Familial Spontaneous Pneumothorax

Hsienchang Thomas Chiu; Christine Kim Garcia


Curr Opin Pulm Med. 2006;12(4):268-272. 

In This Article

Monogenic Disorders Associated With Spontaneous Pneumothorax

Overall, a positive family history is found in 11.5% of individuals who present with a spontaneous pneumothorax.[9] The clustering of familial spontaneous pneumothorax was first reported by Faber in 1921.[10] It has long been recognized that a primary spontaneous pneumothorax may occur in patients with any of several different inherited monogenic disorders. While the appearance of a pneumothorax is not the primary finding in patients with these disorders, they must be considered when evaluating a case of familial spontaneous pneumothorax. The disorders are listed in Table 1 , and include Marfan syndrome, homocystinuria, Ehlers-Danlos syndrome, α1-antitrypsin deficiency and Birt-Hogg-Dubé syndrome.

Marfan syndrome is an autosomal dominant disease caused by mutations in the gene encoding fibrillin 1. Patients display great clinical variability. The major manifestations include increased height, disproportionately long limbs and digits, subluxation of the lens of the eye, and dilation of the aortic root, whereas apical blebs and spontaneous pneumothorax have been described as minor criteria.[11] The frequency of spontaneous pneumothorax in patients with Marfan syndrome is estimated to be 4.4-11%, while other pulmonary conditions such as bullae, bronchiectasis, and upper lobe fibrosis are relatively less common.[12,13]

Homocystinuria is a metabolic disorder caused by cystathionine β-synthase deficiency which shares skeletal and ocular features with Marfan syndrome, in addition to mental retardation and vascular thrombosis. Spontaneous pneumothorax is a minor feature.[14,15]

Ehlers-Danlos syndrome is a genetically heterogeneous collection of disorders characterized by hyperextensible skin, dystrophic scarring, easy bruising, and joint hypermobility.[16] Pulmonary complications have been most commonly reported for patients with the vascular subtype (type IV), which is characterized by facial appearance, thin, translucent skin, extensive bruising, and often catastrophic arterial, intestinal or uterine rupture. Features of cystic lung disease, including subpleural blebs, apical bullae, pneumothorax and hemopneumothorax, have all been reported.[17]

α1-Antitrypsin is a major plasma serine protease inhibitor which plays an important role in the lung, antagonizing the effect of leukocyte elastase. Deficiency of this protein leads to a high risk of developing panacinar emphysema in the third to fifth decades of life.[18] Patients homozygous for the PiZ variant of α1-antitrypsin demonstrate predominantly lower-lobe, basilar emphysema.[19] Rare case reports have noted an association between spontaneous pneumothorax, apical bullae, and α1-antitrypsin deficiency.[20,21]

Birt-Hogg-Dubé syndrome was originally described in 1977[22] as an autosomal dominant skin disorder characterized by multiple fibrofolliculomas, trichodiscomas, and acrochordons. In the subsequent years, the disease was associated with spontaneous pneumothorax and renal cancer with multiple histologic subtypes.[23] The disease is caused by mutations in the folliculin (FLCN) gene.[24] A mutational hotspot involving a tract of eight cytosines in exon 11 has been identified by multiple investigators.[24,25,26*] The function of the folliculin protein is currently unknown, although the gene is highly conserved across species.[24] Study of folliculin mRNA has revealed its widespread expression in various tissues, including skin and skin appendages, type 1 pneumocytes and stromal cells of the lung, distal nephrons of the kidneys, as well as selected cell types in the brain and lymph nodes, and various cells with secretory functions. Two animal models, canine hereditary renal cystadenocarcinoma and nodular dermatofibrosis in the German shepherd[27] and the Nihon rat model of renal cancer,[28,29*] support a tumor-suppressor function for folliculin. Its role as a tumor suppressor is further supported by the loss of the wild-type FLCN allele or a somatic second-hit mutation in renal cancers from patients with Birt-Hogg-Dubé syndrome[25,30*] or from those with sporadic renal cancers.[31,32]

Families with familial spontaneous pneumothorax have been reported in which the affected individuals have none of the characteristic features of the above monogenic disorders. It had been thought previously that familial spontaneous pneumothorax is a disorder distinct from known monogenic diseases at both the clinical and molecular levels. As discussed below, however, research done in the last 18 months has demonstrated mutations in the Birt-Hogg-Dubé syndrome gene, encoding folliculin (FLCN) in multiple cases of familial spontaneous pneumothorax. These cases can now be considered part of the phenotypic spectrum for Birt-Hogg-Dubé syndrome.


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