Heritable Disorders Of Connective Tissue Research Articles

Skin fragility and wound management in Ehlers- Danlos Syndrome: a report by the Ehlers Danlos Syndrome society skin working group.

The Ehlers-Danlos Syndromes (EDS) are a heterogenous group of heritable connective tissue disorders, characterised by joint hypermobility, skin hyperextensibility and generalised tissue fragility. In all types of EDS skin wound healing is impaired to a variable degree. Additional support through wound management plans may help to improve these outcomes, however, there is paucity of evidence regarding clinical management of skin fragility and wounds in EDS. This paper aims to review current evidence and provide recommendations for management of skin wounds in EDS types. Preventative measures to avoid skin injury are strongly recommended, including avoidance of high impact sport and use of appropriate protection such as shin guards. Bruising is common and some types of EDS are associated with haematoma formation with management including compression bandages and consideration of pharmacological therapy. Skin fragility and tears should be managed with a focus on protection of remaining tissue, avoidance of wound tension and low adherence dressings to avoid further injury. This paper provides clear recommendations to address skin management for this group of patients. It highlights the lack of good quality published data to support treatment decisions.

Extra-Skeletal Manifestations in Osteogenesis Imperfecta Mouse Models.

Osteogenesis imperfecta (OI) is a rare heritable connective tissue disorder of skeletal fragility with an incidence of roughly 1:15,000. Approximately 85% of the pathogenic variants responsible for OI are in the type I collagen genes, COL1A1 and COL1A2, with the remaining pathogenic OI variants spanning at least 20 additional genetic loci that often involve type I collagen post-translational modification, folding, and intracellular transport as well as matrix incorporation and mineralization. In addition to being the most abundant collagen in the body, type I collagen is an important structural and extracellular matrix signaling molecule in multiple organ systems and tissues. Thus, OI disease-causing variants result not only in skeletal fragility, decreased bone mineral density (BMD), kyphoscoliosis, and short stature, but can also result in hearing loss, dentinogenesis imperfecta, blue gray sclera, cardiopulmonary abnormalities, and muscle weakness. The extensive genetic and clinical heterogeneity in OI has necessitated the generation of multiple mouse models, the growing awareness of non-skeletal organ and tissue involvement, and OI being more broadly recognized as a type I collagenopathy.This has driven the investigation of mutation-specific skeletal and extra-skeletal manifestations and broadened the search of potential mechanistic therapeutic strategies. The purpose of this review is to outline several of the extra-skeletal manifestations that have recently been characterized through the use of genetically and phenotypically heterogeneous mouse models of osteogenesis imperfecta, demonstrating the significant potential impact of OI disease-causing variants as a collagenopathy (affecting multiple organ systems and tissues), and its implications to overall health.

Unique Features of Cardiovascular Involvement and Progression in Children with Marfan Syndrome Justify Dedicated Multidisciplinary Care.

Marfan syndrome (MIM: # 154700; MFS) is an autosomal dominant disease representing the most common form of heritable connective tissue disorder. The condition presents variable multiorgan expression, typically involving a triad of cardiovascular, eye, and skeletal manifestations. Other multisystemic features are often underdiagnosed. Moreover, the disease is characterized by age related penetrance. Diagnosis and management of MFS in the adult population are well-described in literature. Few studies are focused on MFS in the pediatric population, making the clinical approach (cardiac and multiorgan) to these cases challenging both in terms of diagnosis and serial follow-up. In this review, we provide an overview of MFS manifestations in children, with extensive revision of major organ involvement (cardiovascular ocular and skeletal). We attempt to shed light on minor aspects of MFS that can have a significant progressive impact on the health of affected children. MFS is an example of a syndrome where an early personalized approach to address a dynamic, genetically determined condition can make a difference in outcome. Applying an early multidisciplinary clinical approach to MFS cases can prevent acute and chronic complications, offer tailored management, and improve the quality of life of patients.

