Makindo Medical Notes

Background

Birt-Hogg-Dubé syndrome (BHDS) is a rare autosomal dominant genetic disorder first described in 1977 by three Canadian dermatologists – Birt, Hogg, and Dubé – who identified the syndrome’s hallmark cutaneous manifestations. BHDS is characterized by a combination of: Skin lesions, Pulmonary cysts with a predisposition to pneumothorax, Renal tumors. BHDS has a worldwide distribution but is often underdiagnosed due to its variable presentation. The condition predominantly affects adults, with symptoms and associated risks increasing with age.

Aetiology

• The underlying cause of BHDS is a mutation in the FLCN gene (folliculin gene), located on chromosome 17p11.2.
• This gene encodes folliculin, a protein involved in cellular growth, differentiation, and energy metabolism. Folliculin plays a role in pathways related to:
  • Cell cycle regulation
  • mTOR signaling
  • Response to cellular stress
• Mutations in the FLCN gene disrupt these processes, leading to the characteristic features of BHDS, including the development of skin lesions, lung cysts, and an increased risk of renal tumors.
• The syndrome is inherited in an autosomal dominant manner, meaning each offspring of an affected individual has a 50% chance of inheriting the pathogenic variant.

Clinical Characteristics

• Cutaneous manifestations: Fibrofolliculomas, Acrochordons, Angiofibromas, Oral papules
• Cutaneous collagenomas, Epidermal cysts
• Pulmonary cysts/history of pneumothorax
• Various types of renal tumours

Disease severity can vary significantly even within the same family. Skin lesions typically appear between the second and fourth decades of life, increasing 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, with a median diagnosis age of 48 years. The most common renal tumors are hybrid oncocytic/chromophobe types. Some families may experience renal tumors and/or spontaneous pneumothorax without cutaneous manifestations.

Diagnosis requires

• One major criterion (five or more facial or truncal papules with at least one histologically confirmed fibrofolliculoma, or identification of a heterozygous pathogenic variant in FLCN).
• 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
  • First-degree relative with BHDS

Management

• Treatment of manifestations: Surgical and laser treatments for folliculomas but often recur.
• Pneumothoraces are treated as in the general population.
• When possible, nephron-sparing surgery is preferred for renal tumors, depending on size and location.
• Agents/Circumstances to Avoid: Cigarette smoking, High ambient pressures, Radiation exposure

Surveillance

• Full-body skin examination every six to 12 months due to melanoma risk.
• Annual abdominal/pelvic MRI to assess renal lesions; CT with contrast is an alternative when MRI is not possible, though cumulative radiation exposure effects remain uncertain.
• Annual review for parotid tumors and annual thyroid ultrasound.
• Colonoscopy screening age 40 or earlier if history of colorectal cancer diagnosed before age 40.
• Molecular genetic testing for the family-specific pathogenic variant aids early identification of at-risk family members, enhancing diagnostic certainty and reducing unnecessary screenings for those who do not carry the 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 high-risk pregnancies and preimplantation genetic testing are possible if the FLCN pathogenic variant has been identified in an affected family member.