Comedonal and Cystic Fibrofolliculomas in Birt-Hogg-Dube Syndrome

Research

Case Report/Case Series Comedonal and Cystic Fibrofolliculomas in Birt-Hogg-Dube Syndrome

Ohara Aivaz, MD; Suzanne Berkman, MD; Lindsay Middelton, RN, CGC; W. Marston Linehan, MD; John J. DiGiovanna, MD; Edward W. Cowen, MD, MHSc

IMPORTANCE The differential diagnosis of extensive open comedones includes inherited genetic syndromes and several acquired conditions. Birt-Hogg-Dube syndrome (BHD) is not typically included in the differential diagnosis of syndromes with comedonal lesions. Given the potentially life-threatening systemic complications associated with BHD, early recognition and diagnosis of the condition is important.

OBSERVATIONS We describe comedonal or cystic fibrofolliculomas in 4 patients with BHD. Cutaneous lesions were identified on the face, neck, chest, and abdomen.

CONCLUSIONS AND RELEVANCE Comedonal or cystic fibrofolliculomas are a variant of fibrofolliculomas that have not previously been well characterized in patients with BHD and Author Affiliations: Author represent a novel diagnostic clue to its early detection and diagnosis. Expanding the affiliations are listed at the end of this phenotypic features of BHD facilitates earlier diagnosis of the syndrome, which allows for article. early surveillance of renal cancer in affected patients as well as disease screening in their Corresponding Author: Edward W. relatives. Cowen, MD, MHSc, Dermatology Branch, Center for Cancer Research, National Cancer Institute, National JAMA Dermatol. 2015;151(7):770-774. doi:10.1001/jamadermatol.2015.0215 Institutes of Health, 10 Center Dr, Published online May 13, 2015. Bethesda, MD 20892 ([email protected]).

irt-Hogg-Dube syndrome (BHD) is an uncommon autosomal dominant genodermatosis that is charac- Report of Cases B terized by hair follicle hamartomas as well as increased risk of renal cell carcinoma (RCC), lung cysts, and Case 1 spontaneous pneuomothorax. It is caused by loss-of- A man in his 70s with multiple asymptomatic facial papules function mutations in the BHD gene, FLCN (OMIM 607273), and a history of grade 3 clear cell RCC that was treated with on chromosome 17p11.2.1 The syndrome was described right nephrectomy was referred to the National Institutes of in 1977 by Birt and colleagues2 as a triad of fibrofollic- Health for evaluation for possible BHD. He reported having ulomas, trichodiscomas, and acrochordons. However, 2 a collection of black papules on the left lower abdomen that years earlier, Hornstein and Knickenberg had described a had possibly developed during puberty. The patient had patient with perifollicular fibromas, skin tags, and colonic known bullous emphysematous changes in the lungs but polyps that likely represented the same syndrome.3 Subse- denied having a history of pneumothorax. His family his- quently, multiple lung cysts, spontaneous pneumothorax, tory was significant for a nephew with a history of sponta- and RCC have been firmly established as systemic features neous pneumothorax and a confirmed diagnosis of BHD as of BHD.4 well as 2 brothers with numerous facial papules, 1 of whom Two early case reports3,5 of BHD described individuals died of RCC. with papules that were clinically and histopathologically Findings from the physical examination revealed hun- consistent with comedonal fibrofolliculoma; how- dreds of 1- to 4-mm firm skin-colored papules on the face, ever, these findings, to our knowledge, have not been other- ears, chest, back, and flanks (Figure 1A). On the left side of wise characterized in published articles. We describe 4 the lower abdomen, there was a large collection of open individuals with BHD and fibrofolliculomas with wide- comedones with thick keratin plugs overlying skin-colored spread open comedones and propose that BHD be included papules that ranged from 2 to 6 mm (Figure 1B and C). in the differential diagnosis of acquired and genetic con- Numerous acrochordons were also noted in the bilateral ditions with extensive open comedones. Informed written axilla. consent was obtained from all patients. Protocol was ap- Histopathologic findings from a skin-colored papule on proved by the National Cancer Institute Institutional Review the postauricular skin on the left side revealed a classic Board. fibrofolliculoma with thin epithelial strands emanating

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Figure 1. Comedonal Fibrofolliculomas in a Man With Birt-Hogg-Dube Syndrome

A White noncomedonal fibrofolliculomas across midface B Fibrofolliculomas with central open comedones

Case 1. A, Typical appearance of multiple white noncomedonal fibrofolliculomas extending over the midface. B, Hundreds of small papules on the left abdomen with prominent central open comedones.

