ENVIRONMENTAL AND GENETIC EVALUATION IN 46,XY DISORDERS OF SEX DEVELOPMENT

Abstract

The phenotype of Disorders of Sex Development (DSD)patients depends on many factors including the presence of Copy Number Variation (CNVs) of different genes. The unbalanced rearrangement and the presence of deletions or duplications affect dramatically the phenotypic sex. The aim of this study is to correlate genotypic abnormalities with clinical phenotype in 46,XY DSD patients by Multiplex Ligation dependant Probe Amplification (MLPA) technique for accurate diagnosis in these patients and study possible paternal and maternal exposure to environmental risk factors in these cases. This study reported on forty patients with variable presentations of disorders of sex development (DSD) presenting with ambiguous genitalia, hypospadias, micropenis or with female phenotype with primary amenorrhea or short stature, with exclusion of cases with disorders in androgen synthesis. A complete personal, family history and clinical examination were done. Parents were asked to fill a questionnaire about frequency of dealing with some environmental factors including smoking, caffeine and using some materials having estrogenic effect as plastics, insecticides, and others. Conventional cytogenetics studies and fluorescence in situ hybridization (FISH) on peripheral blood as well as DNA extraction and Multiplex Ligation-dependent Probe Amplification (MLPA) were done for all cases for some genes; DMRT1, CYP17A1, SRD5A2, HSD17B3, DAX1, CXor21, SOX9, SRY, ZFY, WNT4 and SF. Results showed 46,XY was shown in all patients. MLPA analysis showed Copy Number Variation (CNVs) in 15% of cases. The study showed duplication of DMRT1 in 5% patients, deletion of SRY 2.5% patients, deletion of SOX9 in 5% patients, duplication of DAX1 in 12.5% patient, duplication of CYP17A41 in 5% patients, deletion of DMRT1 in 12.5% patient, duplication of SRD5A in 2.5% patient and duplication of HSD17B3 in 2.5% patient. Maternal exposure during pregnancy and paternal exposure to Endocrine Disrupting Compounds (EDCs) were insignificantly associated with DSD compared to control cases. This study demonstrates the importance of proper detection of genetic mutation in DSD patients showing a discrepancy between their karyotype and gonadal phenotype. It was concluded that using MLPA is recommended for better understanding of the phenotype with other recent techniques as for better diagnosis and follow up.