What is Birt-Hogg-Dubé (BHD) syndrome?

From the Guidelines

Birt-Hogg-Dubé syndrome should be managed with regular skin examinations, baseline chest imaging, and periodic kidney imaging every 1-2 years to monitor for renal tumors, as recommended by the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors 1. This condition is a rare genetic disorder caused by mutations in the FLCN gene, characterized by multiple benign skin tumors, lung cysts that can lead to pneumothorax, and an increased risk of kidney cancer. The syndrome follows an autosomal dominant inheritance pattern, meaning a person needs only one copy of the mutated gene to develop the condition. Some key features of Birt-Hogg-Dubé syndrome include:

• Classic skin lesions such as fibrofolliculomas, perifollicular fibromas, trichodiscomas or angiofibromas, and acrochordons
• Bilateral and multifocal renal tumors, including chromophobe clear cell renal carcinoma, renal oncocytoma, oncocytic hybrid tumor, and less often, clear cell renal carcinoma
• Multiple bilateral lung cysts often associated with spontaneous pneumothorax, as noted in the study published in Genetics in Medicine 1 Management of the condition involves:
• Regular skin examinations to monitor for skin lesions
• Baseline chest imaging to detect lung cysts
• Periodic kidney imaging (typically MRI or CT scans every 1-2 years) to monitor for renal tumors, as this is crucial for early detection and treatment of kidney cancer
• Genetic counseling for affected individuals and their families to understand inheritance risks, given the 50% chance of each child inheriting the mutation.

From the Research

Definition and Characteristics of Birt-Hogg-Dubé Syndrome

• Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant disorder characterized by diffuse pulmonary cysts, cutaneous fibrofolliculomas or trichodiscomas, and a variety of renal cell cancers 2, 3, 4.
• The syndrome is caused by pathogenic variants in the FLCN gene located on chromosome 17p11.2 2, 3, 4.
• Clinical expression typically includes multiple pulmonary cysts, recurrent spontaneous pneumothoraces, cutaneous fibrofolliculomas, and renal tumors of various histological types 3.

Diagnosis and Management of Birt-Hogg-Dubé Syndrome

• The diagnosis of BHD is based on a combination of genetic, clinical, and/or skin histopathological criteria 3, 4.
• 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 2.
• 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 2.
• Management mainly consists of early pleurodesis in the case of pneumothorax, periodic renal imaging for tumor detection, and diagnostic work-up in search of BHD in relatives of the index patient 3.

Clinical Features and Complications of Birt-Hogg-Dubé Syndrome

• Multiple bilateral pulmonary cysts are found on chest computed tomography in >80% of patients, and more than half experience one or more episodes of pneumothorax 3.
• Renal tumors affect about 30% of patients during their lifetime, and can be multiple and recurrent 3.
• Cutaneous fibrofolliculomas or trichodiscomas are common skin manifestations of BHD syndrome 2, 3, 5.
• Patients with BHD syndrome are associated with significantly increased risks of kidney cancer, and routine screenings of kidney cancer during their lifetime are recommended 2.

Genetic Testing and Family Management of Birt-Hogg-Dubé Syndrome

• 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 2.
• 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.
• 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 2.