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Advances in Rheumatology (London,... Apr 2024Hereditary connective tissue disorders include more than 200 conditions affecting different organs and tissues, compromising the biological role of the extracellular... (Review)
Review
Hereditary connective tissue disorders include more than 200 conditions affecting different organs and tissues, compromising the biological role of the extracellular matrix through interference in the synthesis, development, or secretion of collagen and/or its associated proteins. The clinical phenotype includes multiple signs and symptoms, usually nonspecific but of interest to rheumatologists because of musculoskeletal involvement. The patient´s journey to diagnosis is long, and physicians should include these disorders in their differential diagnoses of diseases with systemic involvement. In this review, insights for the diagnosis and treatment of osteogenesis imperfecta, hypermobility spectrum disorder/Ehlers-Danlos syndrome, Marfan, Loeys-Dietz, and Stickler syndromes are presented.
Topics: Humans; Arthritis; Collagen; Connective Tissue Diseases; Ehlers-Danlos Syndrome; Hearing Loss, Sensorineural; Joint Instability; Loeys-Dietz Syndrome; Marfan Syndrome; Osteogenesis Imperfecta; Retinal Detachment
PubMed: 38664779
DOI: 10.1186/s42358-024-00373-z -
Arteriosclerosis, Thrombosis, and... Jul 2024Myxomatous valve disease (MVD) is the most common cause of mitral regurgitation, leading to impaired cardiac function and heart failure. MVD in a mouse model of Marfan...
BACKGROUND
Myxomatous valve disease (MVD) is the most common cause of mitral regurgitation, leading to impaired cardiac function and heart failure. MVD in a mouse model of Marfan syndrome includes valve leaflet thickening and progressive valve degeneration. However, the underlying mechanisms by which the disease progresses remain undefined.
METHODS
Mice with gene variant recapitulate histopathologic features of Marfan syndrome, and Wnt (Wingless-related integration site) signaling activity was detected in (T-cell factor/lymphoid enhancer factor-β-galactosidase) reporter mice. Single-cell RNA sequencing was performed from mitral valves of wild-type and mice at 1 month of age. Inhibition of Wnt signaling was achieved by conditional induction of the secreted Wnt inhibitor Dkk1 (Dickkopf-1) expression in periostin-expressing valve interstitial cells of -Cre; mice. Dietary doxycycline was administered for 1 month beginning with MVD initiation (1-month-old) or MVD progression (2-month-old). Histological evaluation and immunofluorescence for ECM (extracellular matrix) and immune cells were performed.
RESULTS
Wnt signaling is activated early in mitral valve disease progression, before immune cell infiltration in mice. Single-cell transcriptomics revealed similar mitral valve cell heterogeneity between wild-type and mice at 1 month of age. Wnt pathway genes were predominantly expressed in valve interstitial cells and valve endothelial cells of mice. Inhibition of Wnt signaling in mice at 1 month of age prevented the initiation of MVD as indicated by improved ECM remodeling and reduced valve leaflet thickness with decreased infiltrating macrophages. However, later, Wnt inhibition starting at 2 months did not prevent the progression of MVD.
CONCLUSIONS
Wnt signaling is involved in the initiation of mitral valve abnormalities and inflammation but is not responsible for later-stage valve disease progression once it has been initiated. Thus, Wnt signaling contributes to MVD progression in a time-dependent manner and provides a promising therapeutic target for the early treatment of congenital MVD in Marfan syndrome.
Topics: Animals; Wnt Signaling Pathway; Disease Progression; Fibrillin-1; Disease Models, Animal; Mitral Valve; Mice; Intercellular Signaling Peptides and Proteins; Mice, Transgenic; Marfan Syndrome; Mitral Valve Insufficiency; Mice, Inbred C57BL; Inflammation; Male; Female; Cell Adhesion Molecules; Adipokines
PubMed: 38660802
DOI: 10.1161/ATVBAHA.123.320388 -
Obstetric Medicine Mar 2024Aortic dilatation and pregnancy are major concerns in women with aortopathy (AOP). This single-centre retrospective analysis focuses on the evolution of aortic diameters...
BACKGROUND
Aortic dilatation and pregnancy are major concerns in women with aortopathy (AOP). This single-centre retrospective analysis focuses on the evolution of aortic diameters during and after pregnancy in women with Marfan syndrome (MS), Turner syndrome (TS) and bicuspid aortic valve (BAV) aortopathy.
