Case of the Month

40 year old man with hundreds of cream colored papules on his face for many years. No facial symptoms. He has a history of 2 spontaneous pneumothoraces and his mother had multiple pneumothoraces and renal cancer.

What's Your Diagnosis?

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Fibrofolliculomas associated with Birt-Hogg-Dubé (BHD) syndrome

Discussion

Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant genodermatosis known to affect approximately 200 families worldwide. It is caused by a germline mutation in the FLCN gene on chromosome 17p11.2, which encodes the protein folliculin. Disease manifestation varies among those affected but can involve the skin, lungs, and kidneys.

The European Birt-Hogg-Dubé consortium proposed guidelines for the diagnosis as fulfilling either one major or two minor criteria.

Major criteria:

1. At least five fibrofolliculomas or trichodiscomas, at least one histologically confirmed, of adult onset.

2. Pathogenic FLCN germline mutation.

Minor criteria:

1. Multiple lung cysts: bilateral basally located lung cysts with no other apparent cause, with or without spontaneous primary pneumothorax.

2. Renal cancer: early onset (50 years) or multifocal or bilateral renal cancer or renal cancer of mixed chromophobe and oncocytic histology.

3. A first degree relative with BHD.

Fibrofolliculomas are benign hamartomas of the hair follicle and are the most common manifestation of BHD. Some believe that the fibrofolliculomas and trichodiscomas listed in the major criteria are the same entity on a histologic spectrum. They generally appear in the second or third decade of life and most commonly affect the face and upper torso. In many patients, new fibrofolliculomas develop over time, and existing lesions may grow in size. Acrochordons may be skin-colored or whitish. When acrochordons are biopsied, histopathologic findings of fibrofolliculoma may be seen.

Approximately 80% of patients develop pulmonary cysts, which can be numerous and bilateral. They commonly affect the base of the lungs. They typically develop between the ages of 30 and 40, but have been described from ages 20-85. BHD patients are at 50-fold increased risk of spontaneous pneumothorax, with approximately 24% of those with pulmonary cysts developing spontaneous pneumothoraces at an average age of 38 years (range: 22-71 years). FLCN-mutation carriers have developed pneumothoraces as early as age 7.

Renal tumors occur in approximately 12%-34% of BHD patients at a mean age of 50.4 years (range: 30-70 years). Patients have a 7-fold increased risk of renal tumors compared to the general population. Renal tumors can be bilateral, unilateral, or multifocal. The most common types of renal tumors in this patient population are chromophobe tumors and hybrid chromophobe / oncocytic tumors; however, clear cell carcinoma, papillary carcinoma, and mixed-type carcinoma may also occur.

For more information, see OMIM.

Codes

ICD10CM:
Q87.89 – Other specified congenital malformation syndromes, not elsewhere classified

SNOMEDCT:
110985001 – Multiple fibrofolliculomas

Look For

Key Cutaneous Signs of BHD:

• Fibrofolliculomas typically appear as 1-5 mm white or skin-colored dome-shaped papules that typically lack any umbilication. The nose and cheeks are generally most affected, but the rest of the face, neck, ears, and upper torso can also be involved.
• Trichodiscomas, angiofibromas, acrochordons, and perifollicular fibromas can also be present.
• Soft, discreet papules involving the oral mucosa, lips, buccal mucosa, and gingiva have been described.

Approximately 25% of FLCN-mutation carriers do not have cutaneous findings.

Noncutaneous Findings of BHD:

• Spontaneous pneumothoraces secondary to rupture of pulmonary cysts may occur, leading to dyspnea, increased respiratory rate, and diminished breath sounds on the affected side.
• Renal tumors are commonly asymptomatic. The classic triad of hematuria, flank mass, and pain occur in only a small percentage of patients. Other signs and symptoms include hypochromic anemia, pyrexia (20%), cachexia, fatigue, and weight loss (33%).

Chest X-Ray Findings:

Often subtle cystic lucencies of various sizes and shapes with the largest cysts positioned within the lower lobes in a patient with a renal cell cancer.

