case-pierce_Layout 1 A 56-year-old woman of average build (height 1.6 m, body mass index 26.4) was referred to the respirology clinic for assessment of recurrent, bilateral, sponta- neous pneumothoraces of unknown cause. She had her first spontaneous pneumothorax at the age of 28 years and had a total of six sponta- neous pneumothoraces, distributed bilaterally, over the next 28 years. Repeated surgical inter- ventions were done, including bullectomies and pleural abrasion. Surgical pathology showed subpleural bullae without generalized emphyse- matous changes or infiltration of smooth mus- cle cells. Aside from these acute events, the patient was asymptomatic and had no other res- piratory symptoms. The patient’s medical history included post- nasal drip, dyslipidemia and hypertension. She had no history of other respiratory illness or abnormalities of the skin, kidneys or central ner- vous system, and she was a lifetime nonsmoker. The patient’s family was of Dutch–Mennonite descent with a strong history of spontaneous pneumothoraces in adulthood, with occurrences in four of seven siblings, the patient’s father and two paternal cousins (Figure 1). The patient’s physical examination was normal except for several small, dome-shaped, pale and flesh-coloured papules on her face, the largest of which appeared on her nose (Figure 2). Biopsies of these papules were consistent with fibrofollicu- lomas (Appendix 1, available at www .cmaj .ca /cgi /content /full /cmaj .092121/DC1). Skin tags were found on the patient’s neck. A radiograph of the patient’s chest showed no abnormalities, but multiple thin-walled cysts were seen bilaterally in the lungs on a computed tomography (CT) scan (Figure 3). Tests of our patient’s pulmonary function showed that her air flows, lung volumes and diffusing capacity for carbon monoxide were all normal. A diagnosis of Birt–Hogg–Dubé syndrome was suspected on the basis of clinical and radi- ographic features, as well as evidence of autoso- mal dominant transmission in the patient’s fam- ily. The diagnosis was confirmed with a skin biopsy, and a DNA test on a peripheral blood sample showed a heterozygous mutation in the gene encoding folliculin (FLCN). Subsequent abdominal imaging to assess for renal tumours showed a small (5 mm) lesion in the patient’s right kidney. The lesion is being closely monitored, and has not increased in size on two subsequent CT scans over a period of one year. Discussion Our patient had a personal and family history of recurrent bilateral pneumothoraces despite other - wise normal lung function and no known previ- ous lung disease. In addition to the lesions on her skin and the multiple, thin-walled, pulmonary cysts that were visible on a CT scan, these fac- tors led us to a clinical diagnosis of Birt–Hogg– Dubé syndrome. This diagnosis was confirmed with a skin biopsy and genetic testing. About 11.5% of spontaneous pneumothoraces occur in the context of a positive family history1 and involve heritable conditions such as α1- antitrypsin deficiency, Marfan syndrome, Ehlers–Danlos syndrome (type IV: vascular type), lymphangioleiomyomatosis (when associ- ated with tuberous sclerosis) and cystic fibrosis.2 Cases Birt–Hogg–Dubé syndrome: an inherited cause of spontaneous pneumothorax Cameron W. Pierce MD, Peter R. Hull MD PhD, Edmond G. Lemire MD PhD, Darcy D. Marciniuk MD Competing interests: See end of article for competing interests. This article has been peer reviewed. Correspondence to: Dr. Cameron W. Pierce, camoplasm@hotmail.com CMAJ 2011. DOI:10.1503 /cmaj.092121 PracticeCMAJ • Because a positive family history is found in about 11.5% of patients presenting with a spontaneous pneumothorax, it is important to consider genetically inherited syndromes among the possible causes. • Birt–Hogg–Dubé syndrome is a genetic condition with autosomal dominant transmission; classic features include skin lesions, renal tumours and pulmonary cysts that increase the patient’s risk for spontaneous pneumothoraces. • Patients with Birt–Hogg–Dubé syndrome should be regularly checked for renal tumours. • Identifying a proband with Birt–Hogg–Dubé syndrome provides an opportunity for genetic counselling and screening in the affected individual’s family. Key points © 2011 Canadian Medical Association or its licensors CMAJ 1 Early release, published at www.cmaj.ca on February 28, 2011. Subject to revision. (Appendix 2 outlines the causes of spontaneous pneumothorax, with clinical features and diag- nostic testing.) Recently added to this list is Birt– Hogg–Dubé syndrome, a rare genodermatosis that was first described in 1977 in a family from Win- nipeg, Manitoba, on the basis of skin lesions that showed a pattern of autosomal dominant inheri- tance.3 The cardinal cutaneous features of this syndrome are follicular hamartomas — fibro - folliculomas, trichodiscomas and acrochordon- like growths — which usually become apparent only in the third or fourth decades of life.4,5 Fibro - folliculomas and trichodiscomas present as multi- ple, small, pale or skin -coloured, dome-shaped papules. They are usually seen on the face but are sometimes found on the neck and upper trunk. Acrochordon-like growths that are simple-to- globoid in shape are found on the neck, trunk and arms and in the axillae. Although the diagnosis has historically been based on the presence of 5– 10 fibrofolliculomas, one of which should be con- firmed histologically,4 there is increasing reliance on non dermatologic findings and genetic testing in the diagnosis of Birt–Hogg–Dubé syndrome. In addition to fibrofolliculomas and related skin findings, Birt–Hogg–Dubé syndrome is associated with cystic lung disease, spontaneous pneumotho- races, and benign and malignant renal tumours.2,4 Cystic lung disease is estimated to occur in 84% of patients with Birt–Hogg–Dubé syndrome, and spontaneous pneumothoraces occur in about 38% of