from a hair follicle. Histopathologic findings from an open vealed numerous dome-shaped white papules, some of which comedo overlying a skin-colored papule showed similar epi- appeared to have dark central cores. On the right flank were thelial strands emanating from a cystic dilated follicle that groups of perifollicular dome-shaped papules coalescing into were consistent with a cystic fibrofolliculoma. a plaque. Axillary acrochordons, verrucous papules of the lower Findings from a computed tomographic scan of the mucosal lip, and 3 lipomas were also noted. chest, abdomen, and pelvis showed scattered lung cysts and Histopathologic findings from multiple papules on the left evidence of right nephrectomy. Findings from magnetic side of the forehead, central chest, and right flank were con- resonance imaging identified 2 small benign cysts in the left sistent with fibrofolliculoma. In addition, results from biopsy kidney. Results from further diagnostic evaluation revealed of the lesion on the right flank showed a cystically dilated hair a heterozygous c.1285dupC mutation in the FLCN gene. follicle surrounded by a zone of fibrosis with thin linear ex- tensions of follicular shaft epithelium into the fibrous stroma Case 2 that was consistent with cystic fibrofolliculoma. A man in his 30s with a history of spontaneous pneumotho- Findings from a computed tomographic scan of the rax and known FLCN mutation presented for evaluation of chest, abdomen, and pelvis did not show lung or kidney asymptomatic white papules on the face. The patient abnormalities, and a consistent germline FLCN mutation that reported that his mother had numerous similar facial pap- segregated with the disease was not detected. Nevertheless, ules. He denied having a personal or family history of RCC the patient fulfilled the clinical diagnostic criteria for BHD. but reported multiple episodes of “pleurisy” in his mother and grandmother. Findings from the physical examination Case 4 revealed 2 single, 4-mm, white, flat-topped papules on the A woman in her 60s with a family history of BHD presented to right cheek and the preauricular skin on the left side. the National Institutes of Health for evaluation. She reported Results from histopathologic examination of one of the having progressive onset of cutaneous papules since her early facial papules revealed a dilated cystic follicle with thin epi- 40s. Her mother had similar papules, as did her son, who had thelial strands emanating from the follicle that was consis- RCC and carried a diagnosis of BHD. Findings from the physi- tent with comedonal fibrofolliculoma. Findings from a com- cal examination revealed hundreds of 1- to 5-mm dome- puted tomographic scan of the chest revealed thin-walled shaped papules that were skin-colored to white and diffusely lung cysts and magnetic resonance imaging of the abdomen covered the face, ears, shoulders, trunk, and extremities. showed a 7-mm hyperintense focus in the right kidney, pre- Some of the lesions were larger and had central, dark, keratin- sumed to be a benign cyst. filled puncta (Figure 2A). Multiple acrochordons were also noted on the patient’s neck and axillae. Histopathologic find- Case 3 ings from 2 biopsy specimens of the supraclavicular skin A man in his 50s presented for evaluation of possible familial revealed comedonal fibrofolliculoma (Figure 2B and C). Find- RCC syndrome. Several family members, including the pa- ings from a computed tomographic scan showed scattered tient’s brother, had been diagnosed with RCC. He denied hav- pneumatocysts in both lung fields and bilateral scattered ing a history of kidney disease or pneumothorax; however, he renal lesions that were consistent with benign cysts. Genetic and several relatives exhibited facial papules. Findings from testing was not conducted; however, the patient fulfilled the examination of the patient’s face, chest, back, and flanks re- clinical diagnostic criteria for BHD.

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Figure 2. Comedonal Fibrofolliculomas in a Woman With Birt-Hogg-Dube Syndrome

A Variably sized fibrofolliculomas B Cystic hair follicle with C Cystic hair follicle with fibrofolliculoma features on the neck fibrofolliculoma features at higher magnification

Case 4. A, Multiple variably sized fibrofolliculomas on the neck, several with cystic follicle, some of which reconnect to the follicular epithelium (hematoxylin-eosin, and/or comedonal appearance. B, Cystically dilated hair follicle containing original magnification ×40). C, Higher magnification shows proliferation of the keratinous debris in the dermis. There is proliferation of the perifollicular fibrous perifollicular fibrous sheath surrounding the infundibular portion of the cystically sheath partially surrounding the infundibular portion of the cystically dilated hair dilated hair follicle, with thin epithelial strands emanating from the infundibular follicle. Thin epithelial strands emanate from the infundibular portion of the hair portion of the hair follicle (hematoxylin-eosin, original magnification ×200).