32 Hypermobile Ehlers-Danlos Syndrome: Phenotypic Presentation, Comorbidity Risk, and Medical Service Utilization in the United States

OBJECTIVES/GOALS: Hypermobile Ehlers-Danlos syndrome (hEDS) is a heritable connective tissue disorder with no known genetic etiology. Its complex phenotypic presentation with multi-system involvement delays proper diagnosis and treatment, especially for females. This study examines the risk for common hEDS comorbidities and medical service utilization. METHODS/STUDY POPULATION: Electronic health records from over 150 million patients across 92 American healthcare servers were queried using the TriNetX database to determine phenotypic presentation of hEDS and risk of receiving comorbid diagnoses. Contingency tables were created with hEDS as the condition and postural orthostatic tachycardia syndrome (POTS) or gastroparesis as the grouping variables. Advanced analytics were conducted to compare outcomes of two cohorts: (1) patients diagnosed with hEDS and both POTS and gastroparesis, and (2) patients with a sole diagnosis of hEDS. After propensity score matching, differences in medical service utilization and mental health diagnoses were assessed between these two cohorts. All analyses restricted age (12-70 years) and employed established exclusion criteria (e.g., diabetes). RESULTS/ANTICIPATED RESULTS: TriNetX national health records (N = 1,968) reveal that hEDS predominantly affects females (87%) and is diagnosed at a mean of 35 years of age. People diagnosed with hEDS have a high prevalence of comorbid nervous system (81%), mental health (76%), and digestive system (69%) disorders. They are 29.7 times more likely to be diagnosed with POTS [95% CI: 27.1, 32.6] and 66.3 times more likely to be diagnosed with gastroparesis [95% CI: 56.5, 77.9], compared to people without hEDS. After propensity score matching for sex, race, and ethnicity, people diagnosed with hEDS and both POTS and gastroparesis have significantly greater service utilization (72.2% vs. 56.7%; z = 2.18, p < .05) but not a greater incidence of mental health disorders (34.4% vs. 24.4%; z = 1.47, p = .14) than people diagnosed with hEDS alone. DISCUSSION/SIGNIFICANCE: This study reveals the phenotypic presentation of hEDS and the elevated risk of co-occurring POTS and/or gastroparesis diagnosis. hEDS and its comorbidities are associated with more frequent medical encounters but not with a greater incidence of mental illness. Findings have implications for both clinical practice guidelines and further research.

Exome sequencing identified mutations in the WNT1 and COL1A2 genes in osteogenesis imperfecta cases.

Osteogenesis imperfecta (OI) is a heritable connective tissue disorder characterized by bone deformities, fractures and reduced bone mass. OI can be inherited as a dominant, recessive, or X-linked disorder. The mutational spectrum has shown that autosomal dominant mutations in the type I collagen-encoding genes are responsible for OI in 85% of the cases. Apart from collagen genes, mutations in more than 20 other genes, such as CRTAP, CREB3L1, MBTPS2, P4HB, SEC24D, SPARC, FKBP10, LEPRE1, PLOD2, PPIB, SERPINF1, SERPINH1, SP7, WNT1, BMP1, TMEM38B, and IFITM5 have been reported in OI. To understand the genetic cause of OI in four cases, we conducted whole exome sequencing, followed by Sanger sequencing. In case #1, we identified a novel c.506delG homozygous mutation in the WNT1 gene, resulting in a frameshift and early truncation of the protein at the 197th amino acid. In cases #2, 3 and 4, we identified a heterozygous c.838G > A mutation in the COL1A2 gene, resulting in a p.Gly280Ser substitution. The clinvar frequency of this mutation is 0.000008 (GnomAD-exomes). This mutation has been identified by other studies as well and appears to be a mutational hot spot. These pathogenic mutations were found to be absent in 96 control samples analyzed for these sites. The presence of these mutations in the cases, their absence in controls, their absence or very low frequency in general population, and their evaluation using various in silico prediction tools suggested their pathogenic nature. Mutations in the WNT1 and COL1A2 genes explain these cases of osteogenesis imperfecta.

Evaluation of the Value of Histological Examination for the Prediction of Genetic Thoracic Proximal Aortopathies.

Background: Heritable connective tissue disorders are often accompanied by an increased risk for thoracic aortic aneurysm and dissection (TAAD). Profound knowledge of the underlying pathology may have an impact on individual treatment, systematic follow-up, and early detection by the screening of offspring. The aim of this study, based in a single high-volume tertiary center, was an analysis of the diagnostic validity of histopathologic findings in patients with TAAD due to these findings' accuracy in diagnosing heritable connective tissue disorders. Methods: Therefore, genetic testing by next-generation sequencing (NGS) was performed to evaluate the correlations. In total, 65 patients with TAAD undergoing surgical treatment before the age of 60 years or with age up to 80 years if they had offspring at the time of the procedure were included in the analysis. Results: In our cohort, no certain correlation of histological findings to the results of genetic diagnostics in patients with clinically relevant aortic pathology could be shown. Patients with histopathologic findings for heritable connective tissue disorder and a positive gene variant were 11.6 years younger than patients without mutation and without histological evidence for connective tissue disorder. Conclusions: Genetic clarification is useful to define the specific genotype of the disease of the aortic wall in the case of non-specific histological characteristics.