patients.6 Both conditions may occur without associated dermatologic or renal findings.1 Plain chest radio graphy may appear normal, and CT scans are often required to detect pulmonary cysts. The prevalence of renal tumours such as oncocy- tomas, chromophobe renal cell carcinomas, clear cell carcinomas and papillary renal cell carcinomas is about 34% among patients with Birt–Hogg– Dubé syndrome.4,6 Genetics The genetic locus responsible for the syndrome has recently been mapped to chromosome 17 (17p11.2) and the gene encoding folliculin (FLCN). The fol- liculin protein is 579 amino acids long. It is expressed in stromal cells, the skin and its appendages, the distal nephron and type I pneumo- cytes.6 Although the exact function of folliculin is not known, there is some evidence to support its role as a tumour suppressor. More than 50 unique germline mutations in FLCN have been reported, most of which are frameshift or nonsense muta- tions predicted to result in premature truncation of the protein. Mutation analysis can detect mutations in nearly 90% of patients clinically suspected of having Birt–Hogg–Dubé syndrome.4,6 In our patient, amplification of exons 4–14 by poly- Practice 2 CMAJ Figure 1: Partial pedigree of a 56-year-old woman with Birt–Hogg–Dubé syn- drome (arrow). Filled symbols identify individuals with a confirmed or reported history of spontaneous pneumothorax. Figure 2: Pale papules (arrows) on the patient’s cheeks and nose. Figure 3: Computed tomography scan of the lower lung fields, showing multi- ple thin-walled cysts bilaterally. merase chain reaction showed a deletion of a sin- gle thymine residue at nucleotide 59 of the FLCN gene (c.59delT) resulting in the premature trunca- tion of the protein at amino acid 54. Management Caring for patients with Birt–Hogg–Dubé syn- drome includes an assessment at baseline, ongo- ing surveillance and treatment of symptoms as needed. High-resolution CT scans of the chest will help identify pulmonary cysts. Subsequent pneumothoraces are treated in the same way as other spontaneous pneumothoraces, with particu- lar consideration given to interventions that will reduce the risk of recurrence. Patients with Birt–Hogg–Dubé syndrome should have a careful dermatologic examination, and any suspicious lesions should be biopsied. Because regular imaging of the abdomen is impor- tant for the surveillance of renal tumours, magnetic resonance imaging is preferred over CT scans to minimize the patient’s exposure to radiation. Com- plementary use of renal ultrasound may help clar- ify the nature of small lesions. It may be possible to follow small (< 3.0 cm) renal lesions before considering surgery; consultation with a urologist is appropriate.5 This report highlights the importance of con- sidering genetically inherited syndromes when a patient presents with recurrent pneumothoraces, especially when there is a positive family his- tory. Meaningful interaction between multiple subspecialty teams facilitates the correct investi- gations and diagnosis. Moreover, establishment of the diagnosis enables the appropriate screen- ing for associated malignant diseases that would not otherwise have been considered. References 1. Graham RB, Nolasco M, Peterlin B, et al. Nonsense mutations in folliculin presenting as isolated familial spontaneous pneu- mothorax in adults. Am J Respir Crit Care Med 2005;172:39-44. 2. Toro JR, Pautler S, 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; 175: 1044-53. 3. Birt A, Hogg GR, Dubé WJ. Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol 1977; 113: 1674-7. 4. Toro JR, Glenn G, Duray P, et al. Birt–Hogg–Dubé syndrome: a novel marker of kidney neoplasia. Arch Dermatol 1999;135: 1195-202. 5. Toro J. Birt–Hogg–Dubé syndrome. GeneReviews. GeneTests: Medical Genetics Information Resource [database]. Seattle (WA): University of Washington; 1993–2010. Available: www .genetests .org (accessed 2009 July 28). 6. Toro JR, Wei M, Glenn G, 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;45:321-31. Competing interests: Darcy Marciniuk is a consultant for AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Health Quality Council, Novartis, Nycomed, Pfizer, the Public Health Agency of Canada and Saskatoon Health Region; he has received grants from AstraZeneca, Boehringer-Ingelheim, the Canadian Agency for Drugs and Technology in Health, the Canadian Institutes of Health Research, GlaxoSmithKline, the Lung Association of Saskatchewan, Novartis, the Royal University Hospital Foundation, the Saskatchewan Ministry of Health and Schering Plough; he has received speaker fees from AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, the Lung Association of Saskatchewan and Pfizer; and he has developed educational presentations for AstraZeneca, Boehringer-Ingelheim and Pfizer. Affiliations: From the Departments of Respirology (Pierce, Marciniuk), Dermatology (Hull) and Genetics (Lemire), Uni- versity of Saskatchewan, Saskatoon, Sask. Contributors: All of the authors saw the patient in consulta- tion, derived the clinical data, helped draft the manuscript, revised it for important intellectual content and approved the final version submitted for publication. Practice CMAJ 3 The section Cases presents brief case reports that convey clear, practical lessons. Preference is given to common presentations of important rare conditions, and important unusual presen- tations of common problems. Articles start with a case presentation (500 words maximum), and a discussion of the underlying condition fol- lows (1000 words maximum). Generally, up to five references are permitted and visual ele- ments (e.g., tables of the differential diagnosis, clinical features or diagnostic approach) are encouraged. Written consent from patients for publication of their story is a necessity and should accompany submissions. 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