Chest CT Findings:

Multiple lung cysts of various size and shape with the largest cysts located in the lower lobes in a patient with history of a renal cell cancer. Lung cysts are differentiated from more common emphysema by findings of a thin wall (<2-3 mm), lack of a central core vessel (pulmonary artery), and lack of an upper lobe predominance commonly seen with smoking-related centrilobular / paraseptal emphysema.

Diagnostic Pearls

• The diagnosis of fibrofolliculoma should be considered in the differential diagnosis of white papules on the face and upper torso. · Multiple facial fibrofolliculomas should raise suspicion for BHD.
• A personal or family history of pulmonary cysts, spontaneous pneumothoraces, and/or renal cancer diagnosed at a young age can provide a helpful clue to diagnosis.
• Presence of fat in a renal tumor should lower suspicion for BHD, as fat is rare in tumors associated with BHD and is much more common in tuberous sclerosis complex and lymphangioleiomyomatosis.

Differential Diagnosis & Pitfalls

Skin Lesions:

The primary clinical differential includes other adnexal neoplasms and often requires histopathologic evaluation and/or looking for other associated organ system involvement for differentiation. Diagnostic entities include:

• Tuberous sclerosis complex
• Fibrous papules of the nose
• Sebaceous lesions including sebaceous hyperplasia or sebaceous adenoma. Both may have more of a yellow coloration and can be umbilicated, unlike classic fibrofolliculomas.
• Brooke-Spiegler syndrome – Spiradenomas and cylindromas are typically larger and may have a cerebriform appearance.
• Cowden syndrome
• Generalized basaloid follicular hamartoma syndrome
• Familial multiple discoid fibromas

Cystic Lung Disease:

• Lymphangioleiomyomatosis
• Pulmonary Langerhans cell histiocytosis
• Emphysema
• Lymphocytic interstitial pneumonia
• Follicular bronchiolitis
• Light-chain deposition disease
• Sjögren syndrome
• Amyloidosis

Familial Spontaneous Pneumothorax:

• Marfan syndrome – Patients with BHD syndrome do not have the body habitus typically associated with Marfan syndrome.
• Homocystinuria
• Ehlers-Danlos syndrome
• Alpha-1 antitrypsin deficiency

Renal Tumors:

• Sporadic hybrid chromophobe / oncocytic tumors
• Hereditary leiomyomatosis and renal cell cancer
• Von Hippel-Lindau syndrome – More commonly clear cell type renal cell carcinoma rather than chromophobe / oncocytic tumors in BHD.

Best Tests

BHD is a syndrome with proposed diagnostic criteria described in Synopsis.

• Punch biopsy of cutaneous papules should be performed to confirm a diagnosis of fibrofolliculoma.
• High-resolution CT scan of the chest is the preferred modality to diagnose lung involvement.
• Abdominal CT or MRI with IV contrast is preferred to evaluate for renal masses.
• Genetic testing and counseling for FLCN mutation should be offered, though a negative test does not necessarily rule out BHD.

Management Pearls

All patients suspected of having BHD should be offered genetic testing and counseling, and FLCN mutation carriers can begin surveillance at age 20.

Pulmonary:

Disease should be assessed by a pulmonologist, and CT imaging should be considered upon diagnosis to characterize the extent of lung disease. Smoking is believed to be a risk factor for pneumothorax, and patients should be strongly discouraged from smoking. Patients should be counseled on the risk of pneumothoraces with air travel and scuba diving as appropriate.

Renal:

Specialist referral to a nephrologist is recommended. There are no formal guidelines regarding surveillance for kidney disease. CT and MRI are the recommended imaging modalities, given concerns that ultrasound may not identify small renal masses. An MRI every 12-36 months beginning at age 20 has been suggested to limit radiation.

Healthcare Maintenance:

Pneumococcal vaccination and annual influenza vaccine, periodic pulmonary function testing if cystic disease is sufficient to impair lung function, and educating about symptoms of pneumothorax are all recommended.

Therapy

There is no medical therapy for BHD currently. However, there are management strategies for the manifestations of the disease, and clinical trials are under way.

Cutaneous:

Fibrofolliculomas are benign and do not require treatment. However, for cosmetic reasons, they can be treated with erbium:YAG, fractional CO2 laser, or curettage and hyfrecation. Recurrence may occur following treatment. Topical rapamycin has been tried but has no effect.

