Birt-Hogg-Dube Syndrome (BHDS)

Updated: Jul 22, 2021

Author: Michelle Bongiorno; Chief Editor: Dirk M Elston, MD

Overview

Background

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

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.[1, 2, 3, 4, 5, 6, 7] However, evidence suggests that these three lesions may actually represent only one lesion, the fibrofolliculoma, cut in various planes of section or during different stages of maturation.[3, 8, 9]

Multiple or bilateral renal carcinomas have been reported in association with this syndrome, most commonly hybrid oncocytic tumors with features of chromophobe renal carcinoma (50%), followed by chromophobe renal cancer, clear cell renal carcinoma, and renal oncocytoma.[10, 11, 12, 13, 14, 15, 16, 17, 18, 19] Of patients with Birt-Hogg-Dubé syndrome, 12-34% develop renal tumors, typically in the fourth and fifth decades of life.[20, 21, 22]

Pulmonary cysts and spontaneous pneumothoraces have also been increasingly reported manifestations of Birt-Hogg-Dubé syndrome.[23, 24, 25, 26, 27, 28, 29, 30] Pulmonary cyst are present in 24-95% of Birt-Hogg-Dubé patients.[25, 31, 32] Additionally, the overall risk of having a pneumothorax in patients with Birt-Hogg-Dubé syndrome is 29%.[20] Even with these pulmonary complications of Birt-Hogg-Dubé syndrome, most patients have preserved pulmonary function or mild obstructive pulmonary disease.[32, 33]

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.[34, 35, 36, 37, 38, 39, 40, 41] Colonic polyps and colonic adenocarcinoma had previously been described with Birt-Hogg-Dubé syndrome; however, several large cohort studies failed to demonstrate such findings.[26, 42, 43] Additionally, medullary thyroid cancer was reported in nine 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.[44]

Pathophysiology

Birt-Hogg-Dubé syndrome is caused by a mutation in the folliculin (FLCN) gene that has been mapped to the short arm of chromosome 17, specifically 17p11.2.[24, 21] Since its discovery, over 100 unique mutations in FLCN, caused by insertion/deletions, nonsense or splice-site mutation, have been identified.[20, 21, 22, 45, 46, 47, 48] While the poly C tract in exon 11 of the folliculin gene is the mutational hotspot, multiple other germline mutations have been detected.[39, 49, 50, 51, 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.[22, 45, 54]

FLNC has two known binding partners, FLNC-interacting protein 1 (FNIP1) and FLNC-interacting protein 2 (FN1P2). These complexes interact with 5’-AMP-activated protein kinase (AMPK) that is part of the mechanistic target of rapamycin (mTOR) pathway, which is involved in cellular energy, cytokinesis, cell motility, cellular adhesion, and nutrient sensing.[38, 39, 55, 56, 57, 58, 59]

FLNC is a tumor suppressor gene, but the manifestations of Birt-Hogg-Dubé syndrome appear to have several mechanisms of activation. 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.[49] Benhammou et al and Nahorski et al noted other changes, besides germline mutations, in FLCN causing a 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.[60, 61, 62]

Etiology of BHDS

The cause is unknown, but Birt-Hogg-Dubé syndrome (BHDS) is inherited in an autosomal dominant pattern. Several reports suggest Birt-Hogg-Dubé syndrome may result from the inactivation of a tumor-suppressor gene, which results in the cutaneous hamartomas associated with internal neoplasia. The Birt-Hogg-Dubé syndrome gene locus has been localized to band 17p11.2.

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 are found in 82-92% of Birt-Hogg-Dubé syndrome patients by age 25 years.[21, 22, 46, 51] Dermatologic manifestations typically have an earlier onset than associated renal cell cancer. Spontaneous pneumothorax develops most frequently before age 40 years.[25]

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.[63] 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.[64] Otherwise, the morbidity of cutaneous lesions is limited to cosmetic appearance.

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.

Presentation

History

Asymptomatic, small, papular skin lesions develop gradually over the scalp, face, neck, and upper trunk, as shown in the image below.

Birt-Hogg-Dube syndrome lesions. Courtesy of Madhero88, via Wikimedia Commons.

