Background: Extensive and time-consuming hormonal and genetic work-up provides a genetic diagnosis in around 20% of 46,XY cases with ambiguous genitalia. It is currently unclear if such extensive screening might also be indicated in 46,XY newborns with milder undervirilization.
Method: All 46,XY neonates and infants (n=32, EMS 212) referred to our pediatric endocrine service for atypical male genitalia in the period 20072013 were investigated according to a standardized hormonal and genetic protocol after clinical evaluation. This included AR, NR5A1, and WT1 sequencing and multiplex ligation-dependent probe amplification (MLPA), array comparative genomic hybridization (array-CGH) in all patients; HSD17B3 and SRD5A2 sequencing in cases with suggestive hormonal results and SRY sequencing in cases with gonadal dysgenesis.
Results: In 3/32 patients Kallmann syndrome was diagnosed based on clinical and hormonal data; for two of them the diagnosis was confirmed genetically (KAL1 deletion, and FGFR1 mutation). In 4/32 patients endocrine work-up suggested a testosterone biosynthesis disorder, however no mutations were identified in HSD17B3 or SRD5A2. Three novel NR5A1 mutations were found in non-syndromic patients (3/26, 11%), with EMS scores 2.5, 3, and 9. No AR or WT1 changes were identified. Array-CGH revealed an underlying copy number variation in 2/6 syndromic patients, leading to a diagnostic yield of 33% in this subgroup.
Conclusion: Overall, a genetic diagnosis was established in 5/26 (19%) non-syndromic and 2/6 (33%) syndromic cases. Our study did not yield a higher diagnostic success rate in patients with low EMS scores compared to higher EMS scores. Our systematic approach could not increase the diagnostic success rate. In view of the time investment, high costs and low success rate of gene by gene screening, whole exome sequencing might be considered instead of serial gene screening, except in syndromic cases, were array-CGH proved to reveal a genetic cause in over one third of cases.
20 - 22 Sep 2014
European Society for Paediatric Endocrinology