Pulmonary:

The recurrence rate of spontaneous pneumothoraces is 75% in BHD patients. Treatments such as video assisted thoracoscopy (VATS) and mechanical or chemical pleurodesis may be appropriate for recurrent or nonhealing cases. Given the high rate of recurrence, some recommend considering these treatments after the first pneumothorax.

Renal:

There are no formal guidelines for surgery, but it is generally recommended to consider active surveillance for tumors (3 cm and parenchyma sparing surgery for tumors)3 cm in size. A phase II clinical trial is ongoing to assess whether everolimus is safe and effective in patients with BHD-associated kidney malignancies. For metastatic renal malignancy, there is some evidence that tyrosine kinase inhibitors sorafenib and sunitinib may be beneficial.

References

(Discussion, above and below, from VisualDx.com, which Dr. Crutchfield is a Dermatology Editor. Visit the website to sign up for excellent educational access and information. Contributors: Nicole S. Gunasekera BA, William M. Lin MD, Susan Burgin MD, Lowell A. Goldsmith MD, MPH, Ryan R. Walsh MD, Joshua J. Jarvis MD, Alastair Moore MD)

Bratslavsky G, Woodford MR, Daneshvar M, Mollapour M. Sixth BHD symposium and first international upstate kidney cancer symposium: latest scientific and clinical discoveries. Oncotarget. 2016 Feb 25;. PubMed ID: 26933819

Kniffin CL, McKusick VA. OMIM#135150: Birt-Hogg-Dube syndrome. OMIM - Online Mendelian Inheritance in Man. http://omim.org/entry/135150. Accessed 2016 Jan 11.

Toro JR. Birt-Hogg-Dubé syndrome. GeneReviews™ [Internet]. http://www.ncbi.nlm.nih.gov/books/NBK1522/. Accessed 2016 Jan 11.

Kuroda N, Furuya M, Nagashima Y, et al. Review of renal tumors associated with Birt-Hogg-Dubé syndrome with focus on clinical and pathobiological aspects. Pol J Pathol. 2014 Jun;65(2):93-9. PubMed ID: 25119168

Gijezen LM, Vernooij M, Martens H, et al. Topical rapamycin as a treatment for fibrofolliculomas in Birt-Hogg-Dubé syndrome: a double-blind placebo-controlled randomized split-face trial. PLoS One. 2014;9(6):e99071. PubMed ID: 24910976

Gupta N, Seyama K, McCormack FX. Pulmonary manifestations of Birt-Hogg-Dubé syndrome. Fam Cancer. 2013 Sep;12(3):387-96. PubMed ID: 23715758

Stamatakis L, Metwalli AR, Middelton LA, Marston Linehan W. Diagnosis and management of BHD-associated kidney cancer. Fam Cancer. 2013 Sep;12(3):397-402. PubMed ID: 23703644

Vera-Badillo FE, Conde E, Duran I. Chromophobe renal cell carcinoma: a review of an uncommon entity. Int J Urol. 2012 Oct;19(10):894-900. PubMed ID: 22715810

Menko FH, van Steensel MA, Giraud S, et al, European BHD Consortium. Birt-Hogg-Dubé syndrome: diagnosis and management. Lancet Oncol. 2009 Dec;10(12):1199-206. PubMed ID: 19959076

Toro JR, Wei MH, Glenn GM, et al. 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. 2008 Jun;45(6):321-31. PubMed ID: 18234728

Toro JR, Pautler SE, Stewart L, et al. Lung cysts, spontaneous pneumothorax, and genetic associations in 89 families with Birt-Hogg-Dubé syndrome. Am J Respir Crit Care Med. 2007 May 15;175(10):1044-53. PubMed ID: 17322109

Pavlovich CP, Walther MM, Eyler RA, et al. Renal tumors in the Birt-Hogg-Dubé syndrome. Am J Surg Pathol. 2002 Dec;26(12):1542-52. PubMed ID: 12459621

Nickerson ML, Warren MB, Toro JR, et al. 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. 2002 Aug;2(2):157-64. PubMed ID: 12204536

Zbar B, Alvord WG, Glenn G, et al. Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome. Cancer Epidemiol Biomarkers Prev. 2002 Apr;11(4):393-400. PubMed ID: 11927500

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