METHODS AND RESULTS
Thirty-eight women who had one or more single pregnancies were included. The ascending aorta was measured during pregnancy and postpartum. During pregnancy, a significant increase of diameters of the sinus aortae (median 1.4 mm; [-1.3; 3.8]) and ascending aorta (median 2.1 mm; [0.0; 4.0]) was noted. Systemic hypertension gives dilation of the aorta, but it did not influence the overall trajectory during pregnancy.
CONCLUSION
Significant aortic dilatation is noted during pregnancy in women with underlying AOP, even persisting in the long term. Pre-existing systemic hypertension is associated with larger aortic diameters prior to pregnancy. More research on a larger study population however is needed.
PubMed: 38660320
DOI: 10.1177/1753495X231156851 -
Head & Face Medicine Apr 2024This study aims to analyze to what extent patients with Marfan syndrome (MFS) are affected by temporomandibular disorders (TMD) and its impact on oral health-related...
BACKGROUND
This study aims to analyze to what extent patients with Marfan syndrome (MFS) are affected by temporomandibular disorders (TMD) and its impact on oral health-related quality of life (OHRQoL). To collect data, an online questionnaire was created to recruit participants from Germany, Austria, and Switzerland through social media and support groups. The questionnaire consists of free-text questions, the German versions of the Oral Health Impact Profile (OHIP-G14), the Depression Anxiety Stress Scale (DASS), and the Graded Chronic Pain Status (GCPS).
RESULTS
A total of 76 participants with diagnosed MFS were included. Of these, 65.8% showed TMD symptoms, the most common being pain or stiffness of the masticatory muscles in the jaw angle (50.0%). Only 14.5% of the participants were already diagnosed with TMD. Of the participants with an increased likelihood of a depression disorder, 76.9% showed TMD symptoms. Of those with a critical score for an anxiety disorder, 90.9% showed TMD symptoms. 73.3% of participants with TMD symptoms reached the critical score for a stress disorder. TMD symptoms were associated with a higher risk for chronic pain. In the median, participants with TMD showed statistically notably higher OHIP-G14 scores than participants without TMD (11.5 [IQR 17] vs. 1 [IQR 3] points, p ≤ 0.001).
CONCLUSION
TMD symptoms had a noticeable impact on OHRQoL in patients with MFS, i.e., chronic pain and psychological impairment. TMD seems underdiagnosed, and more research is needed to prevent the associated chronification of pain and psychological burden to improve the OHRQoL.
Topics: Humans; Marfan Syndrome; Female; Male; Temporomandibular Joint Disorders; Adult; Quality of Life; Germany; Surveys and Questionnaires; Middle Aged; Switzerland; Austria; Young Adult; Oral Health
PubMed: 38659050
DOI: 10.1186/s13005-024-00427-z -
European Heart Journal. Case Reports Apr 2024Aortic regurgitation (AR) associated with detachment of the aortic valve commissure is extremely rare. We present a case of progressively worsening severe chronic AR due...
BACKGROUND
Aortic regurgitation (AR) associated with detachment of the aortic valve commissure is extremely rare. We present a case of progressively worsening severe chronic AR due to detachment of the aortic valve commissure during hospitalization that was confirmed with multimodality imaging.
CASE SUMMARY
A 50-year-old male with Marfan syndrome visited our hospital to receive treatment for cholelithiasis. Pre-operative examination revealed severe AR and aortic root aneurysm. Because the patient was asymptomatic, it was decided that cholecystectomy should be performed first. However, the patient's heart failure worsened acutely when his blood pressure increased just before induction of anaesthesia. The patient required intubation and management of heart failure. Five days later, the patient underwent cholecystectomy. He was treated for heart failure and underwent open heart surgery on the 35th hospital day. Intraoperative transoesophageal echocardiography revealed that his AR was caused by both enlargement of the aortic root and localized dissection of the aortic valve commissure, which was supported by intraoperative findings and histopathological evaluation. Aortic regurgitation was exacerbated by a new localized dissection, resulting in acute worsening of heart failure.
DISCUSSION
Aortic valve commissure detachment can easily lead to sudden onset of severe AR, deteriorating haemodynamics, and acute pulmonary oedema. Since delayed medical treatment leads to poor clinical outcomes, prompt and accurate diagnosis and appropriately timed surgical intervention are essential. This very rare case of severe AR worsening due to spontaneous aortic valve commissure dissection was evaluated with multiple modalities during hospitalization. Understanding this clinical condition will help cardiologists provide better medical care.
PubMed: 38651082
DOI: 10.1093/ehjcr/ytae178 -
Journal of Thoracic Imaging Apr 2024There remains a need for improved imaging markers for risk stratification and treatment guidance in Marfan syndrome (MFS). After aortic root replacement (ARR), vascular...
