Birt-Hogg-Dubé Syndrome

Excerpt

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, renal cysts, 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 mainly in the basal lung regions; most individuals are asymptomatic but at high risk for spontaneous pneumothorax. Renal tumors can be bilateral and multifocal. The most common renal tumors are a hybrid of oncocytoma and chromophobe histologic cell types (oncocytic hybrid tumor); clear cell carcinoma and oncocytoma are also common.

Diagnosis/testing: The clinical diagnosis of BHDS is established in a proband with either one major criteria (>5 fibrofolliculomas/trichodiscomas; one histologically confirmed) or two minor criteria (bilateral basally located lung cysts without other cause, early-onset renal cell cancer [age <50 years], multifocal/bilateral renal cell cancer, renal cell cancer with mixed chromophobe/oncocytic histology, and/or a first-degree relative with BHDS). The molecular diagnosis is established in a proband with any suggestive findings and a germline heterozygous pathogenic variant in FLCN identified by molecular genetic testing.

Management: Treatment of manifestations: Surgical and laser treatment can lead to temporary improvement of fibrofolliculomas, but lesions often recur. Pneumothoraces are treated as in the general population; consider surgical intervention for recurrent pneumothoraces. Renal tumors less than 3.0 cm in diameter can be monitored with imaging; when possible, nephron-sparing surgery is the treatment of choice for larger renal tumors, depending on their size and location.

Surveillance: Assess for pulmonary signs/symptoms of lung cysts/pneumothorax; discuss activities that might increase pneumothorax risk (e.g., working as a pilot, flying in unpressurized aircraft, diving). Annual abdominal/pelvic MRI to assess for renal lesions beginning at age 20 years or earlier in those with a family history of renal tumors before age 30 years; 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.

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

Evaluation of relatives at risk: Molecular genetic testing for the family-specific FLCN 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. Screening for lung cysts, fibrofolliculomas, and trichodiscomas can be performed if the pathogenic variant in the family is not known.

Genetic counseling: BHDS is inherited in an autosomal dominant manner. Most individuals diagnosed with BHDS have an affected parent; some individuals have a de novo FLCN pathogenic variant. Each child of an individual with BHDS is at a 50% risk of inheriting the FLCN pathogenic variant. Once the FLCN pathogenic variant has been identified in an affected family member, predictive testing for at-risk family members and prenatal/preimplantation genetic testing for BHDS are possible.