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  • Clinical phenotype and genetic function analysis of a rare family with hereditary leiomyomatosis and renal cell carcinoma complicated with Birt–Hogg–Dubé syndrome

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Cancer genetics
Short report
Clinical phenotype and genetic function analysis of a rare family with hereditary leiomyomatosis and renal cell carcinoma complicated with Birt–Hogg–Dubé syndrome
  1. Hong-Hong Pan1,2,
  2. Dan-Dan Ruan1,
  3. Min Wu1,
  4. Ting Chen3,
  5. Tao Lu1,
  6. Yu-Mian Gan1,
  7. Chen Wang1,4,
  8. Li-Sheng Liao1,5,
  9. Xin-Fu Lin1,6,
  10. Xin Chen1,4,
  11. Yao-Bin Zhu7,
  12. Zhu-Ting Fang1,
  13. Qing-Hua Yu1,
  14. Guo-Kai Yang1,8,
  15. Lie-Fu Ye1,2,
  16. Jie-Wei Luo1,9
  1. 1 Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
  2. 2 Department of Urology, Fujian Provincial Hospital, Fuzhou, Fujian, China
  3. 3 School of Medicine, Shanghai University, Shanghai, China
  4. 4 Pathology Department, Fujian Provincial Hospital, Fuzhou, Fujian, China
  5. 5 Department of Hematology, Fujian Provincial Hospital, Fuzhou, Fujian, China
  6. 6 Pediatrics Department, Fujian Provincial Hospital, Fuzhou, Fujian, China
  7. 7 Department of Traditional Chinese Medicine, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
  8. 8 Nephrology Department, Fujian Provincial Hospital, Fuzhou, Fujian, China
  9. 9 Department of Traditional Chinese Medicine, Fujian Provincial Hospital, Fuzhou, Fujian, China
  1. Correspondence to Professor Jie-Wei Luo, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou 350001, Fujian, China; docluo0421{at}aliyun.com; Professor Lie-Fu Ye; yeliefu{at}126.com; Guo-Kai Yang; ygk518{at}163.com

Abstract

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
  • Genetics
  • Genetic Variation
  • Genotype
  • Urology

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.

https://doi.org/10.1136/jmg-2023-109328

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    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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    Footnotes

    • 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.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.