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Hypermobile Ehlers-Danlos syndrome (hEDS) is a common heritable connective tissue disorder that lacks a known genetic etiology. To identify genetic contributions to hEDS, whole exome sequencing was performed on families and a cohort of sporadic hEDS patients. A missense variant in Kallikrein-15 (KLK15 p. Gly226Asp), segregated with disease in two families and genetic burden analyses of 197 sporadic hEDS patients revealed enrichment of variants within the Kallikrein gene family. To validate pathogenicity, the variant identified in familial studies was used to generate knock-in mice. Consistent with our clinical cohort, Klk15 G224D/+ mice displayed structural and functional connective tissue defects within multiple organ systems. These findings support Kallikrein gene variants in the pathogenesis of hEDS and represent an important step towards earlier diagnosis and better clinical outcomes.
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Introduction: Patients with Ehlers-Danlos syndromes (EDS) and hypermobility spectrum disorders (HSD) have significant health challenges that are well-documented, however their impact in terms of cost is not known. Our research objective was to examine the cost burden of EDS and HSD in the United States. We focused this analysis on those with commercial insurance plans. Methods: We queried the MarketScan® database for year 2021 for claims that contained an ICD-10 diagnosis code for EDS or hypermobility. Excess costs for patients in the EDS and HSD cohorts were determined by matching each patient to one patient in the database that did not have a claim for EDS or HSD and comparing total costs for the calendar year. We determined whether patients had claims for selected comorbid conditions likely to impact costs during the calendar year. Results: Sample sizes were 5,113 for adult (age ≥ 18) patients with EDS, 4,880 for adult patients with HSD, 1,059 for child (age 5-17) patients with EDS, and 2,427 for child patients with HSD. The mean excess costs were $21,100 for adult EDS patients, $11,600 for adult HSD patients, $17,000 for child EDS patients, and $11,000 for child HSD patients. EDS and HSD cohorts, both adults and children, with any of the comorbidities had greater healthcare costs. The largest difference was found in the EDS cohort with gastrointestinal comorbid conditions, with more than double the costs for adults. Discussion: We found that patients in the MarketScan database, adults and children, who had EDS or HSD had substantially higher associated excess healthcare costs than patients without EDS or HSD when considering age, sex, geographic location, and comorbidities. These disproportionate healthcare costs in this population have health policy and economic implications, including the need for rapid diagnosis, access to treatment, and accelerated research to advance treatments.
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Costo de Enfermedad , Bases de Datos Factuales , Síndrome de Ehlers-Danlos , Humanos , Síndrome de Ehlers-Danlos/economía , Síndrome de Ehlers-Danlos/epidemiología , Estados Unidos , Adulto , Femenino , Masculino , Niño , Persona de Mediana Edad , Adolescente , Preescolar , Adulto Joven , Costos de la Atención en Salud/estadística & datos numéricos , Revisión de Utilización de Seguros/estadística & datos numéricos , Comorbilidad , AncianoRESUMEN
BACKGROUND: The Ehlers-Danlos Syndromes (EDS) are a group of connective tissue disorders that are hereditary in nature and characterized by joint hypermobility and tissue fragility. The complex nature of this unique patient population requires multidisciplinary care, but appropriate centers for such care do not exist in large portions of the country. Need for more integrated services has been identified in Chicagoland, or Chicago and its suburbs. In order to explore and begin to address barriers to seeking appropriate care facing EDS patients in this region, we developed an online survey which we circulated through EDS social media groups for Chicagoland patients. RESULTS: Three hundred and nine unique respondents participated. We found that there exists a strong medical need for and interest in the development of a center in the region, and participants reported that, if made available to them, they would make extensive and regular use of such a facility. CONCLUSIONS: We conclude that the establishment of a collaborative medical center specializing in the diagnosis and treatment of EDS, Hypermobility Spectrum Disorder, and related disorders in the Chicagoland area would greatly benefit patients by providing comprehensive care, alleviate the burden on overworked healthcare providers, and contribute to the sustainability of medical facilities.
