Birt-Hogg-Dubé (BHD) syndrome is characterised by three symptoms: skin lesions; lung cysts with predisposition to pneumothorax; and kidney cancer. Although it is possible to clinically diagnose BHD based on these symptoms, the only conclusive diagnosis is to find pathogenic mutations in the FLCN gene. As BHD is a rare disease, and at first glance the symptoms are not obviously linked, many clinicians have not heard of BHD, which can lead to an incorrect or missed diagnosis. There are several diseases with similar and overlapping features to BHD, and in the past year, a number of papers have been published reviewing the characteristics of the lung cysts found in BHD and other look-alike diseases.
Studies aiming to characterise BHD lung cysts have found that BHD lung cysts are predominantly located in the basal region of the lungs, small (< 1 cm), irregularly-shaped, and do not significantly affect lung function (Fabre et al., 2013, Gupta et al., 2013, Tobino et al., 2011, Tobino et al., 2012). Lung cysts are a highly penetrant symptom of BHD, with 89% of BHD patients in one cohort developing lung cysts (Toro et al., 2007). Additionally, unlike other cystic lung diseases, BHD patients with lung cysts have a strong family history, with nearly half of BHD patients reporting to have second degree relatives that had suffered pneumothorax (Tobino et al., 2012). As BHD is an autosomal dominant disease, FLCN mutation carriers of either sex are at risk of developing lung cysts and pneumothorax. The pulmonary symptoms of BHD can develop at any age: the youngest reported BHD patient to develop pneumothorax was 7 years old (Bessis et al., 2006), whilst the oldest was 73 years old (Kunogi Okura et al., 2013), although the majority of patients are thought to develop pulmonary symptoms between the ages of 30 – 40 (Gupta et al., 2013).
Lymphangioleiomyomatosis (LAM) is caused by an over-proliferation of smooth muscle cells in the lung, causing cysts to develop. LAM lung cysts are round and thin-walled and are found throughout the lung. 10 – 20% of patients progress to complete respiratory failure within ten years of diagnosis, and require a lung transplant. LAM predominantly affects women of child bearing age. Roughly 85% of cases occur sporadically – possibly by somatic mutation of the TSC2 gene – while the remaining 15% of cases occur as part of the kidney cancer syndrome tuberous sclerosis complex (Bhardwaj & Bhardwaj, 2013, Koo & Yoo, 2013, Ryu et al., 2013).
Adult-onset Pulmonary Langerhans’ cell histiocytosis (PCLH) is caused by overproliferation of Langerhans-type histiocytic cells, causing complex shaped cysts to form in the upper lobes of the lung. PLCH is highly associated with smoking, with 95% of patients being current or ex-smokers, and usually develops between the ages of 20 – 40. It is rarely seen in African or Asian populations. While roughly 30% of cases only show pulmonary pathology, PLCH can also affect bones, the pituitary gland, skin, mucous membranes, lymph nodes and the liver (Bhardwaj & Bhardwaj, 2013, Koo & Yoo, 2013, Ryu et al., 2013, Vassallo & Ryu, 2004).
A recent study compared the lung pathology seen in BHD patients with that seen in spontaneous pneumothorax cases caused by smoking, and found distinct histological and radiological differences between the two groups (Fabre et al., 2013). BHD patients generally had numerous (more than 20) punch-out type cysts with no inflammation, showing a basal predominance while the control cohort had fewer cysts showing apical predominance. The control cohort also had a greater prevalence of smoking-related changes such as fibroelastotic scars, respiratory bronchiolitis and emphysema, which BHD patients generally did not. However, one BHD patient, who was a current smoker, had pulmonary changes more similar to the smoking cohort. This suggests that although smoking does not cause the pulmonary changes seen in BHD, smoking is likely to exacerbate lung problems in BHD patients, so should be strongly discouraged.
Taken together, these studies suggest that when a patient is found to have lung cysts, clinicians can use radiological information to determine the most likely cause and therefore order appropriate diagnostic tests. In particular, clinicians should consider a diagnosis of BHD is the patient is a non-smoker with a family history of pneumothorax, if the lung cysts are predominantly located in the lower lobes of the lung and if lung function is not severely affected. As stated in a recent case study by Johannesma et al. it is important that pulmonary specialists are aware of the radiological differences between the various cystic lung diseases, as this will aid the correct diagnosis of patients presenting with pulmonary symptoms alone. This is particularly important in diseases such as BHD and LAM, where patients are at risk of developing kidney cancer, which could otherwise be missed if the pulmonary symptoms are mis-diagnosed.
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Bessis D, Giraud S, & Richard S (2006). A novel familial germline mutation in the initiator codon of the BHD gene in a patient with Birt-Hogg-Dubé syndrome. The British journal of dermatology, 155 (5), 1067-9 PMID: 17034545
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Bhardwaj H,, & Bhardwaj B (2013). Differentiating pulmonary lymphangioleiomyomatosis from pulmonary langerhans cell histiocytosis and Birt-Hogg-Dube syndrome. Lung India, 30 (4), 372-373 DOI: 10.4103/0970-2113.120611
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Fabre A, Borie R, Debray MP, Crestani B, & Danel C (2013). Distinguishing histological and radiological features between pulmonary cystic lung disease in Birt-Hogg-Dubé Syndrome and tobacco-related spontaneous pneumothorax. Histopathology PMID: 24168179
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Gupta N, Seyama K, & McCormack FX (2013). Pulmonary manifestations of Birt-Hogg-Dubé syndrome. Familial cancer, 12 (3), 387-96 PMID: 23715758
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Johannesma PC, Thunnissen E, & Postmus PE (2013). Lung Cysts as Indicator for Birt-Hogg-Dubé Syndrome. Lung PMID: 24146214
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Koo HK, & Yoo CG (2013). Multiple cystic lung disease. Tuberculosis and respiratory diseases, 74 (3), 97-103 PMID: 23579924
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Kunogi Okura M, Yae T, Nagashima O, Hirai S, Kumasaka T, & Iwase A (2013). Pneumothorax Developing for the First Time in a 73-year-old Woman Diagnosed with Birt-Hogg-Dubé Syndrome. Internal medicine (Tokyo, Japan), 52 (21), 2453-5 PMID: 24190151
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Ryu JH, Tian X, Baqir M, & Xu K (2013). Diffuse cystic lung diseases. Frontiers of medicine, 7 (3), 316-27 PMID: 23666611
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Tobino K, Gunji Y, Kurihara M, Kunogi M, Koike K, Tomiyama N, Johkoh T, Kodama Y, Iwakami S, Kikkawa M, Takahashi K, & Seyama K (2011). Characteristics of pulmonary cysts in Birt-Hogg-Dubé syndrome: thin-section CT findings of the chest in 12 patients. European journal of radiology, 77 (3), 403-9 PMID: 19782489
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Tobino K, Hirai T, Johkoh T, Kurihara M, Fujimoto K, Tomiyama N, Mishima M, Takahashi K, & Seyama K (2012). Differentiation between Birt-Hogg-Dubé syndrome and lymphangioleiomyomatosis: quantitative analysis of pulmonary cysts on computed tomography of the chest in 66 females. European journal of radiology, 81 (6), 1340-6 PMID: 21550193
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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 (2007). Lung cysts, spontaneous pneumothorax, and genetic associations in 89 families with Birt-Hogg-Dubé syndrome. American journal of respiratory and critical care medicine, 175 (10), 1044-53 PMID: 17322109
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Vassallo R, & Ryu JH (2004). Pulmonary Langerhans’ cell histiocytosis. Clinics in chest medicine, 25 (3) PMID: 15331192
www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.