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More than fibrofolliculomas: A novel angiomatous lesion enters the Birt-Hogg-Dubé realm


DII small banner By Warren R. Heymann, MD
Dec. 9, 2016


I distinctly remember the first time I saw a case of the Birt-Hogg-Dubé (BHD) syndrome. I was attending the dermatology clinic at the University of Pennsylvania, when Julia Haimowitz and Allan Halpern asked for my opinion about a patient with dome-shaped whitish papules on the head, neck and ears. We all looked at each other quizzically, but agreed that this must be some syndrome! We hit the books that night, and — eureka! — we came across BHD. It has been 20 years since that case has been published (1), and over the past two decades the syndrome has become readily recognized by clinicians and its molecular biology defined (if not completely understood).

The following abstract by Toro (2) is an outstanding summation of the BHD syndrome:

The clinical characteristics of Birt-Hogg-Dubé syndrome (BHDS) include cutaneous manifestations (fibrofolliculomas, trichodiscomas/angiofibromas, perifollicular fibromas, and acrochordons), pulmonary cysts/history of pneumothorax, and various types of renal tumors. Disease severity can vary significantly even within the same family. Skin lesions typically appear during the third and fourth decades of life and typically increase in size and number with age. Lung cysts are mostly bilateral and multifocal; most individuals are asymptomatic but at high risk for spontaneous pneumothorax. Individuals with BHDS are at a sevenfold increased risk for renal tumors that are typically bilateral and multifocal and usually slow growing; median age of tumor diagnosis is 48 years. The most common renal tumors are a hybrid of oncocytoma and chromophobe histologic cell types (so-called oncocytic hybrid tumor) and chromophobe histologic cell types. Some families have renal tumor and/or autosomal dominant spontaneous pneumothorax without cutaneous manifestations.
 
BHDS is diagnosed by clinical findings and by molecular genetic testing. FLCN (also known as BHD) is the only gene known to be associated with BHDS. Sequence analysis detects pathogenic variants in FLCN in 88% of affected families, whereas 3%-5% have partial- or whole-gene deletions identified by other methods. Therefore, approximately 7%-9% of affected individuals who fulfill clinical diagnostic criteria do not have an identifiable FLCN pathogenic variant.

Treatment of manifestations: Laser ablation of folliculoma/trichodiscoma results in substantial improvement for a period of time, but relapse usually occurs. Pneumothoraces are treated as in the general population. When possible, nephron-sparing surgery is the treatment of choice for renal tumors, depending on their size and location. Surveillance: Periodic MRI of the kidneys is the optimal screening modality to assess for kidney lesions; abdominal/pelvic CT scan with contrast is an alternative when MRI is not an option, but the long term effects of cumulative radiation exposure is unknown; full body skin examination at routine intervals to evaluate for melanoma should be considered. Agents/circumstances to avoid: Cigarette smoking, high ambient pressures, and radiation. Evaluation of relatives at risk: Molecular genetic testing for the family-specific pathogenic variant for early identification of at-risk family members improves diagnostic certainty and reduces costly screening procedures in at-risk relatives who have not inherited the family-specific pathogenic variant.
 
BHDS is inherited in an autosomal dominant manner. The offspring of an individual with BHDS have a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the FLCN pathogenic variant of an affected family member has been identified.

As an aside, I was surprised to read about the recommendation about screening for melanoma in BHD patients — the association appears to be rare. To date, 6 such cases have been reported, the most recent in a 54 year-old man with BHD (3).

Nikolaidou et al detail the case of a 27 year old woman who presented with spontaneous pneumothoraces and was found to have mutation of the FCLN gene. She was then referred for a dermatologic evaluation, where the presence of multiple flesh-colored papules on the extremities was observed. Histologically, these lesions demonstrated signet-ring endothelial cells, confirmed by CD-31 and D2-40, within a collagenous stroma. Characteristic cutaneous features of BHD were not present (4).

Even though these lesions are distinctive, I find them reminiscent of angiofibromas. As the folliculin gene may be involved in the mTOR pathway, this should not be a surprise. Interestingly, a classical case of molecularly-proven BHD presented with overlapping features of tuberous sclerosis (TS), notably angiobromas of the nose and digit (Koenen tumor) has been reported (5). If that is the case, shouldn’t topical rapamycin be effective for the cutaneous lesions of BHD? In a split-face study of 19 patients with BHD syndrome treated with topical 0.1% rapamcyin for 6 months, there was no significant difference between rapamycin and placebo (6). Perhaps this is related to the finding that the mTOR pathway is inhibited in BHD and stimulated in TS (5).

Much has been learned about BHD since I saw that case two decades ago. I have little doubt that in 2036, should I be so fortunate to be around, medical students will be in awe that such diseases ever existed.

1. Haimowitz JE, Halpern AC, Heymann WR. Multiple hereditary dome-shaped papules and acrochordons. Birt-Hogg-Dubé syndrome. Arch Dermatol 1997; 133: 1163, 1166.
2. Toro JR. Birt-Hogg-Dubé syndrome. In Pagon RA, et al. GeneReviews [Internet] Seattle, 1993-2016. 2006 Feb 27[updated 2014 Aug 7].
3. Mota-Burgos A, et al. Birt-Hogg-Dubé syndrome in a patient with melanoma and a novel mutation in the FCLN gene. Int J Dermatol 2013: 323-6.
4. Nikolaidou C, et al. Multiple angiomatous nodules: A novel skin tumor in Birt-Hogg-Dubé syndrome. J Cutan Pathol 2016; 43: 1197-1202.
5. DiCicco B, et al. Koenen’s tumor and facial angiofibromas in a case of Birt-Hogg-Dubé syndrome: A cutaneous contribution to growing evidence of a relationship with tuberous sclerosis complex. JAAD Case Rep 2016; 2: 196-8.
6. Gijezen LM, et al. Topical rapamycin as treatment for fibrofolliculomas in Birt-Hogg-Dubé syndrome: A double-blind placebo-controlled randomized split-face trial. PLoS One 2014; 9(6): e99071.

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