Differential Diagnosis of Disorders of Sex Development (DSD) by Molecular Genetic Analyses

ABSTRACT

Sex determination and differentiation require the balanced and sequential activation of transcription factors, signaling molecules, hormones and their receptors. Disorders of sex development (DSD) have heterogeneous groups of etiologies caused by mutations or deletions of genes involved in sex development. The DSD is categorized into 46, XX DSD, 46,XY DSD, sex chromosome DSD, ovotesticular DSD, and 46,XX testicular DSD. Precise diagnosis is essential for sex assignment, surgical correction of external genitalia, prevention of gonadal tumors, psychiatric support, and genetic counseling. The increased genetic knowledge in the field has opened up new diagnostic possibilities. The first line genetic testing for DSD is the assessment of the karyotype and the SRY gene. The follow-up genetic tests are performed for confirmatory diagnosis; the evaluation of copy number variants by array comparative genomic hybridization (CGH), direct sequencing of a specific gene, and functional analyses of mutations. A lot of genes can be analyzed by molecular laboratories and the number of available genes is growing. DNA analyses should be done under clinical assessment on the basis of family history, prenatal history, physical findings focused on external genitalia, endocrinologic data, and radiologic findings. Genetic counseling is essential to help patients and their families understand the disease status and the risk for recurrence in future pregnancies, and participate in the process of sex assignment. Children with DSD should be managed with a multidisciplinary team, including pediatric endocrinology, molecular genetics, cytogenetics, neonatology, urology, and psychiatry.