Hyperviscosity Syndrome in Undifferentiated Connective Tissue Disease: A Diagnostic and Therapeutic Challenge.

Hyperviscosity is an uncommon manifestation of various underlying diseases. Rapid diagnosis and management of the underlying disease is crucial to prevent significant complications, including hypertension, cerebral vascular accidents, pulmonary embolism, bowel ischemia, and ophthalmologic pathologies. Although the acute management of complications arising from hyperviscosity is relatively straightforward, identifying and treating the underlying cause can prove difficult. This case highlights the difficulties of establishing a diagnosis and initiating appropriate management for a patient with hyperviscosity syndrome in a suspected rheumatologic disorder.

Iliac artery dissection and rupture in a patient with classic Ehlers-Danlos syndrome due to COL5A1 null variant.

This is a case of a 46-year-old woman who presented with right common iliac artery dissection preceded by a left common iliac artery dissection and rupture 6 years earlier. Both iliac arteries required repair. Based on her presentation, she met the clinical diagnostic criteria for vascular Ehlers-Danlos syndrome; however, the genetic workup demonstrated that she had classic Ehlers-Danlos syndrome due to a null variant in COL5A1, which is rarely associated with arteriopathy.

An Analysis From a Tertiary Pediatric Hospital: Does Physical Activity Play a Role in the Management of Children and Young Adults With Osteogenesis Imperfecta?

INTRODUCTION: Osteogenesis imperfecta (OI) is a hereditary connective tissue disorder characterized by reduced bone density and increased proneness to fractures. It manifests across a varied clinical spectrum of expressions in children and young adults. It is crucial for children with OI to have a multidisciplinary follow-up, including orthopedics, pediatrics, and physical medicine and rehabilitation. Although exercise may have no effect on the disease itself, it might improve the autonomy, self-esteem, and fitness of these children.  Methods: Retrospective cohort analysis of children and young adults aged three or more years old followed-up in a Level III Pediatric Hospital between 1995 and 2020. Demographic and clinical data were obtained from the hospital records and from the caregivers via phone calls. To our knowledge, this is the first national case series published assessing exercise habits in children with this condition. RESULTS: Among the 21 patients studied, the median age was 14 years, with no gender predominance. Eighteen (86%) practiced regular physical activity, while the remaining three (14%), all of whom were type III OI, were totally dependent. Of the aforementioned 18 children, 12 (67%) considered practicing the same level of physical activity compared to their healthy peers, although most of them needed adaptations. The most reported extracurricular activity was swimming, in 50% of the cases. About 39% engaged in physical activity two times or less per week, and 89% practiced for one hour or less per session. DISCUSSION: Over the years, it has become clear that physical activity is an important part of OI management. While awareness of the importance of exercise already exists, proper planning, follow-up, and monitoring are essential.

A new conceptual model for anorexia nervosa: A role for connective tissue?

The etiology of anorexia nervosa (AN) remains to be fully elucidated, and current theories also fail to account for the direct effect of starvation on the health of the organs and tissues, specifically the connective tissue present in most organs of the body. Individuals with hereditary disorders of connective tissue manifest with clinical symptoms that overlap with AN, as the abnormal connective tissue also contributes to many of the other extra-articular manifestations of these hereditary disorders. This article hypothesizes that a similar pathophysiology may also contribute to the clinical presentation of AN. Therefore, a better understanding is needed to elucidate: (1) the relationship between abnormal connective tissue and AN, (2) the impact of starvation toward the development of abnormal connective tissue and how this manifests clinically, (3) the etiology of autonomic nervous system changes contributing to the dysautonomia in AN, and (4) how the sensory signals sent from potentially abnormal connective tissue to the central nervous system impact interoception in AN. A conceptual model incorporating abnormal connective tissue is provided. PUBLIC SIGNIFICANCE: The etiology of AN remains poorly understood and current theories fail to account for the direct impact of starvation on the health of the organs and tissues of the body. There is significant clinical overlap between AN and hereditary connective tissue disorders. This paper attempts to provide a new conceptual model for AN in which abnormal connective tissue contributes to the underlying pathogenesis.

