14 Birt-Hogg-Dubé Syndrome

Synonyms: None Etiology: Mutation in the folliculin gene, chromosome 17p11.2 Associations: Fibrofolliculomas, trichodiscomas, acrochordons, pulmonary cysts with spontaneous pneumothorax, renal carcinoma, and colorectal carcinoma in some kindreds Clinical: Skin-colored papules of face, neck, ears, and upper trunk, with intertriginous soft papules Histology: Trichodiscoma—interfollicular ovoid nodule with spindled cells in loose fibrillary stroma Fibrofolliculoma—central follicle with extension of irregular epithelial strands into surrounding well-defined cellular fibrous stroma IHC: CD34+, S100− Evaluation: Abdominal and chest CT Treatment: Early tumor excision, laser resurfacing of facial lesions for cosmetic improvement Prognosis: Excellent with early diagnosis and vigilant monitoring

In 1977, Birt, Hogg, and Dubé described a kindred of 70 reported to have histologic fi ndings typical of acrochor- individuals, some of whom presented with small skin- dons (1). However, a subsequent study suggests that colored papules, predominantly of the face. These devel- they have pathologic features of fibrofolliculoma and oped in early adulthood, and were noted to be inherited trichodiscoma (3). in a dominant pattern (1). The histomorphology of the The original kindred described by Birt, Hogg, and Dubé papules was described as “abnormal hair follicles with had several individuals who developed hereditary medul- epithelial strands extending out from the infundibulum lary carcinoma of the thyroid. This tumor susceptibility of the hair follicle into a hyperplastic mantle of specialized was apparently inherited from an individual without the fibrous tissue.” The authors applied the term fibrofollicu- syndrome. Subsequent series have confirmed that thyroid loma to these lesions. Also described in these patients were carcinoma is not a part of the syndrome. While there were trichodiscomas and acrochordons. Trichodiscoma is a no internal manifestations of the syndrome in the original benign tumor of perifollicular mesenchyme. It is thought report, there have been subsequent descriptions of renal to represent a proliferation of the haarscheibe (hair disk), tumors. These include chromophobe renal cell carcino- a perifollicular “richly vascularized dermal pad covered mas, hybrid tumors with features of chromophobe carci- with thick epidermis containing Merkel cells and supplied noma and oncocytoma, oncocytoma, clear cell renal cell by a thick myelinated nerve the branches of which end at carcinoma, and rarely, papillary carcinoma (4). Addi- the lower epidermal surface and on the blood vessels of tional associations include pulmonary cysts with sponta- the dermal pad” (2). It is composed of a dermal interfol- neous pneumothorax (5), collagenomas (6), lipomas (7), licular proliferation of spindle cells in a loose connective angiolipomas (7), oral fibromas (8), parathyroid adeno- tissue matrix with varying amounts of mucin. It may have mas (7) including oncocytoma (9), and flecked chorioreti- an orientation parallel to the skin surface. The haarscheibe nopathy (10). Colonic polyps and adenocarcinoma have is thought to represent a mechanoreceptor in animal skin. been reported, but appear to occur in only some affected Its significance in humans is uncertain. The acrochordons families (11,12). In the largest series of BHD kindreds, reported in the original description of the syndrome were with 152 patients, no such cases were reported (5). 69 70 Deadly Dermatologic Diseases

The Birt-Hogg-Dubé (BHD) gene has been mapped to pression. The second hit can be caused by a somatic muta- chromosome 17p11.2 (13,14). It encodes a novel protein, tion in the normal gene copy, which would result in loss folliculin, which is highly conserved across species (15). of the normal gene product (17). Alternatively, expression Mutations in the BHD gene result in formation of a trun- of the normal gene copy may be suppressed by methyla- cated protein. Expression of BHD gene mRNA occurs in tion of the gene promoter region. Somatic inactivation of a wide variety of normal and neoplastic human tissue, but the BHD gene in sporadic renal cell carcinoma and is markedly reduced in BHD renal tumors, suggesting that colorectal carcinoma has been reported, implicating its the BHD gene product may serve as a tumor suppressor role in the development of a subset of these tumors (18). gene (16). Based on studies in a rat model of inherited A deletion in exon 4 of the BHD gene causes primary renal carcinoma, a germ line mutation is likely transmit- spontaneous pneumothorax without other features of ted as a heterozygote, with the homozygous form being BHD syndrome (19). lethal in fetal life. A “second hit” in the normal gene copy The fibrofolliculomas (FF) and trichodiscomas (TD) of is required for tumorigenesis. This second hit causes loss Birt-Hogg-Dubé syndrome usually develop in early adult- of heterozygosity. In this scenario, only the abnormal gene hood. These patients present with small skin-colored or product is expressed, and there is a loss of expression of white papules that have a predilection for the face, neck, the normal gene copy. This causes a lack of production of ears, and upper trunk (Figure 14.1A and 14.1B). Acrochor- a functional protein product that would aid in tumor sup- dons typically develop in intertriginous areas. The clinical

A B

FIGURE 14.1. (A and B) Trichodiscomas and fibrofolliculomas: dome-shaped skin-colored papules. 14. Birt-Hogg-Dubé Syndrome 71