PURPOSE
There remains a need for improved imaging markers for risk stratification and treatment guidance in Marfan syndrome (MFS). After aortic root replacement (ARR), vascular remodeling and progressive aneurysm formation can occur due to alterations in up- and downstream wall biomechanics and hemodynamics. We aim to compare the ventriculo-vascular properties of patients with MFS with controls, and investigate the correlation between ascending aortic area strain and descending aortic area strain (DAAS) with other clinical variables.
PATIENTS AND METHODS
Nineteen patients with MFS (47% males), including 6 with ARR were studied. In 26 studies, aortic area strain was measured using cross-sectional cardiac magnetic resonance images at the ascending and proximal descending aortic levels. Left atrial, left ventricular longitudinal, and left ventricle circumferential strain (left atrial longitudinal strain, left ventricular longitudinal strain, and left ventricular circumferential strain, respectively) were measured using cardiac magnetic resonance-feature tracking.
RESULTS
Compared with healthy controls, patients with MFS had significantly impaired left ventricular longitudinal strain and left ventricular circumferential strain (-15.8 ± 4.7 vs -19.7 ± 4.8, P = 0.005, and -17.7 ± 4.0 vs -27.0 ± 4.1, P < 0.001). Left atrial longitudinal strain was comparable between patients with MFS and controls. AAAS was significantly reduced (19.0 [11.9, 23.7] vs 46.1 ± 11.3, P < 0.001), whereas DAAS was not significantly decreased. AAAS and DAAS were negatively correlated with age, whereas no significant associations were identified with left ventricle function indices. No significant differences were observed between the ventriculo-vascular properties of patients with MFS who underwent ARR and those who did not.
CONCLUSION
Patients with MFS demonstrated impaired ventricular and vascular function compared with healthy controls. Further investigations are warranted to determine clinical utility of aortic stiffness indices for predicting primary and repeat aortic events.
PubMed: 38624084
DOI: 10.1097/RTI.0000000000000784 -
European Spine Journal : Official... Apr 2024Dural ectasia (DE) may significantly impact Marfan syndrome (MFS) patients' quality of life due to chronic lower back pain, postural headache and urinary disorders. We...
PURPOSE
Dural ectasia (DE) may significantly impact Marfan syndrome (MFS) patients' quality of life due to chronic lower back pain, postural headache and urinary disorders. We aimed to evaluate the association of quantitative measurements of DE, and their evolution over time, with demographic, clinical and genetic characteristics in a cohort of MFS patients.
METHODS
We retrospectively included 88 consecutive patients (39% females, mean age 37.1 ± 14.2 years) with genetically confirmed MFS who underwent at least one MRI or CT examination of the lumbosacral spine. Vertebral scalloping (VS) and dural sac ratio (DSR) were calculated from L3 to S3. Likely pathogenic or pathogenic FBN1 variants were categorized as either protein-truncating or in-frame. The latter were further classified according to their impact on the cysteine content of fibrillin-1.
RESULTS
Higher values of the systemic score (revised Ghent criteria) were associated with greater DSR at lumbar (p < 0.001) and sacral (p = 0.021) levels. Patients with protein-truncating variants exhibited a greater annual increase in lumbar (p = 0.039) and sacral (p = 0.048) DSR. Mutations affecting fibrillin-1 cysteine content were linked to higher VS (p = 0.009) and DSR (p = 0.038) at S1, along with a faster increase in VS (p = 0.032) and DSR (p = 0.001) in the lumbar region.
CONCLUSION
Our study shed further light on the relationship between genotype, dural pathology, and the overall clinical spectrum of MFS. The identification of protein-truncating variants and those impacting cysteine content may therefore suggest closer patient monitoring, in order to address potential complications associated with DE.
PubMed: 38615299
DOI: 10.1007/s00586-024-08252-3 -
The British Journal of Ophthalmology Apr 2024The aim of this study was to analyse the effective lens position (ELP) in patients with Marfan syndrome (MFS) and ectopia lentis (EL).
AIMS
The aim of this study was to analyse the effective lens position (ELP) in patients with Marfan syndrome (MFS) and ectopia lentis (EL).
METHODS
Patients with MFS undergoing lens removal and primary intraocular lens (IOL) implantation were enrolled in the study. The back-calculated ELP was obtained with the vergence formula and compared with the theoretical ELPs. The back-calculated ELP and ELP error were evaluated among demographic and biometric parameters, including axial length (AL), corneal curvature radius (CCR) and white-to-white (WTW).