Web-based survey investigating cardiovascular complications in hypermobile Ehlers-Danlos syndrome after COVID-19 infection and vaccination.

Hypermobile Ehlers-Danlos syndrome is a heritable connective tissue disorder associated with generalized joint hypermobility but also other multisystem comorbidities, many of which may be exacerbated during a viral illness or after a vaccination. We sought to determine whether individuals with hypermobile Ehlers Danlos syndrome report an increase in adverse events, including cardiovascular events, after COVID-19 illness or vaccination. A cross-sectional web-based survey was made available from November 22, 2021, through March 15, 2022. 368 respondents primarily from the United States self-reported data including diagnosis. We used a Cox proportional hazards model with time varying indicators for COVID-19 illness or vaccination in the previous 30 days. We found a significantly increased rate of new abnormal heart rhythms reported in the 30 days following COVID-19 illness. No additional cardiovascular events were reported after COVID-19 illness. 2.5% of respondents with COVID-19 illness were hospitalized. We did not find a statistically significant increased rate of cardiovascular events in the 30 days following any COVID-19 vaccination dose. Post COVID-19 vaccination, 87.2% of hypermobile Ehlers-Danlos syndrome respondents endorsed an expected adverse event (EAE), and 3.1% reported an emergency department visit/hospitalization, of those who received at least one vaccine dose. Events possibly reflecting exacerbation of orthostasis/dysautonomia were common. Respondents did not report an increased rate of any cardiovascular events in the 30 days following COVID-19 vaccination; however, those with hypermobile Ehlers-Danlos syndrome experienced a high rate of expected adverse events after vaccination consistent with a high baseline prevalence of similar symptoms. No cardiovascular events other than new abnormal heart rhythms were reported at any point after a COVID-19 illness.

The IMPACT survey: a mixed methods study to understand the experience of children, adolescents and adults with osteogenesis imperfecta and their caregivers

BackgroundOsteogenesis imperfecta (OI) is a rare, heritable connective tissue disorder associated with a variety of symptoms, that affect individuals’ quality of life (QoL) and can be associated with increased healthcare resource use. While some aspects of OI are well studied, others remain poorly understood. Therefore, the IMPACT survey aimed to elucidate the humanistic, clinical and economic burden of OI on individuals with OI, their families, caregivers and wider society.MethodsWe developed an international mixed methods online survey in eight languages (fielded July–September 2021), aimed at adults (aged ≥ 18 years) or adolescents (aged ≥ 12–17 years) with OI, caregivers (with or without OI) of individuals with OI and other close relatives. All respondents provided data on themselves; caregivers additionally provided data on individuals in their care by proxy. Data were cleaned, coded, and analysed using the pandas Python software package and Excel.ResultsIMPACT collected 2208 eligible questionnaires (covering 2988 individuals of whom 2312 had OI) including 1290 non-caregiver adults with OI, 92 adolescents with OI, 150 caregiver adults with OI, 560 caregivers for individuals with OI, 116 close relatives and 780 proxy care-recipients with OI. Most individuals with OI (direct or proxy) described their OI as moderate (41–52% across populations) and reported OI type 1 (33–38%). Pain (72–82%) was the most reported clinical condition experienced in the past 12 months and was also most frequently rated as severely or moderately impactful. Further, among adults, 67% reported fatigue, 47% scoliosis, and 46% sleep disturbance; in adolescents, fatigue affected 65%, scoliosis and other bone problems 60%, and mental health problems 46%; in children, fractures were common in 67%, fatigue in 47%, and dental problems in 46%.ConclusionIMPACT has generated an extensive dataset on the experience of individuals with OI, their caregivers and relatives. We found that, irrespective of age, individuals with OI experience numerous and evolving symptoms that affect their QoL; however, pain and fatigue are consistently present. Upcoming analyses will provide further insights into the economic impact, healthcare journey and caregiver wellbeing, aiming to contribute to improved treatment and care for the OI community.

