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Birt-Hogg-Dubé syndrome
Background
Overview
Definition
BHD syndrome is a rare, autosomal dominant genetic disorder characterized by the development of fibrofolliculomas/trichodiscomas and acrochordons, along with an increased risk of pulmonary cysts, pneumothorax, and renal tumors.
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Pathophysiology
BHD syndrome is caused by mutations in the FLCN gene located on chromosome 17p11.2, which encodes the protein folliculin, involved in cellular signaling and metabolism.
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Epidemiology
The prevalence of BHD syndrome in the general population is estimated at 2 cases per million, with about 200 families identified worldwide.
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Disease course
BHD syndrome may present with cutaneous manifestations (fibrofolliculomas, trichodiscomas, and acrochordons), pulmonary involvement (pulmonary cysts, recurrent spontaneous pneumothorax), and increases the risk of developing renal tumors (renal cell carcinoma, oncocytoma).
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Guidelines
Key sources
The following summarized guidelines for the evaluation and management of Birt-Hogg-Dubé syndrome are prepared by our editorial team based on guidelines from the European Reference Network on GENetic TUmour RIsk Syndromes (ERN GENTURIS 2024).
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Screening and diagnosis
Diagnosis: as per ERN GENTURIS 2024 guidelines, suspect BHD syndrome in the presence of any of the following:
primary spontaneous pneumothorax
multiple bilateral pulmonary cysts, particularly in lower zone, in the absence of a known cause
bilateral or multifocal renal neoplasia (renal cell carcinomas and/or oncocytomas)
renal cell carcinoma, < 50 years of age or familial
multiple cutaneous papules clinically consistent with fibrofolliculoma/trichodiscoma
any combination of the above mentioned cutaneous, pulmonary, and renal manifestations presenting in the same patient or members of their family, with or without a known family history of BHD syndrome.
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Interpreting genetic variants
Diagnostic investigations
Genetic testing: as per ERN GENTURIS 2024 guidelines, obtai genetic testing for FLCN for the diagnosis of BHD syndrome in patients with any of the following:
primary spontaneous pneumothorax if recurrent and/or familial
multiple bilateral pulmonary cysts, particularly in lower zone, in the absence of a known cause
bilateral or multifocal renal neoplasia (renal cell carcinomas and/or oncocytomas)
familial or early onset (≤ 45 years) renal cell carcinoma
multiple cutaneous papules clinically consistent with fibrofolliculoma/trichodiscoma with at least one histologically confirmed fibrofolliculoma
any combination of the above mentioned cutaneous, pulmonary, and renal manifestations in the same patients or members of their family.
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Diagnostic imaging
Skin examination
Therapeutic procedures
Surgical interventions
Indications for kidney surgery: as per ERN GENTURIS 2024 guidelines, offer surgery when the largest renal tumor reaches 3 cm in diameter. Perform nephron-sparing surgery whenever possible, with percutaneous thermal ablation being an alternative.
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Indications for lung surgery
Follow-up and surveillance
Surveillance for malignancy: as per ERN GENTURIS 2024 guidelines, offer lifelong surveillance for renal cell carcinoma with MRI (or ultrasound if MRI is not available or appropriate), starting at the age of 20 years and obtained every 1-2 years.
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Surveillance for pulmonary disease