[Expert consensus on the diagnosis and management of Birt-Hogg-Dubé syndrome]

Abstract

Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant disorder characterized by diffuse pulmonary cysts often leading to recurrent spontaneous pneumothorax, cutaneous fibrofolliculomas or trichodiscomas, and a variety of renal cell cancers. It is caused by pathogenic variants in the FLCN gene located on chromosome 17p11.2. Although an increasing number of patients with BHD syndrome are being recognized in China, the missed diagnosis and delayed diagnosis are still common. In addition, appropriate management is difficult for most of them. Pulmonary cysts and pneumothorax are the main presenting features, but skin and renal lesions appear to be less common in Chinese subjects than those reported from European and American countries. Therefore, the consensus is established by experts from the related disciplines to improve the diagnosis and management of BHD syndrome. This consensus consists of 15 recommendations related to BHD syndrome, including clinical assessments, diagnosis, differential diagnosis, treatment, follow-up, and family management. In particular, it provides revised diagnostic criteria based on the Chinese situation. We hope to promote scientific and clinical progress in this rare disease and improve the prognosis of the patients.Summary of recommendations[Recommendation 1] The folliculin (FLCN) gene is currently the only affirmative causative gene for Birt-Hogg-Dubé (BHD) syndrome, and the pedigree analysis of genetic testing of family members' samples can assist in the rapid identification of causative gene variants. The genetic testing methods, including Sanger sequencing, Multiplex Ligation-dependent Probe Amplification (MLPA), and Next-Generation Sequencing (NGS), can be chosen based on individual patient's care needs. (43 voting experts; 43 in favor, 0 against, 0 abstention).[Recommendation 2] Patients with BHD syndrome should undergo chest CT scan to evaluate cystic lesions in the lungs, and routine evaluation of the kidneys for tumor foci, using ultrasound, enhanced CT, or MR as appropriate. (43 experts voted; 43 in favor, 0 against, 0 abstention).[Recommendation 3] Clinicians should establish a diagnosis based on the appropriate clinical presentation and in conjunction with genetic test results and/or a family history of BHD syndrome. (43 voting experts; 43 in favor, 0 against, 0 abstention).[Recommendation 4] Lung histopathological biopsy is not recommended as the first choice for patients with suspected BHD syndrome based on clinical and pulmonary imaging manifestations. (43 voting experts; 43 in favor, 0 against, 0 abstention).[Recommendation 5] BHD syndrome should be particularly distinguished from other diffuse cystic lung diseases, such as lymphangioleiomyomatosis (LAM), lymphocyte interstitial pneumonia (LIP), pulmonary Langerhans cell histiocytosis (PLCH), etc. (43 voting experts; 43 in favor, 0 against, 0 abstention).[Recommendation 6] BHD syndrome is clinically rare and often involves multiple disciplines, such as respiratory and critical care medicine, radiology, pathology, thoracic surgery, urology, genetics, and dermatology, and multidisciplinary discussions are recommended to improve the diagnosis of BHD syndrome. (43 voting experts; 43 in favor, 0 against, 0 abstentions).[Recommendation 7] Patients with BHD syndrome should avoid smoking, and are recommended to be vaccinated with influenza, pneumococcal, and SARS-Cov-2 vaccines to prevent infections. (43 voting experts; 43 in favor, 0 against, 0 abstentions).[Recommendation 8] Air travel is not recommended for patients with BHD syndrome who have experienced pneumothorax until it has been recovered. (43 voting experts; 42 in favor, 0 against, 1 abstention).[Recommendation 9] In patients with BHD syndrome complicated by pneumothorax, early pleurodesis is recommended to reduce the risk of recurrence. (43 voting experts; 43 in favor, 0 against, 0 abstention).[Recommendation 10] Observation or topical treatment may be chosen for patients with BHD syndrome complicated by fibrofolliculoma or trichodiscoma. (43 voting experts; 42 in favor, 0 against, 1 abstention).[Recommendation 11] For patients with BHD syndrome complicated by renal tumors, annual abdominal MR examination is recommended when tumors are <1 cm in diameter; when tumors are 1-3 cm in diameter, abdominal MR examination at every 6 months or ablation surgery is recommended; when renal tumors are >3 cm in diameter, local excision of renal tumors with preservation of renal function is recommended. (43 voting experts; 43 in favor, 0 against, 0 abstention).[Recommendation 12] Patients with BHD syndrome are associated with significantly increased risks of kidney cancer, and routine screenings of kidney cancer during their lifetime are recommended. (43 voting experts; 43 in favor, 0 against, 0 abstention).[Recommendation 13] Couples with BHD syndrome are advised to undergo prenatal genetic counseling when preparing for pregnancy, to work with a prenatal diagnostician to assess genetic risk, and to discuss the feasibility of prenatal diagnosis during pregnancy. (43 experts voted; 43 in favor, 0 against, 0 abstention).[Recommendation 14] 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. (43 voting experts; 43 in favor, 0 against, 0 abstention).[Recommendation 15] Improvements in the clinical diagnosis and treatment of BHD syndrome and overall management are needed. Due to the scarcity of effective therapeutic drugs, multicenter, prospective clinical trials are recommended. (43 experts voted; 43 in favor, 0 against, 0 abstention).