Integrating clinical and genetic approaches in the diagnosis of 46,XY disorder of sex development

Kolesinska, Z. et al. (2018) Integrating clinical and genetic approaches in the diagnosis of 46,XY disorder of sex development. Endocrine Connections, 7(12), pp. 1480-1490. (doi: 10.1530/EC-18-0472) (PMID:30496128) (PMCID:PMC6311460)

Abstract

46,XY differences and/or disorders of sex development (DSD) are clinically and genetically heterogeneous conditions. Although complete androgen insensitivity syndrome has a strong genotype-phenotype correlation, the other types of 46,XY DSD are less well-defined and thus the precise diagnosis is challenging. This study focused on comparing the relationship between clinical assessment and genetic findings in a cohort of well-phenotyped patients with 46,XY DSD. The study was an analysis of clinical investigations followed by genetic testing performed on 35 patients presenting to a single center. The clinical assessment included: external masculinisation score (EMS), endocrine profiling and radiological evaluation. Array-comparative genomic hybridization (array-CGH) and sequencing of DSD-related genes were performed. Using an integrated approach, reaching the definitive diagnosis was possible in 12 children. The correlation between clinical and genetic findings was higher in patients with a more severe phenotype (median EMS 2.5 vs 6; P=.04). However, in 13 children, at least one variant of uncertain significance was identified, and most times this variant did not correspond to the original clinical diagnosis. In 3 patients, the genetic studies guided further clinical assessment which resulted in a reclassification of initial clinical diagnosis. Furthermore, we identified 8 patients harboring variants in more than one DSD genes, which was not seen in controls (2.5%; P=.0003). In summary, taking into account potential challenges in reaching the definitive diagnosis in 46,XY DSD, only integrated approach seems to be the best routine practice.

• Item Type: Articles
• Additional Information: This study was supported by the Polish National Science Centre grant (2014/12/N/NZ5/00448). The array-CGH analysis was supported by Poznan University of Medical Science grant (502-14-01126186-09772).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Ahmed, Professor Syed Faisal
• Authors: Kolesinska, Z., Acierno, J., Ahmed, S. F., Xu, C., Kapczuk, K., Skorczyk-Werner, A., Mikos, H., Rojek, A., Massouras, A., Krawczyński, M., Pitteloud, N., and Niedziela, M.
• College/School: College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: Endocrine Connections
• Publisher: Bio Scientifica
• ISSN: 2049-3614
• ISSN (Online): 2049-3614
• Copyright Holders: Copyright © 2018 The Authors
• First Published: First published in Endocrine Connections 7(12):1480-1490
• Publisher Policy: Reproduced under a Creative Commons License