Physical fitness in children with Marfan and Loeys-Dietz syndrome: associations between cardiovascular parameters, systemic manifestations, fatigue, and pain

Children with Marfan (MFS) and Loeys-Dietz syndrome (LDS) report limitations in physical activities, sports, school, leisure, and work participation in daily life. This observational, cross-sectional, multicenter study explores associations between physical fitness and cardiovascular parameters, systemic manifestations, fatigue, and pain in children with MFS and LDS. Forty-two participants, aged 6–18 years (mean (SD) 11.5(3.7)), diagnosed with MFS (n = 36) or LDS (n = 6), were enrolled. Physical fitness was evaluated using the Fitkids Treadmill Test’s time to exhaustion (TTE) outcome measure. Cardiovascular parameters (e.g., echocardiographic parameters, aortic surgery, cardiovascular medication) and systemic manifestations (systemic score of the revised Ghent criteria) were collected. Pain was obtained by visual analog scale. Fatigue was evaluated by PROMIS® Fatigue-10a-Pediatric-v2.0-short-form and PROMIS® Fatigue-10a-Parent-Proxy-v2.0-short-form. Multivariate linear regression analyses explored associations between physical fitness (dependent variable) and independent variables that emerged from the univariate linear regression analyses (criterion p < .05). The total group (MFS and LDS) and the MFS subgroup scored below norms on physical fitness TTE Z-score (mean (SD) −3.1 (2.9); −3.0 (3.0), respectively). Univariate analyses showed associations between TTE Z-score aortic surgery, fatigue, and pain (criterion p < .05). Multivariate analyses showed an association between physical fitness and pediatric self-reported fatigue that explained 48%; 49%, respectively, of TTE Z-score variance (F (1,18) = 18.6, p ≤ .001, r2 = .48; F (1,15) = 16,3, p = .01, r2 = .49, respectively). Conclusions: Physical fitness is low in children with MFS or LDS and associated with self-reported fatigue. Our findings emphasize the potential of standardized and tailored exercise programs to improve physical fitness and reduce fatigue, ultimately enhancing the physical activity and sports, school, leisure, and work participation of children with MFS and LDS.What is Known:• Marfan and Loeys-Dietz syndrome are heritable connective tissue disorders and share cardiovascular and systemic manifestations.• Children with Marfan and Loeys-Dietz syndrome report increased levels of disability, fatigue and pain, as well as reduced levels of physical activity, overall health and health-related quality of life.What is New:• Physical fitness is low in children with Marfan and Loeys-Dietz syndrome and associated with self-reported fatigue.• Our findings emphasize the potential of standardized and tailored exercise programs to improve physical fitness and reduce fatigue, ultimately enhancing the physical activity and sports, school, leisure, and work participation of children with Marfan and Loeys-Dietz syndrome.

Generation of the human induced pluripotent stem cell line (IBKMOLi003-A) from PBMCs of a vascular Ehlers-Danlos syndrome (vEDS) patient carrying the heterozygous nonsense mutation c.430C > T (p.Q105*) in the COL3A1 gene

Ehlers-Danlos syndrome (EDS) belongs to a spectrum of rare heritable connective tissue disorders and is characterised by hyperextensibility, joint hypermobility and tissue fragility. Peripheral blood mononuclear cells (PBMCs) from a vascular EDS (vEDS) patient, known as the rarest EDS subtype, carrying a heterozygous nonsense mutation c.430C > T (p.Q105*) in the COL3A1 gene, which is essential for type III collagen synthesis, were reprogrammed into induced pluripotent stem cells (iPSCs). The generated iPSCs exhibit high expression of pluripotency-associated markers, possess trilineage differentiation capacity and reveal a normal karyotype. This novel patient-specific cell line enables in-depth pathophysiological studies of vEDS.

Diagnosis and treatment of cardiovascular disease in patients with heritable connective tissue disorders or heritable thoracic aortic diseases.

Patients with heritable connective tissue disorders (HCTDs), represented by Marfan syndrome, can develop fatal aortic and/or arterial complications before age 50. Therefore, accurate diagnosis, appropriate medical treatment, and early prophylactic surgical treatment of aortic and arterial lesions are essential to improve prognosis. Patients with HCTDs generally present with specific physical features due to connective tissue abnormalities, while some patients with heritable thoracic aortic diseases (HTADs) have few distinctive physical characteristics. The development of genetic testing has made it possible to provide accurate diagnoses for patients with HCTDs/HTADs. This review provides an overview of the diagnosis and treatment of HCTDs/HTADs, including current evidence on cardiovascular interventions for this population.

