. All children with a 46,XX sex chromosome complement were given a female sex assignment, and nearly all those with a 46,XY sex chromosome complement (93%) were given a male sex assignment (Table 1). In this cohort, one subject had sex reassignment (presumed male sex at birth, evaluation revealed 46,XX chromosomal complement and a diagnosis of CAH, and then was re-assigned to a female sex).
Figure 1.
Subjects enrolled.
Table 1.
Sex of rearing by karyotype and diagnosis (n = 37).
| Initial sex of rearing
|
||
|---|---|---|
| Female | Male | |
| 46,XX | 20 | 0 |
| Congenital adrenal hyperplasia | 20 | 0 |
| 46,XY | 1 | 14 |
| Mixed gonadal dysgenesis | 0 | 2 |
| Partial androgen insensitivitya | 1 | 1 |
| Unclassified/unknown | 0 | 11 |
| 45,X/46,XY or 45,X/46,XY/47,XXY | 1 | 1 |
| Mixed gonadal dysgenesis | 1 | 1 |
One had a known mutation in the androgen receptor gene (AR).
Genitoplasty
Thirty-five children had genitoplasty, and two families declined surgery for their child. The mean age at the time of surgery was 12.6 months (range: 5.4–29.7). Twenty-one children received feminizing genitoplasty, and all procedures were completed in a single stage. The mean ± SD Prader score prior to surgery was 3.6 ± 0.7. The types of procedures performed are listed in Table 2, with clitoroplasty performed in 14 subjects (67%), vaginoplasty in 20 (95%), external feminizing genitoplasty in 19 (90%), and perineoplasty in six (29%). Perineoplasty refers to a procedure used to re-approximate the perineal musculature and perineum soft tissues as part of, or independent of, more complex vaginal, rectal or genital procedures that are functional or cosmetic in nature and are associated with congenital abnormalities of the perineum. All subjects who did not undergo clitoroplasty had a pre-operative Prader rating of 3; one had a diagnosis of mixed gonadal dysgenesis, and the other had a diagnosis of partial androgen insensitivity. No patients had a UTI prior to surgery; one had a UTI within 6 months of feminizing genitoplasty.
Table 2.
Types of feminizing procedures performed (n = 21).
| n | |
|---|---|
| Clitoroplasty | 14 |
| Tucking/plication | 6 |
| Resection of corporal tissue (nerve sparing) | 11 |
| Partial glans resection/debulking | 1 |
| Vaginoplasty | 20 |
| Partial urogenital mobilization | 5 |
| Total urogenital mobilization | 4 |
| Anterior sagittal transrectal approach | 1 |
| Flap | 10 |
| Pull through (separation of urethra and vagina) | 2 |
| External genitoplasty | 19 |
| Labial flap reconstruction | 19 |
| Female urethroplasty | 5 |
| Perineoplasty | 6 |
Note that patients may have had more than one procedure in any given category.
Fourteen children received a masculinizing genitoplasty. Six had a single-stage procedure and eight had the first procedure of a planned two-stage procedure. Ten boys received pre-operative testosterone (four topical and six intra-muscular). The pre-operative Quigley score was 3.5 ± 0.8. Quigley scores ranged from 3 to 5, with no subjects having a score of 6 (completely female appearance of the external genitalia).
Subjects who had a planned one-stage procedure (n = 6) had a mean pre-operative phallus length of 3.4 ± 0.7 cm and width of 1.5 ± 0.4 cm. Hypospadias was present in 83% (n = 5), with scrotal hypospadias present in three subjects and penoscrotal in two subjects. A total of 33% had a bifid scrotum and 33% had scrotal transposition. Chordee was present in 67% (n = 4), with moderate chordee in three subjects and severe in one.
Subjects who had the first stage of a planned two-stage procedure (n = 8) had a mean pre-operative phallus length of 3.4 ± 0.7 cm and width of 1.3 ± 0.4 cm. Hypospadias was present in 100%, with penoscrotal hypospadias present in 50% and scrotal hypospadias present in 50%. A total of 75% (n = 6) had a bifid scrotum and 63% (n = 5) had scrotal transposition. Chordee was present in all subjects, with 88% having severe chordee (n = 7), and one having moderate chordee. The types of procedures performed are shown in Table 3. There were no cases of a UTI prior to or within 6 months of masculinizing genitoplasty.
