Enlarged Dural Sac in Idiopathic Bronchiectasis Implicates Heritable Connective Tissue Gene Variants
M. Leigh Anne DanielsKatherine R. BirchardJared R. LoweMichael V. PatronePeadar G. NooneMichael R. Knowles
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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 anterior–posterior 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 factor-β–related pathway genes.Spontaneous cervical artery dissections (sCAD) often occur in otherwise healthy individuals without known risk factors for stroke and frequently develop spontaneously without relevant trauma. An underlying arteriopathy leading to a so-called 'weakness of the vessel wall' and predisposing certain individuals to dissection has often been postulated. Therefore, the morphology of connective tissue, a main component of vessel wall and environment, was investigated in carotids and skin. While the overall morphology of dermal connective tissue is normal, about half of patients with sCAD show mild ultrastructural connective tissue alterations. These ultrastructural morphological aberrations can be designated either as 'Ehlers-Danlos syndrome (EDS) III-like', resembling mild findings in patients with the hypermobility type of EDS (EDS III); or coined 'EDS IV-like' with collagen fibers containing fibrils with highly variable diameters resembling mild findings in vascular EDS; or the abnormalities are restricted to the elastic fibers (with fragmentation and minicalcifications) without significant alterations in the morphology of the collagen fibrils. These findings had some similarity with the morphology found in heterozygous carriers of pseudoxanthoma elasticum. A grading scale according to the severity of the findings has been introduced. Similar connective tissue abnormalities were detected in some first-degree relatives of patients with sCAD showing hereditary at least in a subgroup. They can serve as a phenotypic marker for further genetic studies in patients with sCAD and large families to possibly identify the underlying basic molecular defect(s). Very few of patients (<5%) with sCAD and connective tissue abnormalities have clinical manifestations of skin, joint, or skeletal abnormalities of a defined heritable connective tissue disorder. In specimens of arterial walls of carotid, aortic, and renal arteries of patients with sCAD, pronounced systemic, histopathological, and ultrastructural abnormalities were detected with elastic fiber fragmentation and medial degeneration, described before only in a few patients with known hereditary connective tissue diseases such as the Marfan syndrome. We hypothesize that a major part of sCAd cases represents a manifestation of a connective tissue disorder with a vascular phenotype.
Cervical Artery
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The anthropologic examination and exploration of phenotypic markers of connective tissue dysplasia (CTD) were conducted in 50 patients with renal anomaly verified by ultrasound investigations and excretory urography. It was established that CTD-associated renal anomalies occur primarily in asthenic and gynecomorphic constitutions. Phenotypic markers of the anomalies are scoliosis, distortion of the nasal septum and blue sclerotics. Thus, the anthropologic examination can provide initial information on possibility of renal developmental anomalies associated with CTD.
Renal dysplasia
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There were examined 80 patients with varicose disease of the lower extremities veins (VDLEV) using elaborated phenotypic cart, the Bayton scale, ECG, echocardiography and ultrasonic triplex phleboscanning. There were defined 24 markers of the connective tissue dysplasia, mostly characteristic for VDLEV. Correlation was established between the phenotypic signs number, the severity of clinical course and the rate of occurrence of the venous diseases complications. Moderate and severe clinical course of VDLEV is associated with various phenotypic markers of the connective tissue dysplasia.
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presented by the authors may have revealed leftward tongue retraction due to a right hemilingual weakness.Among the known causes of a geographic tongue, a fungal infestation from poor hygiene is frequent.This relatively immobile weakened tongue may predispose the patients to decreased spontaneous cleansing, which explains hemigeographic tongue from a contralateral cerebral stroke.
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Rationale: The clinical features of patients infected with pulmonary nontuberculous mycobacteria (PNTM) are well described, but the genetic components of infection susceptibility are not.Objectives: To examine genetic variants in patients with PNTM, their unaffected family members, and a control group.Methods: Whole-exome sequencing was done on 69 white patients with PNTM and 18 of their white unaffected family members. We performed a candidate gene analysis using immune, cystic fibrosis transmembrance conductance regulator (CFTR), cilia, and connective tissue gene sets. The numbers of patients, family members, and control subjects with variants in each category were compared, as was the average number of variants per person.Measurements and Main Results: A significantly higher number of patients with PNTM than the other subjects had low-frequency, protein-affecting variants in immune, CFTR, cilia, and connective tissue categories (35, 26, 90, and 90%, respectively). Patients with PNTM also had significantly more cilia and connective tissue variants per person than did control subjects (2.47 and 2.55 compared with 1.38 and 1.40, respectively; P = 1.4 × 10−6 and P = 2.7 × 10−8, respectively). Patients with PNTM had an average of 5.26 variants across all categories (1.98 in control subjects; P = 2.8 × 10−17), and they were more likely than control subjects to have variants in multiple categories. We observed similar results for family members without PNTM infection, with the exception of the immune category.Conclusions: Patients with PNTM have more low-frequency, protein-affecting variants in immune, CFTR, cilia, and connective tissue genes than their unaffected family members and control subjects. We propose that PNTM infection is a multigenic disease in which combinations of variants across gene categories, plus environmental exposures, increase susceptibility to the infection.