A novel pathogenic variant located just upstream of the C-terminal Ser423-X-Ser425 phosphorylation motif in SMAD3 causing Loeys-Dietz syndrome.

Loeys-Dietz syndrome (LDS) is a heritable disorder of connective tissue closely related to Marfan syndrome (MFS). LDS is caused by loss-of-function variants of genes that encode components of transforming growth factor-β (TGF-β) signaling; nevertheless, LDS type 1/2 caused by TGFBR1/2 pathogenic variants is frequently found to have paradoxical increases in TGF-β signaling in the aneurysmal aortic wall. Here, we present a Japanese LDS family having a novel SMAD3 variant. The proband was tested via clinical, genetic, and histological analyses. In vitro analysis was performed for pathogenic evaluation. The novel heterozygous missense variant of SMAD3 [c.1262G>A, p.(Cys421Tyr)], located just upstream of the C-terminal Ser423-X-Ser425 phosphorylation motif, was found in this instance of LDS type 3. This variant led to reduced phospho-SMAD3 (Ser423/Ser425) levels and transcription activity in vitro; however, a paradoxical upregulation of TGF-β signaling was evident in the aortic wall. Our results revealed the presence of TGF-β paradox in this case with the novel loss-of-function SMAD3 variant. The precise mechanism underlying the paradox is unknown, but further research is warranted to clarify the influence of the SMAD3 variant type and location on the LDS3 phenotype as well as the molecular mechanism leading to LDS3 aortopathy.

Genetic complexity of diagnostically unresolved Ehlers-Danlos syndrome

BackgroundThe Ehlers-Danlos syndromes (EDS) are heritable disorders of connective tissue (HDCT), reclassified in the 2017 nosology into 13 subtypes. The genetic basis for hypermobile Ehlers-Danlos syndrome (hEDS) remains unknown.MethodsWhole exome...

Precision medicine using whole genome sequencing in a cat identifies a novel COL5A1 variant for classical Ehlers-Danlos syndrome.

Ehlers-Danlos syndromes (EDS) are a heterogeneous group of heritable connective tissue disorders occurring in both human and veterinary patients. The genetics of these disorders are poorly described in small animal patients. Define the clinical manifestations and genetic cause of a suspected form of EDS in a cat. A 14-week-old male domestic medium hair cat was presented with skin hyperextensibility and fragility. The classic tragic facial expression was observed as well as chronic pruritus and mild hyperesthesia. Blood samples and a skin biopsy sample were collected from the affected cat. Clinical examinations, histology, electron microscopy and whole genome sequencing were conducted to characterize the clinical presentation and identify possible pathogenic DNA variants to support a diagnosis. Criteria defining variant pathogenicity were examined including human disease variant databases. Histology showed sparse, disorganized collagen and an increase in cutaneous mast cells. Electron microscopy identified ultrastructural defects commonly seen in collagen type V alpha 1 chain (COL5A1) variants including flower-like collagen fibrils in cross-section. Whole genome sequencing and comparison with 413 cats in the 99 Lives Cat Genome Sequencing Consortium database identified a novel splice acceptor site variant at exon 4 in COL5A1 (c.501-2A>C). Our report broadens the current understanding of EDS in veterinary patients and supports the use of precision medicine techniques in clinical veterinary practice. The classification of variants for pathogenicity should be considered in companion animals.

Outcomes of Thoracic Aortic Interventions in Marfan Syndrome in the State of Texas Over Eleven Years.

