Role of endocrine and genetic evaluation for infants with proximal hypospadias

This study aims to determine if: (1) endocrine/genetic evaluation in infants with proximal hypospadias uncovers differences of sex development (DSD), and (2) phenotypic features or abnormal endocrine labs are associated with DSD. We further seek to update a proximal hypospadias testing algorithm that was proposed based on a prior study from our institution.

Infants <6 months of age with proximal hypospadias who underwent endocrine/genetic testing from 7/2018-12/2021 were reviewed. Endocrine and phenotypic characteristics (e.g., meatal location, testicular status, presence of scrotal abnormalities) were compared by diagnosis group using Fisher's exact testing.

Of 118 infants with proximal hypospadias, 43 undergoing endocrine/genetic testing were included. Seventeen (40 %) had severe hypospadias (perineal/scrotal), 34 had bilateral descended testes (79 %) and 28 (65 %) had documented scrotal anomalies. Nine (21 %) had a diagnosis determined by molecular testing: 1 with a non-DSD diagnosis and 8 with DSD (19 %) (Summary Table). Thirty-two (74 %) underwent endocrine testing, with 9 having ≥1 atypical result (28 %). Abnormal endocrine testing results were not associated with presence of DSD. Four of 8 boys (50 %) with DSD had severe hypospadias vs. 13/35 (37 %) without (p = 0.69). Four of 9 infants (44 %) with undescended testis had a DSD vs. 4/34 (12 %) with descended testes (p = 0.046). Of infants with scrotal exams, presence of scrotal abnormalities was similar between infants with (6/7; 86 %) and without (22/26; 85 %) DSD.

Among infants with proximal hypospadias, 21 % had clinical or molecular diagnoses identified (78 % DSD, most uncovered by advanced genetic testing). We did not uncover genetic non-DSD. Our previous institutional cohort found that testicular status, severe hypospadias phenotype, and scrotal abnormalities were associated with DSD; only testicular status was significant in the present study. Limitations include a restricted sample size, due to reasons including family declining testing and unavailability of physical exam data. Based on study results, an updated proximal hypospadias testing algorithm is proposed, which takes into account the poor yield of chromosomal microarray observed in this cohort and more readily incorporates a first tier exome or genome sequencing approach for individuals with congenital anomalies.

While undescended testes were associated with DSD, endocrine abnormalities, severe hypospadias phenotype, and scrotal abnormalities were not. Not all infants with DSD had undescended testes. However, all with DSD had additional genital abnormalities, either testicular, scrotal, or both. Genetic and endocrine evaluation should be considered for all infants with proximal hypospadias with and without undescended testes.