Painful Limb Ulcers: A Case Report on Ulcerative Discoid Lupus Erythematosus.

Lupus erythematosus is an autoimmune disorder with varied clinical features. Discoid Lupus Erythematosus (DLE) presents as erythematous, raised plaques. The patients might present with photosensitivity, arthralgia, and nail changes. However, dermoscopy, clinical features, and laboratory markers like high titers of Antinuclear antibodies (ANA) help in clenching the diagnosis. We report a patient in her mid-60s presented with non-healing ulcers oozing pus discharge associated with pain and joint stiffness. Thus, a series of investigations, treatment modifications, and the healing progression of the lesions highlight the importance of retrospective diagnosis.

EFEMP1 haploinsufficiency causes a Marfan-like hereditary connective tissue disorder.

Phenotypic features of a hereditary connective tissue disorder, including craniofacial characteristics, hyperextensible skin, joint laxity, kyphoscoliosis, arachnodactyly, inguinal hernia, and diverticulosis associated with biallelic pathogenic variants in EFEMP1 have been previously described in four patients. Genome sequencing on a proband and her mother with comparable phenotypic features revealed that both patients were heterozygous for a stop-gain variant c.1084C>T (p.Arg362*). Complementary RNA-seq on fibroblasts revealed significantly reduced levels of mutant EFEMP1 transcript. Considering the absence of other molecular explanations, we extrapolated that EFEMP1 could be the cause of the patient's phenotypes. Furthermore, nonsense-mediated decay was demonstrated for the mutant allele as the principal mechanism for decreased levels of EFEMP1 mRNA. We provide strong clinical and genetic evidence for the haploinsufficiency of EFEMP1 due to nonsense-medicated decay to cause severe kyphoscoliosis, generalized hypermobility of joints, high and narrow arched palate, and potentially severe diverticulosis. To the best of our knowledge, this is the first report of an autosomal dominant EFEMP1-associated hereditary connective tissue disorder and therefore expands the phenotypic spectrum of EFEMP1 related disorders.

TGFß level in healthy and children with Marfan syndrome-effective reduction under sartan therapy.

Introduction: Transforming growth factor ß (TGFß) metabolism plays an important role in the pathogenesis of Marfan syndrome (MFS). Accordingly, drug therapy uses TGFß receptor blockade to slow down the cardiovascular manifestations, above all aortic root dilatation. Angiotensin II type 1 receptor blockers (ARBs) have been shown to reduce TGFß levels in adults. Data on childhood are lacking and are now being investigated in the TiGer For Kids study presented here. Methods: We examined 125 children without chronic disease and 31 pediatric Marfan patients with a proven FBN1 variant with regard to TGFß levels. In addition, we measured TGFß levels during the initiation of ARB therapy in pediatric Marfan patients. Results: In children without chronic disease, TGFß levels were found to decrease from childhood to adolescence (p < 0.0125). We could not measure a relevantly increased TGFß level in pediatric Marfan patients. However, we showed a significant suppression of the TGFß level after treatment with ARBs (p < 0.0125) and a renewed increase shortly before the next dose. Discussion: The TGFß level in childhood changes in an age-dependent manner and decreases with age. The TGFß level drops significantly after taking ARBs. Based on our experience and data, a TGFß receptor blockade in childhood seems reasonable. So far, TGFß level cannot be used as an MFS screening biomarker.

Diagnostic value of combined FVC%/DLCO% and echocardiography in connective tissue disorder­associated pulmonary hypertension.