Table 14.1. Clinical Differential Diagnosis of Facial Papules Associated Distribution Onset Features/Syndrome Trichodiscoma Diffuse Adulthood Birt-Hogg-Dubé syndrome fibrofolliculoma involvement of +/− Oral papules face, extrafacial involvement Syringoma Periocular Adulthood Yellow hue prominence Basaloid follicular Diffuse Variable +/− Pigment, comedos, hamartoma involvement of +/−alopecia face, may have extrafacial involvement Angiofibroma Central face Childhood Tuberous sclerosis Red hue, periungual fibromas, Shagreen patch Trichoepithelioma Central face Adolescence Skin-colored, varied lesion size Tricholemmoma Nose, cheeks Adulthood Cowden’s syndrome Tendency for epidermal change, cobblestone mucosa, acral keratoses

differential diagnosis of the facial papules includes tricho- sometimes retiform configuration, invested within a epithelioma, angiofibroma, tricholemmoma, basaloid well-defined cellular fibrous stroma with spindled cells follicular hamartoma, and syringoma. There are several (Figure 14.3). Much of the spindle cell component of clinical features that may help distinguish these entities both lesions is highlighted by antibodies to CD34, sup- (Table 14.1), but histopathologic evaluation is required for porting perifollicular mesenchyme as the histogenic definitive diagnosis. origin of both lesions (20). The histomorphology of Trichodiscoma is an ovoid superficial dermal nodule fibrofolliculoma is specific, but that of trichodiscoma is filling an interfollicular space (Figure 14.2). There is not. The differential diagnosis includes neurofibroma, generally epidermal flattening, with interwoven fascicles to which it may show considerable similarity. Neuro- of fibrillar collagen with spindled cells in a loose fibroma and trichodiscoma both display immuno- stroma that contains varying amounts of mucin and reactivity with antibodies to CD34, but elements of vascularity. Fibrofolliculoma may contain a similar neurofibroma will also label with antibodies to S100 mesenchymal component, but has a central distorted protein. Clinical presentation also helps distinguish follicle from which thin epithelial strands extend in a these two entities.

FIGURE 14.2. Trichodiscoma: periadnexal collagen is arranged in lamellae, with spindle cells and increased mucin. 72 Deadly Dermatologic Diseases

FIGURE 14.3. Fibrofolliculoma, per ifollicular dense collagen within which are embedded thin follicular epithelial strands.

Once the diagnosis of multiple fibrofolliculomas and References trichodiscomas has been made, a workup for underlying disease is mandatory, particularly because of the associa- 1. Birt AR, Hogg GR, Dubé J. Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. tion of the syndrome with renal carcinoma. A suggested Arch Dermatol 1977; 113: 1674–1677. evaluation is given in Table 14.2. 2. Pinkus H, Coskey R, Burgess GH. Trichodiscoma: A benign Management of the Birt-Hogg-Dubé syndrome is aimed tumor related to haarscheibe (hair disk). J Invest Dermatol at early detection and treatment of tumors and pneumo- 1974; 63: 212–218. thorax. Treatment of cutaneous lesions is principally of 3. De la Torre C, Ocampo C, Doval IG, Losada A, Cruces MJ. cosmetic importance. Laser skin resurfacing of the face Acrochordons are not a component of the Birt-Hogg-Dubé may result in significant improvement in appearance syndrome: Does this syndrome exist? Case reports and (21). review of the literature. Am J Dermatopathol 1999; 21: Birt-Hogg-Dubé syndrome is a more recently 369–374. recognized cancer-susceptibility syndrome that is of 4. Pavlovich CP, Walther MM, Eyler RA, et al. Renal tumors particular importance because of the potential for in the Birt-Hogg-Dubé syndrome. Am J Surg Pathol 2002; 26: 1542–1552. early recognition based on typical cutaneous fi ndings. 5. Toro JR, Glenn G, Duray P, et al. Birt-Hogg-Dubé syndrome: The benefits of diagnosis may be life-saving not A novel marker for kidney neoplasia. Arch Dermatol 1999; only for the index patient, but also for entire 135: 1195–1202. kindreds. 6. Weintraub R, Pinkus H. Multiple fibrofolliculomas (Birt- Hogg-Dubé) associated with a large connective tissue nevus. J Cutan Pathol 1977; 4: 289–299. 7. Chung JY, Ramos-Caro FA, Beers B, Ford MJ, Flowers F. Multiple lipomas, angiolipomas, and parathyroid adenomas in a patient with Birt-Hogg-Dubé syndrome. Int J Dermatol Table 14.2. Evaluation/management of the patient with Birt- 1996; 35: 365–367. Hogg-Dubé syndrome 8. Nadershahi NA, Wescott WB, Egbert B. Birt-Hogg-Dubé 1. Abdominal CT with contrast with attention to kidneys syndrome: A review and presentation of the first case with 2. Chest CT to evaluate for pulmonary cysts oral lesions. Oral Surg Oral Med Oral Pathol Oral Radiol 3. Lower gastrointestinal tract evaluation for polyps/carcinoma age Endod 1997; 83: 496–500. appropriate or as otherwise warranted based on family history 9. Liu V, Kwan T, Page EH. Parotid oncocytoma in the Birt- 4. Patient education regarding informing relatives of disease with Hogg-Dubé syndrome. J Am Acad Dermatol 2000; 43: attendant risks 1120–1122. 14. Birt-Hogg-Dubé Syndrome 73

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