A 45-year-old woman with a history of renal carcinoma was observed for facial, cervical and truncal flesh-colored papules. Relatives had similar skin findings and a brother had repeated episodes of pneumothorax.
The computerized tomography scan revealed multiple cysts on both lungs. A skin biopsy revealed a perifollicular fibroma. The clinical diagnosis of Birt-Hogg-Dubé syndrome (BHDS) was corroborated by identification of a novel frameshift c.573delGAinsT (p.G191fsX31) mutation in heterozygosity on exon 6 of the folliculin gene. The presence of multiple and typical benign hair follicle tumors highlights the role of the dermatologist in the diagnosis
of this rare genodermatosis that is associated with an increased risk of renal cell cancer and pulmonary cysts,
warranting personal and familial follow-up and counseling

Apetato, M

Lencastre, A

Lestre, S

Nunes, L

Ponte, P

Repositório do Centro Hospitalar de Lisboa Central, EPE

An Bras Dermatol. 2013;88(6 Suppl 1):203-5.Birt-Hogg-Dubé Syndrome*Síndrome de Birt-Hogg-Dubé André Lencastre1 Pedro Ponte2 Margarida Apetato3Luis Nunes4 Sara Lestre5Received on 14.10.2012.Approved by the Advisory Board and accepted for publication on 12.11.2012. * Work performed at the  Santo António dos Capuchos Hospital – Hospital Center of Central Lisbon, EPE – Lisbon, Portugal.  Conflict of interest: NoneFinancial Support: None1 MD - Resident in Dermatovenereology, Hospital de Santo António dos Capuchos, Centro Hospitalar de Lisboa Central - Lisbon, Portugal.2 MD - Specialist in Dermatovenereology, Hospital de Santo António dos Capuchos, Centro Hospitalar de Lisboa Central - Lisbon, Portugal.3 MD - Specialist in Dermatovenereology, Hospital de Santo António dos Capuchos, Centro Hospitalar de Lisboa Central - Lisbon, Portugal.4 MD - PhD - Specialist in Medical Genetics, Hospital de Dona Estefânia, Centro Hospitalar de Lisboa Central - Lisbon, Portugal.5 MD - Specialist in Dermatovenereology, Hospital de Santo António dos Capuchos, Centro Hospitalar de Lisboa Central - Lisbon, Portugal.©2013 by Anais Brasileiros de Dermatologias203CASE REPORTDOI: http://dx.doi.org/10.1590/abd1806-4841.20132199Abstract: A 45-year-old woman with a history of renal carcinoma was observed for facial, cervical and truncalflesh-colored papules. Relatives had similar skin findings and a brother had repeated episodes of pneumothorax.The computerized tomography scan revealed multiple cysts on both lungs. A skin biopsy revealed a perifollicularfibroma. The clinical diagnosis of Birt-Hogg-Dubé syndrome (BHDS) was  corroborated by identification of anovel frameshift c.573delGAinsT (p.G191fsX31) mutation in heterozygosity on exon 6 of the folliculin gene. Thepresence of multiple and typical benign hair follicle tumors highlights the role of the dermatologist in the diagno-sis of this rare genodermatosis that is associated with an increased risk of renal cell cancer and pulmonary cysts,warranting personal and familial follow-up and counseling.Keywords: Birt-Hogg-Dube Syndrome; Frameshift mutation; Hair follicleResumo: Uma mulher de 45 anos com história de carcinoma renal foi observada por pápulas cor da pele, faciais,cervicais e tronculares. Referia história familiar de achados cutâneos semelhantes e irmão com episódios repeti-dos de pneumotórax. Identificaram-se múltiplos quistos pulmonares por tomografia computorizada. Uma bió-psia cutânea revelou fibroma perifolicular. O diagnóstico clínico de síndrome de Birt-Hogg-Dubé (BHDS) foi con-tudo corroborado pela identificação de uma nova mutação frameshift c.573delGAinsT (p.G191fsX31) em hetero-zigotia no exão 6 do gene da foliculina. A presença de múltiplos e típicos tumores benignos do folículo piloso,realça o papel do dermatologista no diagnóstico desta rara genodermatose, que está associada a um risco aumen-tado de tumores de células renais e cistos pulmonares, exigindo seguimento e aconselhamento pessoal e familiar.Palavras-chave: Folículo piloso; Mutação da fase de leitura; Síndrome de Birt-Hogg-DubéINTRODUCTIONHornstein-Knickenberg Syndrome or Birt-Hogg-Dubé Syndrome (BHDS), as it came to be more com-monly known, is an apparently rare, autosomal domi-nant genodermatosis caused by mutations of the folli-culin codifying gene (FLCN) located on the 17p11.2region.1,2 The first description of a case of what wouldlater be recognized as BHDS was