Pulmonologists should be more aware of Birt-Hogg-Dubé Syndrome

When BHD was first described in 1977 it was based on the presence of characteristic skin lumps (Birt et al., 1977). In addition BHD is now known to be associated with increased risk of renal cancer, the development of lung cysts and an associated increased risk in pneumothorax. In 2002, the association of BHD with mutations in the folliculin (FLCN) gene provided the definitive mechanism for BHD diagnosis (Nickerson et al., 2002). As such all patients suspected of having BHD should undergo genetic testing to confirm this diagnosis.

Pneumothorax in BHD patients is associated with the development of pulmonary cysts. Numerous research and clinical groups have confirmed high prevalence (up to 90%) of lung cysts in BHD patients (Toro et al., 2008, Agarwal et al., 2011). Whilst the development of lung cysts or blebs is not limited to BHD patients – pulmonary blebs are also associated with other pulmonary disease and smoking – the distribution and formation of the cysts seen in BHD is quite distinct. In BHD patients it is typical to find multiple, thin-walled, elliptical or lentiform, well-defined but with no internal structure, air-filled cysts. These cysts are also predominantly found in the medial or basal sections of the lung and are often subpleural (Tobino et al., 2009, Johannesma et al., 2014d). Toro et al., (2007) reported that BHD patients with a family history of spontaneous pneumothorax and more pulmonary cysts were significantly more likely to develop pneumothoraces.

BHD is underdiagnosed due to a lack of awareness in the medical profession of such a rare disease in combination with its variable presentation and onset. Only a small percentage of BHD diagnoses are suspected based on the presentation of pulmonary pathologies alone. However over the last few years there have been increasing numbers of such case studies where individuals have presented with spontaneous pneumothorax and genetic testing was used to confirm a BHD diagnosis (Predina et al., 2011, Auerbach et al., 2014, Kilinceret al., 2014, Johannesma et al., 2013, Johannesma et al., 2014c, Johannesma et al., 2014fArdilouze et al., 2015).

It has been estimated that BHD patients have a 50-times higher risk of developing pneumothorax than non-BHD individuals (Zbar et al., 2002). Two large cohort studies also looked at the incidence of BHD in cases of primary spontaneous pneumothorax (PSP) and found that approximately 5-10% of PSP patients carried FLCN mutations (Ren et al.,2008, Johannesma et al., 2014f). PSP incidence is 1.2-6/100,000 for women and 7.4-18/100,000 for men, annually (Luh, 2010)) and the global population is 7×109.  This suggests that the total number of PSP annually is 300,000-800,000, with 15,000-80,000 of those patients carrying FLCN mutations.  These suggested figures are vastly more than the current number of diagnosed BHD patients, which might  be  a result of unintentional cohort sampling bias or due to the difficultly of establishing accurate statistics when dealing with such a small sample population as BHD patients. The true number of un- or mis-diagnosed BHD patients is difficult to estimate however it is clear that many BHD patients are being misdiagnosed as PSP patients. This will continue to be the case unless there is more awareness of BHD as a potential cause of spontaneous pneumothorax. The variation in BHD presentation makes it is highly important, especially with younger patients, to obtain a detailed family history with regards to BHD pathologies as these can contain additional differential diagnostic information.

New diagnosis guidelines suggested by Gupta et al., (2013) would allow diagnosis of BHD to be based on the presence of “characteristic BHD-cysts” on a high resolution CT scan in combination with fibrofolliculomas, BHD-related renal cancer, a first or second degree relative with confirmed BHD, or a positive genetic test. Whilst the numerous individual case and cohort studies suggest that the presence of characteristic lung cysts is indicative of BHD, it is only via genetic testing that the diagnosis can be confirmed. Identifying these patients, and any other affected family members, as early as possible is important as it will impact on future monitoring and treatment. Therefore it is of great importance that awareness of BHD and its pulmonary presentation is increased in pulmonologists and associated professions.