Table 3.
Types of masculinizing procedures performed (n = 14).
| Single stage n = 6 |
1st procedure of a planned two-stage procedure n = 8 |
|
|---|---|---|
| Orthoplasty maneuvers to straighten ventral chordee | 6 | 8 |
| Degloving | 6 | 7 |
| Midline dorsal plication without mobilization of neurovascular bundles | 5 | 5 |
| Corporal body grafting | 0 | 3 |
| Proximal division of urethral plate | 0 | 1 |
| Distal division of urethral plate | 0 | 4 |
| Urethroplasty | 5 | 5 |
| Thiersch-Duplay | 1 | 0 |
| Tubularization (TIP) | 4 | 1 |
| Inlay: flap | 0 | 2 |
| Inlay: graft | 0 | 2 |
| Other | 0 | 1 |
| Further coverage layer over urethroplasty | 5 | 1 |
| Dorsal pedicle flap | 5 | 1 |
| Genitoplasty | 6 | 8 |
| Byars flaps | 5 | 7 |
| Simple scrotoplasty | 3 | 1 |
| Complex scrotoplasty | 1 | 2 |
| Scrotal transposition correction | 1 | 4 |
| Reconstruction of penopubic/penoscrotal angles | 2 | 4 |
| Circumcision | 4 | 5 |
| Mean ± SD catheter duration | 9.6 ± 3.6 | 5.4 ± 2.7 |
Note that patients may have had more than one procedure in any given category.
Cosmesis ratings
For the 35 children who had surgery, baseline ratings were available for 34 mothers (one missing), 29 fathers (one missing and five did not participate), and all surgeons. At baseline, 63% of mothers (n = 22), 48% of fathers (n = 14), and 100% of surgeons (n = 35) stated that they were dissatisfied or very dissatisfied with the appearance of the child’s genitalia (Summary Fig.). Mean ± SD cosmesis ratings were: 2.7 ± 1.0 for mothers, 2.5 ± 1.0 for fathers, and 3.4 ± 0.5 for surgeons. There were no significant differences in ratings between mothers and fathers. Surgeons gave significantly worse ratings than mothers (P < 0.001) or fathers (P < 0.001).
At the 6-month postoperative visit, ratings were available from 34 mothers (one missing), 28 fathers (two missing and five did not participate), and all surgeons. Cosmesis ratings for mothers, fathers and surgeons improved significantly from the baseline to 6-month postoperative visit (P < 0.001 for all groups). The majority (94%) of mothers (n = 32), 92% of fathers (n = 26) and 88% of surgeons (n = 31) reported either a good outcome or that they were satisfied (Summary Fig.). There were no significant differences in ratings between mothers and fathers, mothers and surgeons, or fathers and surgeons, and no significant differences by sex of rearing of the child.
There were two subjects who did not have surgery. For one, who was being raised as male, only one parent participated and gave a rating of ‘dissatisfied’ at baseline and then ‘satisfied’ 6 months later; the surgeon gave a baseline rating of ‘very dissatisfied’. For the other subject, who was being raised as female, both parents and the surgeon gave a rating of ‘good’ at baseline, and both parents gave the same rating 6 months later.
Discussion
This prospective, multicenter study found that prior to surgery, most parents and surgeons reported dissatisfaction with the appearance of the child’s genitalia, with surgeons giving less favorable ratings than mothers or fathers. Postoperatively, parents and surgeons gave more favorable ratings as compared with baseline, with no between-group differences.
It was hypothesized that there would be no difference in baseline ratings between parents and surgeons; however, surgeons rated the appearance of the child’s genitalia significantly worse than mothers or fathers at the baseline visit. Surgeons were likely have a better understanding than parents regarding what ‘normal’ newborn genitalia look like, thus giving less favorable ratings as compared with parents. Alternatively, the baseline ratings given by the surgeons may have represented unconscious bias to justify the surgery that they anticipated performing. It was hypothesized that the surgeons’ ratings would be better than the parents’ ratings postoperatively, yet there were no significant differences in ratings between either mothers or fathers and surgeons. Prior studies have shown ‘good’ cosmetic postoperative outcomes, as rated by surgeons [6–9], and the present data show that parent ratings are concordant with surgeon ratings postoperatively. It is notable that parents gave favorable ratings, even when the procedures were not yet complete. Perhaps the positive ratings by the parents stemmed from their desire to see the surgical procedure as a success.