The main objective of the present study was to investigate whether forced vital capacity (FVC)%/diffusing capacity of the lungs for carbon monoxide (DLCO)% can be used to predict the presence of pulmonary hypertension (PH) in connective tissue disorders (CTDs). For this purpose, a total of 53 individuals who were diagnosed with CTDs and had undergone right heart catheterization between July, 2019 and July, 2022 were included in the present study. Based on the mean pulmonary artery pressure (mPAP) measured during right heart catheterization, the participants were divided into the PH and non-PH groups. The differences in demographic characteristics, including sex, age, body mass index, smoking index, FVC%/DLCO% and pulmonary artery systolic pressure (PASP) were determined by echocardiography; moreover, the 6-min walk distance, plasma brain natriuretic peptide (BNP) levels, white blood cell count, red blood cell distribution width, erythrocyte sedimentation rate and C-reactive protein levels were compared between the two groups to identify independent predictors of PH. The independent predictors were subsequently evaluated for their correlation with mPAP to assess their predictive value for PH. FVC%/DLCO%, echocardiographic PASP, and plasma BNP levels were identified as independent predictors of PH. FVC%/DLCO% and echocardiographic PASP exhibited a significant correlation with mPAP, while the correlation between plasma BNP and mPAP levels was not statistically significant. The area under the curve (AUC) value for FVC%/DLCO% alone in predicting PH was 0.791, with an optimal diagnostic threshold of 1.35, a sensitivity of 0.794 and a specificity of 0.789. The AUC for echocardiographic PASP alone in predicting PH was 0.783, with an optimal diagnostic threshold of 39.5 mmHg, a sensitivity of 0.794 and a specificity of 0.684. When combined, the AUC of the two factors in predicting PH was 0.872, with a sensitivity of 0.941 and a specificity of 0.684. Collectively, the data of the present study indicate that FVC%/DLCO% may be used as a predictive factor for CTD-PH, and its combined application with echocardiographic PASP measurement may provide additional evidence for the clinical diagnosis of CTD-PH.

Midterm Clinical Outcomes of Reimplantation Versus Remodeling Valve-Sparing Aortic Root Replacement in Patients With Connective Tissue Disorders: A Meta-Analysis.

This meta-analysis aimed to compare the midterm clinical outcomes of reimplantation versus remodeling techniques for valve-sparing aortic root replacement (VSARR) in patients with connective tissue disorders (CTDs). Studies were screened and identified after the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines from the PubMed, Web of Science, and Embase databases. Forest plots were produced using Review Manager 5.3 (Cochrane, UK). Studies comparing early and midterm clinical outcomes of reimplantation versus remodeling VSARR in patients with CTD with a mean age ≥18 years were included. The sensitivity analysis excluded studies and subgroups of patients that received ring or suture annuloplasty in addition to remodeling surgery. The study selection identified 9 eligible studies. After analysis of the study period and location for patient crossover, 7 retrospective studies consisting of 597 patients (301 reimplantation and 296 remodeling) were pooled. The pooling revealed no significant difference in postoperative mortality (estimated mean follow-up of 10.5 years) (odds ratio [OR] 0.66, 95% confidence interval [CI] 0.30 to 1.48, I2 = 30%, p = 0.32), reoperation (OR 0.35, CI 0.04 to 3.30, I2 = 81%, p = 0.36), or occurrence of postoperative aortic regurgitation of ≥2 (OR 0.56, CI 0.31 to 1.02, I2 = 47%, p = 0.06). The sensitivity analysis excluding annuloplasty demonstrated improved mortality (OR 0.19, CI 0.06 to 0.64, I2 = 0%, p = 0.007) and decreased aortic regurgitation of ≥2 (OR 0.23, CI 0.10 to 0.53, I2 = 47%, p = 0.0005) in reimplantation VSARR. The rates of reoperation remained insignificant in the sensitivity analysis (OR 0.43, CI 0.05 to 3.53, I2 = 71%, p = 0.43). In conclusion, this meta-analysis has demonstrated no significant difference in the midterm clinical outcomes of reimplantation versus remodeling techniques of VSARR. The sensitivity analysis excluding studies and patient subgroups that received remodeling and annuloplasty suggests remodeling alone to be inferior to reimplantation in patients with CTDs. Further research is required to assess remodeling and annuloplasty against reimplantation in patients of this demographic because the current body of knowledge does not allow sufficient analysis.

