Birt-Hogg-Dubé Syndrome

Clinical characteristics: The clinical characteristics of Birt-Hogg-Dubé syndrome (BHDS) include cutaneous manifestations (fibrofolliculomas, acrochordons, angiofibromas, oral papules, cutaneous collagenomas, and epidermal cysts), pulmonary cysts/history of pneumothorax, and various types of renal tumors. Disease severity can vary significantly even within the same family. Skin lesions typically appear between the second and fourth decades of life and typically increase in size and number with age. Lung cysts are often bilateral and multifocal; most individuals are asymptomatic but at high risk for spontaneous pneumothorax. Individuals with BHDS are at a sevenfold increased risk for renal tumors that can be bilateral and multifocal; median age of renal tumor diagnosis is 48 years. The most common renal tumors are a hybrid of oncocytoma and chromophobe histologic cell types (oncocytic hybrid tumor) and chromophobe histologic cell types. Some families have renal tumor(s) and/or spontaneous pneumothorax without cutaneous manifestations.

Diagnosis/testing: The diagnosis of BHDS is established in a proband with either one major criteria (five or more facial or truncal papules with at least one histologically confirmed fibrofolliculoma or identification of a heterozygous pathogenic variant in FLCN) or two minor criteria (early-onset [age <50 years] renal cell cancer, multifocal/bilateral renal cell cancer, renal cell cancer with mixed chromophobe/oncocytic histology, multiple lung cysts with or without spontaneous pneumothorax, and/or first degree relative with BHDS).

Management: Treatment of manifestations: Surgical and laser treatment can lead to temporary improvement of folliculomas, but lesions often recur. Pneumothoraces are treated as in the general population. When possible, nephron-sparing surgery is the treatment of choice for renal tumors, depending on their size and location.

Surveillance: Full-body skin examination every six to 12 months for possible risk of melanoma. Annual abdominal/pelvic MRI to assess for renal lesions; abdominal/pelvic CT with contrast is an alternative when MRI is not an option, but the long term-effects of cumulative radiation exposure are unknown. Consider annual review of signs/symptoms of parotid tumors and annual thyroid ultrasound. Begin screening colonoscopies at age 40 years, or earlier in those with a family history of colorectal cancer diagnosed prior to age 40 years.

Agents/circumstances to avoid: Cigarette smoking, high ambient pressures, and radiation exposure.

Evaluation of relatives at risk: Molecular genetic testing for the family-specific pathogenic variant for early identification of at-risk family members improves diagnostic certainty and reduces costly screening procedures in at-risk relatives who have not inherited the family-specific pathogenic variant.

Genetic counseling: BHDS is inherited in an autosomal dominant manner. The offspring of an individual with BHDS have a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic testing are possible if the FLCN pathogenic variant has been identified in an affected family member.