ESPE Abstracts (2018) 89 P-P2-361

Towards an Integrated Approach to Diagnosis of 46,XY Disorder of Sex Development

Zofia Kolesinskaa, James Jr Aciernob, S. Faisal Ahmedc, Karina Kapczukd, Anna Skorczyk-Wernere, Hanna Mikosa, Aleksandra Rojeka, Maciej Krawczynskie, Nelly Pitteloudb & Marek Niedzielaa


aDepartment of Paediatric Endocrinology and Rheumatology, Poznan University of Medical Sciences, Poznan, Poland; bEndocrinology, Diabetology & Metabolism Service, Lausanne, Switzerland; cDevelopmental Endocrinology Research Group, School of Medecine, Dentistry & Nursing, University of Glasgow, Glasgow, UK; dDivision of Gynaecology, Department of Perinatology and Gynaecology, Poznan University of Medical Sciences, Poznan, Poland; eDepartment of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland


Background and objective: Given phenotype variability as well as limited utility of conventional endocrine investigations in reaching the diagnosis in a 46,XY patient suspected of a disorder of sex development (DSD), there is an increasingly stronger argument for considering targeted genetic sequencing at an earlier stage of the evaluation process. This study focused on identifying the relationship between clinical examination, endocrine and radiological assessment, as well as the result of targeted 46,XY DSD gene panel.

Methods: The study group consisted of 35 patients, 21 (60%) were raised as boys and 14 (40%) were raised as girls. External appearance of the genitalia was described by the external masculinization score. The endocrine investigations assessing hypothalamic-pituitary-gonadal axis including AMH and Inhibine b (Gen II ELISA assay, Beckman Coulter, Diagnostic Systems Laboratories, Inc., USA) were performed. The assessment of internal genitalia (presence or absence of uterus, localization of undescended gonads) was undertaken by transabdominal ultrasound examination. Targeted gene panel sequencing was performed (TruSight One gene panel, Illumina, Inc., San Diego, CA USA) on the MiSDefault (Illumina) and 54 known diagnostic genes implicated in 46,XY DSD were selected for evaluation (Saphetor, Lausanne, Switzerland).

Results: Findings from an integrated approach established a definitive diagnosis in 12 patients (34%), three boys (out of 21, 14%) and nine girls (out of 14, 64%). In all those cases raised as girls and suspected of a disorder of androgen action or disorder of androgen synthesis (n, 9), the agreement with the results of genetic tests was complete. However, in those raised as boys (n, 21), the genetic analysis led to identification of at least one variant of uncertain significance in more than half of them (n, 12; 57%) mainly due to incomplete consistency between the genetic and conventional tests. Due to targeted massive parallel sequencing oligogenic variants were identified in 29% (10 out of 35) of patients.

Conclusions: Due to discrepancy between the genetic tests and the detailed phenotypic assessment, especially in patients raised as boys, as well as the presence of multiple oligogenic variants, the targeted genetic sequencing should be performed alongside other investigations.