Abstract
Birt-Hogg-Dubé (BHD) is an autosomal dominant genetic syndrome caused by germline mutations in the FLCN gene that predisposes patients to develop renal tumors. Renal angiomyolipoma (AML) is not a renal tumor sub-type associated with BHD. AML is, however, a common phenotypic manifestation of Tuberous Sclerosis Complex (TSC) syndrome caused by mutations in either the TSC1 or TSC2 tumor suppressor genes. Previous case reports of renal AML in patients with BHD have speculated on the molecular and clinical overlap of these two syndromes as a result of described involvement of the gene products in the mTOR pathway. Our recent work provided a new molecular link between these two syndromes by identifying FLCN and Tsc2 as clients of the molecular chaperone Hsp90. Folliculin interacting proteins FNIP1/2 and Tsc1 are important for FLCN and Tsc2 stability as new Hsp90 co-chaperones. Here we present a case of sporadic AML as a result of somatic Tsc1/2 loss in a patient with BHD. We further demonstrate that FNIP1 and Tsc1 are capable of compensating for each other in the chaperoning of mutated FLCN tumor suppressor. Our findings demonstrate interconnectivity and compensatory mechanisms between the BHD and TSC pathways.
Highlights
Birt-Hogg-Dubé (BHD) is an autosomal dominant genetic syndrome caused by germline mutations in the FLCN gene on chromosome 17p11.2, which encodes the protein Folliculin (FLCN) [1,2,3,4]
We present a case of renal AML, a kidney neoplasm typically associated with Tuberous Sclerosis Complex (TSC) syndrome, in a patient with BHD
Previous case reports of AML in the setting of BHD in the literature posit on a phenotypic overlap between TSC and BHD, suggesting that renal AML may be a manifestation of BHD in those affected patients [13, 15]
Summary
Birt-Hogg-Dubé (BHD) is an autosomal dominant genetic syndrome caused by germline mutations in the FLCN gene on chromosome 17p11.2, which encodes the protein Folliculin (FLCN) [1,2,3,4]. In addition to neural associations that include epilepsy, subependymal giant cell astrocytomas (SEGA), intellectual disability, and autism, TSC is characterized by cutaneous, pulmonary, and renal manifestations, to BHD [10]. These include cutaneous facial angiofibromas, pulmonary lymphangioleiomyomatosis (LAM), and renal AMLs
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