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Enfermedades del Tejido Conjuntivo , Síndrome de Ehlers-Danlos , Inestabilidad de la Articulación , Humanos , Síndrome de Ehlers-Danlos/diagnóstico , Inestabilidad de la Articulación/diagnóstico , Encuestas y CuestionariosRESUMEN
Craniocervical instability (CCI) is increasingly recognized in hereditary disorders of connective tissue and in some patients following suboccipital decompression for Chiari malformation (CMI) or low-lying cerebellar tonsils (LLCT). CCI is characterized by severe headache and neck pain, cervical medullary syndrome, lower cranial nerve deficits, myelopathy, and radiological metrics, for which occipital cervical fusion (OCF) has been advocated. We conducted a retrospective analysis of patients with CCI and Ehlers-Danlos syndrome (EDS) to determine whether the surgical outcomes supported the criteria by which patients were selected for OCF. Fifty-three consecutive subjects diagnosed with EDS, who presented with severe head and neck pain, lower cranial nerve deficits, cervical medullary syndrome, myelopathy, and radiologic findings of CCI, underwent open reduction, stabilization, and OCF. Thirty-two of these patients underwent suboccipital decompression for obstruction of cerebral spinal fluid flow. Questionnaire data and clinical findings were abstracted by a research nurse. Follow-up questionnaires were administered at 5-28 months (mean 15.1). The study group demonstrated significant improvement in headache and neck pain (p < 0.001), decreased use of pain medication (p < 0.0001), and improved Karnofsky Performance Status score (p < 0.001). Statistically significant improvement was also demonstrated for nausea, syncope (p < 0.001), speech difficulties, concentration, vertigo, dizziness, numbness, arm weakness, and fatigue (p = 0.001). The mental fatigue score and orthostatic grading score were improved (p < 0.01). There was no difference in pain improvement between patients with CMI/LLCT and those without. This outcomes analysis of patients with disabling CCI in the setting of EDS demonstrated significant benefits of OCF. The results support the reasonableness of the selection criteria for OCF. We advocate for a multi-center, prospective clinical trial of OCF in this population.
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Síndrome de Ehlers-Danlos , Enfermedades de la Médula Espinal , Enfermedades de la Columna Vertebral , Fusión Vertebral , Humanos , Estudios Retrospectivos , Dolor de Cuello/etiología , Dolor de Cuello/cirugía , Estudios Prospectivos , Síndrome de Ehlers-Danlos/complicaciones , Síndrome de Ehlers-Danlos/cirugía , Fusión Vertebral/métodos , Cefalea , Vértebras Cervicales/cirugíaRESUMEN
The Ehlers-Danlos syndromes (EDS), a group of uncommon connective tissue disorders, are, paradoxically, an increasingly common referral to genetics specialists. Of the 13 types of EDS, the most common is hypermobile EDS (hEDS), which lacks a known genetic etiology and for which diagnosis is achieved via a robust set of clinical criteria. While previous investigations have characterized many clinical aspects of EDS as a syndrome and patients' lived experiences, a gap in the literature exists regarding clinicians' experience caring for these individuals. This study sought to understand the effects of hEDS patient referrals from genetic counselors' perspectives. To capture these novel views and values, we conducted semi-structured interviews with 15 participants who were members of the National Society of Genetic Counselors (NSGC) and had experience working with the hEDS patient population. Interview questions explored the frequency of hEDS referrals in their clinic, investigated their roles and responsibilities as genetic counselors when working with this population, analyzed their workflow for this indication, assessed the impacts on their professional satisfaction, and explored potential options for improving workflow and care for the hEDS patient population. Reflexive thematic analysis yielded four themes: (1) Referrals for hEDS have generally increased over time and many institutions have implemented new policies to control this influx, (2) genetic counselors' primary roles include education and addressing psychosocial matters for this population, (3) genetic counselors feel both rewarded and challenged by these referrals, and (4) genetic counselors call for more education and training on hEDS for all healthcare specialties. Our findings provide a better understanding of the goals of the hEDS patient referrals to genetics specialists and the opportunities and challenges those referrals present. Genetic counselors have specific training and skills in psychosocial counseling and communication, in some ways making them ideal care providers for this population. However, they are simultaneously a scarce resource and the complex medical issues presented by many patients with hEDS make multidisciplinary management essential. We conclude with potential avenues for improving interactions with this population.