Neurological Manifestations of Connective Tissue Disorders.

Connective tissue disorders (CTD) are a group of disorders affecting the connective tissues. Usually the musculoskeletal and the vascular system is impacted. Along with these systems, the nervous system is also involved in CTD, which leads to various neurological manifestations. The pathophysiology of neurological complications of CTD is caused by various factors and is complicated. Disturbed immune complexes, chronic inflammation, and autoimmunity in which the body attacks its cells are considered to be responsible for the neurological complications of CTD. Additionally, the vascular symptoms that lead to decreased blood flow to the brain are also responsible for the neurological manifestations of CTD in diseases like systemic lupus erythematosus (SLE). In SLE, vessel wall integrity is compromised, which may lead to decreased blood flow leading to neurological complications. CTD can manifest a variety of neurological complications. These neurological complications can be classified into symptoms affecting the peripheral nervous system, central nervous system, and the autonomic nervous system. Some of the common neurological complications of CTD are headaches, seizures, ataxia, neuropathies leading to cranial nerve palsies, myelopathies, tremors, encephalitis, and cerebral infarction. Cranial nerve palsies can disturb sensations, vision, hearing, and mastication. Neuropsychiatric symptoms are also commonly observed in CTD. Cognitive dysfunction can be caused due to neuropsychiatric problems. Some of the cognitive dysfunctions are lack of concentration, memory loss, confusion, and coma. In this review, we will address various neurological manifestations of CTD.

First application of GammaTile cesium-131 brachytherapy with maximal safe resection of a glioma in a patient with limited scleroderma.

The purpose of this report is to present the first documented application of GammaTile to an intra-cranial tumor of a patient with a symptomatic radiosensitive connective tissue disorder, a case where there were significant concerns with standard oncologic strategies. We hypothesized that GammaTile® (GT Medical Technologies, Tempe, Arizona, USA) would also be advantageous in the application of intra-cranial tumors in patients with conditions of increased radiosensitivity. We generated a standard external beam radiation therapy (EBRT) plan consisting of an overall 1.5 cm expansion to 59.4 Gy in 1.8 Gy fractions. Also, we developed a CyberKnife (Accuray, Sunnyvale, CA, USA) plan with a 5 mm expansion on the surgical cavity prescribed to 60 Gy in 30 fractions, to make an EBRT comparison using the same prescription volume as GammaTile. We report the first published application of GammaTile® brachytherapy to an intra-cranial malignancy in a patient with limited scleroderma. The dose delivered by GammaTile was compared to the dose that would be delivered with both typical volumes and small volumes of EBRT. The maximum dose delivered to the scar and scalp by GammaTile was reduced to half of that from other external beam techniques (~25 Gy vs. ~55 Gy). MRI imaging at 6 months and 12 months post-resection demonstrated no evidence of disease recurrence nor radiation necrosis. At the 12-month follow-up visit, the surgical scar was well-healed with no skin changes to the surrounding scalp. Dosimetrically and clinically, this report highlights the successful application of GammaTile to an intra-cranial tumor bed in a patient with scleroderma.

Spontaneous cervical artery dissection: is it really a connective tissue disease? A comprehensive review.

