Birt-Hogg-Dube syndrome (BHD; 135150) is an allelic disorder characterized by spontaneous pneumothorax, as well as fibrofolliculomas of the skin and increased risk of renal and colonic tumors. Gunji et al. (2007) suggested that isolated primary spontaneous pneumothorax associated ... Birt-Hogg-Dube syndrome (BHD; 135150) is an allelic disorder characterized by spontaneous pneumothorax, as well as fibrofolliculomas of the skin and increased risk of renal and colonic tumors. Gunji et al. (2007) suggested that isolated primary spontaneous pneumothorax associated with FLCN mutations may be part of the clinical spectrum of BHD, showing incomplete disease penetrance. Spontaneous pneumothorax is a complication of certain heritable disorders of connective tissue, particularly the Marfan syndrome (154700) and the Ehlers-Danlos syndrome (see, e.g., 130000). Pulmonary bullae can also occur with alpha-1-antitrypsin deficiency (613490).
Brock (1948) observed recurrent and chronic spontaneous pneumothorax and suggested that hereditary lung cysts were the anatomic substrate. Berlin (1950) and Boyd (1957) observed familial occurrence of spontaneous pneumothorax in patients without other stigmata of connective tissue disease. ... Brock (1948) observed recurrent and chronic spontaneous pneumothorax and suggested that hereditary lung cysts were the anatomic substrate. Berlin (1950) and Boyd (1957) observed familial occurrence of spontaneous pneumothorax in patients without other stigmata of connective tissue disease. Stephenson (1976) discussed an association between spontaneous pneumothorax and apical bullae, apical scars, and sharpness of the inner border of the first or second ribs. Leman and Dines (1973) described a family in which 4 members, a man and 3 daughters, including identical twins, had recurrent spontaneous pneumothorax. Wilson and Aylsworth (1979) described unilateral pneumothorax in a newborn whose maternal grandmother and 2 maternal uncles had had pneumothorax; 1 maternal uncle died at age 2 months of bilateral pneumothorax. Rashid et al. (1986) described concurrent spontaneous pneumothorax in 71-year-old male twins. Sugiyama et al. (1986) described brothers, aged 18 and 20 years, with spontaneous pneumothorax. Although one of them was said to have had the Walker-Murdoch wrist sign characteristic of the Marfan syndrome (Walker and Murdoch, 1970), he showed no evidence of ectopia lentis or aortic root and mitral valve abnormalities on appropriate studies. Morrison et al. (1998) described a family in which the father and 3 of 6 offspring, 2 sons and 1 daughter had episodes of spontaneous pneumothorax. The age of onset varied by up to 13 years within the family. The father had pneumothorax at the age of 32 years. The older brother, a smoker, had pneumothorax at age 30; the younger brother, a nonsmoker, had 3 episodes of pneumothorax within a period of 1 year. Their sister, a smoker, presented with pneumothorax at the age of 17 years. Examination showed no signs of Marfan syndrome, Ehlers-Danlos syndrome, or other connective tissue disorders. Alpha-1-antitrypsin assays were normal. Chest radiographs showed no bullae, and respiratory function tests, including diffusion studies, were all within normal limits. Gunji et al. (2007) reported 5 unrelated patients with multiple lung cysts and recurrent spontaneous pneumothorax. The mean age at onset of first pneumothorax was 30.4 years; none of the patients had skin or renal features. All patient reported a family history of the condition. In 1 family, the proband and his affected brother inherited the disorder from their mother, who did not have pneumothorax by age 56 but did have multiple pulmonary cysts on CT scan. A sister of the mother was reportedly affected. A second family had 9 affected members, and the proband's paternal aunt had pneumothorax and renal cancer. Gunji et al. (2007) suggested that isolated pulmonary cysts and pneumothorax may be a milder form of BHD syndrome and that patients should be monitored for renal or skin lesions.
In affected members of a large Finnish family with autosomal dominant spontaneous pneumothorax, Painter et al. (2005) identified a heterozygous 4-bp deletion in the FLCN gene (607273.0009). All carriers of the deletion had bullous lung lesions as the ... In affected members of a large Finnish family with autosomal dominant spontaneous pneumothorax, Painter et al. (2005) identified a heterozygous 4-bp deletion in the FLCN gene (607273.0009). All carriers of the deletion had bullous lung lesions as the only manifestation with 100% penetrance. Because of the strong association between primary spontaneous pneumothorax and the Birt-Hogg-Dube syndrome, Painter et al. (2005) suggested that patients with familial PSP may be at greater risk of developing renal cancer. In 5 of 8 patients with multiple lung cysts and recurrent spontaneous pneumothorax, Gunji et al. (2007) identified heterozygous mutations in the FLCN gene (see, e.g., 607273.0001; 607273.0010; 607273.0011). In 10 of 102 Chinese probands with spontaneous pneumothorax, Ren et al. (2008) identified 4 different mutations in the FLCN gene (see, e.g., 607273.0001; 607272.0012-607272.0013). Although only 5 of the probands reported a family history of the disorder, genetic analysis showed that 8 of the probands had family members with pneumothorax or pulmonary cysts as determined by imaging studies. Two mutation carriers from 2 different families did not have pulmonary cysts. The findings indicated reduced penetrance of both the pneumothorax phenotype and the cyst phenotype. Kunogi et al. (2010) screened the FLCN gene by DHPLC in 36 Japanese patients with multiple lung cysts of undetermined causes, all but 1 of whom had suffered at least 1 pneumothorax, and identified 13 different germline mutations in 23 of the patients, respectively. The remaining 13 patients were further analyzed by quantitative PCR, and large genomic deletions were found in 2 (see, e.g., 607273.0017); thus 25 (69.4%) of the 36 patients had germline FLCN mutations. Only 6 of the mutation-positive patients had skin lesions, and 2 others had renal tumors, 1 of which was an angiomyolipoma and the other a renal cancer (histopathologic information unavailable). Kunogi et al. (2010) noted that 13 (52%) of the 25 mutations were located in the 3-prime end of the FLCN gene, and that these Japanese patients with FLCN mutations had a very low incidence of skin and renal involvement.