Background: 46,XY DSD is a heterogeneous group of pathologies characterized by a wide spectrum of phenotypes and aetiologies. While advances in molecular genetics have permitted discovery of numerous genes implicated in testicular development, the diagnosis still remains uncertain for most patients with 46,XY DSD.
Objective: To identify the aetiologies of 46,XY DSD in Algerian patients.
Methods: We conducted a multicentre prospective study. All patients referred for DSD (excluding Turner and Klinefelter syndromes) were investigated and classified as 46,XX DSD; sex chromosome DSD and 46,XY DSD. In this last group, clinical, ultrasonography, MRI, genitography and hormonal analysis helped sub-classify the patients as having: disorders of androgen synthesis or action, gonadal dysgenesis, persistent Müllerian duct syndrome (PMDS), ovo-testicular DSD or syndromic DSD. Mutational analysis was performed for patients with disorders of androgen action (AR gene and SRD5A2 gene, MAMLD1) and gonadal dysgenesis (SRY, NR5A1, WT1).
Results: Of 237 patients in the study 119 had 46, XX DSD (due to congenital adrenal hyperplasia in 92), 102 had 46,XY DSD and 16 had sex-chromosome DSD. Aetiology among the patients with 46,XY DSD was disorder of androgen action (52), defective androgen synthesis (7), varying degrees of gonadal dysgenesis (31), PMDS (2), ovo-testicular DSD (1) and syndromic DSD (9). Mutational analysis revealed two different mutations in two pairs of siblings in the NR5A1 gene (including one new mutation), one new mutation in the SRD5A2 gene, one mutation in the AR gene and one new mutation in MAMLD1. Furthermore, V89L polymorphism in the SRD5A2 gene was found in eight patients with androgen resistance, and the p.Gly146Ala polymorphism in the NR5A1 gene was found in four patients. Genetic analysis was negative and cause of DSD unknown in 33/83 patients (77.11%).
Conclusion: Disorders of androgen action were the most frequent cause of 46,XY DSD in this large series, but a mutation of the AR gene itself was rarely found. However, pV89L polymorphism in the SRD5A2 gene is not rare in our patient population. This finding is in keeping with the hypothesis that functional polymorphisms may play an important role in complex conditions such as DSD, with several factors contributing to the defect.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology