Dermatology

Birt-Hogg-Dubé syndrome (Hornstein-Knickenberg syndrome)

Are You Confident of the Diagnosis?

What you should be alert for in the history

A personal or family history of multiple facial lesions, spontaneous pneumothoraces or renal tumors strongly suggests the diagnosis of Birt-Hogg-Dubé syndrome.

Characteristic findings on physical examination

Multiple small dome-shaped flesh-colored papules usually on the face, neck or upper trunk are the most reliable cutaneous finding (Figure 1). The lesions usually appear in the third to fourth decade and slowly increase in number. Some patients may also have papules on the lips or buccal mucosa. While some reports have emphasized acrochordons, they are very common in adults and not at all specific for Birt-Hogg-Dubé syndrome.

Figure 1.

Multiple flesh-colored dome-shaped papules on the medial cheek that are very characteristic of Birt-Hogg-Dube syndrome (Courtesy of Chad Hivnor, MD).

Expected results of diagnostic studies

DERMATOPATHOLOGY

The papules represent a unique benign follicular tumor. While there is only one tumor, it has been designated fibrofolliculoma, perifollicular fibroma and trichodiscoma. The three names refer to stages in the evolution of the tumor, initially with prominent lacy follicular strands, then with perifollicular fibrosis and finally with dense focal fibrosis with no follicular remnants. Multiple biopsies are often needed to establish the diagnosis; excision or punch biopsies are preferred over shave biopsies.

HISTOPATHOLOGY

The renal tumors have a variety of microscopic patterns including oncocytic hybrid tumor (65%), chromophobe renal cell carcinoma (25%), renal oncocytoma (3%) and occasionally clear cell or papillary renal cell carcinoma. The tumors tend to be multiple and bilateral.

SEROLOGIC TESTS: None

IMAGING

About 90% of patients have multiple bilateral lung cysts with an average of 16 cysts; these are best identified with chest computed tomography (CT). Of this group, about 25% have a history of at least one spontaneous pneumothorax. All patients with Birt-Hogg-Dubé syndrome who have a pneumothorax will have multiple lung cysts.

The best imaging approach to the renal tumors has not been established. Both contrast CT and magnetic resonance imaging (MRI) have proponents; the role of ultrasonography is being investigated.

GENETIC TESTS

FLCN (folliculin) is the only gene known to be associated with Birt-Hogg-Dubé syndrome. Sequence analysis detects mutations in 90% of clinically affected individuals.

Who is at Risk for Developing this Disease?

Birt-Hogg-Dubé syndrome is a rare disorder; several hundred families have been described in the literature. Estimates of incidence and prevalence are not available. Individuals and families with multiple renal tumors or multiple pneumothoraces and no cutaneous findings are likely to be overlooked but generally still have Birt-Hogg-Dubé syndrome with FLCN mutations.

What is the Cause of the Disease?

Etiology

Pathophysiology

Birt-Hogg-Dubesyndrome is inherited in an autosomal dominant fashion. The offspringof an affected individual have a 50% chance of inheriting an abnormal FLCN gene and developing the disease. Some 10% of clinically diagnosed cases do not have mutations in FLCN.Some patients may have only renal tumors, lung cysts or cutaneouslesions, reflecting incomplete gene expression, perhaps explained bydifferent mutations.

FLCNappears to be a tumor-suppressor gene in the kidney. It up-regulatesthe mTOR complex via phosphorylation of RPS6 (ribosomal protein S6),thus working as a counterbalance to the TSC2 gene of tuberous sclerosis.

Systemic Implications and Complications

The two main systemic problems are multiple, bilateral renal tumors and multiple pulmonary cysts often leading to spontaneous pneumothoraces.

The renal tumors are best diagnosed with contrast CT or MRI. It is unclear if ultrasonography is sufficiently sensitive. The tumors are usually asymptomatic and generally not aggressive. Patients with Birt-Hogg-Dubé syndrome have a sevenfold increased risk of developing renal carcinomas.

The pulmonary cysts are asymptomatic but the patients have a 50-fold increased risk of developing spontaneous pneumothoraces. They present like sporadic pneumothoraces with signs and symptoms ranging from none to chest pain and dyspnea. Most pneumothoraces can be recognized on chest X-ray, but sometimes CT is needed to detect a small lesion.

Treatment Options

Table I. Options for treatment of Birt-Hogg-Dubé syndrome

Table I.

Options for treatment of Birt-Hogg-Dubé syndrome
Surgical Procedures
Laser ablation
Dermabrasion

Optimal Therapeutic Approach for this Disease

There is no totally satisfactory treatment of the multiple adnexal tumors, but fortunately none is really needed, as the lesions are invariably benign, and generally well accepted by patients. Laser ablation with a CO2 laser (10 watt, spot size 2mm, continuous mode) or erbium:YAG laser (4 to 5J/cm2) may produce temporary improvement, but recurrence is almost inevitable. Older ablative methods such as dermabrasion or curettage and cautery carry a much greater risk of scarring. See Table 1 on treatment options.

Patients should be encouraged not to smoke, as it may exacerbate their pulmonary problems. Pneumothoraces generally resolve without intervention, especially if small. Larger lesions may require aspiration or a chest tube.

The renal tumors usually grow slowly and are rarely aggressive. They cause problems primarily by reducing the amount of functional renal parenchyma. Tumors are usually monitored and first excised when they approach 3cm in diameter. Because of the risk of additional tumors, as much renal tissue as possible should be conserved (nephron-sparing surgery).

Patient Management

Patients in whom the diagnosis is suspected should be offered genetic testing and counseling. If the diagnosis is confirmed, then family members at risk should also be tested and counseled. A precise genetic diagnosis eliminates the need for continued monitoring of patients theoretically at risk who do not have a FLCN mutation.

Prenatal genetic analysis is possible if a specific FLCN mutation has been identified in one parent. No routine follow-up is required for the skin tumors.

No routine imaging is required for the pulmonary cysts once a baseline CT has been obtained.

A reasonable approach to the renal tumors is to start annual imaging at 20 years of age. Both contrast CT and MRI can be employed; ultrasonography is probably not sensitive enough. If renal lesions are found, then the frequency of re-examination must be adjusted individually depending on the number and size of the tumors. If a patient has Birt-Hogg-Dubé syndrome or an FLCN mutation but normal imaging studies, then these should be repeated every 2 to 3 years.

Unusual Clinical Scenarios to Consider in Patient Management

Patients may present with only part of the triad--thus anyone with a personal or family history of any of the components (fibrofolliculomas/trichodiscomas, pulmonary cysts, renal tumors) should be considered at risk. Children and young adults with multiple cutaneous lesions sometimes fail to develop the expected systemic complications.

A number of other tumors have been reported in Birt-Hogg-Dubé syndrome. The early reports included both gastrointestinal polyposis and thyroid disease but neither association is well established. The role in gastrointestinal carcinoma is controversial; perhaps a few specific mutations may predispose to malignancies. Parotid oncocytomas appear more common, so any salivary gland mass should be investigated promptly. Melanomas have also been reported with increased frequency, but this may just reflect closer surveillance. The best approach is to monitor closely for any systemic tumor which has already appeared in other family members.

What is the Evidence?

Kluger, N, Giraud,, S, Coupier, I, Avril, MF, Dereure, O, Guillot, B. " Birt-Hogg-Dubé syndrome: clinical and genetic studies of 10 French families". Br J Dermatol. vol. 162. 2010. pp. 527-37.

(Detailed study of 10 large French pedigrees as well as extensive review.)

Misago, N, Kimura, T, Narisawa, Y. "Fibrofolliculoma/trichodiscoma and fibrous papule (perifollicular fibroma/angiofibroma): a revaluation of the histopathological and immunohistochemical features". J Cutan Pathol. vol. 36. 2009. pp. 943-51.

(Reviews cutaneous overlap between Birt-Hogg-Dubé syndrome and tuberous sclerosis.)

Nickerson, ML, Warren, MB, Toro, JR, Matrosova, V, Glenn, G, Turner, ML. "Mutations in a novel gene lead to kidney tumors, lung wall defects and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome". Cancer Cell. vol. 2. 2002. pp. 157.

(First description of gene.)

Menko, FH, van Steensel, MA, Giraud, S, Friis-Hansen, L, Richard, S, Ungari, S. "Birt-Hogg-Dubé syndrome: diagnosis and management". Lancet Oncol. vol. 10. 2009. pp. 1199-206.

(Review from European Birt Hogg Dube Consortium on current diagnosis and treatment.)

Schulz, T, Hartschuh, W. "Birt-Higg-Dubé syndrome and Hornstein-Knickenberg syndrome are the same. Different sectioning technique as the cause of different histology". J Cutan Pathol. vol. 26. 1999. pp. 55-61.

(Classic paper showing that there is only one cutaneous tumor with multiple overlapping microscopic patterns.)

Toro, JR, Glenn, G, Duray, P, Darling, T, Weirich, G, Zbar, B. ". Birt-Hogg-Dubé syndrome: a novel marker of kidney neoplasia". Arch Dermatol. vol. 135. 1999. pp. 1195-202.

(First detailed paper from National Cancer Institute showing link to renal tumors and describing oral lesions.)

Toro, JR, Pautler, SE, Stewart, L, Glenn, GM, Weinreich, M, Toure, O. "Lung cysts, spontaneous pneumothorax and genetic associations in 89 families with Birt-Hogg-Dubé syndrome". Am J Respir Crit Care Med. vol. 175. 2007. pp. 1044-53.

(Best discussion of pulmonary manifestations.)

Toro, JR, Wei, MH, Glenn, GM, Weinreich, M, Toure, O, Vocke, C. "BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports". J Med Genet. vol. 45. 2008. pp. 321-31.

(Update on genetic aspects.)

Toro, JR. "Birt-Hogg-Dubé syndrome".

(Detailed, regularly updated website.)

Zbar, B, Alvord, WG, Glenn, G, Turner, M, Pavlovich, CP, Schmidt, L. "Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome". Cancer Epidemiol Biomarkers Prev. vol. 11. 2002. pp. 393-400.

(Best estimation of risks.)
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