Self-reported throat symptoms in Ehlers-Danlos syndromes and hypermobility spectrum disorders: A cross-sectional survey study.

Objectives: This study identified the frequency and severity of dysphagia, dysphonia, and laryngopharyngeal reflux symptoms in people with Ehlers-Danlos syndromes (EDS) or hypermobility spectrum disorders (HSD) and explored differences between diagnostic groups. Methods: Participants were recruited via non-probability convenience sampling. Information was gathered via online survey, including the Reflux Symptom Index (RSI; Belafsky et al., J Voice. 2002;16:274-277), the Eating and Drinking Assessment Tool (EAT-10; Belafsky et al., Ann Otol Rhinol Laryngol. 2008;117:919-924), and the Voice Handicap Index (VHI; Jacobson et al., Am J Speech Lang Pathol. 1997;6(3):66-70). These were analyzed using ANOVAs. Results: There were 1620 participants (96.6% female, 2.8% male) that met the inclusion criteria. The mean age was 38.09 (SD 12.22). 75.51% had hypermobile EDS (hEDS), 17.83% had HSD and 3.33% had classic EDS (cED). The cohort's mean scores were RSI = 22.95 (SD 9.01), EAT-10 = 11.91 (SD 9.66), and VHI score = 31.99 (SD 24.36). The hEDS group had significantly higher mean scores than the HSD group on RSI score and on some RSI items, on EAT-10 score and on all EAT-10 items, and on one VHI item. Conclusion: People with EDS/HSD experience symptoms of acid reflux, dysphagia, and dysphonia to varying degrees with significant differences between hEDS than HSD. Awareness of the impact of EDS/HSD on throat symptoms will enable health care professionals to anticipate throat symptoms more readily in this population, providing individualized and effective management plans. Level of Evidence: IV.

Pediatric joint hypermobility: a diagnostic framework and narrative review.

BACKGROUND: Hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are debilitating conditions. Diagnosis is currently clinical in the absence of biomarkers, and criteria developed for adults are difficult to use in children and biologically immature adolescents. Generalized joint hypermobility (GJH) is a prerequisite for hEDS and generalized HSD. Current literature identifies a large proportion of children as hypermobile using a Beighton score ≥ 4 or 5/9, the cut off for GJH in adults. Other phenotypic features from the 2017 hEDS criteria can arise over time. Finally, many comorbidities described in hEDS/HSD are also seen in the general pediatric and adolescent population. Therefore, pediatric specific criteria are needed. The Paediatric Working Group of the International Consortium on EDS and HSD has developed a pediatric diagnostic framework presented here. The work was informed by a review of the published evidence. OBSERVATIONS: The framework has 4 components, GJH, skin and tissue abnormalities, musculoskeletal complications, and core comorbidities. A Beighton score of ≥ 6/9 best identifies children with GJH at 2 standard deviations above average, based on published general population data. Skin and soft tissue changes include soft skin, stretchy skin, atrophic scars, stretch marks, piezogenic papules, and recurrent hernias. Two symptomatic groups were agreed: musculoskeletal and systemic. Emerging comorbid relationships are discussed. The framework generates 8 subgroups, 4 pediatric GJH, and 4 pediatric generalized hypermobility spectrum disorders. hEDS is reserved for biologically mature adolescents who meet the 2017 criteria, which also covers even rarer types of Ehlers-Danlos syndrome at any age. CONCLUSIONS: This framework allows hypermobile children to be categorized into a group describing their phenotypic and symptomatic presentation. It clarifies the recommendation that comorbidities should be defined using their current internationally accepted frameworks. This provides a foundation for improving clinical care and research quality in this population.

Initial description and evaluation of EDS ECHO: An international effort to improve care for people with the Ehlers-Danlos syndromes and hypermobility spectrum disorders.

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.

Resistance to local anesthesia in people with the Ehlers-Danlos Syndromes presenting for dental surgery.

