Background: This study aims to determine if endocrine/genetic evaluation in boys with proximal hypospadias uncovers differences of sex development (DSD) or other genetic conditions, to potentially improve clinical management opportunities. We also aim to determine if physical exam features or abnormal endocrine labs are associated with the presence of a DSD.
Methods: Boys with proximal hypospadias who underwent endocrine/genetic testing at a freestanding pediatric hospital between 7/2018 and 12/2021 were retrospectively reviewed. Demographics, phenotype, comorbidities, testing type and results, and final clinical and molecular diagnoses were characterized. Endocrine and phenotypic characteristics were compared by final diagnosis group (DSD vs. no DSD) using Fisher’s exact testing.
Results: Of 118 boys with proximal hypospadias, 43 who underwent endocrine/genetic testing and had an exam by a pediatric urologist were included. Seventeen boys (40%) had a severe phenotype (perineal/scrotal meatus). Thirty-four boys had bilateral descended testes (79%). Scrotal anomalies (bifid scrotum, transposition) were documented in 28 (65%). Thirty-two boys (74%) underwent endocrine testing between 6 and 24 months of age; 9 had at least 1 atypical result for age (28%). Common genetic evaluations included chromosome analysis (95%), microarray (35%), DSD multi-gene panel (16%), and whole exome sequencing (14%). In total, 9 boys (21%) had a clinical or genetic diagnosis determined by molecular testing-1 with a non-DSD diagnosis and 8 with a DSD (19%) (Table 1). Of boys who underwent endocrine testing, 2 of 8 with a DSD had ≥1 abnormal endocrine lab value vs. 7 of 24 without a DSD (25% vs. 29%, p=1.0). Four of 8 boys with a DSD had a severe phenotype vs. 13 of 35 without a DSD (50% vs. 37%, p=0.69). Four of 9 boys with 1 or 2 undescended testes had a DSD vs. 4 of 34 with bilateral descended testes (44% vs. 12%, p=0.046).
Conclusions: Among 43 boys with proximal hypospadias and endocrine/genetic evaluation, 21% had clinically actionable diagnoses identified, of which 78% were molecularly confirmed DSD. Genetic testing, particularly sequencing, uncovered the most diagnoses. While undescended testis was more often associated with DSD, endocrine lab abnormalities and severe proximal hypospadias phenotype were not. Further, not all boys found to have a DSD had undescended testes. Endocrine/genetic evaluation should be considered for boys with proximal hypospadias with and without undescended testes.
