Gupta et al. (2016b) recently published a review about Birt-Hogg-Dubé Syndrome (BHD) exploring the key points and research advances in genetics and pathogenesis, clinical manifestations, diagnosis and disease management.
The review introduces BHD and its first descriptions in the 1970s (Hornstein et al., 1975; Birt et al., 1977), then discusses its genetics and pathogenesis with a focus on the FLCN gene mutations and FLCN’s role as a tumour suppressor. The authors discuss that alterations in energy and nutrient sensing through the mammalian target of rapamycin (mTOR) pathway or impaired cell-cell adhesion are mechanisms by which FLCN mutation can lead to formation of renal tumours and pulmonary cysts.
The authors then discuss the phenotypic variability in the clinical features of BHD and summarize the disease’s clinical, radiographic and pathological features, dividing them into cutaneous, pulmonary and renal. The pulmonary and renal radiographic features of BHD are discussed in more detail, including distinguishing it from similar diseases. High-resolution computed tomography (HRCT) can provide essential evidence as to the presence of BHD, and the specific HRCT pattern seen in BHD can differentiate it from other diffuse cystic lung diseases, such as lymphangioleiomyomatosis (LAM). However, further characterization of the morphologic and immunohistochemical features of BHD-associated lung cysts is still needed to distinguish BHD from emphysema. Regarding the renal manifestations, the presence of a fat-containing renal tumour on abdominal MRI or CT is characteristic of patients with LAM but not BHD. Association of BHD with intestinal polyps and possible increased risk of colon cancer and other malignant and nonmalignant conditions is also mentioned: however, authors point out that there is no evidence showing that BHD causes these other conditions.
The review then discusses diagnostic of BHD. Many BHD patients are often misdiagnosed as having a primary spontaneous pneumothorax or emphysema due to doctors’ unfamiliarity with BHD. Authors mention that it is important to consider diagnosis of BHD in patients presenting with a family history of pneumothorax. This is particularly true when skin lesions or renal tumours are present, but the variability in the clinical manifestations of BHD means that the absence of skin and renal symptoms should not exclude a diagnosis of BHD. Some of the authors recently published study that shows that performing an HRCT chest scan in patients presenting with a spontaneous pneumothorax is a cost-effective method to screen for the presence of BHD (Gupta et al., 2016a). Multiple diagnostic criteria exist in the literature for diagnosing BHD (Menko et al., 2009; Gupta et al., 2013; Schmidt et al., 2015). The authors suggest that a diagnosis of BHD in patients with typical clinical and radiographic should include a biopsy of skin lesions, if present, followed by genetic testing for FLCN mutations. Given that the combination of pulmonary cysts and renal tumours is seen in patients with LAM as well as those with BHD, the authors summarize the key differences in the clinical features of the two conditions to help differentiate them.
Finally, the authors discuss the management of BHD. Ongoing management primarily involves surveillance and treatment of renal cancers and prevention and treatment of pneumothoraces. Patients with BHD are at a higher risk of developing recurrent pneumothoraces, so pleurodesis is recommended after the first episode of pneumothorax. Renal cancer is the most complicated manifestation of BHD and regular screening is essential in the management of patients to identify tumours at an early stage.
Research in the BHD field has advanced significantly in the last few years, and there is now a better understanding of the cellular and molecular mechanisms leading to the development of BHD. However, further studies are still needed to understand exactly how pulmonary and renal cysts are formed in BHD and to find early biomarkers that can predict an aggressive RCC subtype. Raising awareness of BHD within the medical community is important, so that BHD is considered when evaluating patients in order to apply measures to prevent recurrent pneumothoraces and to promote regular screening for renal tumours.
Gupta N, Sunwoo BY, & Kotloff RM (2016). Birt-Hogg-Dubé Syndrome. Clinics in chest medicine, 37 (3), 475-86 PMID: 27514594