Frasier syndrome

Frasier syndrome is a rare genetic disorder characterized by the combination of progressive kidney disease (focal segmental glomerulosclerosis, FSGS) and disorders of sex development (DSD) in individuals with a 46,XY karyotype. It is caused by specific mutations in intron 9 of the WT1 (Wilms tumor 1) gene located on chromosome 11p13, which disrupt the normal splicing balance between the +KTS and -KTS isoforms of the WT1 protein. Frasier syndrome is considered an allelic disorder to Denys-Drash syndrome, which involves different types of WT1 mutations and has a distinct clinical presentation. The hallmark features of Frasier syndrome include slowly progressive nephropathy presenting as nephrotic syndrome due to focal segmental glomerulosclerosis, and gonadal dysgenesis. Affected 46,XY individuals typically present with female or ambiguous external genitalia due to complete or partial gonadal dysgenesis, with streak gonads that carry a significant risk of developing gonadoblastoma. Unlike Denys-Drash syndrome, Wilms tumor is not typically associated with Frasier syndrome. The kidney disease usually progresses to end-stage renal disease (ESRD), though often at a later age compared to Denys-Drash syndrome, frequently during adolescence or young adulthood. Affected 46,XX individuals may present with primary amenorrhea and streak gonads but typically have normal female external genitalia. There is no cure for Frasier syndrome. Management is multidisciplinary and includes monitoring and treatment of progressive nephropathy, which may ultimately require dialysis and kidney transplantation. Prophylactic gonadectomy is strongly recommended for 46,XY individuals due to the high risk of gonadoblastoma in dysgenetic gonads. Hormonal replacement therapy may be necessary following gonadectomy. Psychological support and appropriate management of disorders of sex development are also important components of care. Genetic counseling is recommended for affected families.

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