AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

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.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

History

Asymptomatic, small, papular skin lesions develop gradually over the scalp, face, neck, and upper trunk.

Physical

• 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.
• 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, and deforming lipomas also have been reported in association with BHDS.

Causes

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

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Differential diagnosis of genetic disorders with multiple firm papules of the face has been categorized according to the origin of the lesions, as follows:

Epithelial origin - Trichoepithelioma associated with Brooke-Spiegler syndrome and Rombo syndrome, trichilemmomas associated with Cowden disease, basaloid follicular hamartoma associated with basaloid follicular hamartoma syndrome

Mesodermal origin - Trichodiscoma, perifollicular fibroma, adenoma sebaceum of Pringle disease

Mixed origin - Fibrofolliculoma

Several authors have reported that Hornstein-Knickenberg syndrome (characterized by multiple perifollicular fibromas) may be the same syndrome as BHDS. The flesh-colored papules distributed over the head, neck, and upper trunk in each syndrome are similar. Both syndromes are autosomal dominant and have been associated with colonic polyposis and neoplasms. Several other authors suggest perifollicular fibromas simply may represent a portion of the spectrum of fibrofolliculomas and trichodiscomas.

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Imaging Studies

• Conduct a renal ultrasound, CT scans of the abdomen and pelvis, and a chest x-ray.
• BHDS recently has been reported in association with various types of renal tumors, such as oncocytoma and a variant of papillary renal cell carcinoma. BHDS is autosomal dominant; therefore, screen patients and their relatives for renal cancer. Since 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 BHDS association with recurrent spontaneous pneumothorax, bullous emphysema, and lung cysts.

Other Tests

• Consider colonoscopy.
• Colonic polyps and colonic adenocarcinoma have been previously reported as associated findings of BHDS; however, a recent study in a large cohort of patients with BHDS did not confirm those findings.

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. Recent evidence suggests that trichodiscomas and acrochordons may actually represent a spectrum of fibrofolliculoma.

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. Recent studies suggest that trichodiscomas also may be related closely to fibrofolliculomas, and their histologic appearance may relate to the plane of sectioning.

Acrochordons usually demonstrate papillomatosis, hyperkeratosis, and regular acanthosis. In BHDS, papules identified clinically as acrochordons are not evaluated histologically as a routine; however, recent reports of clinically appearing acrochordons associated with BHDS 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. Recent histologic study of perifollicular fibromas revealed that sectioning techniques may have skewed interpretation of the lesions. Lesions described as perifollicular fibroma on horizontal sections were reexamined in vertical cuts and demonstrated similar histologic features of 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.

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Medical Care

No specific medical treatment exists for the cutaneous lesions of BHDS.

Surgical Care

• Surgical removal has provided definitive treatment of solitary perifollicular fibromas.
• Electrodesiccation may be helpful in removal of multiple lesions; however, lesions can recur.
• Dermabrasion has been suggested as a treatment option. Lesions may recur.
• Several cases of BHDS cutaneous lesions treated successfully with carbon dioxide and Er:YAG laser skin resurfacing have been reported.

Consultations

The principle concern of BHDS is comorbid internal neoplasms. Associated conditions most commonly include renal cell carcinoma, pulmonary cysts, and spontaneous pneumothoraces.

• Refer patients with BHDS to family medicine or internal medicine for annual physical examinations and screening using renal ultrasound and CT scans 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, since BHDS is a genodermatosis.

FOLLOW-UP

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Deterrence/Prevention:

• BHDS cannot be prevented, but associated findings of renal carcinoma, pulmonary cysts, and pneumothoraces can be monitored.

Prognosis:

• Prognosis depends on associated internal disease.
• Papillary renal cell carcinoma has malignant potential, while pure renal oncocytomas are benign.
• Evaluate colonic polyps for malignant potential.

Patient Education:

• Instruct patients with BHDS to encourage family members to be screened using renal ultrasounds and CT scans of the abdomen and pelvis because BHDS is autosomal dominant.

MISCELLANEOUS

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to diagnose BHDS correctly can hinder patients from undergoing appropriate imaging studies
• Failure to offer genetic counseling, since BHDS is a genodermatosis

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Feb 26, 2007