Enlarged Dural Sac in Idiopathic Bronchiectasis Implicates Heritable Connective Tissue Gene Variants

Abstract

Rationale: Patients with idiopathic bronchiectasis are predominantly female and have an asthenic body morphotype and frequent nontuberculous mycobacterial respiratory infections. They also demonstrate phenotypic features (scoliosis, pectus deformity, mitral valve prolapse) that are commonly seen in individuals with heritable connective tissue disorders.Objectives: To determine whether lumbar dural sac size is increased in patients with idiopathic bronchiectasis as compared with control subjects, and to assess whether dural sac size is correlated with phenotypic characteristics seen in individuals with heritable connective tissue disorders.Methods: Two readers blinded to diagnosis measured anteriorposterior and transverse dural sac diameter using L1-L5 magnetic resonance images of 71 patients with idiopathic bronchiectasis, 72 control subjects without lung disease, 29 patients with cystic fibrosis, and 24 patients with Marfan syndrome. We compared groups by pairwise analysis of means, using Tukey's method to adjust for multiple comparisons. Dural sac diameter association with phenotypic and clinical features was also tested. Measurements and Main Results:The L1-L5 (average) anterior-posterior dural sac diameter of the idiopathic bronchiectasis group was larger than those of the control group (P , 0.001) and the cystic fibrosis group (P = 0.002). There was a strong correlation between increased dural sac size and the presence of pulmonary nontuberculous mycobacterial infection (P = 0.007) and long fingers (P = 0.003). A trend toward larger dural sac diameter was seen in those with scoliosis (P = 0.130) and those with a family history of idiopathic bronchiectasis (P = 0.149).Conclusions: Individuals with idiopathic bronchiectasis have an enlarged dural sac diameter, which is associated with pulmonary nontuberculous mycobacterial infection, long fingers, and family history of idiopathic bronchiectasis. These findings support our hypothesis that "idiopathic" bronchiectasis development reflects complex genetic variation in heritable connective tissue and associated transforming growth factorb-related pathway genes.Keywords: bronchiectasis; nontuberculous mycobacteria; heritable connective tissue disorders; dural sac diameter Correspondence and requests for reprints should be addressed to M.

Advances in bronchiectasis: endotyping, genetics, microbiome, and disease heterogeneity

“…These patients have physical characteristics such as a tall, asthenic morphotype, scoliosis, pectus excavatum, mitral valve prolapse, and dural ectasia that overlap with heritable connective tissue disorders such as Marfan and Ehlers Danlos syndromes. 43, 44 Both bronchiectasis and pulmonary NTM infections have been noted in a well characterized population of these heritable connective tissue disorders. 45 Conversely, key characteristics such as bronchiectasis, NTM infection, and connective tissue disease features have been reported in a high proportion of 1 st and 2 nd degree relatives of carefully phenotyped idiopathic bronchiectasis patients with pulmonary NTM infections, strongly suggesting a genetic component to the disease.…”

Mycobacterium abscessus: It’s Complex

“…Some NTM-LD patients have a greater than expected preponderance of abnormalities within the thoracic cage region, such as pectus excavatum and scoliosis [ 46 , 65 , 66 , 67 , 75 , 79 , 80 ]. We and others have postulated that thoracic cage abnormalities may be a marker for an underlying and yet-to-be identified genetic predisposition, perhaps related to a minor variant of Marfan syndrome (due to mutations of fibrillin-1) or ciliary dysfunction (due to mutations of different genes that encode for ciliary proteins) [ 65 , 66 ], [ 75 , 80 , 81 , 82 ]. Pectus excavatum and scoliosis have also been described in other connective tissue disorders, such as Loeys–Dietz syndrome (LDS, due to gain-of-function mutation of transforming growth factor-beta receptors 1/2—TGFβR1/2) and Shprintzen–Goldberg Syndrome (SGS, due to mutation of the Sloan Kettering Institute (SKI) protein, a downstream inhibitor of TGFβ signaling) [ 83 ].…”

“…In light of this, the whole blood of NTM patients was found to produce more TGFβ, and lower levels of IFNγ upon ex vivo stimulation with various Toll-like receptor agonists or with M. intracellulare as compared to similarly stimulated whole blood from uninfected controls [ 65 ]. Daniels et al analyzed for the presence of dural ectasia—an enlarged dural sac seen in MFS, LDS, and SGS—in patients with idiopathic bronchiectasis, CF subjects, MFS, and controls and found that the L1–L5 dural sac diameter was significantly greater in patients with idiopathic bronchiectasis as compared to controls and to CF subjects, suggesting the possibility of an underlying connective tissue disorder in those with idiopathic bronchiectasis [ 82 ]. They also found a strong correlation between dural sac size and NTM-LD, as well as dural sac size and long fingers [ 82 ].…”

Non-tuberculous mycobacterial lung disease due to multiple “minor” risk factors: an illustrative case and a review of these “lesser elements”

“…The occurrence of NTM lung disease in individuals without any known predisposing condition is well recognized; a number of these patients possess Marfanoid features such as life-long slender body habitus and thoracic cage abnormalities such as pectus excavatum and scoliosis (50,51,53,(67)(68)(69)(70)(71). We and others have postulated that the aforementioned thoracic cage abnormalities may be a marker for an underlying and yet-to-be identified genetic predisposition, perhaps related to a minor variant of Marfan syndrome or ciliary dysfunction (16,50,51,69,70,(72)(73)(74).…”