The European Birt-Hogg-Dubé consortium proposed guidelines for the diagnosis as fulfilling either one major or two minor criteria.
- At least five fibrofolliculomas or trichodiscomas, at least one histologically confirmed, of adult onset.
- Pathogenic FLCN germline mutation.
- Multiple lung cysts: bilateral basally located lung cysts with no other apparent cause, with or without spontaneous primary pneumothorax.
- Renal cancer: early onset (<50 years) or multifocal or bilateral renal cancer or renal cancer of mixed chromophobe and oncocytic histology.
- A first degree relative with BHD.
Approximately 80% of patients develop pulmonary cysts, which can be numerous and bilateral. They commonly affect the base of the lungs. They typically develop between the ages of 30 and 40, but have been described from ages 20-85. BHD patients are at 50-fold increased risk of spontaneous pneumothorax, with approximately 24% of those with pulmonary cysts developing spontaneous pneumothoraces at an average age of 38 years (range: 22-71 years). FLCN-mutation carriers have developed pneumothoraces as early as age 7.
Renal tumors occur in approximately 12%-34% of BHD patients at a mean age of 50.4 years (range: 30-70 years). Patients have a 7-fold increased risk of renal tumors compared to the general population. Renal tumors can be bilateral, unilateral, or multifocal. The most common types of renal tumors in this patient population are chromophobe tumors and hybrid chromophobe / oncocytic tumors; however, clear cell carcinoma, papillary carcinoma, and mixed-type carcinoma may also occur.
Q87.89 – Other specified congenital malformation syndromes, not elsewhere classified
110985001 – Multiple fibrofolliculomas
The primary clinical differential includes other adnexal neoplasms and often requires histopathologic evaluation and/or looking for other associated organ system involvement for differentiation. Diagnostic entities include:
- Tuberous sclerosis complex
- Fibrous papules of the nose
- Sebaceous lesions including sebaceous hyperplasia or sebaceous adenoma. Both may have more of a yellow coloration and can be umbilicated, unlike classic fibrofolliculomas.
- Brooke-Spiegler syndrome – Spiradenomas and cylindromas are typically larger and may have a cerebriform appearance.
- Cowden syndrome
- Generalized basaloid follicular hamartoma syndrome
- Familial multiple discoid fibromas
- Pulmonary Langerhans cell histiocytosis
- Lymphocytic interstitial pneumonia
- Follicular bronchiolitis
- Light-chain deposition disease
- Sjögren syndrome
- Marfan syndrome – Patients with BHD syndrome do not have the body habitus typically associated with Marfan syndrome.
- Ehlers-Danlos syndrome
- Alpha-1 antitrypsin deficiency