Background: Spontaneous cervical artery dissection (sCeAD) is an important cause of stroke in young adults. The underlying pathophysiology remains unclear, without validated biomarkers to identify subjects at risk. Previous studies suggested the role of abnormalities in the connective component of the arterial wall. Purpose: To assess dermal ultrastructural aberrations of connective tissue by skin biopsy and genetic variations in sCeAD patients. Method: We searched the PubMed and Scopus databases until August 2023 with PRISMA guidelines. Original articles assessing skin biopsy in sCeAD patients were included. Two reviewers independently conducted the screening. Findings: We included 16 studies compromising 459 patients. Thirteen studies assessed ultrastructural changes and found aberrations of collagen and elastic fibers, described as irregular contours and calibers of collagen fibrils, composite flower-like fibrils, fragmented moth-eaten elastin, and microcalcifications, cumulatively in 50.5% of patients. Seven studies showed no causative mutations in collagen type I, III, V, or elastin genes. One study showed linkage between connective tissue alterations and mutation on chromosomes 15q2 and 10q26 using genome-wide linkage analysis, while another study found significant copy number variant enrichments in genes involved in extracellular matrix (COL5A2/COL3A1/SNTA1) and collagen fibril organizations (COL5A2/COL3A1). Finally, differential expression of extracellular proteins was linked to connective tissue disorder in patients with recurrent sCeAD using a quantitative proteomics approach. Conclusion: Current literature supports the hypothesis that an underlying, subclinical connective tissue disorder, likely genetically determined, may predispose to arterial wall weakness and sCeAD. Further studies with larger sample sizes and robust methodology are needed to better define the role of connective tissue in sCeAD pathogenesis.

Imaging in a Rare Case of Neonatal Arterial Tortuosity Syndrome.

Arterial tortuosity syndrome (ATS) is a very rare autosomal recessive disorder that affects the connective tissue. The incidence of ATS is not well known and to date only 106 patients have been described in the literature. ATS affects medium and large size arteries, leading to widespread elongation and intensification of the average vessel tortuousness, responsible of several loops and kinks. Like other connective tissue disorders, ATS can present with joint laxity, hernias, pectus excavatum, scoliosis or other musculoskeletal abnormalities, and ocular defects. Due to the extreme variability of clinical symptoms and the fact that ATS has no curative management, prompt diagnosis is of tremendous importance to prevent disease-associated complications. In this situation, imaging techniques have a central role. In this study, we describe a rare case of a male newborn with tortuosity and lengthening of the main arterial and venous medium and large caliber branches with associated aortic coarctation who passed away prematurely. The finding of aortic coarctation in a newborn with ATS has rarely been described in the literature.

NGS analysis of collagen type I genes in Polish patients with Osteogenesis imperfecta: a nationwide multicenter study.

Osteogenesis imperfecta (OI) is a rare genetic disorder of the connective tissue. It presents with a wide spectrum of skeletal and extraskeletal features, and ranges in severity from mild to perinatal lethal. The disease is characterized by a heterogeneous genetic background, where approximately 85%-90% of cases have dominantly inherited heterozygous pathogenic variants located in the COL1A1 and COL1A2 genes. This paper presents the results of the first nationwide study, performed on a large cohort of 197 Polish OI patients. Variants were identified using a next-generation sequencing (NGS) custom gene panel and multiplex ligation probe amplification (MLPA) assay. The following OI types were observed: 1 (42%), 2 (3%), 3 (35%), and 4 (20%). Collagen type I pathogenic variants were reported in 108 families. Alterations were observed in α1 and α2 in 70% and 30% of cases, respectively. The presented paper reports 97 distinct causative variants and expands the OI database with 38 novel pathogenic changes. It also enabled the identification of the first glycine-to-tryptophan substitution in the COL1A1 gene and brought new insights into the clinical severity associated with variants localized in "lethal regions". Our results contribute to a better understanding of the clinical and genetic aspects of OI.

Variable clinical expression of a Belgian TGFB3 founder variant suggests the presence of a genetic modifier.