BACKGROUND: People with the Ehlers-Danlos Syndromes (EDS), a group of heritable disorders of connective tissue, often report experiencing dental procedure pain despite local anesthetic (LA) use. Clinicians have been uncertain how to interpret this apparent LA resistance, as comparison of EDS and non-EDS patient experience is limited to anecdotal evidence and small case series. The primary goal of this hypothesis-generating study was to investigate the recalled adequacy of pain prevention with LA administered during dental procedures in a large cohort of people with and without EDS. A secondary exploratory aim asked people with EDS to recall comparative LA experiences. METHODS: We administered an online survey through various social media platforms to people with EDS and their friends without EDS, asking about past dental procedures, LA exposures, and the adequacy of procedure pain prevention. Among EDS respondents who both received LA and recalled the specific LA used, we compared agent-specific pain prevention for lidocaine, procaine, bupivacaine, mepivacaine, and articaine. RESULTS: Among the 980 EDS respondents who had undergone a dental procedure LA, 88% (n = 860) recalled inadequate pain prevention. Among 249 non EDS respondents only 33% (n = 83) recalled inadequate pain prevention (P < 0.001 compared to EDS respondents). The agent with the highest EDS-respondent reported success rate was articaine (30%), followed by bupivacaine (25%), and mepivacaine (22%). CONCLUSIONS: EDS survey respondents reported nearly three times the rate of LA non-response compared to non-EDS respondents, suggesting that LAs were less effective in preventing their pain associated with routine office dental procedures.

Use of Cluster Analysis to Delineate Symptom Profiles in an Ehlers-Danlos Syndrome Patient Population.

CONTEXT: The Ehlers-Danlos Syndromes (EDSs) are a set of rare heritable disorders of connective tissue, characterized by defects in the structure and synthesis of extracellular matrix elements that lead to a myriad of problems including joint hypermobility and skin abnormalities. Because EDS affects multiple organ systems, defining clear boundaries and recognizing overlapping clinical features shared by disease phenotypes is challenging. OBJECTIVES: The objective of this study was to seek evidence of phenotypic subgroups of patients with distinctive symptom profiles and describe these resulting subgroups. METHODS: Data were extracted from a repository assembled 2001-2013 by the National Institute on Aging Intramural Research Program. Agglomerative hierarchical clustering was used to form distinct subgroups of patients with respect to the domains of pain, physical and mental fatigue, daytime sleepiness, and nighttime sleep. Domains were selected based on literature review, clinician expertise, and guidance from patient advisors. RESULTS: One hundred seventy-five patients met all inclusion criteria. Three subgroups were identified. The Pain Dominant subgroup (39 patients) had the highest mean pain values, but lowest mean values of other symptoms. The High Symptom Burden subgroup (71 patients) had high mean values in all domains. The Mental Fatigue subgroup (65 patients) had a high mean value for mental fatigue and daytime sleepiness, but a lower mean value for pain. CONCLUSION: The subgroups aligned with clinical observation of the heterogeneous nature of EDS, with overlapping symptoms between subtypes and a wide divergence in degree of symptoms within subtypes. This exploratory study helps characterize the various phenotypes and comorbidities of patients with EDS.

A prospective evaluation of undiagnosed joint hypermobility syndrome in patients with gastrointestinal symptoms.

BACKGROUND & AIMS: The Joint Hypermobility Syndrome (JHS) is a common connective tissue disorder characterized by joint hyperflexibility, dysautonomia, and chronic pain. Gastrointestinal (GI) symptoms are reported in JHS patients attending rheumatology clinics, but the prevalence and symptom pattern of previously undiagnosed JHS in GI clinics are unknown. METHODS: By using validated questionnaires, a prospective cross-sectional study in secondary care GI clinics estimated the prevalence of JHS in new consecutively referred patients, compared GI symptoms in patients with and without JHS, and by using multiple regression determined whether the burden of GI symptoms in JHS patients was dependent on chronic pain, autonomic, psychological, and medication related factors. A positive control group consisted of JHS patients referred from rheumatology clinics with GI symptoms (JHS-Rh). RESULTS: From 552 patients recruited, 180 (33%) had JHS (JHS-G) and 372 did not (non-JHS-G). Forty-four JHS-Rh patients were included. JHS-G patients were more likely to be younger, female with poorer quality of life (P = .02) than non-JHS-G patients. After age and sex matching, heartburn (odds ratio [OR], 1.66; confidence interval [CI], 1.1-2.5; P = .01), water brash (OR, 2.02; CI, 1.3-3.1; P = .001), and postprandial fullness (OR, 1.74; CI, 1.2-2.6; P = .006) were more common in JHS-G vs non-JHS-G. Many upper and lower GI symptoms increased with increasing severity of JHS phenotype. Upper GI symptoms were dependent on autonomic and chronic pain factors. CONCLUSIONS: JHS is common in GI clinics, with increased burden of upper GI and extraintestinal symptoms and poorer quality of life. Recognition of JHS will facilitate multidisciplinary management of GI and extra-GI manifestations.

Arachnodactyly--a key to diagnosing heritable disorders of connective tissue.