located sebaceous lobules.9 Acrochordons, the third cutane- Discussion ous sign of BHD, are common in the general population and therefore lack diagnostic utility. Furthermore, acrochordon- Currently, FLCN is the only gene known to cause BHD.1 This like lesions may be a phenotypic variant of fibrofolliculoma.8 gene encodes the protein folliculin, which is expressed in the Other cutaneous lesions that are reported to occur in patients kidneys, lungs, and skin.6 Although the precise tumor- with BHD include facial angiofibromas, lipomas, angiolipo- suppressor function of folliculin is still unclear, Baba and mas, and oral mucosal fibromas.8 colleagues7 identified folliculin-interacting protein 1, which in- Patients with BHD have a 7-fold increased risk of develop- teracts with folliculin through its C terminus. Many of the re- ing renal tumors compared with unaffected siblings. The tumors ported pathogenic mutations in patients with BHD led to trun- are often multifocal or bilateral and are diagnosed at a mean age cation of the C-terminal end of the protein, thereby preventing of 50 years.1,4 In a study of 130 renal tumors in 30 patients with folliculin from binding to folliculin-interacting protein 1. The BHD, a chromophobe/oncocytic hybrid was most common 5′ adenosine monophosphate (AMP)–activated protein ki- (50%), followed by chromophobe RCC (34%), clear cell RCC (9%), nase is believed to interact with folliculin-interacting protein oncocytoma (5%), and papillary RCC (2%).10 More than 80% of 1 and to negatively regulate mammalian target of rapamycin adult patients with BHD have multiple lung cysts, often in the activity. Interestingly, several other syndromes, including tu- basal lung regions, and affected individuals have a 50-fold in- berous sclerosis complex and Peutz-Jeghers syndrome, also re- creased risk of spontaneous pneumothorax compared with their sult from mutations in the 5′ AMP-activated protein kinase and unaffected siblings.6 Other tumors reported in patients with BHD mammalian target of rapamycin pathways, emphasizing the include colorectal polyps, colorectal cancer, melanoma, pa- importance of these pathways in harmatomatous cell growth.7 rotid gland tumors, and breast cancer.4,6 A causal relationship Fibrofolliculomas and trichodiscomas in BHD typically between these tumors and BHD has not yet been established.8 develop in the third to fourth decades of life. Both are hair Menko and colleagues8 proposed criteria for the diagno- follicle hamartomas that are clinically indistinguishable, sis of BHD. Suggested major criteria include 5 or more adult- appearing as small, dome-shaped, white papules on the face, onset fibrofolliculomas or trichodiscomas (at least 1 must be neck, and upper trunk. Fibrofolliculomas and trichodiscomas histologically confirmed) or a pathogenic FLCN germline mu- also have overlapping histological features and punch skin tation. Minor criteria are multiple lung cysts that are bilateral biopsy, rather than shave biopsy, is preferred to examine the and basally located, with no other apparent cause (with or with- overall architecture of the skin lesions.8 A fibrofolliculoma out spontaneous pneumothorax); RCC that is either (1) early appears as a proliferation of the perifollicular fibrous sheath onset (age, <50 years), multifocal, or bilateral or (2) of mixed surrounding the infundibular portion of the hair follicle, with chromophobe and oncocytic histologic features; or a first- thin epithelial strands emanating from this infundibulum degree relative with BHD. Individuals who fulfill 1 major or 2 into a dense collagenous stroma.9 A trichodiscoma, which minor criteria are given a clinical diagnosis of BHD.8 also emanates from a hair follicle, is a fibrous tumor com- Patients with BHD may manifest a variety of skin lesions posed of thin-walled blood vessels and often has peripherally ranging from classic-appearing, white, 1- to 2-mm fibrofollicu-

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Table 1. Syndromes Associated With Multiple Comedones