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Patients with hypermobile Ehlers Danlos Syndrome often experience psychological distress resulting from the perceived hostility and disinterest of their clinicians. We conducted 26 in-depth interviews with patients to understand the origins of this trauma and how it could be addressed in practice. We found that the cumulative effects of numerous negative encounters lead patients to lose trust in their healthcare providers and the healthcare system, and to develop acute anxiety about returning to clinic to seek further care. We describe this as clinician-associated traumatization. Ultimately, our interviewees described the result of this traumatization as worse - but preventable - health outcomes.
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The heritable disorders of connective tissue (HDCTs) are a heterogeneous group of inherited disorders caused by pathogenic variants in genes encoding a wide range of molecules involved in the structure and function of the extracellular matrix. Currently, more than 450 HDCTs are recognized. These include the Ehlers-Danlos syndrome (EDS), Marfan syndrome, Loeys-Dietz syndrome (LDS), Stickler syndrome, and a wide range of skeletal dysplasias. Recent evidence suggests that people with the HDCTs are at an increased risk of Chiari I malformation (CM1).
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Artritis , Enfermedades del Tejido Conjuntivo , Síndrome de Loeys-Dietz , Desprendimiento de Retina , Humanos , Tejido Conectivo , Enfermedades del Tejido Conjuntivo/genética , Síndrome de Loeys-Dietz/genéticaRESUMEN
OBJECTIVE: Joint hypermobility in Ehlers-Danlos Syndromes (EDS) predisposes persons with EDS to frequent subluxations and dislocations, chronic arthralgia, and soft-tissue rheumatism. Epidemiologic trends of rheumatologic conditions among persons with EDS are lacking. Prescription claims databases can reflect underlying disease burdens by using medication claims as disease proxies. We examined the prevalence of prescription claims for commonly prescribed immunomodulator and antiinflammatory (IMD) drugs among persons with EDS compared with their matched control person, and hypothesized peripubertal increases among female persons with EDS. METHODS: We compared the percentages of IMD drug prescription claims among 3,484 persons with EDS (ages 5-62 years) against their age-, sex-, state of residence-, and earliest claim date-matched control persons using 10 years (2005-2014) of private prescription claims data and a minimum 2-year enrollment inclusion criterion. RESULTS: Our cohort comprised 70% adults and 74% female persons. At least 1 IMD medication was prescribed to 65.4% of persons with EDS compared with 47.4% of control persons. We observed 1.3 to 4.2 times higher odds (P < 0.0001) for 5 out of 6 IMD drug classes among persons with EDS compared with matched control persons, except for biologic agents (conditional odds ratio 1.3, 95% confidence interval 0.8-2.0). Peripubertal increases were observed for nonsteroidal antiinflammatory drugs, oral, and injectable steroids. CONCLUSIONS: To our knowledge, our study is the first to examine the full range of IMD drug prescription claim trends among persons with EDS. We believe our research findings can have notable diagnostic and management implications for EDS patients who present with multiple comorbidities and generally require a more granular assessment of their medical conditions.
