Etiologic classification of severe hypospadias: Implications for prognosis and management

Objective: Classification of severe hypospadias employing a broad array of diagnostic tools. Standardization of a diagnostic approach to children with hypospadias. Identification of patients at risk of having malignancies and endocrine problems. Design: Retrospective analysis of patients in a single-center study. Subjects: Thirty-three patients with severe (scrotal or penoscrotal) hypospadias, aged 1 to 18 years. Methods: Clinical assessment, ultrasonography, karyotyping, endocrine evaluation including adrenal steroid concentrations, sex hormone-binding globulin test for androgen sensitivity, human chorionic gonadotropin stimulation with determination of testosterone and dihydrotestosterone concentrations to exclude 5α-reductase deficiency, and molecular genetic analysis of the androgen receptor gene and the 5α- reductase gene. Results: In 12 patients the cause was clarified. Diagnoses included Drash syndrome with Wilms tumor in infancy (3 patients), partial androgen insensitivity resulting from androgen receptor mutations (2), true hermaphroditism (2), chromosomal aberration (1), deficiency of antimullerian hormone (1), gonadal dysgenesis (1), partial 5α-reductase deficiency caused by a novel point mutation (1), and XX-male syndrome (1). Twelve patients had associated findings such as cardiac malformations (3 patients), rectal atresia (1), dilation of urinary tract (2), cystinuria (1), and others. Conclusions: Patients with severe hypospadias should be submitted to a standardized set of diagnostic procedures in infancy. A stepwise diagnostic study avoids unnecessary, invasive, and expensive testing. A high proportion of classified causes can be expected. Patients at risk of having malignancies or hormonal disorders must remain under close surveillance.