Table 1.
Consensus recommendations relevant to the diagnosis of BHD syndrome.
| Recommendations | Strength | |
|---|---|---|
| Rec. 1 | A potential diagnosis of BHD syndrome should be considered* in the presence of ANY of the following: | |
| a. Primary spontaneous pneumothorax. | strong | |
| b. Multiple bilateral pulmonary cysts, particularly in lower zone, in the absence of a known cause. | strong | |
| c. Bilateral or multifocal renal neoplasia (i.e. renal cell carcinomas and/or oncocytomas). | strong | |
| d. Renal cell carcinoma, below 50 years of age or familial. | strong | |
| e. Multiple cutaneous papules clinically consistent with fibrofolliculoma/trichodiscoma. | strong | |
| f. Any combination of the above mentioned cutaneous (e.g. multiple fibrofolliculomas/trichodiscomas), pulmonary (e.g. pulmonary cysts) or renal manifestations (e.g. renal cell carcinoma) presenting in the same individual or members of their family, with or without a known family history of BHD syndrome. | strong | |
| * Please note that this recommendation entails to consider a diagnosis of BHD syndrome, indicating that other clinical features and family history should be looked for. Recommendations to perform genetic testing to diagnose BHD syndrome can differ and are detailed in recommendation 6. | ||
| ^ Criteria for early onset renal cell carcinoma might vary between countries and centres: specific country age recommendations for early onset renal cell carcinoma might apply. | ||
| Rec. 2 | A diagnosis of BHD syndrome should be considered at all ages (not just young persons) in the presence of suggestive features. | strong |
| Rec. 3 | If BHD syndrome is considered as underlying diagnosis, appropriate further investigations, such as skin examination, CT scan of the lungs and/or genetic testing should be initiated. | strong |
| Rec. 4 | A definitive diagnosis of BHD syndrome should be made when a genetic test is positive for a constitutive pathogenic/likely pathogenic variant in FLCN. | strong |
| Rec. 4a | Not all patients with clinical evidence of BHD syndrome will have a detectable FLCN pathogenic/likely pathogenic variant. | strong |
| Rec. 4b | A clinical diagnosis of BHD syndrome* can be made even in the absence of a detectable FLCN pathogenic/likely pathogenic variant if one major criterion ( >5 fibrofolliculomas or trichodiscomas, at least one histologically confirmed, of adult onset) or two minor criteria (1. Lung: bilateral basally located pulmonary cysts with no other apparent cause; 2. Kidney: early onset ( <50 years), multifocal or bilateral renal cancer, or renal cancer of mixed chromophobe and oncocytic histology; or 3. Family history: a first-degree relative with BHD syndrome) are present. | strong |
| * According to the European BHD consortium criteria (Menko et al., 2009). | ||
| Rec. 4c | Variants of uncertain significance (VUSs) in FLCN should be assessed according to international guidelines (e.g. ACMG/AMP) and interpreted in the context of the clinical presentation and familial segregation studies. Additional clinical or imaging assessments in order to detect subclinical features of BHD syndrome can also be performed. | strong |
| Rec. 5 | Clinicians should be aware that BHD syndrome displays variable expression and that expecting classical features (skin lesions, pulmonary cysts and pneumothoraces) or only considering BHD syndrome in more extreme presentations (e.g. renal cell carcinoma at <40 years, pneumothorax at <40 years) might lead to the diagnosis being overlooked. | strong |
| Rec. 6 | Genetic testing for FLCN to diagnose BHD syndrome should be a part of the genetic evaluation offered in the presence of ANY of the following: | |
| a. Primary spontaneous pneumothorax if recurrent and/or familial. | strong | |
| b. Multiple bilateral pulmonary cysts, particularly in lower zone, in the absence of a known cause. | strong | |
| c. Bilateral or multifocal renal neoplasia (i.e. renal cell carcinomas and oncocytomas). | strong | |
| d. Familial or early onset (45 years or under)* renal cell carcinoma. | strong | |
| e. Multiple cutaneous papules clinically consistent with fibrofolliculoma/ trichodiscoma with at least one histologically confirmed fibrofolliculoma. | strong | |
| f. Any combination of these cutaneous (multiple fibrofolliculomas/trichodiscomas), pulmonary (e.g. pulmonary cysts) and renal manifestations (e.g. renal cell carcinoma) in the same individual or members of their family. | strong | |
| * Criteria for early onset renal cell carcinoma might vary between countries and centres. From a practical perspective, specific country age recommendations for early onset RCC can be applied. | ||
| Rec. 7 | Predictive genetic testing for familial BHD syndrome is not generally performed until 18 years unless required for specific indications (e.g. clinical management, planning for diving activities). | strong |
| Rec. 8 | First degree adult relatives of individuals with a likely pathogenic/pathogenic FLCN variant should be offered predictive genetic testing. | strong |
| Rec. 9 | Lung ultrasound should not be used as a diagnostic test for pulmonary cysts in people with or suspected of having BHD | strong |
| Rec. 9a | A baseline low dose high-resolution computed tomography (HRCT) scan can be offered to patients with or suspected of having BHD syndrome to diagnose pulmonary cysts. This can be offered from time of diagnosis, but not usually to asymptomatic patients before 20 years of age. | moderate |