What is Birt-Hogg-Dube syndrome and how is it managed?

Birt-Hogg-Dubé Syndrome Explained

Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant genetic disorder caused by mutations in the FLCN gene on chromosome 17p11.2, characterized by the triad of skin fibrofolliculomas, pulmonary cysts with recurrent pneumothoraces, and renal tumors—requiring lifelong surveillance for kidney cancer. 1, 2, 3

Genetic Basis

• The FLCN gene mutation is the definitive genetic cause, inherited in an autosomal dominant pattern with each child of an affected parent having a 50% chance of inheriting the condition 1, 4
• The FLCN gene encodes folliculin, a tumor suppressor protein whose exact function remains incompletely understood 5, 3
• Genetic testing methods include Sanger sequencing, Multiplex Ligation-dependent Probe Amplification (MLPA), and Next-Generation Sequencing (NGS) 4

Clinical Manifestations

Pulmonary Features

• Multiple bilateral pulmonary cysts occur in >80% of patients, typically appearing in the third or fourth decade of life 3
• The cysts are characteristically located in the basilar and medial lung regions, distinguishing them from other cystic lung diseases 2, 3
• More than half of patients experience at least one episode of spontaneous pneumothorax, with high recurrence rates even after surgical intervention 3, 6
• Unlike lymphangioleiomyomatosis or pulmonary Langerhans cell histiocytosis, BHD does not cause progressive loss of lung function or chronic respiratory insufficiency 3

Cutaneous Manifestations

• Skin lesions typically appear in the 30s and 40s, increasing with age 7
• Fibrofolliculomas, perifollicular fibromas, trichodiscomas, or angiofibromas are the characteristic skin findings, though they may be less common in Chinese populations compared to European/American cohorts 1, 4
• Referral for genetic assessment should be considered for individuals with ≥5 BHD-associated facial or truncal papules 7

Renal Manifestations

• Approximately 30% of patients develop renal tumors during their lifetime, with a median age at diagnosis of 48 years (range 31-71 years) 7, 3
• The renal tumor spectrum includes chromophobe renal cell carcinoma, renal oncocytoma, hybrid oncocytoma-chromophobe tumors (the most characteristic), and less commonly clear cell carcinoma 7, 1
• Tumors are frequently multiple and bilateral with slightly different histologies 1
• Microscopic foci of oncocytic cell clusters ("oncocytosis") in non-neoplastic kidney tissue are a distinctive feature 1
• Broad uniparental disomy (copy-neutral loss of heterozygosity) is observed on molecular analysis 1

Diagnostic Approach

Clinical Criteria

• Diagnosis is established based on clinical presentation combined with genetic testing results and/or family history 4
• A family history of pneumothorax is a critical diagnostic clue that should prompt consideration of BHD 2, 3
• Referral for cancer predisposition assessment is indicated for individuals with early-onset (<50 years) renal cell carcinoma or characteristic skin lesions 7

Imaging Evaluation

• Chest CT scan is essential to evaluate pulmonary cystic lesions 4
• Renal imaging with ultrasound, enhanced CT, or MRI should be performed to assess for tumor foci 4
• Lung histopathological biopsy is NOT recommended as a first-line diagnostic approach in suspected BHD based on clinical and imaging findings 4

Differential Diagnosis

BHD must be distinguished from other diffuse cystic lung diseases 4:

• Lymphangioleiomyomatosis (LAM)
• Lymphocytic interstitial pneumonia (LIP)
• Pulmonary Langerhans cell histiocytosis (PLCH)

Multidisciplinary evaluation involving respiratory medicine, radiology, pathology, thoracic surgery, urology, genetics, and dermatology is recommended to improve diagnostic accuracy 4

Management Strategy

Pneumothorax Management

• Early pleurodesis is recommended to reduce the risk of recurrence in patients who develop pneumothorax 4, 3
• Air travel should be avoided until pneumothorax has fully recovered 4
• Patients should be counseled that pneumothoraces often recur despite surgical intervention 6

Renal Tumor Surveillance

A risk-stratified surveillance protocol is recommended 4:

• Tumors <1 cm: Annual abdominal MRI
• Tumors 1-3 cm: Abdominal MRI every 6 months OR ablation surgery
• Tumors >3 cm: Local excision with nephron-sparing surgery to preserve renal function

Lifelong routine screening for kidney cancer is mandatory given the significantly increased risk 4, 5

Skin Lesion Management

• Observation or topical treatment may be chosen for fibrofolliculomas or trichodiscomas 4

Preventive Measures

• Smoking cessation is essential 4
• Vaccination with influenza, pneumococcal, and SARS-CoV-2 vaccines is recommended to prevent respiratory infections 4

Family Management

• Family members should receive health education and genetic counseling 4
• FLCN gene testing is recommended for asymptomatic adult relatives to enable early detection and surveillance 4
• Couples with BHD should undergo prenatal genetic counseling when planning pregnancy, with discussion of prenatal diagnosis feasibility 4
• Pedigree analysis of family members' samples can assist in rapid identification of causative gene variants 4

Special Considerations

• East Asian patients may present with recurrent pneumothoraces before developing cutaneous manifestations, making early diagnosis challenging 6
• The condition has implications for military fitness for duty and occupational activities involving altitude changes 6
• Unlike other hereditary renal cancer syndromes, BHD-associated renal tumors show distinctive pathologic features including the characteristic "hybrid oncocytic tumor" histology 7, 5