Background: Most published studies on 46,XY DSD focused on genetic findings without association with biochemical work-up.
Objectives: To retrospectively analyze the clinical and genetic findings of a large cohort of 46,XY DSD patients.
Methods: 285 non-syndromic 46,XY DSD individuals (192 sporadic and 89 familial cases) were studied. LH, FSH, testosterone (T), androstenedione (A) were measured by immunoradiometric or immunofluorimetric assays and dihydrotestosterone (DHT) by RIA after celite chromatography or by liquid chromatography tandem mass spectrometry. Based on hormonal and imaging assessment, the patients were classified as: gonadal dysgenesis (GD; n= 60); androgen insensitivity syndrome [AIS; n= 61: 34 with complete AIS (CAIS) and 27 with partial AIS (PAIS) form]; defects in testosterone production [DTP; n=81, includes SRD5A2 (n=37), HSD17B3 (n=17), CYP17A1 (n=15) and HSD3B2 (n=5) deficiencies and Leydig cell hypoplasia (n=7)]; persistent mullerian duct syndrome (n=4) and DSD of unknown etiology (n=79). Sanger sequencing was performed in 90% of the patients and massively parallel sequencing was performed in 88 patients without a previous molecular diagnosis. The identified variants were classified according to the ACMG criteria.
Results: Pathogenic or likely pathogenic variants were identified in 20 GD patients (33%), in 50 (81%) AIS patients (94% of CAIS and 66% of PAIS), in 81 patients (95%) with DTP and in 20 patients (25.6%) with unknown etiology, including variants in gonadal development (n= 8), in AR (n=8), in SRD5A2 (n=2), in HSD17B3 (n=1) and in AMH (n=1) genes. Defects in NR5A1 and DHX37 were identified in 11 and 8 probands, respectively, being the most frequent cause of GD. Six patients with variants in gonadal development genes (five with NR5A1 and one with MAP3K1 variants) had preserved gonadal function and absence of uterus. Two post-pubertal patients with SRD5A2 defects had a normal T/DHT (reference 14±5.2) and 9% of patients (3/32) with other diagnosis had an altered ratio. A T/A ratio < 0.8 was observed in 17/18 of the patients with molecular diagnosis of HSD17B3 deficiency and also in 2/49 patients with other diagnoses, both patients were under 6 months of age and the ratio was obtained in baseline condition.
Conclusion: The molecular diagnosis was established in 55% of the 46,XY DSD individuals, mainly in patients with AIS and DTP, with a lower diagnostic yield in GD patients. Clinical assessment was accurate in most cases, however six cases of GD, two of SRD5A2 and one of HSD17B3 deficiencies would have been missed, emphasizing the importance of the molecular studies in diagnosing 46,XY DSD patients.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology