Birt-Hogg-Dube Syndrome

Updated: Oct 22, 2015
  • Author: Krista K Buckley, DO; Chief Editor: Dirk M Elston, MD  more...
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Overview

Background

 

In 1977, Birt, Hogg, and Dubé 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-Dubé syndrome (BHDS). [1, 2, 3, 4, 5, 6, 7] However, evidence suggests that these 3 lesions may actually represent only 1 lesion, the fibrofolliculoma, cut in various planes of section. [3, 8]

Multiple or bilateral renal carcinomas, commonly chromophobe renal carcinoma and renal oncocytomas, and rarely, clear cell renal carcinomas have been reported in association with this syndrome. [9, 10, 11, 12, 13, 14, 15] The overall lifetime risk of renal cancer in patients with Birt-Hogg-Dubé syndrome was noted to be 16% by Houweling et al. [16]

Pulmonary cysts and spontaneous pneumothoraces have also been increasingly reported manifestations of Birt-Hogg-Dubé syndrome. [17, 18, 19, 20, 21, 22, 23, 24] In one study, Toro et al reported 89% of patients with Birt-Hogg-Dubé syndrome had pulmonary cysts on CT scans. Further, the study demonstrated 24% of Birt-Hogg-Dubé syndrome patients and 34% of Birt-Hogg-Dubé syndrome family members screened for lung cysts had a history of spontaneous pneumothorax. [19] Additionally, the overall risk of having a pneumothorax in patients with Birt-Hogg-Dubé syndrome was noted to be 29%. [16]

Other, less commonly 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 (including neurilemomas), multiple facial angiofibromas, and desmoplastic melanoma. [25, 26, 27, 28, 29, 30, 31, 32] Colonic polyps and colonic adenocarcinoma had previously been described with Birt-Hogg-Dubé syndrome; however, a large cohort study by Zbar et al failed to demonstrate such findings. [20] Additionally, medullary thyroid cancer was reported in 9 members of the original family described by Birt, Hogg, and Dubé, but it has not been reported in subsequent cases. A case of neuroendocrine cancer of prostate or bladder origin has also been reported. [33]

In summary, Birt-Hogg-Dubé syndrome is an autosomal dominant disorder clinically manifested by fibrofolliculomas, renal cell carcinoma, lung cysts, and spontaneous pneumothorax.

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Pathophysiology

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 Birt-Hogg-Dubé syndrome (BHDS). Schmidt et al demonstrated that Birt-Hogg-Dubé syndrome maps to band 17p11.2. [18, 34] Further, Nickerson et al used recombination mapping to delineate the susceptibility focus to 700 kB on band 17p11.2. They also demonstrated a Birt-Hogg-Dubé syndrome tumor-suppressor protein, folliculin. [35] Expression of the Birt-Hogg-Dubé syndrome protein has been widespread in a variety of tissues, including the kidneys, lungs, and skin. [36]

The exact origin of the folliculin mutation remains under investigation. Several possible mechanisms exist. In recent studies, renal and pulmonary tumors in Birt-Hogg-Dubé syndrome appear to follow the two-hit tumorigenesis theory relating to the interaction of folliculin with the FLCN-interacting protein 1 (FNIP1) and FLCN-interacting protein 2 (FNIP2). [29, 30, 37] FNIP1 then interacts with 5'-AMP (activated protein kinase), which interacts with mammalian target of rapamycin (mTOR) that is involved in cellular energy, cytokinesis, cell motility, cellular adhesion, and nutrient sensing. [38, 39, 40] The formation of pulmonary cysts may be related to the dysregulation of mTOR signaling, which facilitates S6-mediated protein synthesis and HIF-1-alpha–mediated angiogenesis. [41]

Gaur et al suggest FLCN acts as a tumor suppressor by negatively regulating rRNA synthesis. [42] Another study by Nahorski et al demonstrated tumor suppression by the interaction of p0071 (plakophilin-4, a potential novel folliculin-interacting protein) and the regulation of RhoA. [43] Additionally, knockdown of slingshot 2 (SSH2) serine phosphatase was demonstrated to induce caspase 3/7 activation that can trigger apoptosis in human carcinoma cells with a FLCN mutation. [44] Possik et al demonstrated FLCN is an AMPK-binding partner and considered to act as a negative regulator of AMPK, therefore serving as a tumor suppressor. [45, 46]

Pradella et al suggest that FLCN may not always follow a classic two-hit model of tumorigenesis and may alternatively be a noncanonical tumor suppressor gene. This was demonstrated by the somatic PTEN deletion in parotid tumors in addition to the germline loss of FLCN, thereby following a model of compound heterozygosity, instead of the classic two-hit mutation. [47]

Benhammou et al and Nahorski et al noted other changes, besides germline mutations, in FLCN causing folliculin mutation. FLCN protein instability or deletion of a FLCN exon caused reduced protein production, thus supporting the theory of haploinsufficiency and contributing to disease pathogenesis. [48, 49]

While the poly C tract in exon 11 of the folliculin gene is the mutational hotspot, multiple other germline mutations have been detected. [50, 51, 47, 30, 52, 53] The folliculin mutation detection rate was 88% by direct bidirectional DNA sequencing in the National Cancer Institute Birt-Hogg-Dubé syndrome cohort. Folliculin mutation databases have been established by Wei and colleagues at the National Cancer Institute and by the European BHDS Consortium. [54, 55, 56]

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Epidemiology

Frequency

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

Race

No racial predilection is reported in Birt-Hogg-Dubé syndrome. Perifollicular fibromas may represent a part of the spectrum of lesions in Birt-Hogg-Dubé syndrome and are reported only in white and light-skinned persons.

Sex

No sexual predilection is reported in Birt-Hogg-Dubé syndrome. 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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Prognosis

The prognosis depends on associated internal disease. Mortality and morbidity associated with Birt-Hogg-Dubé syndrome may be related to associated internal manifestations, such as renal cell carcinoma, pulmonary cysts, and spontaneous pneumothoraces. [57] Papillary renal cell carcinoma has malignant potential, while pure renal oncocytomas are benign. Evaluate colonic polyps for malignant potential. Birt-Hogg-Dubé syndrome patients with a history of smoking appear to have more severe lung disease than those who do not smoke. [58] Otherwise, the morbidity of cutaneous lesions is limited to cosmetic appearance.

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Patient Education

Instruct patients with Birt-Hogg-Dubé syndrome to encourage family members to be screened using renal ultrasonography and CT scanning of the abdomen and pelvis because Birt-Hogg-Dubé syndrome is autosomal dominant.

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