Marfan Syndrome is a heritable connective tissue disorder with significant aortopathy and conveys substantial cardiovascular morbidity. This study characterizes the mortality and morbidities of thoracic aortic interventions in the Marfan Syndrome population in the state of Texas from 2009-2019. A retrospective review of the Texas Inpatient Discharge Dataset from 1/1/2009-31/12/2019. Discharges from acute care hospitals with a Marfan Syndrome diagnosis by International Classification of Diseases 9/10 codes and a procedure code for thoracic aortic intervention were analyzed utilizing descriptive, univariate, and multivariable regression statistics. There were 4,641 Marfan Syndrome discharges identified, of whom 644(13.9%) underwent thoracic aortic intervention. Thoracic or thoraco-abdominal aortic dissection or rupture was noted in 223(34.6%). Thirty-three(5.1%) had a concomitant coronary artery intervention. There were 30(4.7%) in-hospital mortalities, 126(19.6%) diagnoses of acute renal failure, 52(8.1%) had mechanical ventilation >96 hours, and the median length of stay was 10[IQR : 7-16] days. After adjustment, concomitant coronary artery intervention was associated with in-hospital mortality (OR : 3.69[IQR : 1.15-11.90], p = 0.029) and acute renal failure (OR : 2.66[IQR : 1.19-5.94], p = 0.017). Aortic dissections/ruptures were associated with acute renal failure (OR : 1.73[IQR : 1.14-2.63], p = 0.010), ventilation >96 hours (OR : 2.19[IQR : 1.21-3.97], p = 0.010), and 15% longer length of stay (95% CI : 2.4-29.1%, p = 0.038). Thoracic aortic interventions are frequent amongst the hospitalized Marfan Syndrome population. Concomitant coronary intervention is associated with increased risk of death and aortic dissections/ruptures are associated with increased morbidity. The high prevalence of aortic dissections/ruptures points to a potential target for improving imaging surveillance, adherence to treatment guidelines, and preventative management of Marfan Syndrome aortopathy.

The Language of Pain in the Hypermobile Ehlers-Danlos Syndrome: Metaphors as a Key to Understanding the Experience of Pain and as a Rehabilitation Tool.

Ehlers-Danlos syndromes are a heterogeneous group of Heritable Connective Tissue Disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Among the different types, the hypermobile Ehlers-Danlos syndrome is the most frequent and includes generalized joint hypermobility as the major diagnostic criterion. Joint hypermobility in hypermobile Ehlers-Danlos syndrome is often associated with pain that does not always allow the use of effective pain-reducing treatments. Patients with hEDS constantly describe their pain in detail. Eighty-nine patients with hEDS diagnoses were recruited and evaluated. They were asked to describe their pain in writing. The texts were examined through Linguistic Inquiry and Word Count. Correlational analyses were conducted between pain perception and language. A comparison of high/low pain perception and the quality of metaphors was carried out. The results showed that language quality varies depending on how much pain is perceived. The greater the pain is perceived, the lesser the positive effects and the greater the negative effects and dehumanizing metaphors are being used. Moreover, a greater pain seems to be related to a verbal experience of greater isolation and less self-care. In conclusion, the use of metaphors is a useful tool for examining illness experience and may help clinicians in the rehabilitation program.

Sensory Profiling in Classical Ehlers-Danlos Syndrome: A Case-Control Study Revealing Pain Characteristics, Somatosensory Changes, and Impaired Pain Modulation

Pain is one of the most important yet poorly understood complaints in heritable connective tissue disorders (HCTDs) caused by monogenic defects in extracellular matrix molecules. This is particularly the case for the Ehlers-Danlos syndrome (EDS), paradigm collagen-related disorders. This study aimed to identify the pain signature and somatosensory characteristics in the rare classical type of EDS (cEDS) caused by defects in type V or rarely type I collagen. We used static and dynamic quantitative sensory testing and validated questionnaires in 19 individuals with cEDS and 19 matched controls. Individuals with cEDS reported clinically relevant pain/discomfort (Visual Analogue Scale ≥5/10 in 32% for average pain intensity the past month) and worse health-related quality of life. An altered somatosensory profile was found in the cEDS group with higher (P = .04) detection thresholds for vibration stimuli at the lower limb, indicating hypoesthesia, reduced thermal sensitivity with more (P < .001) paradoxical thermal sensations (PTSs), and hyperalgesia with lower pain thresholds to mechanical (P < .001) stimuli at both the upper and lower limbs and cold (P = .005) stimulation at the lower limb. Using a parallel conditioned pain modulation paradigm, the cEDS group showed significantly smaller antinociceptive responses (P-value .005–.046) suggestive of impaired endogenous pain modulation. In conclusion, individuals with cEDS report chronic pain and worse health-related quality of life and present altered somatosensory perception. This study is the first to systematically investigate pain and somatosensory characteristics in a genetically defined HCTD and provides interesting insights into the possible role of the ECM in the development and persistence of pain. PerspectiveChronic pain compromises the quality of life in individuals with cEDS. Moreover, an altered somatosensory perception was found in the cEDS group with hypoesthesia for vibration stimuli, more PTSs, hyperalgesia for pressure stimuli, and impaired pain modulation.

