Birt-Hogg-Dubé syndrome (ORPHA:122)
A rare inherited cancer-predisposing syndrome characterized by skin lesions, benign and malignant kidney tumors, and pulmonary cysts that may be associated with pneumothorax.
Epidemiology
The prevalence of Birt-Hogg-Dubé syndrome (BHD) is estimated at 1/200,000 but the exact incidence is unknown. More than 500 families affected by BHD have been reported so far.
Clinical description
Numerous pleural and subpleural cysts are present in more than 80% of adult BHD patients. They can cause single or recurrent spontaneous pneumothorax, mainly between 20-40 years old. The estimated prevalence of pneumothorax is about 22-38%. The lifetime risk for malignant renal cell carcinoma is estimated to be 20%, with a mean age at diagnosis around 50 years old. The kidney tumors in BHD patients can be multifocal and bilateral and range from benign oncocytomas to malignant renal cell carcinomas including chromophobe, clear cell or papillary subtypes. Chromophobe/oncocytoma hybrid renal cell cancer tumors are characteristic for BHD. Possible associations of BHD with additional tumor types, including colon cancer, thyroid cancer, parotic gland tumors and malignant melanoma, have been reported. The typical skin lesions are fibrofolliculomas that often start to appear between 20-40 years of age and tend to increase in number. Fibrofolliculomas are typically located on the face (especially paranasal and on the forehead) and in the retroauricular regions and on the neck / upper trunk and present as multiple small (2-5 mm) whitish papules. Histopathologically, they are characterized by sharply demarcated intradermal tumors due to a proliferation of collagen and epithelial strands from the upper part of the follicle epithelium protruding into surrounding thickened, basophil, fibro-mucinous stroma. Patients also might develop trichodiscomas and acrochordons.
Etiology
BHD syndrome is transmitted in an autosomal dominant fashion. The causative gene, FLCN, is located on chromosome 17p11.2. The FLCN gene encodes folliculin, a protein involved in different important cell functions, including autophagy, regulation of transcription factors, amino acid sensing and lysosomal signaling.
Diagnostic methods
Clinical diagnosis relies on recognition of typical combinations of clinical manifestations, such as multiple lung cysts, fibrofolliculomas and/or chromophobe/oncocytoma hybrid renal cell cancer tumors. The diagnosis can be confirmed by detection of pathogenic variants in the FLCN gene.
Differential diagnosis
Sporadic pulmonary lymphangioleiomyomatosis (LAM) also can present with multiple lung cysts.
Antenatal diagnosis
Antenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
The disorder is autosomal dominant, genetic counseling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy.
Management and treatment
So far there are no consensus recommendations for clinical surveillance. Provisional recommendations: BHD patients should receive abdominal/pelvic MRI to screen for renal tumor(s) every 1-2 years, starting at 20 years of age. Pneumothoraces are treated as usual; regular screening of the lung by CT is not recommended. Fibrofolliculomas are benign lesions but can be a cosmetic concern for the patients. The definitive treatment for solitary or very prominent lesions is surgical removal. Ablative laser treatment or dermabrasion are treatment options for more extensive areas, but lesions may recur and patients must be aware that scarring can be a possible side effect. Patients with BHD should be screened and pulmonary, renal, and gastrointestinal findings should be managed. Coloscopy every three years, starting at age 40 years and annual ultrasound screening of thyroid and parotid glands should be considered.
Prognosis
The prognosis for patients with BHD depends mainly on early detection and treatment of renal cell cancer. Recurrent pneumothoraxes might affect quality of life and multiple fibrofolliculomas might be perceived disfiguring by the patient.

                            Last update: 
                            November 2023


                            - Expert reviewer(s): 
                            Dr Elke SATTLER  - Pr Ortrud STEINLEIN