  • Agarwal PP, Gross BH, Holloway BJ, Seely J, Stark P, Kazerooni EA. Thoracic CT findings in Birt-Hogg-Dube syndrome. AJR Am J Roentgenol. 2011 Feb;196(2):349-52. PubMed PMID: 21257886.
  • Ardilouze P, Jacquin J, Ait Ali T, Schneider S. Birt-Hogg-Dubé syndrome: A little known cause of pulmonary cysts. Diagn Interv Imaging. 2015 Jan;96(1):99-101. Epub 2014 Jul 9. PubMed PMID: 25022726.
  • Auerbach A, Roberts DH, Gangadharan SP, Kent MS. Birt-Hogg-Dubé syndrome in a patient presenting with familial spontaneous pneumothorax. Ann Thorac Surg. 2014 Jul;98(1):325-7 PubMed PMID: 24996715.
  • Birt AR, Hogg GR, Dubé WJ. Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol. 1977 Dec;113(12):1674-7. PubMed PMID: 596896.
  • Gupta N, Seyama K, McCormack FX. Pulmonary manifestations of Birt-Hogg-Dubé syndrome. Fam Cancer. 2013 Sep;12(3):387-96. Review. PubMed PMID:23715758.
  • Johannesma PC, Thunnissen E, Postmus PE. Lung cysts as indicator for Birt-Hogg-Dubé syndrome. Lung. 2013; Epub 2013 Oct 22. PubMed PMID: 24146214.
  • Johannesma PC, van den Borne BE, Gille JJ, Nagelkerke AF, van Waesberghe JT, Paul MA, van Moorselaar RJ, Menko FH, Postmus PE. Spontaneous pneumothorax as indicator for Birt-Hogg-Dubé syndrome in paediatric patients. BMC Pediatr. 2014c Jul 3;14:171. PubMed PMID: 24994497.
  • Johannesma PC, Houweling AC, van Waesberghe JH, van Moorselaar RJ, Starink TM, Menko FH, Postmus PE. The pathogenesis of pneumothorax in Birt-Hogg-Dubé syndrome: a hypothesis. Respirology. 2014d Nov;19(8):1248-50. PubMed PMID: 25302759.
  • Johannesma PC, Reinhard R, Kon Y, Sriram JD, Smit HJ, van Moorselaar RJ, Menko FH, Postmus PE; on behalf of the Amsterdam BHD working group. Prevalence of Birt-Hogg-Dubé syndrome in patients with apparently primary spontaneous pneumothorax. Eur Respir J. 2014f Dec 23. pii: ERJ-01969-2014. [Epub ahead of print] PubMed PMID: 25537564.
  • 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. PubMed PMID: 25610314.
  • Nickerson ML, Warren MB, Toro JR, Matrosova V, Glenn G, Turner ML, Duray P, Merino M, Choyke P, Pavlovich CP, Sharma N, Walther M, Munroe D, Hill R, Maher E, Greenberg C, Lerman MI, Linehan WM, Zbar B, Schmidt LS. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome. Cancer Cell. 2002 Aug;2(2):157-64. PubMed PMID: 12204536.
  • Ren HZ, Zhu CC, Yang C, Chen SL, Xie J, Hou YY, Xu ZF, Wang DJ, Mu DK, Ma DH, Wang Y, Ye MH, Ye ZR, Chen BF, Wang CG, Lin J, Qiao D, Yi L. Mutation analysis of the FLCN gene in Chinese patients with sporadic and familial isolated primary spontaneous pneumothorax. Clin Genet. 2008 Aug;74(2):178-83. Epub 2008 May 25. PubMed PMID: 18505456.
  • Predina JD, Kotloff RM, Miller WT, Singhal S. Recurrent spontaneous pneumothorax in a patient with Birt-Hogg-Dubé syndrome. Eur J Cardiothorac Surg.  2011 Mar;39(3):404-6.. Epub 2010 Aug 6. PubMed PMID: 20692178.
  • 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 Epub 2009 Sep 25. PubMed PMID: 19782489.
  • Toro JR, Pautler SE, Stewart L, Glenn GM, Weinreich M, Toure O, Wei MH, Schmidt LS, Davis L, Zbar B, Choyke P, Steinberg SM, Nguyen DM, Linehan WM. Lung  cysts, spontaneous pneumothorax, and genetic associations in 89 families with Birt-Hogg-Dubé syndrome. Am J Respir Crit Care Med. 2007 May 15;175(10):1044-53.  Epub 2007 Feb 22. PubMed PMID: 17322109
  • Toro JR, Wei MH, Glenn GM, Weinreich M, Toure O, Vocke C, Turner M, Choyke P, Merino MJ, Pinto PA, Steinberg SM, Schmidt LS, Linehan WM. BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports. J Med Genet. 2008 Jun;45(6):321-31. Epub 2008 Jan 30. Review. PubMed PMID:18234728.
  • 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. PubMed PMID: 11927500.

2 thoughts on “Pulmonologists should be more aware of Birt-Hogg-Dubé Syndrome

  1. Our son tested negative for the FLCN gene but it has been suggested that he may have a variation. He has had VATS surgery on both lungs with mechanical pleurodesis at ages 15 and 16. He is now 20, 6’4″ and continues to have SP’s in both lungs. His older brother and sister have had two SP’s each that resolved without surgery. An aunt also had two SP’s at a young age.

    Are there known variations to this gene and should we have any further testing?

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