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An unknown connective tissue defect might predispose for the development and rupture of intracranial aneurysms in some patients. This study of connective tissue samples of a series of patients with intracranial aneurysms investigates the morphology of the extracellular matrix with methods that are currently used in the routine diagnosis of inherited connective tissue disorders.Skin biopsies from 21 patients with intracranial aneurysms, many with multiple aneurysms, were studied by electron microscopy. None of the patients included in this study showed clinical signs of a known connective tissue disorder.In 7 patients (33%), we observed repetitive aberrations in the morphology of collagen fibrils and elastic fibers of the reticular dermis. The observed ultrastructural findings were somewhat similar to those typically observed in patients with Ehlers-Danlos syndrome (EDS) and in a subgroup of patients with spontaneous cervical artery dissections. The patterns of abnormalities fell into 2 classes: 4 patients displayed abnormalities that resembled those found in patients with EDS type III, and the electron microscopic findings in the skin biopsies from 3 patients resembled those of EDS type IV patients. The sequence of the COL3A1 gene from the patients with EDS type IV-like alterations of the connective tissue morphology was analyzed. No mutation was detected.Connective tissue alterations were found in skin biopsies from a minority of patients with intracranial aneurysms. Electron microscopic investigation of skin biopsies from patients and their relatives might become valuable for clinical diagnostics, identification of persons at risk, and basic studies of the pathogenesis of this vascular disease.
Reticular connective tissue
Reticular Dermis
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Etiology
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Arterial dissection
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Rationale: Pulmonary nontuberculous mycobacterial (PNTM) disease has increased over the past several decades, especially in older women. Despite extensive investigation, no consistent immunological abnormalities have been found. Using evidence from diseases such as cystic fibrosis and primary ciliary dyskinesia, in which mucociliary dysfunction predisposes subjects to high rates of nontuberculous mycobacterial disease that increase with age, we investigated correlates of mucociliary function in subjects with PNTM infections and healthy control subjects.Objectives: To define ex vivo characteristics of PNTM disease.Methods: From 2009 to 2012, 58 subjects with PNTM infections and 40 control subjects were recruited. Nasal nitric oxide (nNO) was determined at the time of respiratory epithelial collection. Ciliary beat frequency at rest and in response to Toll-like receptor (TLR) and other agonists was determined using high-speed video microscopy.Measurements and Main Results: We found decreased nNO production, abnormally low resting ciliary beat frequency, and abnormal responses to agonists of TLR2, -3, -5, -7/8, and -9 in subjects with PNTM compared with healthy control subjects. The low ciliary beat frequency in subjects with PNTM was normalized ex vivo by augmentation of the NO–cyclic guanosine monophosphate pathway without normalization of their TLR agonist responses.Conclusions: Impaired nNO, ciliary beat frequency, and TLR responses in PNTM disease epithelium identify possible underlying susceptibility mechanisms as well as possible avenues for directed investigation and therapy.
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Summary. Four clinical phenotypes of respiratory syndrome have been identified in patients with connective tissue dysplasia using the mathematical modeling method. All phenotypes were characterized by different clinical manifestations and functional disorders and had different independent predictors. The most common chronic bronchitis phenotype was related to tobacco smoking and included early obstructive disorders. Bullous phenotype also predominantly occurred in smokers and comprised apical subpleural bullae or blebs. A probable genetic basis of the bullous phenotype is mutations in alleles of the matrix metalloproteinases MMP1 and MMP9. Thoracodiaphragmatic phenotype was typical for patients with the chest and the spine deformities and was characterized by restrictive disorders. Hyperventilation phenotype was closely related to autonomic dysfunction and increased anxiety, predominantly in females.
Connective Tissue Disorder
Chronic bronchitis
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