RESULTS
A total of 292 eyes from 200 patients were included. The back-calculated ELP was lower in patients undergoing scleral-fixated IOL than those receiving in-the-bag IOL implantation (4.54 (IQR 3.65-5.20) mm vs 4.98 (IQR 4.56-5.67) mm, p<0.001). The theoretical ELP of the SRK/T formula exhibited the highest accuracy, with no difference from the back-calculated ELP in patients undergoing in-the-bag IOL implantation (5.11 (IQR 4.83-5.65) mm vs 4.98 (IQR 4.56-5.67) mm, p=0.209). The ELP errors demonstrated significant correlations with refraction prediction error (PE): a 1 mm ELP error led to PE of 2.42D (AL<22 mm), 1.47D (22 mm≤AL<26 mm) and 0.54D (AL≥26 mm). Multivariate analysis revealed significant correlations of ELP with AL (b=0.43, p<0.001), CCR (b=-0.85, p<0.001) and WTW (b=0.41, p=0.004).
CONCLUSION
This study provides novel insights into the origin of PE in patients with MFS and EL and potentially refines existing formulas.
PubMed: 38604620
DOI: 10.1136/bjo-2023-325017 -
Connective Tissue Research May 2024Congenital contractural arachnodactyly (CCA) is an extremely rare autosomal dominant connective tissue genetic disorder caused by pathogenic variants in FBN2. CCA is...
PURPOSE
Congenital contractural arachnodactyly (CCA) is an extremely rare autosomal dominant connective tissue genetic disorder caused by pathogenic variants in FBN2. CCA is characterized by arachnodactyly, camptodactyly, contracture of major joints, scoliosis, pectus deformities, and crumpled ears, but rarely with lethal cardiovascular manifestations as in Marfan syndrome. It is imperative to conduct a comprehensive analysis and review of the pathogenesis of CCA resulting from pathogenic variants in FBN2 gene.
MATERIALS AND METHODS
Using whole-exome sequencing and Sanger sequencing, we identified a novel pathogenic splice-altering variant (c.4472-3C>A) in intron 34 of FBN2 gene in a CCA pedigree. The transcriptional result of the splicing-altering variant was analyzed by RNA sequencing. We systematically analyzed the clinical manifestations of all reported cases of CCA caused by splicing-altering pathogenic variants and focused on all the pathogenic variants in FBN2 gene that are associated with severe cardiovascular manifestations.
RESULTS
The splice-altering variant (c.4472-3C>A) in FBN2 was demonstrated to result in the exon 35 skipping and cause an in-frame deletion. Furthermore, we identified exons 31 to 35 may be a hotspot region in FBN2 gene associated with severe cardiovascular phenotype.
CONCLUSIONS
This study enriched the pathogenic spectrum of CCA and identified a hotspot region in FBN2 gene associated with severe cardiovascular manifestations. We recommend that patients carrying pathogenic variants in exons 31 to 35 of FBN2 pay more attention to cardiac evaluation.
Topics: Fibrillin-2; Humans; Arachnodactyly; Contracture; Male; Female; Pedigree; Mutation
PubMed: 38602424
DOI: 10.1080/03008207.2024.2340004 -
Arteriosclerosis, Thrombosis, and... May 2024AGT (angiotensinogen) is the unique precursor for the generation of all the peptides of the renin-angiotensin system, but it has received relatively scant attention... (Review)
Review
AGT (angiotensinogen) is the unique precursor for the generation of all the peptides of the renin-angiotensin system, but it has received relatively scant attention compared to many other renin-angiotensin system components. Focus on AGT has increased recently, particularly with the evolution of drugs to target the synthesis of the protein. AGT is a noninhibitory serpin that has several conserved domains in addition to the angiotensin II sequences at the N terminus. Increased study is needed on the structure-function relationship to resolve many unknowns regarding AGT metabolism. Constitutive whole-body genetic deletion of in mice leads to multiple developmental defects creating a challenge to use these mice for mechanistic studies. This has been overcome by creating -floxed mice to enable the development of cell-specific deficiencies that have provided considerable insight into a range of cardiovascular and associated diseases. This has been augmented by the recent development of pharmacological approaches targeting hepatocytes in humans to promote protracted inhibition of AGT synthesis. Genetic deletion or pharmacological inhibition of has been demonstrated to be beneficial in a spectrum of diseases experimentally, including hypertension, atherosclerosis, aortic and superior mesenteric artery aneurysms, myocardial dysfunction, and hepatic steatosis. This review summarizes the findings of recent studies utilizing AGT manipulation as a therapeutic approach.
Topics: Animals; Humans; Cardiovascular Diseases; Angiotensinogen; Metabolic Diseases; Renin-Angiotensin System; Molecular Targeted Therapy
PubMed: 38572647
DOI: 10.1161/ATVBAHA.124.318374