Physical Examination

Multiple, small (2-4 mm), white–to–flesh-colored, smooth, dome-shaped papules are distributed predominately over the scalp, face, oral cavity, neck, and upper trunk. Rarely, these fibrofolliculomas can be comedonal or cystic in appearance.[65] Acrochordons are small, soft, furrowed, 1- to 2-mm papules that may occur on the eyelids, neck, axilla, and upper half of the trunk. Oral mucosal polyps, collagenomas, angiolipomas, deforming lipomas, perifollicular fibromas, and multiple facial angiofibromas also have been reported in association with Birt-Hogg-Dubé syndrome (BHDS).[66, 67, 68, 69]

Menko et al proposed diagnostic criteria for Birt-Hogg-Dubé syndrome (patients should meet 1 major or 2 minor criteria for diagnosis).[70]

Major criteria are as follows:

At least 5 fibrofolliculomas or trichodiscomas, at least 1 histologically confirmed and of adult onset
FLCN germline mutation

Minor criteria are as follows:

Multiple lung cysts - Bilateral basally located lung cysts (with no other apparent cause)
Renal cancer - Early onset (< 50 y) or multifocal or bilateral renal cancer, or renal cancer of mixed chromophobe and oncocytic histology
A first-degree relative with BHDS

DDx

Diagnostic Considerations

Several other genodermatosis are associated with small papules on the nose and mid face, including the following:

Angiofibromas in either tuberous sclerosis complex or multiple endocrine neoplasia type 1
Trichoepitheliomas in Brooke-Spiegler syndrome
Trichilemmomas in Cowden syndrome

Differential Diagnoses

Workup

Imaging Studies

Conduct renal ultrasonography, MRI or CT; CT scanning of the abdomen and pelvis; chest radiography.

Birt-Hogg-Dubé syndrome (BHDS) has been reported in association with various types of renal tumors, such as oncocytoma and a variant of papillary renal cell carcinoma.[71] Birt-Hogg-Dubé syndrome is autosomal dominant; therefore, screen patients and their relatives for renal cancer. Because renal neoplasms often are asymptomatic during the growth phase, an earlier onset of fibrofolliculomas and trichodiscomas may serve as a marker.

Screening chest radiography should be advised for patients and family members because of the Birt-Hogg-Dubé syndrome association with recurrent spontaneous pneumothorax, bullous emphysema, and lung cysts. A significant association is apparent between the number and location of lung cysts and pneumothorax.[25]

Other Tests

Consider colonoscopy. Colonic polyps and colonic adenocarcinoma have been previously reported as associated findings of Birt-Hogg-Dubé syndrome; however, one study in a large cohort of patients with Birt-Hogg-Dubé syndrome did not confirm a colorectal cancer association.[26]

Procedures

Skin biopsy is necessary to confirm trichodiscomas, fibrofolliculomas, and perifollicular fibromas.

Histologic Findings

Fibrofolliculoma consists of a well-formed hair follicle with a dilated infundibulum containing laminated keratin. Radiating from the epithelium of the hair follicle are anastomosing epithelial strands of 2- to 4-mm thickness within a well-circumscribed mantle of loose mucinous connective tissue. These strands may arise from sebaceous epithelium deeply situated in the epidermis.[72] The entire tumor is embedded in a fibrous or fibromucinous orb.

In its classic description, trichodiscoma represents a small hamartomatous tumor of the hair disk (Haarscheibe). Pinkus et al described a constant topographic relationship of the hair follicle to the periphery of the papule. Other prominent features of trichodiscomas include a proliferation only of the fibrovascular component of the hair disk, small melanin-granule–containing cells in the substance of the tumor, and occasional myelinated nerves at the base of the lesion. Studies suggest that trichodiscomas also may be closely related to fibrofolliculomas, and their histologic appearance may relate to the plane of sectioning.[73, 74] The term mantleoma has been used to describe the continuum of appearance between the two tumors.[75]

Acrochordons usually demonstrate papillomatosis, hyperkeratosis, and regular acanthosis. In Birt-Hogg-Dubé syndrome, papules identified clinically as acrochordons are not evaluated histologically as a routine; however, reports of clinically appearing acrochordons associated with Birt-Hogg-Dubé syndrome were evaluated and showed histologic findings consistent with fibrofolliculomas. Histologic study of 12 biopsy specimens of acrochordonlike lesions revealed infundibular structures within a core of fibrovascular mesenchyme, with epithelial strands extending from the basal layer. Future studies may confirm these findings.

