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Proximal Hypospadias: More Than Meets the Eye?
By: Lauren E. Corona, MD; Emilie K. Johnson, MD, MPH, FACS | Posted on: 01 Jan 2022
Hypospadias is a congenital genital abnormality that affects ∼1/300 live male births.1 Proximal hypospadias is the most severe form and involves the urethral opening in a penoscrotal or perineal location (see figure for example). Boys with proximal hypospadias frequently also have significant ventral chordee (penile curvature) and may have associated scrotal abnormalities and/or undescended testes. The significance and recommended work-up for patients with proximal hypospadias are debated among pediatric urologists, largely due to the social and medicolegal implications of labeling proximal hypospadias a “difference/disorder of sex development” (DSD).2
What Is the Significance of a Proximal Hypospadias Diagnosis?
While proximal hypospadias can be an isolated genital condition, boys are at increased risk for genetic diagnoses (DSD and others) and multisystem comorbidities. The genetic diagnoses found can affect clinical prognosis, medical screening recommendations and surgical counseling.
Finding a proximal hypospadias may mean the patient has a specific, named DSD condition. In a recent series from our institution, mixed gonadal dysgenesis (MGD; 45,X/46,XY [or similar] karyotype with atypical genitalia) was the most frequently diagnosed DSD condition among infant boys presenting with proximal hypospadias.3 Proximal hypospadias is also a feature of multiple nonDSD genetic syndromes that have other systemic health implications. For example, loss of function changes in the transcription factor myelin regulatory factor are associated with proximal hypospadias, congenital diaphragmatic hernia, microphthalmia and cardiac anomalies.4 The DSD diagnoses and other genetic conditions that include proximal hypospadias identified through genetic and endocrine testing at our institution are shown in table 1. Notably, most boys (11/17, 65%) who had a specific diagnosis that was not MGD had a 46,XY karyotype!
Table 1. Diagnoses among 60 boys presenting with proximal hypospadias3
| Diagnosis | Karyotypes | No. (%) |
|---|---|---|
| DSD conditions (N=9) | ||
| Mixed gonadal dysgenesis | 45,X/46,XY,45,X/46,X,idic(Y)(q11.2),46,XY | 5 (8.3) |
| 3-Beta hydroxysteroid dehydrogenase deficiency | 46,XY | 1 (1.6) |
| Ovotesticular DSD | 46,XX | 1 (1.6) |
| NR5A1 (SF1) pathogenic variant | 46,XY | 1 (1.6) |
| Denys-Drash syndrome (WT1 pathogenic variant) | 46,XY | 1 (1.6) |
| Other genetic conditions (N=8) | ||
| 9p24.3p23 Deletion | 46,XY | 2 (3.3) |
| 15q13.3 Microduplication | 46,XY | 2 (3.3) |
| 14q11.1q32.22 Mosaic Duplication and Xp22.31 Deletion | 47,XY,+14[3]/46,XY[59] | 1 (1.6) |
| 1p36.33 Duplication | 46,XY | 1 (1.6) |
| 9p13p24 Duplication | 46,XY | 1 (1.6) |
| Hereditary hemochromatosis (HFE Pathogenic Variant)* | 46,XY | 1 (1.6) |
| No specific DSD or other genetic diagnosis identified (N=43) | ||
| No diagnosis | 46,XY, 45,XY,der(13;14)(q10;q10) (Robertsonian Translocation, incidental, expect normal phenotype) | 43 (72) |
| *Included in multigene panel due to association with infertility. | ||
Establishing a specific diagnosis for patients with proximal hypospadias can have important implications for short and long-term counseling and outcomes, as outlined in table 2. As examples, patients with partial androgen insensitivity syndrome may not respond well when given testosterone in hopes of increasing phallic size, and patients with MGD should have the same health screenings (eg cardiac, audiology) as patients with Turner syndrome without atypical genitalia. Also, surgical counseling will likely be different when additional testing results in a DSD with increased risk for gender dysphoria when compared to counseling without this additional information. Finally, there currently is debate about whether patients with named DSD conditions have an increased risk of surgical complications.
Table 2. Potential implication of a DSD or other genetic diagnosis
| Topic | Implication |
|---|---|
| Sex of rearing/future gender identity | If genital ambiguity, specific DSD diagnosis can help inform sex of rearing in infancy Certain DSDs have increased risk for later gender dysphoria |
| Medical treatments | Certain conditions may have a poor response to testosterone if given in hopes of increasing phallic size (eg partial androgen insensitivity syndrome) |
| Surgical counseling | Possible higher hypospadias surgical complication rates5–7 |
| Fertility potential | Predict fertility potential by DSD diagnosis Determine eligibility for experimental gonadal tissue cryopreservation8 |
| Multisystem comorbidities | Targeted screening for multisystem conditions |
| Genetic transmission | Counseling about future pregnancies, possibility of transmission of condition to future offspring |
What Should Urologists Consider When Evaluating a Patient with Proximal Hypospadias?