probably presentedby Burnier and Rejsek.3 BHDS predisposes to: 1) benignhair follicle hamartomas known as fibrofolliculoma(FF) and trichodiscoma (TD), acrochorda and angiofi-broma; 2) pulmonary lesions (bibasilar cysts and, lessfrequently, pneumothorax); and 3) mainly malignantrenal tumours (of various histologic types).2,4CASE REPORTA 45-year-old woman with a prior history of: 1)total right nephrectomy due to clear cell carcinoma(T1, N0, M0) at 41 years of age; 2) multinodular goiter;3) fibrocystic mammary disease; was referred to ourdepartment for evaluation of long-standing multiplefacial, cervical and upper thoracic small, flesh-coloredpapules (Figure 1). Scarce improvement was noted inthe past with topical aluminum oxide or alpha-hydroxy-acids treatment.The patient denied any respiratory signs orsymptoms and mentioned a family history of similardermatological findings (father, brother and paternalaunts). Her father died of colon cancer and her broth-An Bras Dermatol. 2013;88(6 Suppl 1):203-5.204 Lencastre A, Ponte P, Apetato M, Nunes L, Lestre Ser had a history of repeated episodes of spontaneouspneumothoraxes.Computerized tomography scan (CT-scan) ofthe chest, abdomen and pelvis revealed multiplesmall-sized cysts in both lungs. Thyroid ultrasonogra-phy and scintigraphy were performed and cytology ofotherwise suspicious nodules did not reveal any can-cer findings. Colonoscopy was normal.Skin biopsies of the face, neck and abdomenrevealed findings consistent with angiofibroma, cellu-lar fibroma and fibroma (acrochordon). Only onebiopsy of a lesion of the face showed a discrete dermalproliferation of basaloid epithelial nests around a nor-mal hair follicle, with surrounding fibrosis, consistentwith perifollicular fibroma (Figure 2).Despite the absence of FF or TD identification, aclinical diagnosis of BHDS was made, corroborated bythe identification of a previously undescribed,frameshift c.573delGAinsT (p.G191fsX31) mutation inheterozygosity on exon 6 of the FLCN gene (Figure 3).Carbon-dioxide laser ablation produced unsat-isfactory results in the patient’s opinion, who declinedfurther treatment. The patient and her immediate fam-ily are annually screened for the development of renalneoplasia. The patient’s brother refused medical care.DISCUSSIONThe pathogenesis of BHDS remains ill-defined.Several different  FLCN gene mutations have beenreported, with unknown phenotype-altering implica-tions. Folliculin is expressed in most major adult tis-sues, including skin, lung and kidney. Changes in theactivity of this protein, presumably with still uncon-firmed tumor suppressor activity (via mTOR signal-ing), may favor the appearance of several of these skinmalformations, lung cysts and renal cancer, denotingthe higher severity of this syndrome’s prognosis.2FF and TD, the hallmarks of BHDS, present asasymptomatic single or multiple, smooth, skin-colored,dome-shaped papules commonly located on the head,neck, back, and arms. Fibrous papules/Angiofibromamay be similar and are mainly located on the head andupper trunk. Perifollicular fibromas (PFF) favor thehead and neck.5 Clinically these are virtually indistin-guishable and further differentials of these similarpapules include dermatofibroma, trichilemmoma, neu-rofibroma and trichoepitheliomas.Several authors point out that FF and TD (andeven acrochorda) may actually represent differentstages of evolution within one same lesion. They areimmunophenotypically similar and thus derived fromthe same histiogenic precursor. Differences in histol-ogy might also be related to differences in planes ofsection.5 Some have also pointed out the possibilitythat PFFs may actually represent FF in the setting ofBHDS, an event that may be related to sectioning aswell.6-8 In fact, the first cases ever described to be com-patible with BHDS were characterized by numerousPFF.3 Again, the association of PFF with BHD has beenrecently reviewed in a recent series of four cases.9We believe that FF, TD and PFF are hamartoma-tous hair-follicle tumours, and should be consideredas a part of BHDS in the appropriate clinical setting,along with achrocordon and angiofibroma.According to the diagnostic criteria proposedby Menko et al., our patient met 1 major and 2 minorcriteria.10 Despite the fact that BHDS is characteristi-cally associated with FF and/or TD, surgical pursuitof diagnostic histological findings is not alwaysrewarding. Selection of appropriate lesions for biopsyFIGURE 1: Detail of the left aspect of the face where skin-coloredpapules are observed in the nasal and malar regionFIGURE 2: Detail of epithelioid cell nests and perifollicular dermalfibrosis (H&Ex100)An Bras Dermatol. 