Challenges in the Diagnosis and Consequential Management of Patients 46, XY DSD

Background: Disorders of sex development (DSD) are clinical conditions that cause an incongruity between the chromosomal and phenotypic sex of an individual. A high variable group of congenital disorders can arise depending upon the timing and location of defect involved in sex determination and differentiation. 46, XY DSD occurs in 1:20,0000 male births; with external genitalia ranging from ambiguous to normal female. Such conditions can be psychologically stressful for patients and their families and have been historically difficult to diagnose, especially at genetic level. Failure to diagnose exact mutation may make the therapeutic approach, genetic counseling and risk assessment even more challenging. Clinical case: Full term baby is born to non -consanguineous parents after an uneventful pregnancy. Mother denied any history of acne/hirsutism, hormone or substance use during pregnancy. At birth, external genitalia showed non-rugated labia majora with posterior fusion, absence of labia minora and vaginal opening. Enlarged clitoris/ Penile like structure measuring 1.5 cm with palpable corpora and hypospadias was present. No palpable gonads were appreciated. No other dysmorphic features were present and rest of the physical exam was unremarkable. Cosyntropin stim test on day 4 of life showed appropriate adrenal response. Pelvic ultrasound and MRI showed an elongated structure posterior to the bladder presumably uterus with no identifiable gonads. Chromosome analysis revealed an XY karyotype. FISH for SRY and microarray were unremarkable. Further testing at 4 weeks of life showed sub optimal elevation of Gonadotropins and Testosterone. Female gender was assigned due to parents’ preference and endocrine/ Urology recommendations. The 46,XY DSD genetic panel including testing for non-syndromic DSD, steroid abnormalities, skeletal dysplasia syndromes, and multiple malformation syndromes was unremarkable. Conclusion: Although a number of cytogenetic or single-gene defects have been associated with DSD, the true incidence of pathogenic variants has not been established. Many cases of 46, XY DSD remain unexplained likely due to an unidentified pathogenic variant of genes not routinely included in the panel or not yet identified to be associated with DSD. Without a clear diagnosis, genetic counseling and risk assessment is difficult. Parents should be informed about future options regarding sexual development, hormonal therapy and surgical treatments available. The determination of social sex must be made in consideration of underlying possible etiology, phenotypic sex, ethnic traditions, sexual identity and the acceptance of the assigned social sex by the parents. The affected child and his/her family must be followed throughout life to determine the patient’s adjustment to his/her social sex.