Birt-Hogg-Dubé syndrome (BHD), also known as Hornstein–Knickenberg syndrome is an inherited disease associated with skin lesions, lung cysts, pneumothorax and kidney cancer.
Jensen et al. (2017) present a new case report of BHD and a review of the literature. This is a great opportunity to review the genetics, clinical manifestations, diagnosis, treatment, prognosis and follow-up strategies and to draw attention to BHD, unknown to many physicians. Early diagnosis is crucial so that patients can have access to systematic screening for kidney cancer.
The new case report is of a 29-year old female presenting with a spontaneous pneumothorax (SP) two days after running a marathon. The patient also had 11 relatives with cases of SP, therefore she was referred for follow-up. A high-resolution computed tomography (HRCT) scan showed multiple cysts in the lungs, which led to the suspicion of BHD. Genetic testing revealed a mutation (c.1285delC) in the FLCN gene which confirmed the diagnosis of BHD. Family members were offered genetic counselling and 11 family members were diagnosed. The patient and her affected family members were offered a follow-up program with MRI of the kidneys and pulmonary function tests.
A search on PubMed and Embase with the terms ‘Birt-Hogg-Dubé syndrome’ and ‘Hornstein-Knickenberg syndrome’ identified 330 papers. Additional articles were identified from reference lists of the already identified papers (snow ball search).
The authors then reviewed what is known about BHD based on these publications, some of which we highlight here:
- BHD is named after 3 Canadian doctors, who described the syndrome in 1977. They reported a family of 70 members with 15 family members who developed skin lesions on the face, neck, and torso.
- The autosomal dominant inheritance of the combination of skin manifestations and renal cell carcinoma (RCC) in BHD was first described by Toro et al. in 1999. In this study, lung manifestations were also noticed.
- In 2001, Schmidt et al. and Khoo et al. located the gene locus of BHD to be on the short arm of chromosome 17 and in 2002 Nickerson et al. linked BHD to the FLCN gene on chromosome 17, which encodes the protein folliculin.
- Zbar et al. (2002) reported that patients with BHD had a 50-fold risk of SP and a 7-fold increased risk of developing RCC. The histology of renal tumours in BHD is diverse.
- Several FLCN interacting proteins including FNIP1 and FNIP2 have been identified (Baba et al., 2005; Hasumi et al., 2008).
- FLCN regulates numerous signalling pathways, including the mammalian target of rapamycin (mTOR) pathway.
- Neither gender, nor smoking, nor other risk factors have been reported as predictors of the development of cysts or SP. Lung function is rarely affected.
- Almoosa et al. (2006) found that pleurodesis decreases the pneumothorax recurrence rate, and pleurodesis after the first SP in BHD has been recommended.
- Skin manifestations are common in BHD and are seen in approximately 58–90% of patients. Fibrofolliculomas are the most frequent, but also trichodiscomas and acrochordons have been described. Fibrofolliculomas present as multiple, pale yellow or white, slightly elevated, dome-shaped, and smooth tumours with a diameter of 2–4 mm. Fibrofolliculomas are predominantly located in the face, neck, and upper torso.
- A recent double-blind placebo-controlled randomized clinical trial showed no effect of the topical mTOR inhibitor rapamycin on fibrofolliculomas in BHD patients.
- Since 2008, six BHD symposia have been held where researchers, clinicians, and patients meet and discuss the progress in the BHD field.
- Currently, the BHD foundation is aware of over 600 BHD families worldwide.
- Due to its rarity and to the variable presentation of the symptoms, the diagnosis of BHD is often delayed for years. The European BHD consortium has proposed a set of criteria for the diagnosis of BHD. Upon diagnosis of BHD, the patients should undergo examination of the skin, CT imaging of the chest, abdominal MR or CT imaging for renal tumours as well as genetic screening for pathogenic FLCN mutations.
In summary, knowledge in the BHD field is still limited. The variable clinical manifestations of BHD and the fact that no genotype-phenotype correlations have been found, makes early diagnosis and management of BHD complex. Further research is needed to investigate the exact mechanisms of pathogenesis and to optimize the management of BHD patients.
- Jensen, D., Villumsen, A., Skytte, A., Madsen, M., Sommerlund, M., & Bendstrup, E. (2017). Birt–Hogg–Dubé syndrome: a case report and a review of the literature European Clinical Respiratory Journal, 4 (1) DOI: 10.1080/20018525.2017.1292378