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Síndrome de Ehlers-Danlos , Inestabilidad de la Articulación , Adulto , Humanos , Femenino , Preescolar , Niño , Adolescente , Adulto Joven , Persona de Mediana Edad , Masculino , Síndrome de Ehlers-Danlos/diagnóstico , Comorbilidad , Prescripciones de Medicamentos , Factores InmunológicosRESUMEN
Introduction: Individuals with Ehlers-Danlos syndromes (EDS) often have complex and multi-faceted symptoms across the lifespan. Pain and the related symptoms of fatigue and sleep disorders are common. The objective of this qualitative study was to understand how participants manage their pain and related symptoms. Methods: The design was a qualitative thematic content analysis. Twenty-eight interviews were conducted to collect data from individuals who were participants in a prior quantitative longitudinal study. A semi-structured interview guide was designed to focus on and understand the trajectory of pain, sleep, fatigue, and general function. The interview continued with questions about coping mechanisms and obstacles to maintaining a sense of well-being. Results: Symptoms reported by participants were widespread and often interwoven. Pain was universal and often resulted in fatigue and disordered sleep which impacted physical function. Most participants reported that their symptoms worsened over time. Participants reported a wide range of effective interventions and most reported developing self-care strategies to adapt to their disabilities/limitations. Solutions included complementary interventions discovered when conventional medicine was unsuccessful. Very few relied on a "system" of health care and instead developed their own strategies to adapt to their disabilities/limitations. Discussion: EDS symptoms are often debilitating, and their progression is unknown. For most participants, symptoms worsened over the time. Even though participants in our study, by experience, were self-reliant, the importance of knowledgeable medical providers to help guide self-care should be emphasized.
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Mitochondrial dysfunction can be associated with a range of clinical manifestations. Here, we report a family with a complex phenotype including combinations of connective tissue, neurological, and metabolic symptoms that were passed on to all surviving children. Analysis of the maternally inherited mtDNA revealed a novel genotype encompassing the haplogroup J - defining mitochondrial DNA (mtDNA) ND5 m.13708G>A (A458T) variant arising on the mtDNA haplogroup H7A background, an extremely rare combination. Analysis of transmitochondrial cybrids with the 13708A-H7 mtDNA revealed a lower mitochondrial respiration, increased reactive oxygen species production (mROS), and dysregulation of connective tissue gene expression. The mitochondrial dysfunction was exacerbated by histamine, explaining why all eight surviving children inherited the dysfunctional histidine decarboxylase allele (W327X) from the father. Thus, certain combinations of common mtDNA variants can cause mitochondrial dysfunction, mitochondrial dysfunction can affect extracellular matrix gene expression, and histamine-activated mROS production can augment the severity of mitochondrial dysfunction. Most important, we have identified a previously unreported genetic cause of mitochondrial disorder arising from the incompatibility of common, nonpathogenic mtDNA variants.
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ADN Mitocondrial , Histamina , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Haplotipos , Histamina/metabolismo , Mitocondrias/genética , Mitocondrias/metabolismo , Tejido Conectivo/metabolismoRESUMEN
Introduction Tethered cord syndrome (TCS) was first reported as a potential complication of Ehlers-Danlos Syndrome in 2009. However, there have been few publications on the subject since that time, and optimal treatment of TCS in the setting of the hypermobile Ehlers-Danlos Syndrome (hEDS) population remains unknown. The purpose of this study was to determine the safety and efficacy of surgical release of the filum terminale (FT) for the treatment of TCS in this patient population. Methods We performed a retrospective chart review of consecutive hEDS patients with TCS who were treated with surgical release after providing informed surgical consent over a 4.5-year period by a single neurosurgeon. Eighty-four patients were identified and asked to complete surveys with items regarding pre and postoperative symptoms, pain levels, and satisfaction. Results Thirty patients with a mean age of 30.8 ± 11.9 years, all female, were included. Low back pain was significantly improved across the entire cohort. For patients with both pre and postoperative data available, the distance they were able to walk also improved significantly. The majority of patients were "highly satisfied" with surgery (66%), followed by 21% "satisfied", 10% "neutral", and one patient who was "dissatisfied". One patient required repair of a dural leak one week postoperatively, and no other complications were noted. Conclusions Surgical release of the FT for TCS in patients with hEDS was safe and effective in this cohort. For most patients, there was a significant improvement in low back pain, urinary symptoms, and ability to ambulate distance. The majority of respondents reported subjective satisfaction with this operation. A further prospective study is warranted.
