Birt-Hogg-Dubé syndrome_0813 Derm Look 2
A white woman, aged 43 years, presented for facial lesions. The lesions were first noted approximately 10 years ago and had since grown in number and in size. She had previously been prescribed a number of acne medications and topical steroids, but nothing proved to be effective.
The woman’s father and paternal grandmother had similar lesions. Medical history revealed three episodes of spontaneous pneumothoraxes as a young adult. Family history was significant for renal cancer in her father. Physical examination revealed numerous firm, white, smooth, and dome-shaped papules across the cheeks and forehead.
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The histologic evaluation of a biopsy of a papule was diagnostic for a fibrofolliculoma, a rare and benign follicular hamartoma. The presence of a fibrofolliculoma in an individual with a history of spontaneous pneumothorax and family history of renal cancer led to the diagnosis of Birt-Hogg-Dubé (BHD) syndrome.
First described in 1977, this syndrome is a multisystem disorder characterized by the cutaneous triad of fibrofolliculomas, trichodiscomas, and acrochordons.1 Patients with BHD have an increased risk of internal malignancy and spontaneous pneumothorax.
BHD is a genetic condition that is inherited in an autosomal-dominant fashion with high penetrance; however, sporadic mutations have been described. In 2002, the genetic defect was identified as a germline defect in the folliculin (FLCN) gene on chromosome 17p11.2.2 This is the only gene known to be associated with BHD and is found in 88% of affected individuals.7
Current evidence suggests that the FLCN gene may have tumor-suppressor effects within the skin, kidneys, and lungs. As a result, the clinical constellation of BHD includes fibrofolliculomas, multiple pulmonary cysts, pneumothorax, and renal tumors that are often bilateral or multifocal.
The spectrum of cutaneous hamartomas associated with BHD includes fibrofolliculomas, angiofibromas or trichodiscomas, perifollicular fibromas, and acrochordons.3 However, the fibrofolliculoma is the only true hallmark specific for BHD. Lesions generally arise during the third decade of life and may be single or innumerable; areas typically affected include the scalp, forehead, face, and neck.4
A punch biopsy is necessary to confirm the diagnosis.5 The histologic pattern of a fibrofolliculoma demonstrates a hair follicle filled with multiple anastomosing epithelial strands surrounded by a well-circumscribed proliferation of mucin-rich stroma.6,7 The histologic pattern of a trichodiscoma, which is similar to an angiofibroma, shows a hamartomatous proliferation of fibrous and vascular stroma in the reticular dermis.7 Some suggest that fibrofolliculomas and trichodiscomas are opposite ends of the spectrum of the same disorder, with the trichodiscoma being the more mature form and the fibrofolliculoma the more immature.8 Although the conditions may be related, only the fibrofolliculoma is diagnostic for BHD; however, the presence of a trichodiscomas should raise one’s suspicion.7
Treatment for any of these lesions is limited. Several case reports have shown that laser ablation provides temporary improvement, but relapse is common.7 Alternative options include shave and cautery or curettage and hyfrecation.3 Lesion removal or destruction may leave unacceptable scarring. A modality to halt lesion development or growth has not yet been found.
The most life-threatening consequence of BHD is renal cancer. First documented in 1993, this association is now well-established. Kindred studies have indicated that most renal cancers occur later than the cutaneous findings; however, renal cancers have been described in the rare 20-year-old patient.9
Various histologic subtypes of renal cancer have been described, but a hybrid of chromophobe and oncocytoma renal carcinoma appears to be the most predominant.1 When associated with BHD, renal tumors are found to be bilateral and multifocal in more than half of those affected.5 In addition to renal carcinoma, benign renal cysts are also found, although the prevalence is largely unknown.