Condition Inheritance/Gene Age at Onset of Comedones Clinical Findings Birt-Hogg-Dube AD/FLCN Third or fourth decade Dome-shaped white papules with or syndrome of life without central keratin plug Generalized basaloid AD/PTCH Birth to early childhooda Open comedones, milia, small follicular hamartoma skin-colored to hyperpigmented syndrome11 papules; palmoplantar pitting, hypohidrosis, hypotrichosis; increased risk of BCC, may be associated with multiple sclerosis Bazex syndrome12 XLD/unknown Birth to early childhooda Open comedones, milia; multiple BCCs (usually on face); hypotrichosis, hypohidrosis, follicular atrophoderma Dowling-Degos disease AD/KRT5 Late adolescence Comedolike hyperkeratotic follicular to early 20s papules, reticulated pigmentation of flexures, pitted perioral scars Familial dyskeratotic AD/unknown Childhood or adolescence Generalized comedones (spare face, comedones13 scalp, palms, soles) Comedonal Darier AD/ATP2A2 Variable (adolescence to Large open and closed comedones on disease14 seventh decade of life) face and scalp, classic Darier lesions also present Abbreviations: AD, autosomal Tuberous sclerosis AD/TSC1, TSC2 Childhood Folliculocystic and collagen dominant; BCC, basal cell carcinoma; complex15 hamartomas with multiple comedolike XLD, X-linked dominant. openings and keratin-filled infundibular a cysts; angiofibromas, ungual fibromas, Hypotrichosis and hypohidrosis Shagreen patch, hypomelanotic present at birth. b macules b Not a complete list.

Table 2. Acquired Causes of Multiple Comedones

Condition Causative Agent Clinical Characteristics Acne vulgaris Sebum production due to hormonal stimulation, Papules; pustules; open comedones corneocyte adhesion/proliferation, and Propionibacterium acnes; medications Acne from radiation treatment Previous exposure to therapeutic ionizing radiation Open comedones at site of previous irradiation Pseudoacne of the transverse nasal crease Unknown Linear arrangement of comedones along the lower third of the nose Favre-Racouchot syndrome Actinic damage Numerous periorbital open comedones Nevus comedonicus Unknown Clusters of dilated follicular openings containing keratin plugs, often distributed linearly Occupational/environmental acne Chloracne Halogenated aromatic compounds Open and closed comedones; straw-colored cysts in malar region, posterior auricular region, axillae, scrotum Oil acne Cutting oils containing large amounts of mineral oil Comedones and inflammatory papules on dorsal (often seen in mechanics and those operating hands and extensor surfaces of arms machine tools) Pitch- or coal-tar acne Pitch or coal tar (often seen in roofers and road Numerous open comedones on malar region paving–crew members) Trichostasis spinulosa Unknown Comedolike lesions containing vellus hairs and keratin on face and trunk Childhood flexural comedones Unknown Double-orifice comedones in flexures, often axillae or groin, of prepubescent children

lomas to larger comedonal or cystic fibrofolliculomas. Clini- cally, comedonal folliculomas consist of open comedones cen- Conclusions tered in skin-colored to white papules or cysts. Histologically, cystically dilated hair follicles that contain keratinous debris We describe comedonal or cystic fibrofolliculomas in 4 pa- are present along with the classic features of fibrofollicu- tients with BHD. Birt-Hogg-Dube syndrome should be in- loma. Comedonal fibrofolliculomas are a variant of fibrofol- cluded in the differential diagnosis of conditions with exten- liculomas that are not previously well characterized in pa- sive open comedones to assist in the early detection and tients with BHD. However, multiple open comedones are a diagnosis of BHD. Because BHD is a condition with variable feature of several genodermatoses (Table 1) and acquired con- clinical presentation, broader characterization of the pheno- ditions (Table 2). We propose that BHD be included in the dif- typic variations of this syndrome will allow for further clues ferential diagnosis of multiple comedonal papules to facili- to diagnose the condition and thus screen for the associated tate early diagnosis of the syndrome. life-threatening systemic complications.