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Hereditary alpha-tryptasemia (HαT) is an autosomal dominant (AD) genetic trait characterized by elevated basal serum tryptase ≥8 ng/mL, caused by increased α-tryptase-encoding TPSAB1 copy number. HαT affects 5% to 7% of Western populations and has been associated with joint hypermobility. Hypermobility disorders are likewise frequently AD, but genetic etiologies are often elusive. Genotyping of individuals with hypermobility spectrum disorder (n = 132), hypermobile Ehlers-Danlos syndrome (n = 78), or axial skeletal abnormalities with hypermobility (n = 56) was performed. Clinical features of individuals with and without HαT were compared. When analyzing our combined cohorts, dysphagia (p = 0.007) and retained primary dentition (p = 0.0003) were significantly associated with HαT, while positive associations with anaphylaxis (p = 0.07) and pruritus (P = 0.5) did not reach significance likely due to limited sample size. Overall, HαT prevalence is not increased in individuals with hypermobility disorders, rather linked to a unique endotype, demonstrating how HαT may modify clinical presentations of complex patients.
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Our study extends a cross-sectional dataset on the Ehlers-Danlos syndromes (EDS) assembled by the National Institute on Aging (NIA), under a protocol entitled Clinical and Molecular Manifestations of Heritable Disorders of Connective Tissue. We were successful in contacting 171 of the original 252 participants with EDS. Our study cohort included 91 participants who completed at least one of the following surveys: Brief Pain Inventory (BPI), Pittsburgh Sleep Quality Index (PSQI), Multidimensional Fatigue Inventory (MFI-20), and Short Form (SF-36) Health Survey, at both baseline and follow-up. Follow-up surveys occurred a median of 11.6 years after the baseline survey. We used mixed effects linear regression models to examine the change in scores for multiple indices reported by participants. There were small mean changes reflected in our estimates for the EDS population as a whole. There was wide heterogeneity between reported individual experiences, with some participants markedly improved and some dramatically worse. Men had a greater increase in mean pain severity over time than women. This is the first study to report a decade of longitudinal data in EDS.
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Síndrome de Ehlers-Danlos , Estudios de Cohortes , Estudios Transversales , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/epidemiología , Síndrome de Ehlers-Danlos/genética , Femenino , Humanos , Masculino , Dimensión del Dolor , Encuestas y CuestionariosRESUMEN
In late 2017, the global nonprofit, The Ehlers-Danlos Society (TEDS), was awarded a "Pipeline to Proposal" Tier A award from the Patient-Centered Outcomes Research Institute (PCORI). The goal of this application was to form a team of patients, researchers, other community support groups and stakeholders who are focused on establishing the Ehlers-Danlos Comorbidity Coalition to address the common health issues associated with this group of high morbidity, high disease burden conditions. The ongoing Coalition that is now funded by individual donors and expanding in its mission and members, is an example of successful collaboration spanning over borders and priorities.
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Apoyo Comunitario , Evaluación del Resultado de la Atención al Paciente , HumanosRESUMEN
We previously reported increased pain and gastrointestinal (GI) medication prescription claims among persons with Ehlers-Danlos syndromes (EDS) and peripubertal increase in opioid and anti-emetic claims among women with EDS. Herein, we hypothesized a higher proportion of respiratory and co-occurring respiratory and GI medication prescription claims among persons with EDS compared to their matched controls with increases among peripubertal women with EDS. We compared the proportions of respiratory and co-occurring respiratory and GI medication prescription claims among persons with EDS (aged 5-62) against their age-, sex-, state of residence-, and earliest claim date-matched controls using 10 years of private prescription claims data. Prescription claims among persons with EDS versus matched controls were increased for eight medication classes (p < .0001): intranasal/inhaled corticosteroids (ICS) (30.8% vs. 19.0%), oral steroids (30.0% vs. 16.5%), H1-antihistamines (26.2% vs. 12.2%), short-acting beta agonists (22.7% vs. 11.6%), decongestants (21.6% vs. 15.9%), leukotriene modifiers (8.9% vs. 3.6%), ICS/long-acting beta agonists (5.7% vs. 2.9%), muscarinic antagonists (2.5% vs. 0.9%), and co-occurring prescriptions (29% vs. 10%). Our results suggest a critical time window for peripubertal intervention and research and a need to focus on the pathogenesis and clinical evaluation of EDS-specific respiratory and aerodigestive disorders.