Background: TGFB3 variants cause Loeys-Dietz syndrome type 5, a syndromic form of thoracic aortic aneurysm and dissection. The exact disease phenotype is hard to delineate because of few identified cases and highly variable clinical representation. Methodology: We provide the results of a haplotype analysis and a medical record review of clinical features of 27 individuals from 5 different families, originating from the Campine region in Flanders, carrying the NM_003239.5(TGFB3):c.787G>C p.(Asp263His) likely pathogenic variant, dbSNP:rs796051886, ClinVar:203492. The Asp263 residue is essential for integrin binding to the Arg-Gly-Asp (RGD) motif of the TGFß3-cytokine. Results: The haplotype analysis revealed a shared haplotype of minimum 1.92 Mb and maximum 4.14 Mb, suggesting a common founder originating >400 years ago. Variable clinical features included connective tissue manifestations, non-aneurysmal cardiovascular problems such as hypertrophic cardiomyopathy, bicuspid aortic valve, mitral valve disease, and septal defects. Remarkably, only in 4 out of the 27 variant-harboring individuals, significant aortic involvement was observed. In one family, a 31-year-old male presented with type A dissection. In another family, the male proband (65 years) underwent a Bentall procedure because of bicuspid aortic valve insufficiency combined with sinus of Valsalva of 50 mm, while an 80-year-old male relative had an aortic diameter of 43 mm. In a third family, the father of the proband (75 years) presented with ascending aortic aneurysm (44 mm). Conclusion: The low penetrance (15%) of aortic aneurysm/dissection suggests that haploinsufficiency alone by the TGFB3 variant may not result in aneurysm development but that additional factors are required to provoke the aneurysm phenotype.

Clinical and molecular delineation of classical-like Ehlers-Danlos syndrome through a comprehensive next-generation sequencing-based screening system.

Classical-like Ehlers-Danlos syndrome (clEDS) is an autosomal recessive disorder caused by complete absence of tenascin-X resulting from biallelic variation in TNXB. Thus far, 50 patients from 43 families with biallelic TNXB variants have been identified. Accurate detection of TNXB variants is challenging because of the presence of the pseudogene TNXA, which can undergo non-allelic homologous recombination. Therefore, we designed a genetic screening system that is performed using similar operations to other next-generation sequencing (NGS) panel analyses and can be applied to accurately detect TNXB variants and the recombination of TNXA-derived sequences into TNXB. Using this system, we identified biallelic TNXB variants in nine unrelated clEDS patients. TNXA-derived variations were found in >75% of the current cohort, comparable to previous reports. The current cohort generally exhibited similar clinical features to patients in previous reports, but had a higher frequency of gastrointestinal complications (e.g., perforation, diverticulitis, gastrointestinal bleeding, intestinal obstruction, rectal/anal prolapse, and gallstones). This report is the first to apply an NGS-based screening for TNXB variants and represents the third largest cohort of clEDS, highlighting the importance of increasing awareness of the risk of gastrointestinal complications.

The Maastricht Acquisition Platform for Studying Mechanisms of Cell-Matrix Crosstalk (MAPEX): An Interdisciplinary and Systems Approach towards Understanding Thoracic Aortic Disease.

Current management guidelines for ascending thoracic aortic aneurysms (aTAA) recommend intervention once ascending or sinus diameter reaches 5-5.5 cm or shows a growth rate of >0.5 cm/year estimated from echo/CT/MRI. However, many aTAA dissections (aTAAD) occur in vessels with diameters below the surgical intervention threshold of <55 mm. Moreover, during aTAA repair surgeons observe and experience considerable variations in tissue strength, thickness, and stiffness that appear not fully explained by patient risk factors. To improve the understanding of aTAA pathophysiology, we established a multi-disciplinary research infrastructure: The Maastricht acquisition platform for studying mechanisms of tissue-cell crosstalk (MAPEX). The explicit scientific focus of the platform is on the dynamic interactions between vascular smooth muscle cells and extracellular matrix (i.e., cell-matrix crosstalk), which play an essential role in aortic wall mechanical homeostasis. Accordingly, we consider pathophysiological influences of wall shear stress, wall stress, and smooth muscle cell phenotypic diversity and modulation. Co-registrations of hemodynamics and deep phenotyping at the histological and cell biology level are key innovations of our platform and are critical for understanding aneurysm formation and dissection at a fundamental level. The MAPEX platform enables the interpretation of the data in a well-defined clinical context and therefore has real potential for narrowing existing knowledge gaps. A better understanding of aortic mechanical homeostasis and its derangement may ultimately improve diagnostic and prognostic possibilities to identify and treat symptomatic and asymptomatic patients with existing and developing aneurysms.