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ARTICLE INFORMATION approval of the manuscript; and decision to submit 7. Baba M, Hong SB, Sharma N, et al. Folliculin Accepted for Publication: January 28, 2015. the manuscript for publication. encoded by the BHD gene interacts with a binding Additional Contributions: Chyi-Chia Richard Lee, protein, FNIP1, and AMPK, and is involved in AMPK Published Online: May 13, 2015. and mTOR signaling. ProcNatlAcadSciUSA. 2006; doi:10.1001/jamadermatol.2015.0215. MD, PhD, Laboratory of Pathology, National Cancer Institute, provided assistance with interpretation of 103(42):15552-15557. Author Affiliations: Department of Dermatology, the pathologic sample and photomicrograph 8. Menko FH, van Steensel MA, Giraud S, et al; Georgetown University Hospital/Washington production and Maria L. Turner, MD, Dermatology European BHD Consortium. Birt-Hogg-Dubé Hospital Center, Washington, DC (Aivaz); Suzanne Branch, National Cancer Institute, gave helpful syndrome: diagnosis and management. Lancet Oncol. L. Berkman, MD, Inc, Beverly Hills, California comments regarding the manuscript. They were 2009;10(12):1199-1206. (Berkman); Urologic Surgery and the Urologic not financially compensated. Oncology Branch, National Cancer Institute, 9. Misago N, Kimura T, Narisawa Y. National Institutes of Health, Bethesda, Maryland Disclaimer: Dr Cowen is an editorial board member Fibrofolliculoma/trichodiscoma and fibrous papule (Middelton, Linehan); Dermatology Branch, Center and was not involved in the editorial evaluation or (perifollicular fibroma/angiofibroma): a revaluation for Cancer Research, National Cancer Institute, decision to accept this work for publication. of the histopathological and immunohistochemical National Institutes of Health, Bethesda, Maryland features. J Cutan Pathol. 2009;36(9):943-951. (DiGiovanna, Cowen); Section Editor, “The Cutting REFERENCES 10. Pavlovich CP, Walther MM, Eyler RA, et al. Renal Edge,” JAMA Dermatology (Cowen). 1. Nickerson ML, Warren MB, Toro JR, et al. tumors in the Birt-Hogg-Dubé syndrome. Am J Surg Author Contributions: Drs Aivaz and Cowen had Mutations in a novel gene lead to kidney tumors, Pathol. 2002;26(12):1542-1552. full access to all the data in the study and take lung wall defects, and benign tumors of the hair 11. Wheeler CE Jr, Carroll MA, Groben PA, responsibility for the integrity of the data and the follicle in patients with the Birt-Hogg-Dubé Briggaman RA, Prose NS, Davis DA. Autosomal accuracy of the data analysis. syndrome. Cancer Cell. 2002;2(2):157-164. dominantly inherited generalized basaloid follicular Study concept and design: Aivaz, Berkman, Linehan, 2. Birt AR, Hogg GR, Dubé WJ. Hereditary multiple hamartoma syndrome: report of a new disease in a Cowen. fibrofolliculomas with trichodiscomas and North Carolina family. J Am Acad Dermatol. 2000; Acquisition, analysis, or interpretation of data:All acrochordons. Arch Dermatol. 1977;113(12):1674-1677. 43(2, pt 1):189-206. authors. 3. Happle R. Hornstein-Birt-Hogg-Dubé syndrome: 12. Goeteyn M, Geerts ML, Kint A, De Weert J. The Drafting of the manuscript: Aivaz, Berkman, Linehan. a renaming and reconsideration. Am J Med Genet A. Bazex-Dupré-Christol syndrome. Arch Dermatol. Critical revision of the manuscript for important 2012;158A(6):1247-1251. 1994;130(3):337-342. intellectual content: Middleton, Linehan, DiGiovanna, Cowen. 4. Zbar B, Alvord WG, Glenn G, et al. Risk of renal 13. Hall JR, Holder W, Knox JM, Knox JM, Verani R. Obtained funding: Linehan. and colonic neoplasms and spontaneous Familial dyskeratotic comedones: a report of three Administrative, technical, or material support: pneumothorax in the Birt-Hogg-Dubé syndrome. cases and review of the literature. J Am Acad Linehan, DiGiovanna. Cancer Epidemiol Biomarkers Prev. 2002;11(4): Dermatol. 1987;17(5, pt 1):808-814. Study supervision: Linehan, DiGiovanna. 393-400. 14. Chung J, Kim JY, Gye J, et al. A case of familial Conflict of Interest Disclosures: None reported. 5. Weintraub R, Pinkus H. Multiple fibrofolliculomas comedonal Darier’s disease. Ann Dermatol. 2011;23 (Birt-Hogg-Dubé) associated with a large connective (suppl 3):S398-S401. Funding/Support: This study was supported by the tissue nevus. J Cutan Pathol. 1977;4(6):289-299. Center for Cancer Research, National Cancer 15. Torrelo A, Hadj-Rabia S, Colmenero I, et al. Institute, National Institutes of Health. 6. Toro JR, Wei MH, Glenn GM, et al. BHD Folliculocystic and collagen hamartoma of tuberous mutations, clinical and molecular genetic sclerosis complex. J Am Acad Dermatol. 2012;66 Role of the Funder/Sponsor: The National Institutes investigations of Birt-Hogg-Dubé syndrome: a new (4):617-621. of Health had no role in the design and conduct of the series of 50 families and a review of published study; collection, management, analysis, and reports. J Med Genet. 2008;45(6):321-331. interpretation of the data; preparation, review, or

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