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| COMMENTARY |
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| Year : 2013 | Volume
: 59
| Issue : 4 | Page : 324-325 |
Primary spontaneous pneumothorax and the Birt-Hogg-Dubé syndrome
PA Koul
Department of Internal and Pulmonary Medicine, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India
| Date of Web Publication | 17-Dec-2013 |
Correspondence Address:
P A Koul
Department of Internal and Pulmonary Medicine, Sher-I-Kashmir Institute of Medical Sciences, Srinagar
India
 Source of Support: None, Conflict of Interest: None  | Check |
PMID: 24430303 
How to cite this article:
Koul P A. Primary spontaneous pneumothorax and the Birt-Hogg-Dubé syndrome. J Postgrad Med 2013;59:324-5 |
Primary spontaneous pneumothorax is a global problem with a reported incidence of 18-28/100,000 per year for men and 1.2-6/100,000 per year for women. [1] About 11% of spontaneous pneumothorax patients have a positive family history, and the various heritable causes include Marfan syndrome, Ehlers-Danlos syndrome More Details, α1-antitrypsin deficiency, lymphangioleiomyomatosis, Langerhan's cell hisiocytosis, cystic light chain disease, and cystic fibrosis. [2] Birt-Hogg-Dubé syndrome (BHDS) is a genodermatosis that, in addition to the dermatological manifestations, is characterized by predisposition to lung cysts and renal neoplasms. [3],[4] The cutaneous manifestations include fibrofolicullomas, trichodiscomas, and achrodons, [3],[4] whereas the renal neoplasms include renal oncocytoma, chromophobe renal cell carcinoma, oncocytic hybrid tumor, and clear cell renal cell carcinoma. While renal cell carcinoma is the most common and feared neoplasm reported in association with BHDS, non-renal tumors have been reported as well.
Even as the primary focus of care in BHDS is the management of renal tumors, pulmonary manifestations are among the most common manifestations. Cystic lung disease is seen in up to 90% of patients with BHDS, whereas spontaneous pneumothorax occurs in about 38%, [5] with a family history of pneumothorax in about 35%. [6] The syndrome typically exhibits clinical heterogeneity and the patients do not always have the three characteristic phenotypes (that of skin, kidney, and lung involvement). Lung disease (both cysts as well as pneumothoraces) may exist without the cutaneous manifestations, [7] and may be the earliest involvement. On radiological imaging, the cysts generally are elliptical or lentiform in shape with basilar and peripheral predominance and have a perivascular and periseptal localization. [6] As against cysts in other pulmonary conditions, cysts in BHDS are located in the middle and lower lobes toward the mediastinum and have an intimate association with interlobular septa and/or visceral pleura. These characteristic computed tomographic (CT) imaging features help clinicians differentiate the cysts from other cystic lung diseases. [8] Histopathologically, these cysts lack subpleural fibroelastic scars and changes of smoking, whereas cysts associated with pneumothorax in other pulmonary conditions show changes of respiratory bronchiolitis and fibroelastic scars. [9] Recently, it has been demonstrated that in BHDS, the cyst wall expands toward visceral pleura and gets incorporated partially into the interlobular septum, parenchyma, and/or bronchovascular bundle. [10] The cysts are lined on the inside by alveolar cells which may at times be attenuated and on occasion interspersed with cuboidal cells resembling type II pneumocytes. [10] The structural architecture of the cysts, however, gets distorted in pneumothorax-associated cysts. [10]
BHDS is caused by heterozygous mutations in the folliculin (FLCN) gene that is located on the short arm of chromosome 17 (17p 11.2). Folliculin is a 579-amino acid protein that is expressed in skin, skin appendages, stromal cells, the distal nephron, and pneumocytes. [5] It has 14 exons, and even as its exact molecular functions are unknown, it is believed to be a conserved tumor suppressor gene. [11] More than 100 germline mutations have been reported in the FLCN gene. They are seen in around 88% of cases of BHDS and include splice, deletions, insertions, nonsense, deletion/insertion, and missense mutations. [5] Geographic variation has been noted in these mutations. Whereas a cytosine duplication or deletion in the C8 tract of exon 11 is known to be a hotspot in Western patients, c.1347_1353dupCCACCCT in exon 12 and c.1533_1536delGATG in exon 13 are the hotspots in Asian kindreds. [12],[13]
Specific germline mutations or mutation types have not been associated with distinct phenotypic expression in BHDS due to the sheer lack of numbers to record such associations. [5] In this issue of the journal, a Taiwanese kindred with mutation c.1579_1580insA in exon 14 has been presented and the authors conclude that this mutation is associated with predominant lung involvement in BHDS without any renal involvement. Sequence analysis of select exons has shown that 53% of the families with BHDS had deletion or duplication of a C-nucleotide in the polycytosine tract in exon 11, which is a mutational hotspot, [5] with c.1733insC or c.1733delC being the most common BHDS mutation reported to date. [14],[15],[16],[17],[18],[19],[20],[21],[22] In a recent review of about 89 families, the most common 5' BHDS mutation was reported to have occurred at nucleotide 454 (c. 458delG) in exon 4 affecting the initiator codon of FLCN, [22] whereas the most common 3' mutation was reported to have occurred at nucleotide 2034 (c.2034 C>T) in exon 14. [5] The c.1579_1580insA reported by the authors in exon 14 is unique in being the only insertion mutation reported in this exon, although recently, an FLCN exon 14 deletion mutation has been reported from Spain and Japan. [13],[23] Predominant pulmonary manifestations were also reported in a Finnish kindred in whom a 4-bp deletion in exon 4 (c.235_238delTCGG) was detected with 100% penetrance. [24] Furuya and Nakatani also reported a 4-bp deletion in exon 13 (c.1533 1536delGATG) causing pulmonary cysts with 100% penetrance. [10] The size and volume of the lung cysts were demonstrated recently to be greater in individuals with FLCN mutation in exons 9 and 12 than in those with mutations in other exons, suggesting that there may be an association between the cyst size, number, and the underlying mutation. [25] While mutations in exon 14 have been rare, a novel deletion mutation (p.F519LfsX17 [c.1557delT]) in the BHDS gene exon 14 of the patient was reported recently from a Korean patient. [26] Pertinently, a 7-bp duplication in exon 12 (c.1347_1353dupCCACCCT) [12],[13] and mutations of a splice acceptor site in intron 5 [13],[19] have been reported only in Asian kindreds and not in American and European pedigrees.
All the mutations reported in FLCN gene result in truncation in the protein leading to its dysfunction. Recent evidence, however, suggests that FLCN also localizes to cilia, centrosomes, and the mitotic spindle, and alteration of FLCN levels can cause changes to the onset of ciliogenesis, without abrogating it. [27] FLCN mutants with BHDS may retain partial functionality and the clinical features in such patients may be due to abnormal levels rather than a complete loss of FLCN function. [27]
Establishing the links between the germline mutation and the phenotype may be possible in future by combining clinical and FLCN mutation data on clinically well-described BHDS patients and families from different centers. That should help our understanding of the BHDS and the peculiar organ involvement seen in certain kindreds. Currently, however, the data are too scant to imprint the association without conjecture.
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