Historically, genetic and endocrine evaluation has only been recommended in boys with undescended testes or other phenotypic features of DSD (eg penoscrotal transposition).8 Indeed, high rates of genetic diagnoses and DSD have been reported when proximal hypospadias is associated with at least one undescended testis. In our series, all boys with proximal hypospadias and DSD had a bifid scrotum and/or penoscrotal transposition. Additionally, 75% of boys with ≥1 nonpalpable testis and 53% of those with ≥1 undescended testis had a genetic diagnosis. Genetic diagnoses also varied by meatal location (41% with scrotal/perineal vs 12% with penoscrotal meatus location).
The approach of only pursuing further testing for boys with proximal hypospadias and undescended testes or overt genital ambiguity risks missing multisystem conditions that would warrant further medical evaluation/screening or a DSD. Genetic diagnoses have been reported to range from 10%–21% with isolated proximal hypospadias.9,10 This has led some pediatric urologists to adopt the practice of pursuing further genetic and endocrine testing in all boys with proximal hypospadias, even when isolated. This practice has the disadvantages of costly testing, low diagnostic yield for some subgroups, and the identification of variants of unknown significance leading to unnecessary parental distress. A tailored algorithm based on anatomy (eg features of genital ambiguity) and comorbidities would be more appropriate but is not yet available.
A multidisciplinary approach to caring for patients with proximal hypospadias has advantages, but our experience when offering it to all was that it led to a high incidence of confusion for families and low diagnostic yield, and presented a challenge for clinical capacity. Therefore, we now recommend multidisciplinary evaluation when further testing yields a definitive or possible DSD or other genetic diagnosis, when further testing results in a change in sex assignment in the neonatal period, or when it is felt that the family or patient could benefit from the additional psychosocial support offered by the multidisciplinary clinic (table 3).
Table 3. Initial diagnostic approach for boys with proximal hypospadias
*If ≤8 months old: Luteinizing hormone, follicle-stimulating hormone, total testosterone, dihydrotestosterone, 17-hydroxypregnenolone, dehydroepiandrosterone, androstenedione; if >8 months old: 17-hydroxypregnenolone, dehydroepiandrosterone, androstenedione.| Visit 1: Urology |
|
| Visit 2: Genetics and Endocrinology |
|
| Visit 3: DSD Multidisciplinary Team (if needed based on diagnosis, family factors, ie need for psychosocial support) |
|
Taken together, given high rates of DSD and genetic conditions in boys with proximal hypospadias, we recommend at minimum a karyotype in the initial diagnostic approach for these patients. It is prudent to pursue further genetic and endocrine evaluation in the setting of concomitant undescended testicle(s) or in the presence of multiple congenital anomalies. Further testing should be considered if scrotal abnormalities (eg bifid, penoscrotal transposition) are present. Finally, it is also appropriate to pursue further testing when this is the preference of the family.
Recommendations and Conclusions
When evaluated with genetic and endocrine testing, many boys with proximal hypospadias are found to have DSD and other systemic genetic conditions that affect future care and prognosis. All boys with proximal hypospadias should have a karyotype. Further genetic and endocrine testing should be considered for boys with:
- Proximal hypospadias and undescended testes
- Multiple congenital anomalies
- Scrotal abnormalities
- Families who desire more information
We expect that emerging data will refine the population of boys with proximal hypospadias who will benefit most from endocrine and advanced genetic testing options. We are hopeful that a tailored algorithm based on anatomy (eg features of genital ambiguity) and comorbidities will be available in the coming years to further guide urologists who care for boys with proximal hypospadias.
- Mai CT, Isenburg J, Langlois PH et al: Population-based birth defects data in the United States, 2008 to 2012: presentation of state-specific data and descriptive brief on variability of prevalence. Birth Defects Res A Clin Mol Teratol 2015; 103: 972.
- Snodgrass W, Macedo A, Hoebeke P et al: Hypospadias dilemmas: a round table. J Pediatr Urol 2011; 7: 145.
- Johnson EK, Jacobson DL, Finlayson C et al: Proximal hypospadias: isolated genital condition or marker of more? J Urol 2020; 204: 345.
- Pinz H, Pyle LC, Li D et al: De novo variants in myelin regulatory factor (MYRF) as candidates of a new syndrome of cardiac and urogenital anomalies. Am J Med Genet A 2018; 176: 969.
- Saltzman AF, Carrasco A Jr, Colvin A et al: Patients with disorders of sex development and proximal hypospadias are at high risk for reoperation. World J Urol 2018; 36: 2051.
- Ochi T, Ishiyama A, Yazaki Y et al: Surgical management of hypospadias in cases with concomitant disorders of sex development. Pediatr Surg Int 2019; 35: 611.
- Palmer BW, Reiner W and Kropp BP: Proximal hypospadias repair outcomes in patients with a specific disorder of sexual development diagnosis. Adv Urol 2012; 2012: 708301.
- Johnson EK, Finlayson C, Finney EL et al: Gonadal tissue cryopreservation for children with differences of sex development. Horm Res Paediatr 2019; 92: 84.
- Rowe CK, Adam MP, Ahn JJ et al: Yield of modern genetic evaluation for patients with proximal hypospadias and descended gonads. J Pediatr Urol 2019; 15: 527.e1.
- Sekaran P, O’Toole S, Flett M et al: Increased occurrence of disorders of sex development, prematurity and intrauterine growth restriction in children with proximal hypospadias associated with undescended testes. J Urol 2013; 189: 1892.
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