There are currently no set guidelines regarding surveillance of BHD. An annual renal MRI may be the best screening option; ultrasound is not sensitive enough to detect small lesions, and annual CT scans would subject the patient to an unacceptably high cumulative radiation dose.10
More than 80% of patients with BHD have pulmonary cysts detectable on CT.7 The number of reported cysts ranges widely, from zero to a staggering 166, with a mean count of 16 per patient. Although most of these lesions are asymptomatic, a cyst may be the presenting sign of this syndrome. In general, spontaneous pneumothorax is more frequently associated with cysts in the pulmonary apices; in BHD cases, most cysts are in the basal layer. Interestingly, Toro reported one or more pneumothoraces to develop in 24% of patients with BHD.7
Despite cystic changes, lung function in most BHD patients appears to be largely unaffected.3 Routine screening for pulmonary cysts is not indicated, but an individual with BHD should be educated as to the risk in addition to the signs and symptoms so that he or she may seek appropriate attention if necessary.2 Patients with BHD should also be encouraged not to smoke and to avoid unnecessary changes in external air pressure, which may cause rupture of pulmonary cysts.3
Alternatively, BHD should be suspecgted in patients who develop presumed idiopathic, spontaneous pneumothoraces. However, because of the clinical subtleties of BHD, practitioners must have a high index of suspicion to make the diagnosis.
Other genetic conditions with cutaneous lesions need to be in the differential diagnosis of BHD. Tuberous sclerosis, which has such overlapping clinical features as angiofibromas, cysts, and renal tumors, must be excluded. Additional conditions to be considered include familial trichoepitheliomas, multiple endocrine neoplasia type 1, and Cowden syndrome.7
Diagnostic criteria include the presence of five or more cutaneous papules with at least one histologically confirmed fibrofolliculoma.3 Although the original criteria for the diagnosis was based on skin pathology, recent investigations have shown that some individuals with BHD have pulmonary and renal involvement without skin findings.7 Genetic testing is now available.
Once the diagnosis is made, a systemic evaluation is warranted. Current recommendations include a thorough history and physical, an MRI scan of the abdomen to evaluate for renal lesions, and possibly a chest x-ray to assess for lung cysts. Since recent studies have suggested an association with intestinal polyps, surveillance for colorectal neoplasia should also be considered in all patients with BHD.
Fortunately, no malignancy was detected on evaluation in this case. Serial imaging studies will follow on a periodic basis. The woman declined genetic testing.
Allison Pagano is a fourth-year student at Medical College of Virginia Hospitals, Virginia Commonwealth University, in Richmond, where Julia Nunley, MD, is a professor of dermatology.
- Lindor NM, Hand J, Burch PA, Gibson LE. Birt-Hogg-Dube syndrome: an autosomal dominant disorder with predisposition to cancers of the kidney, fibrofolliculomas, and focal cutaneous mucinosis. Int J Dermatol. 2001;40:653-656.
- Reese E, Sluzevich J, Kluijt I, et al. Birt-Hogg-Dubé Syndrome. In: Riegert-Johnson DL, Boardman LA, Hefferon T, et al., eds. Cancer Syndromes. Bethesda, Md.: National Center for Biotechnology Information; 2009. Available from www.ncbi.nlm.nih.gov/books/NBK45326/.
- Menko FH, van Steensel MA, Giraud S, et al. Birt-Hogg-Dubé syndrome: diagnosis and management. Lancet Oncol. 2009;10:1199-1206.
- Mahto A. Birt-Hogg-Dubé syndrome. J Am Acad Dermatol. 2012;66 (Suppl 1):AB92.
- Garg A, Herts BR. Birt-Hogg-Dube syndrome. J Urol. 2012;188:1343-1344.
- Vincent A, Farley M, Chan E, James WD. Birt-Hogg-Dubé syndrome: a review of the literature and the differential diagnosis of firm facial papules. J Am Acad Dermatol. 2003;49:698-705.
- Toro JR. Birt-Hogg-Dubé Syndrome. In: Pagon RA, Adam MP, Bird TD, et al, eds. GeneReviews. Seattle, Wa.: University of Washington, Seattle; 1993-2013. Available from www.ncbi.nlm.nih.gov/books/NBK1522/.
- Scalvenzi M, Argenziano G, Sammarco E, Delfino M. Hereditary multiple fibrofolliculomas, trichodiscomas and acrochordons: syndrome of Birt-Hogg-Dubè. J Eur Acad Dermatol Venereol. 1998;11:45-47.
- Fahmy W, Safwat AS, Bissada NK, et al. Multiple/bilateral renal tumors in patients with Birt-Hogg-Dubé syndrome. Int Urol Nephrol. 2007;39:995-999.
- López V, Jordá E, Monteagudo C. [Birt-Hogg-Dubé syndrome: an update]. Actas Dermosifiliogr. 2012;103:198-206. Available at www.actasdermo.org/en/birthoggdube-syndrome-an-update/articulo/90140428/.
All electronic documents accessed August 9, 2013.