BHD can be suggested by clinical findings but is definitively diagnosed by molecular genetic testing to detect mutations in the FLCN gene. The classical clinical triad includes benign growths of the hair follicles, pulmonary cysts and spontaneous pneumothorax, and bilateral, multifocal renal tumors. Clinical triad The cutaneous manifestations of BHD were originally described as fibrofolliculomas (abnormal growths of a hair follicle), trichodiscomas (hamartomatous lesions with a hair follicle at the periphery, often found on the face), and acrochordons (skin tags). Cutaneous manifestations are confirmed by histology. Most individuals (89%) with BHD are found to have multiple cysts in both lungs, and 24% have had one or more episodes of pneumothorax. The cysts can be detected by chest CT scan. Renal tumors can manifest as multiple types of renal cell carcinoma, but certain pathological subtypes (including chromophobe, oncocytoma, and oncocytic hybrid tumors) are more commonly seen. Although the original syndrome was discovered on the basis of cutaneous findings, individuals with BHD may only manifest the pulmonary and/or renal findings, without any skin lesions. Though these signs indicate BHD, it is only confirmed with a genetic test for FLCN mutations. Genetic testing FLCN mutations are detected by sequencing in 88% of probands with this syndrome. This means that some people with the clinical diagnosis have mutations that are not detectable by current technology, or that mutations in another currently unknown gene could be responsible for a minority of cases. In addition, amplifications and deletions in exonic regions are also tested. Genetic testing can be useful to confirm the clinical diagnosis and to provide a means of determining other at-risk individuals in a family even if they have not yet developed BHD symptoms. Differential diagnosis The person in this image has tuberous sclerosis. The skin lesions caused by tuberous sclerosis (angiofibromas) must be distinguished from the characteristic fibrofolliculomas of BHD, which also occur primarily on the face. BHD can be difficult to diagnose from symptoms alone, because hereditary renal cancers, pneumothorax, and cutaneous tumors occur with other syndromes. Hereditary bilateral, multifocal kidney tumors similar to those seen in BHD can occur with von Hippel–Lindau disease (clear cell renal cell carcinoma), hereditary papillary renal cancer (papillary renal cell carcinoma), and hereditary leiomyomatosis and renal cell cancer syndrome. They are differentiated with examination of the tumors' histology. Hereditary recurrent pneumothorax or pulmonary cysts are associated with Marfan syndrome, Ehlers–Danlos syndrome, tuberous sclerosis complex, alpha1-antitrypsin deficiency, and cystic fibrosis. Nonhereditary recurrent pneumothorax and/or pulmonary cysts can occur with Langerhans cell histiocytosis and lymphangioleiomyomatosis. These conditions are differentiated from BHD through examining the patient history and performing a physical examination. In women suspected to have the disease, ruling out pulmonary or thoracic endometriosis may be necessary. Though fibrofolliculomas are unique to BHD, they may present with an ambiguous appearance and must be confirmed histologically. Other diseases can mimic the dermatologic manifestations of BHD, including tuberous sclerosis complex, Cowden syndrome, familial trichoepitheliomas, and multiple endocrine neoplasia type 1. Tuberous sclerosis must be distinguished because both disorders can present with angiofibromas on the face, though they are more common in tuberous sclerosis.
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