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Síndrome de Ehlers-Danlos , Enfermedades Gastrointestinales , Estudios de Casos y Controles , Niño , Síndrome de Ehlers-Danlos/tratamiento farmacológico , Femenino , Enfermedades Gastrointestinales/tratamiento farmacológico , Enfermedades Gastrointestinales/etiología , Humanos , Dolor , PrescripcionesRESUMEN
The Ehlers-Danlos Society Extension for Community Health Care Outcomes (EDS ECHO) is a portfolio of teleconferencing programs developed around the principles and practices of Project ECHO®, aimed at increasing awareness of Ehlers-Danlos syndromes (EDS) and hypermobility spectrum disorders (HSD) among clinicians, enhancing their confidence in the assessment and management of these complex conditions, and generating networks of clinicians across specialties. We assessed the outcomes of the first EDS ECHO program, launched in April 2019, with two hub locations: Indiana University Health, Indianapolis, Indiana, USA, and The Royal Society of Medicine, London, UK. Clinicians were surveyed before and 6 months after their participation. We describe the initial outcomes of the first four EDS ECHO programs, each comprising nine sessions. Participants reported increased levels of knowledge and confidence in providing care (93% and 95%, respectively) and an increase in referral network participation (65%). Additionally, 80% reported that their interest in EDS and HSD increased; 57% reporting a great increase. Also, 59% reported a decrease in feeling overwhelmed by EDS and HSD, and nearly half reported a decrease in their level of frustration because of participating in EDS ECHO. Clinicians participating in EDS ECHO programs know more, have more confidence in their ability to provide care, and feel energized by their participation.
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Síndrome de Ehlers-Danlos , Inestabilidad de la Articulación , Síndrome de Ehlers-Danlos/terapia , Humanos , Inestabilidad de la Articulación/diagnóstico por imagen , Encuestas y CuestionariosRESUMEN
Persons with the Ehlers-Danlos syndromes (EDS) report a wide range of respiratory symptoms, most commonly shortness of breath, exercise limitation, and cough. Also reported are noisy breathing attributed to asthma, difficulty with deep inhalation, and inspiratory thoracic pain. The literature consists of case reports and small cross-sectional and cohort studies. One case-control study estimated twofold to threefold greater respiratory disease burden among persons with EDS as compared to controls. The differential diagnosis for symptoms is broad. Structural alterations include pectus deformities, scoliosis, recurrent rib subluxations, and tracheobronchomalacia, associated with varying degrees of physiologic impairment. Those with vascular EDS have an increased risk of pneumothorax, intrapulmonary bleeding, cysts, and nonmalignant fibrous nodules. Functional aerodigestive manifestations such as inducible laryngeal obstruction may be misdiagnosed as asthma, with gastro-esophageal dysmotility and reflux as common contributing factors. Inflammatory manifestations include costochondritis, bronchiectasis, and localized respiratory allergic and nonallergic mast cell activation. Cranio-cervical instability can dysregulate respiratory control pathways. There is a need for careful phenotyping using standardized clinical tools and patient-reported outcomes and continuing collaboration with aerodigestive specialists including otolaryngologists and gastroenterologists. Also needed is further evaluation of respiratory symptoms in persons with hypermobility spectrum disorders. Personalized monitoring strategies are invaluable for interpretation and long-term management of respiratory symptoms.