2013;88(6 Suppl 1):203-5.Birt-Hogg-Dubé Syndrome 205How to cite this article: Lencastre A, Ponte P, Apetato M, Nunes L, Lestre S. Birt-Hogg-Dubé Syndrome. An BrasDermatol. 2013;88(6 Suppl 1):S203-5.REFE REN CESBirt AR, Hogg GR, Dubé WJ. Hereditary multiple fibrofolliculomas with trichodisco-1.mas and acrochordons. Arch Dermatol. 1977;113:1674-7.Adley BP, Smith ND, Nayar R, Yang XJ. Birt-Hogg-Dubé Syndrome. Clinicopathologic2.Findings and Genetic Alterations. Arch Pathol Lab Med. 2006;130:1865-70.Burnier MM, Rejsek P. Fibromes sous-cutanes peripilares multiples du cou. Bull Soc3.Fr Dermatol Syphiligr. 1925;32:242-3.Schaffer JV, Gohara MA, McNiff JM, Aasi SZ, Dvoretzky I. Multiple facial angiofibro-4.mas: a cutaneous manifestation of Birt-Hogg-Dubé syndrome. J Am Acad Dermatol.2005;53:S108-11.Misago N, Kimura T, Narisawa Y. Fibrofolliculoma/trichodiscoma and fibrous papule5.(perifollicular fibroma/angiofibroma): a revaluation of the histopathological andimmunohistochemical features. J Cutan Pathol. 2009;36:943-51.Schulz T, Hartschuh W. Birt-Hogg-Dubé syndrome and Hornstein-Knickenberg syn-6.drome are the same. Different sectioning technique as the cause of different histolo-gy. J Cutan Pathol. 1999;26:55-61.Junkins-Hopkins JM, Cooper PH. Multiple perifollicular fibromas: report of a case7.and analysis of the literature. J Cutan Pathol. 1994;21:467-71.Cunha Filho RR, Gervini RL, Cartell A. Do you know this syndrome? An Bras8.Dermatol. 2005;80:639-42.Shvartsbeyn M, Mason AR, Bosenberg MW, Ko CJ. Perifollicular fibroma in Birt-9.Hogg-Dubé syndrome: an association revisited. J Cutan Pathol. 2012;39:675-9. Menko FH, van Steensel MA, Giraud S, Friis-Hansen L, Richard S, Ungari S, et al.10.European BHD Consortium. Birt-Hogg-Dubé syndrome: diagnosis and management.Lancet Oncol. 2009;10:1199-206MAILING  ADDRESS:André Lencastre Alameda Santo António dos Capuchos 1169-050 -Lisboa - PortugalE-mail: lencastre.derm@gmail.comis troublesome, due to the relatively dubious differen-tial diagnosis with other similar-looking lesions thatmay be associated with the disease as well (e.g. acro-chorda). On the other hand, multiple excision mayperhaps be unreasonable. These assumptions appliedto this case. Furthermore, others have highlighted theexistence of BHDS in the absence of FF/TD.4Since renal cell carcinomas are reputably clini-cally silent and late detection associated with worseprognosis, they must be specifically addressed inBHDS patients and their families. When we firstobserved our patient, she had already undergonetreatment for a renal tumor that had been an inciden-tal finding, 4 years before.Other well-recognized components of BHDsyndrome are pulmonary cysts, detectable by CT-scanin about 90% of BHDS patients. Pneumothorax occursin 25% of BHDS patients and is not spontaneous, butrather secondary to rupture of pulmonary cysts underpressure of inhalation.2Currently there are no published guidelines forscreening renal cancer or pulmonary cysts in asympto-matic BHDS patients or their relatives. Provisional rec-ommendations include surveillance of: 1) renal cancer,starting at age 20 (through magnetic resonance imag-ing or ultrasound, to avoid long time exposure to CT-scan radiation), with individualized intervals; 2) pul-monary cysts, with an initial baseline high resolutionCT-scan and follow-up every 3-5 years. Symptomaticpatients with lung lesions should have individualizedfollow-up and all should be reminded of the higherrisk of pneumothorax with general anesthesia or trav-eling to high altitudes (including air travel).When examining patients with multiple facialpapules and a personal and/or family history of renalcancer, the dermatologist should consider BHDS.Maintaining a low threshold for clinical suspicion isperhaps advisable, as the diagnosis may imply anearly detection of cancer in affected patients and theirfamilies. qFIGURE 3: Automatic sequencing of exon 6 of the FLCN gene (the arrow shows the point where the frameshift mutation started)

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