Respiratory Complications in Patients with Ehlers-Danlos Syndrome: A Systematic Review

The Ehlers-Danlos Syndromes (EDS) are genetic connective tissue disorders that are currently categorized into 14 subtypes. Symptoms of each subtype overlap, with some distinct manifestations

Serum KL-6 as predictive and prognostic marker of interstitial lung disease in childhood connective tissue diseases: a pilot study

This study was aimed to evaluate serum KL-6 levels to determine if this marker can be used for diagnosing and assessing severity of interstitial lung disease (ILD) in children with connective tissue disorders. In total, 40 patients [18 patients with juvenile systemic lupus erythematosus (JSLE), 10 patients with juvenile idiopathic arthritis (JIA), 8 patients with juvenile mixed connective tissue disease (JMCTD), 3 patients with juvenile systemic sclerosis (JSSc), and 1 patient with juvenile dermatomyositis (JDM)] and 20 healthy controls were included in this study. Age, sex, and duration of CTD and ILD (if any) were recorded. Blood samples from all the patients and controls were examined by ELISA. 20 of the 40 patients with CTD (50%) had ILD, 12 were mild and 8 were severe as assessed by spirometry. The median serum KL-6 level was 102.7 U/mL (76.1-180.8) in the CTD with severe ILD group, 72.2 U/mL (58.4- 100.5) in the CTD with mild ILD group, 56.7 U/mL (35.8-68.5) in the CTD without ILD group, and 52.3 U/mL (32.8-62.4) in the control group. KL-6 levels were significantly higher in the CTD with ILD (p<0.05), at a cutoff of 63.4 U/ml identified by ROC curve, serum KL-6 showed a sensitivity of 95.2% and specificity of 89.7%. KL-6 is a valuable biomarker for diagnostic purposes and to detect severity in ILD in childhood CTD.

Role of MUC1 rs4072037 polymorphism and serum KL-6 levels in patients with antisynthetase syndrome

Mucin 1/Krebs von den Lungen-6 (KL-6) is proposed as a serum biomarker of several interstitial lung diseases (ILDs), including connective tissue disorders associated with ILD. However, it has not been studied in a large cohort of Caucasian antisynthetase syndrome (ASSD) patients. Consequently, we assessed the role of MUC1 rs4072037 and serum KL-6 levels as a potential biomarker of ASSD susceptibility and for the differential diagnosis between patients with ILD associated with ASSD (ASSD-ILD +) and idiopathic pulmonary fibrosis (IPF). 168 ASSD patients (149 ASSD-ILD +), 174 IPF patients and 523 healthy controls were genotyped for MUC1 rs4072037 T > C. Serum KL-6 levels were determined in a subgroup of individuals. A significant increase of MUC1 rs4072037 CC genotype and C allele frequencies was observed in ASSD patients compared to healthy controls. Likewise, MUC1 rs4072037 TC and CC genotypes and C allele frequencies were significantly different between ASSD-ILD+ and IPF patients. Additionally, serum KL-6 levels were significantly higher in ASSD patients compared to healthy controls. Nevertheless, no differences in serum KL-6 levels were found between ASSD-ILD+ and IPF patients. Our results suggest that the presence of MUC1 rs4072037 C allele increases the risk of ASSD and it could be a useful genetic biomarker for the differential diagnosis between ASSD-ILD+ and IPF patients.

Aortic complications in pregnancy: the less remembered chapter—a narrative review

Pregnancy increases the risk of common vascular events and also the rarer events like aortic dissection (AD)/aortic rupture and this is even more pronounced in patients with predisposing aortopathies. AD was found to occur in 0.0004% of all pregnancies, and it is more pronounced in patients with underlying connective tissue disorders. The normal hemodynamic changes on a weak aorta will lead to AD and/or rupture, more so with increase in the period of gestation. Hence the haemodynamic and hormonal changes during pregnancy make pregnancy itself a risk factor for AD. It is advised that women with Marfan syndrome who are planning pregnancy should go through prophylactic aortic repair if the diameter of the ascending aorta exceeds 4 cm. Pre-pregnancy counselling is very important in these patients and must include complete history taking, including family history, physical examination and advanced aortic imaging. There is a general consensus among various authors advising against surgery during pregnancy in stable patients due to increased maternal and fetal morbidity but it is justified if the condition is refractory to medical management or in life threatening stage like acute AD. Though the incidence of aortopathy in pregnancy is rare, there is a high maternal and fetal mortality associated with this condition.

