Birt-Hogg-Dubé syndrome (BHDS) is a rare autosomal dominant inherited disease characterised by skin lesions, renal tumours and pulmonary cysts with or without pneumothorax . In 1975 a pedigree with cutaneous tumours (“perifollicular fibromas” on face, neck and trunk) in combination with adenomatous colon polyps (one being transformed into carcinoma) was primarily published by Otto P. Hornstein and Monika Knickenberg . Finally, the syndrome was named after Arthur R. Birt, Georgina R. Hogg and W. James Dubé, who in 1977 described a family with similar skin tumours named “fibrofolliculomas” .
BHDS is caused by mutations in the gene that encodes folliculin (FLCN) on chromosome 17p11.2 . Except some trends, no clear correlation between type of mutation or location within the FLCN gene and any of the phenotype manifestations has been identified . However, two FLCN mutations were identified in a German cohort of 197 patients with increased risk for pneumothorax .
Folliculin is expressed in many organs and tissues (i.e., skin, distal nephron of the kidney, and the pneumocytes of the lung). In consequence, BHDS is clinically characterised by a typical triad of skin lesions (i.e., fibrofolliculomas, trichodiscomas and acrochordons) predominantly in the midface, renal tumours, and pulmonary cysts, with or without spontaneous pneumothorax [2,6,9]. Despite several theories, the development of each of these pathologies in BHDS like, i.e., lung cysts and the relationship between lung cysts and pneumothorax is not fully clarified [4,7]. Generally, clinical appearance of BHDS may vary and some patients do not show any skin lesions [6,12].
Skin: lesions in the field of nose, cheeks, neck and sometimes on upper trunk or ears. These benign hair follicle tumours are also called fibrofolliculomas. Furthermore, trichodiscomas, acrochordons or angiofibromas may appear. Mucosal lesions may occur as papules involving lips, buccal mucosa, and gingiva .
Lungs: more than 80 % of patients with BHDS show pulmonary cysts, (in contrast to other cystic lung diseases), mostly located in basal and paramediastinal regions [9,17]. However, lung function is usually not impaired due to these (often multiple) cysts [7,9,12]. Nevertheless, there is a highly increased risk of spontaneous, sometimes recurrent, pneumothorax in comparison to patients without BHDS [9,17].
Kidneys: patients with BHD are at risk for multiple renal tumours that are often malignant and may metastasise . In up to 34 % of the patients, renal neoplasms (bilateral or multifocal) can appear and is usually the most threatening component of BHDS . Most renal cell tumours are oncocytomas or renal cell carcinoma (RCC) of chromophobe or hybrid chromophobe-oncocytoma histology [1,9,14].
Other clinical findings: there are a lot of benign as well as malignant tumours, that are associated with BHDS. However, a causal relationship between these tumours (i.e., colorectal carcinoma/adenoma, arteriovenous malformation) and BHDS has not been proven yet [8,9,16].
Skin lesions as well as renal and pulmonary affection usually appear after the age of 20 years in BHDS [4,9].
BHDS is found worldwide, but clinical appearance differs depending on the region. Skin lesions are very frequent in patients from the USA or Europe, but rare in Asian patients with BHDS. An equal distribution was found for renal impairment. There are only a few hundred affected families with BHDS described worldwide. However, the disease is probably underdiagnosed due to its clinically varying appearance [9,12].
Diagnosis is usually based on clinical presentation and, i.e., histological examination of skin lesions or genetic testing, primarily to confirm the diagnosis . One should be aware of BHDS in case of bilateral or multifocal renal tumour in patients with accompanying (family) anamnesis of pneumothorax, lung cysts or skin lesions [8,9]. There is no clear indication for chest CT as a routine screening in these patients, but pulmonary cysts and pneumothorax are found in 90 % and 24 % of patients with BHDS . In summary, there are diagnostic criteria proposed for BHDS – patients should fulfill one major or two minor criteria for diagnosis :
Major criteria :
– at least five fibrofolliculomas or trichodiscomas, at least one histologically confirmed, of adult onset,
– pathogenetic FLCN germline mutation.
Minor criteria :
– multiple lung cysts: bilateral basally located lung cysts with no other apparent cause, with/without spontaneous primary pneumothorax,
– renal cancer: early onset (< 50 years) or multifocal/bilateral renal cancer, or renal cancer of mixed chromophobe and oncocytic histology,
– a first-degree relative with BHD.
To date there is no causative therapy for patients with BHDS. Generally, skin lesions are resected for cosmetic reasons only. Therapy of choice for renal tumours is usually surgical intervention. Whenever possible (after a period of active surveillance), growing kidney tumours (> 3 cm diameter) should be removed in a nephron-sparing way, but nevertheless hemodialysis may be necessary post-operative in some cases . Moreover, renal transplantation is discussed for patients with BHDS and severe renal impairment [3,11]. Pneumothorax needs to be relieved if clinically apparent and in patients with recurrent pneumothorax, i.e., pleurodesis is recommended to reduce the risk of new episodes. Furthermore, affected patients should avoid activities with fluctuations in air pressure (i.e., diving).
Genetic testing in patients suspected of having BHDS may help to verify diagnosis as well as allow identification and counselling of family members at risk.
Although there is no generally recommended surveillance programme for patients with BHDS, surveillance and a personalised follow-up of these patients (as well as lifelong screening of relatives) is important, especially to monitor progress of renal cancer [8,9,18].