What is the etiology, diagnosis, and treatment of Birt-Hogg-Dubé syndrome?

Etiology, Diagnosis, and Treatment of Birt-Hogg-Dubé Syndrome

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder caused by germline mutations in the FLCN gene on chromosome 17p11.2, characterized by skin fibrofolliculomas, pulmonary cysts with risk of pneumothorax, and renal tumors that require specific surveillance and management protocols to reduce morbidity and mortality. 1

Etiology

BHD syndrome results from pathogenic variants in the FLCN gene, which encodes the protein folliculin. This protein functions as a tumor suppressor gene that:

• Interacts with FNIP1, FNIP2, and AMPK (a negative regulator of mTOR)
• Modulates the AKT-mTOR pathway
• Regulates TFE3/TFEB transcriptional activity
• Influences amino acid-dependent mTOR activation through Rag GTPases
• Affects TGFβ signaling and mitochondrial biogenesis 2

The syndrome follows an autosomal dominant inheritance pattern, meaning each child of an affected individual has a 50% chance of inheriting the mutation. Most renal tumors in BHD demonstrate inactivation of the wild-type FLCN allele through somatic mutation or chromosomal loss, confirming the classic two-hit model of tumor suppressor genes 2.

Clinical Manifestations

BHD syndrome typically manifests in the third or fourth decade of life with three cardinal features:

1. Cutaneous manifestations:

   • Fibrofolliculomas or trichodiscomas (small, dome-shaped, whitish papules)
   • Acrochordons (skin tags)
   • Usually appear on the face, neck, and upper trunk

2. Pulmonary manifestations:

   • Multiple bilateral lung cysts (present in >80% of patients)
   • Recurrent spontaneous pneumothorax (affects >50% of patients)
   • Unlike other cystic lung diseases, BHD does not lead to progressive loss of lung function 3

3. Renal manifestations:

   • Bilateral and multifocal renal tumors (affect ~30% of patients)
   • Most commonly hybrid oncocytic tumors and chromophobe renal cell carcinoma
   • Can also include clear cell renal carcinoma and oncocytoma 1

Diagnosis

The diagnosis of BHD syndrome is based on a combination of genetic, clinical, and/or histopathological criteria:

Diagnostic Criteria

Diagnosis should be established based on one or more of the following:

1. Genetic confirmation: Identification of a pathogenic FLCN gene mutation
2. Clinical presentation: Multiple fibrofolliculomas/trichodiscomas with histopathological confirmation
3. Radiological findings: Multiple bilateral pulmonary cysts, especially in the basilar regions
4. Family history: Confirmed BHD syndrome in a first-degree relative 4

Diagnostic Workup

1. Genetic testing:

   • Sanger sequencing, Multiplex Ligation-dependent Probe Amplification (MLPA), or Next-Generation Sequencing (NGS) of the FLCN gene
   • First-line diagnostic approach for suspected cases 4

2. Imaging studies:

   • Chest CT scan to evaluate pulmonary cysts (characteristic features include lower zone predominance, irregular shape, and perivascular location)
   • Abdominal imaging (ultrasound, CT, or MRI) to screen for renal tumors 4

3. Skin examination:

   • Identification of characteristic skin lesions (fibrofolliculomas, trichodiscomas)
   • Skin biopsy if needed for histopathological confirmation 1

Differential Diagnosis

BHD syndrome must be differentiated from other diffuse cystic lung diseases:

• Lymphangioleiomyomatosis (LAM)
• Lymphocytic interstitial pneumonia (LIP)
• Pulmonary Langerhans cell histiocytosis (PLCH)
• Tuberous sclerosis complex (TSC) 4

Management

Management of BHD syndrome focuses on surveillance and early intervention to prevent complications:

Pulmonary Management

1. Preventive measures:

   • Smoking cessation
   • Vaccination against influenza, pneumococcal disease, and SARS-CoV-2
   • Avoidance of air travel for patients with recent pneumothorax 4

2. Pneumothorax management:

   • Early pleurodesis is strongly recommended to reduce recurrence risk
   • Consider pleurodesis even after first pneumothorax due to high recurrence rate 4, 3

Renal Management

1. Surveillance protocol:

   • Begin renal imaging at diagnosis regardless of age
   • Annual abdominal MRI for tumors <1 cm
   • Biannual MRI for tumors 1-3 cm or consider ablation
   • Nephron-sparing surgery for tumors >3 cm 4

2. Surgical approach:

   • Nephron-sparing surgery is preferred over radical nephrectomy to preserve renal function
   • Partial nephrectomy for tumors >3 cm in diameter
   • Consider ablative techniques for smaller tumors in appropriate cases 4

Dermatological Management

1. Skin lesions:
   • Observation for asymptomatic lesions
   • Topical treatments for symptomatic lesions
   • Surgical or laser removal for cosmetically concerning lesions 4

Family Management and Genetic Counseling

1. Family screening:

   • FLCN genetic testing for first-degree relatives of affected individuals
   • Clinical evaluation of family members with the mutation 4

2. Reproductive counseling:

   • Prenatal genetic counseling for couples with BHD planning pregnancy
   • Discussion of prenatal diagnosis options 4

Prognosis and Follow-up

The prognosis for BHD syndrome is generally favorable with appropriate surveillance and management:

• Pulmonary function typically remains stable despite cysts
• Renal tumors are often slow-growing but require lifelong monitoring
• Early detection and treatment of renal tumors significantly improves outcomes 3

Pitfalls to Avoid

1. Delayed diagnosis: Consider BHD in patients with recurrent pneumothorax, especially with family history
2. Inadequate renal surveillance: Lifelong monitoring is essential as renal tumors can develop at any age
3. Misdiagnosis: BHD can be misdiagnosed as other cystic lung diseases or sporadic renal cancer
4. Insufficient family screening: All first-degree relatives should be offered genetic testing 4, 3

BHD syndrome requires a multidisciplinary approach involving pulmonologists, urologists, dermatologists, geneticists, and radiologists for optimal management and improved patient outcomes.