33. Variability in sex and phenotype: Impact of a familial pathogenic DHX37 variant leading to 46,XY gonadal dysgenesis

Our patient, assigned female at birth, was evaluated at age 17 for delayed puberty and short stature. She also had amenorrhea and no breast development. Cytogenetic analysis revealed an unexpected 46,XY karyotype. FISH confirmed a single X and SRY probe in each cell, and cytogenomic microarray analysis was consistent with these results. Endocrine labs indicated gonadal failure, trans-abdominal ultrasound identified no uterine or gonadal tissue, and a bone age x-ray showed delayed bone age. This clinical presentation and diagnostic testing suggested a 46,XY difference of sex development (DSD) with gonadal failure, or complete gonadal dysgenesis. Interestingly, the family history described a younger brother (assigned male at birth with microphallus) with a finding of premature testicular failure with vanishing testes, indicating a possible genetic component. Exome sequencing identified a missense variant in DHX37 (NM_032656.3, c.1784C>T, p.Ser595Phe), a gene not included on the patient's negative DSD gene panel. Pathogenic DHX37 variants (including this variant) have been recently reported as a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome (PMID: 31337883, 31287541). Our patient and her brother inherited this variant from an unaffected mother. Two older sisters (assigned female at birth and without evidence of DSD) both had the DHX37 variant and 46,XX chromosomes like their mother, which explained the lack of gonadal dysgenesis. These findings are consistent with a sex-limited autosomal dominant pattern for the DHX37 variant and confirm that individuals in this family with a 46,XY karyotype are at a high risk to have a 46,XY DSD. Clinical management for DSDs is difficult with psychosocial impacts for the patient and their family and this family's complexities including a language barrier and cultural differences created additional challenges for genetic counseling. Our case highlights the importance of diagnostic testing and genetic counseling for individuals with DSDs.

留言 (0)

沒有登入
gif