PhD Scientific Days 2018

Budapest, April 19–20, 2018

Identification of a rare DSD

Pinti, Éva

1. dr.Pinti Éva; Semmelweis University, 2nd Department of Pediatrics
2. dr.Lengyel Anna; Semmelweis University, 2nd Department of Pediatrics

Language of the presentation

Hungarian

Text of the abstract

Introduction
The sex-determining region on chromosome Y (SRY) initiates male sex determination in humans. One of many important target genes regulated by SRY is SOX9. High expression of SOX9 can trigger male development in 46,XX fetuses, but will result in incomplete masculinisation.
Aim
Molecular cytogenetic evaluation of a family presenting with disorders of sexual development.
Method
The phenotypes of two brothers were assessed by exploration and physical examination. Karyotype analysis was preformed using Giemsa staining, fluorescent in situ hybridization and array comparative genomic hybridization for both children and their parents.
Results
Both boys had 46,XX G-banded karyotypes. Fluorescent in situ hybridization analysis could not identify the SRY gene. Array comparative genomic hybridization analysis identified a 143 kb duplication of SOX-9 in the older brother and a 155 kb duplication in the younger child and the healthy 46,XY father. The sons inherited the abnormal chromosome 17 with the duplicated SOX-9 regulatory element from their father. The mother had normal female karyotype.
The brothers showed incomplete masculine phenotypes with bilaterally palpable gonads and hypospadiasis. The older brother had a prostate, one scrotal ovotestis and one atrophic testis with decreased cellcount and germinal cell aplasia. He had increased free and total testosterone and low estradiol. The younger boy had bilateral scrotal ovaries and a closed tubular structure behind the bladder that may be a Müllerian duct remnant. He had increased estradiol levels and negligible testosterone.
Conclusion
New-throughput technologies have revealed the importance of non-coding DNA in the process of gene regulation. The presented cases provide new evidence that remote cis-acting enhancer elements may affect SOX-9 gene regulation by gain of function and result in gene overexpression. The regulatory landscape of the genome should be included in research for disease-causing CNVs. Our findings should also be considered in genetic counseling in this family’s future.

Data of the presenter

Doctoral School of Clinical Medicine, 2
Program: Clinical application of basic science results, 17