Ischaemic stroke caused by spontaneous unilateral carotid artery dissection in patient with connective tissue disorder

Background: Spontaneous cervical artery dissection is a major cause of ischaemic stroke in young patients. It is supposed that genetic variants associated with connective tissue disorders often lead to neurovascular complications, the management of which remains a challenge. Case presentation: A 30-year-old female was admitted to the Department of Neurology with an episode of visual disturbances, speech problems, and concomitant headache. Computed tomography angiography revealed left internal carotid artery dissection. Magnetic resonance of the brain showed cortical and subcortical acute ischaemic lesions in the left cerebral hemisphere. The patient was diagnosed with vascular Ehlers–Danlos syndrome based on the clinical course of the disease. Conservative treatment was administered with full neurological recovery. Conclusion: It is very important for clinicians to consider the coexistence of genetically determined connective tissue disorders in young patients who develop arterial dissections.

Osteogenesis Imperfecta: Current and Prospective Therapies

Osteogenesis Imperfecta (OI) is a group of connective tissue disorders with a broad range of phenotypes characterized primarily by bone fragility. The prevalence of OI ranges from about 1:15,000 to 1:20,000 births. Five types of the disease are commonly distinguished, ranging from a mild (type I) to a lethal one (type II). Types III and IV are severe forms allowing survival after the neonatal period, while type V is characterized by a mild to moderate phenotype with calcification of interosseous membranes. In most cases, there is a reduction in the production of normal type I collagen (col I) or the synthesis of abnormal collagen as a result of mutations in col I genes. Moreover, mutations in genes involved in col I synthesis and processing as well as in osteoblast differentiation have been reported. The currently available treatments try to prevent fractures, control symptoms and increase bone mass. Commonly used medications in OI treatment are bisphosphonates, Denosumab, synthetic parathyroid hormone and growth hormone for children therapy. The main disadvantages of these therapies are their relatively weak effectiveness, lack of effects in some patients or cytotoxic side effects. Experimental approaches, particularly those based on stem cell transplantation and genetic engineering, seem to be promising to improve the therapeutic effects of OI.

Outcomes of endovascular management of the aorta in connective tissue disorders

Background Endovascular management of type B aortic dissection has been well established and accepted in the community. However, due to the lack of information on long-term outcome, endovascular management remains controversial in the setting of connective tissue disorders such as Marfan syndrome. Although surgical repair is recommended in type B aortic dissection with connective tissue disorders, recent studies demonstrated both feasibility and safety of endovascular interventions in those patients at least short term. Purpose Single centre experience and documentation of long-term outcomes after endovascular management of aortic conditions in patients with connective tissue disorders. Methods All patients with genetic confirmation of connective tissue disorders who underwent endovascular repair of the thoracic aorta were identified and evaluated retrospectively. Perioperative, procedure-specific and follow-up data were extracted from medical records of a structured surveillance program. Results Between 2002 and 2020, 18 patients were identified having undergone TEVAR procedures and protocol follow-up. The median age was 35.5 (IQL 30.0 – 42.7), and 12 (66.7%) were males; median ACEF II score was 0.6 (IQL 0.5 – 0.925). This cohort comprised 15 (83.3%) patients with genetically confirmed Marfan syndrome, two (11.1%) with Loeys-Dietz, and one (5.6%) with Ehlers-Danlos syndrome. Of these, 13 (72.2%) patients had undergone aortic root or aortic root/ascending aorta replacement independently in the past. The indication for a TEVAR procedure was seen in one case for degenerative aneurysmal disease (5.6%), in one case for elephant trunk stenosis (5.6%), in five cases for residual aortic dissection (27.8%), and in 11 cases for new type B dissection (61.1%). The most frequently used stent-graft was Valiant™ (Medtronic) in 10 cases (55.6%), followed by TAG® (Gore®) in four cases (22.2%), Zenith® (COOK®) in two cases (11.1%), and for Relay® (Bolton) and Sinus-XL® (Optimed) in one case each (5.6%). The average total covered length was 192.2±40.2 mm. Median follow-up duration was 77.5 months (IQR 35.8 - 131); three (16.7%) cases revealed failure of TEVAR and led to conversion to open surgery. Two patients (11.1%) had died including one patient in the perioperative phase. At the last follow-up, complete thrombosis of the false lumen was observed in 14 cases (82.3%), and 15 cases (88.2%) showed no aortic expansion or progression during the follow-up period resulting in an overall endovascular success rate of 72.2%. Conclusion Thoracic endovascular aortic repair can be performed for selected patients with connective tissue disorders at relatively low long-term mortality and morbidity. With improved devices and technical skills, mid- and long-term surveillance revealed promising outcomes and a low rate of aneurysmal degeneration. Structured surveillance remains crucial to detect emerging late complications and to accumulate more long-term data. FUNDunding Acknowledgement Type of funding sources: None.