A qualitative exploration of patient perspectives on psychosocial burdens and positive factors in adults with osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a pleiotropic, heritable connective tissue disorder associated with a wide range of health implications, including frequent bone fracture. While progress has been made to understand the spectrum of these physical health implications, the impact of OI on psychosocial well-being, as well as protective factors that buffer against adverse psychosocial outcomes, remain understudied. This present study relies on a qualitative approach to assess patient perspectives on both protective and adverse psychosocial factors specific to OI in 15 adults with varying disease status. Semi-structured interviews were conducted, subsequently coded, and themes extracted. Themes concerning psychosocial burdens (i.e., negative affective and behavioral impacts of disease status) and protective factors were identified from cooperatively-coded transcripts (two coders per transcript). Participants reported experiencing an increase in negative affect and disease-related distress after fracturing a bone and during recovery. Fear and concern specific to the uncertainty of future bone fractures and negative self-image was common. In contrast to these negative impacts, participants additionally described positive orientations toward their disease and attributed positive traits to their lived experience with a chronic disease. While limited due to small sample size and lack of ethno-racial diversity, findings highlight a need for continued research on the relationship between OI disease status and psychosocial outcomes, as well as the development of psychological interventions designed for OI populations. Findings have relevant clinical applications for healthcare providers working with those diagnosed with OI.

Health Supervision for Children and Adolescents With Marfan Syndrome

Marfan syndrome is a heritable connective tissue disorder that affects many different organ systems. In some cases, features of Marfan syndrome can be recognized at birth, but the majority will have manifestations that emerge throughout childhood and into adulthood. Significant morbidity and mortality are associated with this syndrome, and its features are best managed using a multidisciplinary approach. This clinical report is designed to assist the pediatrician in recognizing the features of Marfan syndrome as well as caring for the individual with Marfan syndrome to maximize their health and quality of life.

Physical activity and physical fitness in children with heritable connective tissue disorders.

Health problems in patients with heritable connective tissue disorders (HCTD) are diverse and complex and might lead to lower physical activity (PA) and physical fitness (PF). This study aimed to investigate the PA and PF of children with heritable connective tissue disorders (HCTD). PA was assessed using an accelerometer-based activity monitor (ActivPAL) and the mobility subscale of the Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT). PF was measured in terms of cardiovascular endurance using the Fitkids Treadmill Test (FTT); maximal hand grip strength, using hand grip dynamometry (HGD) as an indicator of muscle strength; and motor proficiency, using the Bruininks-Oseretsky Test of Motor Proficiency-2 (BOTMP-2). A total of 56 children, with a median age of 11.6 (interquartile range [IQR], 8.8-15.8) years, diagnosed with Marfan syndrome (MFS), n = 37, Loeys-Dietz syndrome (LDS), n = 6, and genetically confirmed Ehlers-Danlos (EDS) syndromes, n = 13 (including classical EDS n = 10, vascular EDS n = 1, dermatosparaxis EDS n = 1, arthrochalasia EDS n = 1), participated. Regarding PA, children with HCTD were active for 4.5 (IQR 3.5-5.2) hours/day, spent 9.2 (IQR 7.6-10.4) hours/day sedentary, slept 11.2 (IQR 9.5-11.5) hours/day, and performed 8,351.7 (IQR 6,456.9-1,0484.6) steps/day. They scored below average (mean (standard deviation [SD]) z-score -1.4 (1.6)) on the PEDI-CAT mobility subscale. Regarding PF, children with HCTD scored well below average on the FFT (mean (SD) z-score -3.3 (3.2)) and below average on the HGD (mean (SD) z-score -1.1 (1.2)) compared to normative data. Contradictory, the BOTMP-2 score was classified as average (mean (SD) z-score.02 (.98)). Moderate positive correlations were found between PA and PF (r(39) = .378, p < .001). Moderately sized negative correlations were found between pain intensity and fatigue and time spent actively (r(35) = .408, p < .001 and r(24) = .395 p < .001, respectively). This study is the first to demonstrate reduced PA and PF in children with HCTD. PF was moderately positively correlated with PA and negatively correlated with pain intensity and fatigue. Reduced cardiovascular endurance, muscle strength, and deconditioning, combined with disorder-specific cardiovascular and musculoskeletal features, are hypothesized to be causal. Identifying the limitations in PA and PF provides a starting point for tailor-made interventions.