To date, over 200 families with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) and over 600 families with Birt–Hogg–Dubé (BHD) syndrome have been reported, with low incidence. Here, we describe a patient with suspected rare HLRCC complicated by BHD syndrome. The proband (II1) had characteristic cutaneous leiomyoma-like protrusions on the neck and back, a left renal mass and multiple right renal, liver and bilateral lung cysts. Three family members (I1, II2, II3) had a history of renal cancer and several of the aforementioned clinical features. Two family members (II1, II3) diagnosed with fumarate hydratase (FH)-deficient papillary RCC via pathological biopsy carried two heterozygous variants: FH (NM_000143.3) missense mutation c.1189G>A (p.Gly397Arg) and FLCN (NM_144997.5) frameshift mutation c.1579_1580insA (p.Arg527Glnfs*75). No family member carrying a single variant had renal tumours. In HEK293T cells transfected with mutant vectors, mRNA and protein expression after FLCN p.Arg527Glnfs*75 and FH p.Gly397Arg mutations were significantly lower than those in wild-type (WT) cells. Cell immunofluorescence showed altered protein localisation and reduced protein expression after FLCN p.Arg527Glnfs*75 mutation. The FH WT was uniformly distributed in the cytoplasm, whereas FH protein expression was reduced after the p.Gly397Arg mutation and scattered sporadically with altered cell localisation. Patients with two variants may have a significantly increased penetrance of RCC.
- Gene Expression
- Genetic Variation
Data availability statement
Data available upon reasonable request. The data that underlie and support the findings of this study are available from the corresponding author upon reasonable request.
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H-HP, D-DR, MW, TC and TL contributed equally.
Contributors G-KY, L-FY and J-WL conceived and designed the study. H-HP, D-DR and MW collected the data. TC, CW, H-HP, D-DR and XC conducted the data analysis and interpretation. Y-MG, TL, J-WL and Y-BZ wrote the manuscript. X-FL, Z-TF, L-SL, Q-HY and L-FY critically revised the important contents of the manuscript.
Funding This work was supported by the Fujian Province Natural Science Fund Project (2021J02053, 2020J011064, 2021J01704, 2022J01996), Startup Fund for Scientific Research of Fujian Medical University (2021QH1272), Special Research Foundation of Fujian Provincial Department of Finance (No. 2020-822, 2021-848, 2021-917, 2022-840), National Famous and Old Chinese Medicine Experts (Xuemei Zhang, Xiaohua Yan) inheritance studio construction project, and the Fujian Province Medical Innovation Foundation (No. 2021CXB001).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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