Birt-Hogg-Dubé syndrome – Drexel – May 16, 2016

Presented by: Catherine Warner, MD, Jaryd Freedman, MD, and Mark Abdelmalek, MD

Drexel University College of Medicine

May 16, 2016

Birt-Hogg Dubé Syndrome (BHDS) presents with a triad of multiple fibrofolliculomas, trichodiscomas and achrochordons associated with pulmonary cysts, pneumothoraces and renal tumors. The lesions usually appear after the second decade of life predominantly on the nose and cheeks. Rarely, angiofibromas and collagenomas can be seen. Clinically, fibrofolliculomas and trichodiscomas are indistinguishable, and both present as firm dome-shaped papules ranging from 2-5 mm in size. The face, scalp and neck are predominantly involved, although lesions can also be found on the trunk. Fibrofolliculomas are specific for this condition.

BHDS has an autosomal dominant pattern of inheritance and is caused by germline mutations in the FLCN gene, which encodes for the folliculin protein. The disease can have incomplete penetrance and variable phenotypic expression. Twenty five percent of individuals with FLCN gene mutation have absence of skin lesions.

Histologically, a fibrofolliculoma consists of a centrally distorted hair follicle that is surrounded by a fibrous stroma. Emanating from the follicle are thin, anastamosing strands of follicular epithelium. Although fibrofolliculomas and trichodiscomas were initially described as separate entities, some experts now believe that the two are, in reality, the same lesion and the distinction seen on histology is related to differences in sectioning techniques.

Renal tumors and spontaneous pneumothoraces are strongly linked to BHDS. In patients with BHDS, there is a fifty -fold increased risk of spontaneous pneumothoraces. The majority of lung cysts were found at the bases in contrast to apical cysts commonly seen in patients with sporadic pneumothoraces. In BHDS patients, the risk of spontaneous pneumothoraces is inversely related to the age, unlike renal tumors, which usually occur in older, male patients. Individuals with BHDS are about nine times more likely to develop renal tumors, particularly chromophobe renal carcinoma and renal oncocytomas. In addition, BHDS has been associated with colon polyps, medullary thyroid cancer, thyroid and parathyroid adenomas, parotid oncocytoma, and neural tissue tumors; however, most of these associations are based on anecdotal evidence.

Unfortunately, treatment for the cutaneous manifestations of BHDS is difficult. Multiple modalities, ranging from topical tretinoin to ablative laser therapy to surgical excision have been reported. While surgical excision is the only definitive treatment for individual lesions, there is a risk of scarring, and therefore, is not a reasonable option for multiple lesions. Most importantly, appropriate imaging for renal tumors and lung cysts should be conducted in all BHDS patients.

Vincent A, Farley M, Chan E, James WD. Birt-Hogg-Dube syndrome: a review of the literature and the differential diagnosis of firm facial papules. J Am Acad Dermatol. 2003; 49:698-705.
Menko FH, van Steensel MA, Giraud S et al. Birt-Hogg-Dube syndrome: diagnosis and management. Lancet Oncol. 2009; 10:1199-1206.
Maffe A, Toschi B, Circo G et al. Constitutional FLCN mutations in patients with suspected Birt-Hogg-Dube syndrome ascertained for non-cutaneous manifestations. Clin Genet 2011; 79:345-354.

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