Perifollicular fibroma classically is characterized by an unaltered hair follicle, commonly containing a hair shaft and surrounded by a distinct, circumferentially arranged, collagen fibrous sheath. Histologic study of perifollicular fibromas has revealed that sectioning techniques may skew interpretation of the lesions. Lesions described as perifollicular fibroma on horizontal sections were reexamined in vertical cuts and demonstrated histologic features similar to fibrofolliculoma, such as mantlelike strands of epithelium and sebaceous lobules at deeper levels of the epidermis. Thus, the entity of perifollicular fibroma may represent a transverse cut of a fibrofolliculoma, rather than a perifollicular fibroma.[8, 67, 76]

Treatment

Medical Care

No specific medical treatment exists for the cutaneous lesions of Birt-Hogg-Dubé syndrome (BHDS). Topical rapamycin failed to demonstrate cosmetic improvement of fibrofolliculomas in Birt-Hogg-Dubé syndrome patients.[77]

Surgical Care

Surgical removal has provided definitive treatment of solitary perifollicular fibromas.

Electrodesiccation may be helpful for the removal of multiple lesions; however, lesions can recur.[78] Dermabrasion has been suggested as a treatment option. Lesions may recur. Several cases of Birt-Hogg-Dubé syndrome cutaneous lesions treated successfully with carbon dioxide and Er:YAG laser skin resurfacing have been reported.[79, 80, 81]

Consultations

The principle concern of Birt-Hogg-Dubé syndrome is comorbid internal neoplasms. Associated conditions most commonly include renal cell carcinomas, pulmonary cysts, and spontaneous pneumothoraces.

Refer patients with Birt-Hogg-Dubé syndrome to a family medicine or internal medicine physician for annual physical examinations and screening using renal ultrasonography and CT scanning of the abdomen and pelvis. Screening chest radiography should also be performed.

Consider referral of patients to a gastroenterologist for colonoscopy.

Refer patients to a genetic counselor, because Birt-Hogg-Dubé syndrome is a genodermatosis. Consider genetic testing to confirm the diagnosis in patients suspected of having Birt-Hogg-Dubé syndrome.

Prevention

Birt-Hogg-Dubé syndrome cannot be prevented, but associated findings of renal carcinomas, pulmonary cysts, and pneumothoraces can be monitored.

Advise Birt-Hogg-Dubé syndrome patients regarding the increased risk of pneumothorax with activities altering ambient pressure, such as scuba diving and air travel, particularly if they have chest pain or shortness of breath.[25]

Encourage smoking cessation in Birt-Hogg-Dubé syndrome patients as smoking may be a risk factor for spontaneous pneumothorax and renal cancer.

Questions & Answers

Overview

What is Birt-Hogg-Dube syndrome?

What is the pathophysiology of Birt-Hogg-Dube syndrome?

What causes Birt-Hogg-Dube syndrome?

What is the prevalence of Birt-Hogg-Dube syndrome?

What are the racial predilections of Birt-Hogg-Dube syndrome?

What are the sexual predilections of Birt-Hogg-Dube syndrome?

Which age groups have the highest prevalence of Birt-Hogg-Dube syndrome?

What is the prognosis of Birt-Hogg-Dube syndrome?

What is included in the patient education about Birt-Hogg-Dube syndrome?

Presentation

Which clinical history findings are characteristic of Birt-Hogg-Dube syndrome?

Which physical findings are characteristic of Birt-Hogg-Dube syndrome?

What are the diagnostic criteria for Birt-Hogg-Dube syndrome?

DDX

What other genodermatosis are associated with small papules on the nose and mid face?

What are the differential diagnoses for Birt-Hogg-Dube Syndrome (BHDS)?

Workup

What is the role of imaging studies in the workup of Birt-Hogg-Dube syndrome?

What is the role of colonoscopy in the workup of Birt-Hogg-Dube syndrome?

What is the role of skin biopsy in the workup of Birt-Hogg-Dube syndrome?

Which histologic findings are characteristic of Birt-Hogg-Dube syndrome?

Treatment

How is Birt-Hogg-Dube syndrome treated?

What is the role of surgery in the treatment of Birt-Hogg-Dube syndrome?

Which specialist consultations are beneficial to patients with Birt-Hogg-Dube syndrome?

How is Birt-Hogg-Dube syndrome prevented?

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