Birt - Hogg - Dube disorder: case reports

Birt - Hogg - Dubd (BHD) disorder is a rare inherited autosomal dominant disorder caused by germline mutations in the tumor suppressor gene FLCN, which encodes the protein folliculin. BHD disorder is characterized by benign skin hamartomas, kidney cancer, pulmonary cysts, and spontaneous pneumothorax. Currently, more than 600 cases of this disease have been described worldwide. Diagnosis of BHD disorder is based on clinical manifestations, family history, and genetic testing. We describe two patients (43 and 51 years old) who presented with a history of longstanding dyspnea and spontaneous pneumothorax. Based on the radiological characteristics and skin lesions, the patients were referred for genetic testing to confirm the diagnosis of BHD disorder.

Aim. To study the current management of adult patients with BCD disorder. Timely diagnosis of BHD disorder has important preventive value because patients with this disease are at much higher risk for kidney cancer.

Conclusion. The presented clinical cases demonstrate typical manifestations of BCD disorder with predominant involvement of the lungs and skin. The final diagnosis is confirmed by genetic testing of the coding sequence of the FLCN gene by direct automated sequencing. To date, there are no specific therapies for BCD disorder and treatment of the respiratory manifestations is limited to prevention and treatment of pneumothorax.

1. Marziali V, Geropoulos G, Frasca L, Longo F, Patrini D, Panagiotopoulos N, Crucitti P. Focus on the pulmonary involvement and genetic patterns in Birt-Hogg-Dubè syndrome: Literature review. Respir Med. 2020; 168: 105995. doi: 10.1016/j.rmed.2020.105995. Epub 2020 May 6. PMID: 32469710.

2. Gupta N, Sunwoo BY, Kotloff RM. Birt-Hogg-Dubé Syndrome. Clin Chest Med. 2016 Sep;37(3):475-86. doi: 10.1016/j.ccm.2016.04.010. Epub 2016 Jun 25. PMID: 27514594.

3. Daccord C, Good JM, Morren MA, Bonny O, Hohl D, Lazor R. Birt-Hogg-Dubé syndrome. Eur Respir Rev. 2020 Sep 17;29(157):200042. doi: 10.1183/16000617.0042-2020. PMID: 32943413; PMCID: PMC9489184.

4. Lim DH, Rehal PK, Nahorski MS, Macdonald F, Claessens T, Van Geel M, Gijezen L, Gille JJ, Giraud S, Richard S, van Steensel M, Menko FH, Maher ER. A new locus-specific database (LSDB) for mutations in the folliculin (FLCN) gene. Hum Mutat. 2010 Jan;31(1): E1043-51. doi: 10.1002/humu.21130. PMID: 19802896.

5. Menko FH, Johannesma PC, van Moorselaar RJ, et al. A de novo FLCN mutation in a patient with spontaneous pneumothorax and renal cancer; a clinical and molecular evaluation. Fam Cancer 2013; 12: 373–379. doi:10.1007/s10689-012-9593-8

6. Schmidt LS, Linehan WM. Molecular genetics and clinical features of Birt-Hogg-Dubé syndrome. Nat Rev Urol. 2015 Oct;12(10):558-69. doi: 10.1038/nrurol.2015.206. Epub 2015 Sep 1. PMID: 26334087; PMCID: PMC5119524.

7. Sattler EC, Syunyaeva Z, Mansmann U, et al. Genetic risk factors for spontaneous pneumothorax in Birt–Hogg–Dubé syndrome. Chest 2020; 157: 1199–1206.

8. Daccord C, Cottin V, Prévôt G, et al. Lung function in Birt–Hogg–Dubé syndrome: a retrospective analysis of 96 patients. Orphanet J Rare Dis 2020; 15: 120.

9. Abolnik IZ, Lossos IS, Zlotogora J, Brauer R. On the inheritance of primary spontaneous pneumothorax. Am J Med Genet 40: 155- 158, 1991.

10. Tobino K, Gunji Y, Kurihara M, Kunogi M, Koike K, Tomiyama N, Johkoh T, Kodama Y, Iwakami S, Kikkawa M, Takahashi K, Seyama K. Characteristics of pulmonary cysts in Birt-Hogg-Dubé syndrome: thin-section CT findings of the chest in 12 patients. Eur J Radiol. 2011 Mar;77(3):403-9. doi: 10.1016/j.ejrad.2009.09.004. Epub 2009 Sep 25. PMID: 19782489.

11. Tobino K, Hirai T, Johkoh T, Kurihara M, Fujimoto K, Tomiyama N, Mishima M, Takahashi K, Seyama K. Differentiation between Birt-Hogg-Dubé syndrome and lymphangioleiomyomatosis: quantitative analysis of pulmonary cysts on computed tomography of the chest in 66 females. Eur J Radiol. 2012 Jun;81(6):1340-6. doi: 10.1016/j.ejrad.2011.03.039. Epub 2011 May 7. PMID: 21550193.

12. Kilincer A, Ariyurek OM, Karabulut N. Cystic lung disease in birt-hogg-dubé syndrome: a case series of three patients. Eurasian J Med. 2014 Jun;46(2):138-41. doi: 10.5152/eajm.2014.31. PMID: 25610314; PMCID: PMC4261454.

13. Zbar B, Alvord WG, Glenn G, Turner M, Pavlovich CP, Schmidt L, Walther M, Choyke P, Weirich G, Hewitt SM, Duray P, Gabril F, Greenberg C, Merino MJ, Toro J, Linehan WM. Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome. Cancer Epidemiol Biomarkers Prev. 2002 Apr;11(4):393-400. PMID: 11927500.

14. Adam MP, Ardinger HH, Pagon RA, et al., Birt–Hogg–Dubé syndrome. In: MP Adam, HH Ardinger, RA Pagon, et al., eds. GeneReviews®. 1993-2020. Seattle, University of Washington, Seattle, 2020