Combined germline pathogenic variants in FLCN and TP53 are associated with early onset renal cell carcinoma and brain tumors

Abstract

Background: We present a family consisting of a father and his two children with an exceptional phenotype of childhood renal cell carcinoma and brain tumors. Extensive genetic testing revealed two inherited tumor predisposition syndromes in all three family members: Birt-Hogg-Dubé syndrome and Li-Fraumeni syndrome. The corresponding genes (FLCN and TP53) are both located on the short arm of chromosome 17.

Methods: We describe the phenotype and performed single nucleotide polymorphism (SNP)-based loss of heterozygosity (LOH) analysis of the tumors.

Results: All examined tumors showed somatic loss of the wild-type alleles of both FLCN and TP53.

Conclusions: We hypothesize that a synergistic effect of both mutations caused the unusual phenotype of childhood renal cell carcinoma in this family. This family emphasizes the importance of further genetic testing if a tumor develops at an unexpected young age in an inherited cancer predisposition syndrome.

Keywords: Birt-Hogg-Dubé syndrome; Li-Fraumeni syndrome; loss of heterozygosity; renal cell carcinoma.