Excerpt from Birt-Hogg-Dube Syndrome

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Background

In 1977, Birt, Hogg, and Dube reported small papular skin lesions distributed over the scalp, forehead, face, and neck in 15 of 70 members in a kindred study. Histologic examination of the lesions revealed fibrofolliculomas, trichodiscomas, and acrochordons. The presence of this triad has been termed Birt-Hogg-Dube syndrome (BHDS). Recent evidence, however, suggests that these 3 lesions may actually represent only 1 lesion, the fibrofolliculoma.

Multiple or bilateral renal carcinomas, particularly chromophobe renal carcinoma, and renal oncocytomas have been reported in association with this syndrome. Pulmonary cysts and spontaneous pneumothoraces have also been increasingly reported manifestations of BHDS. Other associated features include a large connective-tissue nevus, parathyroid adenomas, flecked chorioretinopathy, bullous emphysema, lipomas, angiolipomas, parotid oncocytomas, multiple oral mucosal papules, neural tissue tumors, and multiple facial angiofibromas. Colonic polyps and colonic adenocarcinoma had previously been described with BHDS; however, a large cohort study by Zbar et al failed to demonstrate such findings. Additionally, medullary thyroid cancer was reported in 9 members of the original family described by Birt, Hogg, and Dube, but it has not been reported in subsequent cases.

Pathophysiology

Little is known about the pathophysiology of BHDS. Several authors have theorized that an ectodermal-mesodermal interaction stimulates hair development and growth of adjacent dermal structures. The cause of mesodermal proliferation is unknown, but autosomal dominant inheritance has been identified in patients with BHDS. Recently, Schmidt et al demonstrated that BHDS maps to band 17p11.2. Furthermore, Nickerson et al used recombination mapping to delineate the susceptibility focus to 700 kB on band 17p11.2. They also demonstrated a novel BHDS protein called folliculin. The function of folliculin remains unknown, although evidence suggests that folliculin may have a role as a tumor suppressor gene. Expression of the BHDS protein has been widespread in a variety of tissues, including the kidneys, lungs, and skin.

Frequency

United States

BHDS is uncommon in the United States. Several families have been reported since Birt, Hogg, and Dube described the original kindred in 1977.

Mortality/Morbidity

Mortality and morbidity associated with BHDS may be related to comorbid factors, such as renal cell carcinoma, pulmonary cysts, and spontaneous pneumothoraces. Otherwise, the morbidity of cutaneous lesions is limited to cosmetic appearance.

Race

No racial predilection is reported in BHDS. Perifollicular fibromas may represent a part of the spectrum of lesions in BHDS and are reported only in Caucasian and light-skinned persons.

Sex

No sexual predilection is reported in BHDS. Reports of patients with perifollicular fibromas have demonstrated no predilection for either sex.

Age

Cutaneous lesions usually develop in the third and fourth decades of life and persist indefinitely. Dermatologic manifestations typically have an earlier onset than associated renal cell cancer.

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