What is the management approach for a patient with Birt-Hogg-Dube (BHD) syndrome, a rare genetic disorder characterized by multiple hamartomas in the skin, lungs, and kidneys?

Birt-Hogg-Dubé Syndrome: Diagnosis and Management

Overview

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder caused by FLCN gene mutations, requiring genetic confirmation, systematic surveillance for renal tumors starting in adulthood, and early pleurodesis for pneumothorax to prevent recurrence. 1, 2, 3

Genetic Basis and Diagnosis

Genetic Testing Criteria

• Refer for genetic assessment if a patient presents with ≥5 facial or truncal papules (fibrofolliculomas/trichodiscomas), multiple pulmonary cysts with recurrent pneumothorax, or renal tumors, especially if there is a family history of any BHD manifestation. 1, 4

• The FLCN gene on chromosome 17p11.2 is the only definitive causative gene for BHD syndrome, inherited in autosomal dominant pattern. 1, 2

• Genetic testing methods include Sanger sequencing, Multiplex Ligation-dependent Probe Amplification (MLPA), and Next-Generation Sequencing (NGS), chosen based on clinical needs. 2

• FLCN mutations are detected in approximately 47% of patients selected for kidney and/or lung manifestations alone, but detection increases substantially when patients have ≥2 components of the clinical triad or a single component with positive family history. 4

Clinical Diagnostic Criteria

• Establish diagnosis based on appropriate clinical presentation in conjunction with genetic test results and/or family history of BHD syndrome. 2

• The classic triad includes: cutaneous fibrofolliculomas/trichodiscomas, pulmonary cysts with spontaneous pneumothorax risk, and renal cell carcinoma. 2, 3

• Important caveat: Typical cutaneous lesions are present in only 38% (8 of 21) of FLCN mutation carriers aged >20 years, and appear less common in Chinese populations compared to European/American cohorts. 2, 4

Initial Diagnostic Workup

Imaging Studies

• Perform chest CT scan to evaluate pulmonary cystic lesions—this is the primary imaging modality for lung assessment. 1, 2

• Conduct renal imaging with ultrasound, enhanced CT, or MRI to assess for tumor foci at initial diagnosis. 1, 2

• Lung histopathological biopsy is NOT recommended as first-line diagnostic approach for suspected BHD syndrome based on clinical and pulmonary imaging findings. 2

Multidisciplinary Approach

• BHD syndrome requires multidisciplinary evaluation involving respiratory medicine, radiology, pathology, thoracic surgery, urology, genetics, and dermatology. 2

Differential Diagnosis

Distinguish BHD syndrome from other diffuse cystic lung diseases: 2

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

Renal Tumor Surveillance Protocol

Risk-Stratified Surveillance

Follow this specific algorithm based on tumor size: 1, 2

• 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

Renal Tumor Characteristics

• Approximately 30% of patients develop renal tumors during their lifetime, with median age at diagnosis of 48 years (range 31-71 years). 1

• The renal tumor spectrum includes chromophobe renal cell carcinoma, renal oncocytoma, hybrid oncocytoma-chromophobe tumors, and less commonly clear cell carcinoma. 1

• Tumors are frequently multiple and bilateral with slightly different histologies, and may show broad uniparental disomy (copy-neutral loss of heterozygosity) on molecular analysis. 1

• Routine lifetime kidney cancer screening is mandatory for all patients with BHD syndrome due to significantly increased cancer risk. 2

Management of Pulmonary Manifestations

Pneumothorax Management

• For patients with BHD syndrome complicated by pneumothorax, perform early pleurodesis to reduce recurrence risk—this is a critical intervention. 2

• Air travel is contraindicated for patients who have experienced pneumothorax until complete recovery is documented. 2

Preventive Measures

• Patients must avoid smoking. 2

• Vaccinate against influenza, pneumococcal disease, and SARS-CoV-2 to prevent respiratory infections. 2

Management of Cutaneous Manifestations

• For fibrofolliculomas or trichodiscomas, observation or topical treatment may be chosen. 2

• Cutaneous lesions present as multiple smooth skin-colored to grayish-white papules on face, auricles, neck, and upper trunk. 5

Family Management and Genetic Counseling

Family Screening

• Family members of patients with BHD syndrome should receive health education, and FLCN gene testing is recommended for asymptomatic adults to rule out BHD syndrome in a timely manner. 2

• Pedigree analysis of family members' samples can assist in rapid identification of causative gene variants. 2

Reproductive Counseling

• Couples with BHD syndrome should undergo prenatal genetic counseling when preparing for pregnancy, work with a prenatal diagnostician to assess genetic risk, and discuss feasibility of prenatal diagnosis during pregnancy. 2

Additional Clinical Features

Less commonly recognized manifestations include: 5

• Deforming lipomas
• Collagenomas
• Oral papules
• Acrochordons
• Parotid oncocytoma (bilateral involvement has been documented with reduction of wild-type FLCN allele in tumor DNA) 4

Critical Pitfalls to Avoid

• Do not assume BHD syndrome requires the full clinical triad—pulmonary manifestations alone with family history or genetic confirmation is sufficient for diagnosis. 4, 6

• Do not delay genetic testing in patients with multiple lung cysts and recurrent pneumothorax even without skin or renal disease—germline BHD mutations are found in these isolated pulmonary phenotypes. 6

• Do not perform invasive lung biopsy as initial diagnostic step when clinical and imaging features suggest BHD syndrome. 2