Birt-Hogg-Dubé Syndrome is caused by inactivating mutations in the FLCN gene, characterised by skin lesions on the face and upper body; lung cysts and predisposition to pneumothorax; and kidney cancer. Although symptoms typically appear in the third and fourth decade of life, Johannesma et al. (2014) suggest that pneumothorax in patients under the age of 18 might be underdiagnosed.
In two large cohort studies, 24% were found to have had one or more episodes of pneumothorax, with a predicted lifetime risk of29% of developing a pneumothorax (Houweling et al., 2011, Toro et al., 2007). The age range of patients’ initial pneumothorax episodes was 18 – 74 years, with a median age of 36 – 38 years, suggesting that the age of onset of this symptom can vary widely (Houweling et al., 2011, Toro et al., 2007). However, the majority of families in both of these studies were recruited via dermatology clinics, meaning that there might be some ascertainment bias in these cohorts.
Johannesma et al. report the cases of two unrelated Dutch BHD patients who suffered their first pneumothorax at the age of 14. Both patients were given chest CT scans, as they suffered recurrent episodes as teenagers, and revealed the presence of lung cysts in the lower lobes of the lungs. Genetic testing confirmed each had a pathogenic FLCN mutation, confirming a diagnosis of BHD.
This report follows three other reports of BHD patients suffering pneumothoraces as teenagers: a 7 year old French boy (Bessis et al., 2006); a 16 year old Japanese girl (Gunji et al., 2007); and an 18 year old Dutch girl (Houweling et al., 2011). Thus, although pneumothorax during childhood is rare in BHD patients, both clinicians and BHD patients with children should be aware that it is a possibility.
It is possible that BHD is underdiagnosed in cases of paediatric spontaneous pneumothorax as BHD is normally considered to be an adult-onset disease. Additionally, CT scans – which would help diagnose BHD if lung cysts were found – are not normally administered to paediatric patients, unless deemed to be absolutely necessary, due to the low dose of radiation patients are exposed to during the scan (Balfour-Lynn et al., 2005).
Given that both patients reported by Johannesma et al. were found to have lung cysts as teenagers but neither had yet developed skin or kidney symptoms, it is possible that lung cysts are the first symptom of BHD to develop, but are not normally found unless the patient receives a chest CT for some other reason. Indeed, pneumothorax risk is strongly correlated with increased number and size of lung cysts (Toro et al., 2007), and it has subsequently been hypothesised that lung collapses are caused by air-filled cysts rupturing and releasing air into the chest cavity (Furuya and Nakatani, 2013). Thus it is likely that all the reported paediatric patients also developed lung cysts in childhood.
Four of the five paediatric BHD patients did have recurrent episodes, with one patient having four recurrent lung collapses before the age of 18 (Johannesma et al. 2014), and another having six episodes between the ages of 16 and 38 (Gunji et al., 2007). Given that the average number of pneumothoraces per patient was found to be two in the cohort studied by Toro et al. this does suggest that BHD patients who have their first pneumothorax in childhood might be at higher risk of recurrent episodes than other BHD patients.
Thus, although BHD patients suffer pneumothoraces during childhood only in rare cases, as childhood pneumothorax is itself rare, only affecting 4 in 100,000 boys and 1 in 100,000 girls, Johannesma et al. recommend that a thorough family history, a low dose CT scan, and genetic testing should be considered for paediatric patients who experience repeated episodes of spontaneous pneumothorax.
- Balfour-Lynn IM, Abrahamson E, Cohen G, Hartley J, King S, Parikh D, Spencer D, Thomson AH, Urquhart D, & Paediatric Pleural Diseases Subcommittee of the BTS Standards of Care Committee (2005). BTS guidelines for the management of pleural infection in children. Thorax, 60, i1-21 PMID: 15681514
- 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
- Furuya M, & Nakatani Y (2013). Birt-Hogg-Dube syndrome: clinicopathological features of the lung. Journal of Clinical Pathology, 66 (3), 178-86 PMID: 23223565
- Gunji Y, Akiyoshi T, Sato T, Kurihara M, Tominaga S, Takahashi K, Seyama K. (2007) Mutations of the Birt Hogg Dube gene in patients with multiple lung cysts and recurrent pneumothorax. Journal of Medical Genetics, 44 (9), 588-93 PMID: 17496196
- Houweling AC, Gijezen LM, Jonker MA, van Doorn MB, Oldenburg RA, van Spaendonck-Zwarts KY, Leter EM, van Os TA, van Grieken NC, Jaspars EH, de Jong MM, Bongers EM, Johannesma PC, Postmus PE, van Moorselaar RJ, van Waesberghe JH, Starink TM, van Steensel MA, Gille JJ, & Menko FH (2011). Renal cancer and pneumothorax risk in Birt-Hogg-Dubé syndrome; an analysis of 115 FLCN mutation carriers from 35 BHD families. British journal of cancer, 105 (12), 1912-9 PMID: 22146830
- Johannesma PC, van den Borne BE, Gille JJ, Nagelkerke AF, van Waesberghe JT, Paul MA, van Moorselaar RJ, Menko FH, & Postmus PE (2014). Spontaneous pneumothorax as indicator for Birt-Hogg-Dubé syndrome in paediatric patients. BMC pediatrics, 14 PMID: 24994497
- 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