Arachnodactyly literally means spidery fingers, and describes the long, slender fingers typical of patients with Marfan syndrome (MFS). Many clinicians regard arachnodactyly as pathognomonic of MFS; however, this view is misleading as arachnodactyly is a key element of the marfanoid habitus, which is present in several heritable disorders of connective tissue (HDCTs). Other features of the marfanoid habitus include long hands and feet, increased skin stretch, joint hypermobility and characteristic changes in the physiology of the pectum. Here, we focus on the differential diagnosis of diseases with features of the marfanoid habitus. Ectopia lentis (lens dislocation) and aortic root dilation or dissection are cardinal features of MFS. Distinguishing MFS from other HCDTs has important implications for treatment, as cardiovascular and ocular complications commonly seen in patients with MFS are not seen in all HDCTs. Joint hypermobility syndrome and Ehlers-Danlos syndrome are also HDCTs, neither of which is associated with ectopia lentis or aortic changes. Some of the rarer forms of Ehlers-Danlos syndrome are associated with severe vascular, dental and skin pathologies. This Review serves as a guide for correctly diagnosing members of the HDCT family.

Association between DHEAS and bone loss in postmenopausal women: a 15-year longitudinal population-based study.

Our aim was to examine the association between serum dehydroepiandrosterone sulfate (DHEAS) at baseline and BMD change at the femoral neck (FN) and lumbar spine (LS) in postmenopausal women during a 15-year follow-up. All participants were from the Chingford Study. BMD at the FN and LS were measured eight times during the 15-year follow-up by dual-energy X-ray absorptiometry. DHEAS at baseline was measured using radioimmunoassay. Data on height, weight, and hormone-replacement therapy (HRT) status were obtained at each visit. Multilevel linear regression modeling was used to examine the association between longitudinal BMD change at the FN and LS and DHEAS at baseline. Postmenopausal women (n = 1,003) aged 45-68 years (mean 54.7) at baseline were included in the study. After adjustment for baseline age, estradiol, HRT, and BMI, BMD at the FN decreased on average 0.49% (95% CI 0.31-0.71%) per year; and the decline was slowed down by 0.028% per squared year. Increase of DHEAS (each micromole per liter) was associated with 0.49% less bone loss at the FN (95% CI 0.21-0.71%, P = 0.001). However, this strong association became slightly weaker over time. Similar but weaker results were obtained for LS BMD. Our data suggest that high serum DHEAS at baseline is associated with less bone loss at both FN and LS and this association diminishes over time. The nature of the association is unclear, but such an association implies that, in managing BMD loss, women might benefit from maintaining a high level of DHEAS.

Serum branched-chain amino acid to histidine ratio: a novel metabolomic biomarker of knee osteoarthritis.

OBJECTIVE: There is a pressing need to develop reliable molecular biomarkers in osteoarthritis. The aim of the study was to identify novel serum biomarkers for osteoarthritis using a metabolomics approach. METHODS: A two-stage study design was utilised. 123 knee osteoarthritis cases and 299 controls were selected from the TwinsUK cohort as a discovery sample. 76 knee osteoarthritis cases and 100 controls from the Chingford Study were used as replication. Knee osteoarthritis was defined as either radiographic, medically diagnosed or total knee joint replacement due to primary osteoarthritis. All the subjects were unrelated white women. Their serum samples were assessed for targeted metabolite profiling by electrospray ionisation tandem mass spectrometry using the AbsoluteIDQ kit. 163 serum metabolites were assessed and their concentrations obtained. The ratios of metabolite concentrations as proxies for enzymatic reaction rates were calculated and tested for the association with knee osteoarthritis. Significance was assessed after adjustment for multiple testing (Bonferroni method) and potential confounders. RESULTS: In the discovery stage, the authors identified 14 ratios significantly associated with knee osteoarthritis with p < or = 1.9 x 10(-6). Two of these 14 ratios were successfully confirmed in the replication stage-the ratios of valine to histidine and xleucine to histidine, with p=0.002. The significance remained after adjustment for age and body mass index. CONCLUSION: This is the first serum-based metabolomic study of osteoarthritis in humans. The branched-chain amino acids to histidine ratio has potential clinical use as an osteoarthritis biomarker and shows the clinical potential of metabolomics.

Hypermobility.