Cosmetic outcomes among women with CAH who have undergone feminizing genitoplasty have been mixed [7–10], and outcomes may differ by age and over time. Parents and surgeons gave favorable ratings after feminizing genitoplasty, with most children that were reared female having CAH. Yet, satisfaction with postoperative cosmesis does not necessarily equate with satisfaction with the functional outcome later in life.
Although families are counseled that no surgery or delaying surgery is an option, most children in this study received genitoplasty. One potential reason for the high rates of genitoplasty is ascertainment bias, as families who present to a DSD clinic may be more likely to pursue genitoplasty for their child. Furthermore, only children with moderate-to-severe genital atypia were included in this study. It is controversial whether to perform a clitoroplasty among those infants with CAH [16]. Two-thirds of the subjects in this cohort who had feminizing genitoplasty also had a clitoroplasty. However, the study only included children with moderate-to-severe genital atypia, so if children with a Prader 2 rating were included, rates of clitoroplasty may have been lower. All patients had anatomical preservation of the neurovascular bundle, which represents a shift in practice from several decades ago [17].
Historically, children with DSD were more often raised as female, which was consistent with the prevalence of 46,XX CAH as an etiology; thus, relatively more feminizing, as compared to masculinizing surgeries, were performed. Rates of masculinizing surgery and male sex assignment have been increasing in recent decades [18]. The present study showed that nearly all individuals with a 46,XY karyotype were raised as male, which is consistent with other studies and represents a historical shift [18].
Little is known about the short-term and long-term complications of genital surgeries for children with atypical external genitalia and/or DSD. Consistent with the published literature [19], the present study showed that UTIs are infrequent after feminizing genitoplasty. Less is known about frequency of UTIs after masculinizing genitoplasty. Among those with hypospadias repair, UTIs are a relatively uncommon complication, although this may vary by type of procedure performed [20].
Limitations included: a relatively small number of patients due to strict exclusion criteria precluding finer analysis of the data, such as whether cosmesis ratings differ by type of surgery performed. The study only enrolled English-speaking and Spanish-speaking families, so these data may not be generalizable to those who primarily speak another language. Additionally, many parental cosmesis ratings were obtained after surgical counseling, which may have affected their perception of the appearance of their child’s genitalia. Each center had one pediatric urologist who performed cosmesis ratings; the child may have had surgery by that urologist or by another pediatric urologist at the same center. It is unknown if the surgeons rated the appearance differently depending on whether or not they performed the child’s surgery.
One objective of this study was to describe the frequency of sex assignment and types of surgery performed in a cohort of patients followed with moderate-to-severe genital ambiguity. Given the observational nature of this study, it neither specified the extent of hormonal and genetic evaluation nor the type(s) of surgical procedures performed. While a high proportion of those with a 46,XY DSD lacked a specific genetic diagnosis; that is common, despite extensive genetic testing [21]. While these data were very heterogeneous, they revealed the modern practices occurring at major DSD centers in the USA.
Conclusion
In this prospective, multicenter, observational study, the majority of children with moderate-to-severe genital atypia underwent surgery early in life. Parents and surgeons generally rated the cosmetic appearance of the genitalia unfavorably before surgery, with surgeons giving less favorable ratings than parents, but parents and surgeons reported equally favorable results after surgery.
Supplementary Material
Acknowledgments
Thank you to the parents and children who participated in this study. The National Institutes of Health (R01HD074579), PIs Amy Wisniewski and Larry Mullins supported this work. Dr. Nokoff is supported by a T32 grant (T32 DK 63687).
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.jpurol.2016.08.017.
Footnotes
Conflicts of interest
Dr. Paul Austin serves on the pediatric advisory group and is a clinical investigator for Allergan. Dr. Dix Poppas is the co-founder of Promethean Surgical Devices, Inc. Neither are directly related to the funding or design of the study.
Ethics approval
The local institutional review boards at all sites approved this study.
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