PURPOSE OF REVIEW: Joint hypermobility is widely prevalent in all communities yet its clinical effects are poorly understood and often overlooked by rheumatologists worldwide. They may observe the hypermobility but fail to appreciate its significance in terms of overall morbidity and, more specifically, its strong link with chronic pain, fatigue, dysautonomia and the adverse impact on quality of life. RECENT FINDINGS: This last year's publications shed further light on this fascinating and, as yet, largely unexplored terrain within rheumatology. Perhaps the most compelling new knowledge is the finding that hypermobility, if sought, is the most common finding amongst patients presenting to a rheumatologist; more often than not, it is being overlooked. There is an urgent need for rheumatologists to accept the challenges posed by hypermobility-related disorders, which have, in the past, fallen by default to clinical geneticists untrained in rheumatology. SUMMARY: Hypermobility, a largely unacknowledged though epidemiologically important area within rheumatology, affects almost every bodily system. Recent medical literature attests to the breadth of clinical science encompassed by the seemingly trivial term, hypermobility. Drawing readers' attentions to this fascinating, challenging, but neglected area of rheumatology will hopefully entice them to explore these conditions with greater zeal.

Joint hypermobility and skin elasticity: the hereditary disorders of connective tissue.

The hereditary disorders of connective tissues (HDCTs) encompass a spectrum of conditions linked pathophysiologically by abnormalities of collagen, fibrillin, and matrix proteins. The clinical picture ranges from morbidity because of musculoskeletal, skin, ocular and visceral pathologies to mortality from acute vascular collapse. For many of the conditions, there is a considerable overlap in clinical features, although severity varies; appreciating the subtle differences in presentation is vital to the clinician in determining the diagnosis. Though conditions associated with severe vascular pathology are rare, other hereditary disorders of connective tissues such as the joint hypermobility syndrome and Stickler's disease are common and probably underrecognized. Abnormal skin elasticity and scaring, joint hypermobility, and chronic arthralgia are important clues that should trigger the clinician to search for underlying hereditary disorders of connective tissues. In this article, we discuss the spectrum of clinical findings, management, and genetic screening of the more common hereditary disorders of connective tissues, highlighting their diagnostic criteria and their differences.

The genetic epidemiology of joint hypermobility: a population study of female twins.

OBJECTIVE: To estimate the genetic influence on joint hypermobility in an unselected population using a classic twin study design. METHODS: A self-report questionnaire on joint hypermobility as well as data on age, height, weight, estrogen replacement therapy, and menopause status were obtained from 483 monozygotic (MZ) and 472 dizygotic (DZ) unselected female twin pairs ages 21-81 years who were registered with the St Thomas' Adult Twin Registry in the UK. RESULTS: The overall prevalence of hypermobility was 19.5% in MZ twins and 22.1% in DZ twins. The prevalence of hypermobile joints declined with age, falling from 34% in subjects ages 20-30 years to 18.4% in those ages 60 years or older. Significantly greater concordance for joint hypermobility was observed in the MZ twins when compared with the DZ twins (60% versus 36%), consistent with a genetic influence. In variance components analysis, the age- and body mass index-adjusted heritability of joint hypermobility was estimated to be 70% (95% confidence interval 57-89%). CONCLUSION: Genetic factors have a substantial contribution to joint hypermobility in the adult female population.

The genetic contribution to carpal tunnel syndrome in women: a twin study.

OBJECTIVE: To assess the relative genetic and environmental contribution to carpal tunnel syndrome (CTS) using a classic twin study of monozygotic (MZ) and dizygotic (DZ) twins. METHODS: The study group comprised unselected female twin pairs, between 20 and 80 years of age, from the St Thomas' UK Adult Twin Registry. Individuals completed a questionnaire that included details on potential risk factors for CTS. The diagnosis of CTS was made using a standardized hand pain diagram and validated criteria. The genetic contribution to CTS was assessed using variance component and regression methods, the heritability was adjusted for environmental confounders. The role of individual risk factors was assessed by a nested case-control study. RESULTS: An overall prevalence of 14.2% for CTS was found in a population of 4,488 females, comprising 867 MZ and 970 DZ twin pairs, and 814 singletons. The concordance for CTS was significantly higher in MZ compared with DZ twins (case-wise concordance values of 0.35 and 0.24 respectively, with a significantly increased MZ:DZ ratio of 1.48; P = 0.03). Modeling produced a heritability estimate of 0.46 (95% CI 0.34-0.58) that was essentially unchanged after adjustment for environmental risk factors including age, body mass index, physical activities, and hormonal/reproductive factors. No major influence of any individual risk factor was seen in the case-control analysis of 520 cases and 3,154 controls, apart from a modest association with menopausal status with an increased risk of 1.53 and 1.43 in the peri and postmenopausal groups. There was no overall effect of age or body mass index. CONCLUSION: This is the first study to explore the genetic component of CTS. Our data show that up to half of the liability to CTS in women is genetically determined, and this appears to be the single strongest risk factor, with only minor contributions from known environmental factors. Further studies should focus on genetic mechanisms that may lead to tests for susceptibility and detection of those at risk of developing CTS.