Joint Hypermobility Research Articles

Exploring signs of central sensitization in adolescents with hypermobility Spectrum disorder or hypermobile Ehlers‐Danlos syndrome

AbstractBackgroundHypermobility Spectrum Disorder (HSD) and Hypermobile Ehlers‐Danlos Syndrome (hEDS) are two overlapping heritable connective tissue disorders characterized by joint hypermobility, chronic pain, impaired body perception, and musculoskeletal symptoms. Central sensitization has been proposed as a plausible explanation for symptoms like widespread pain, fatigue, mood disorders, and sleep disturbances in patients with HSD/hEDS.ObjectiveThe aim of this study was to investigate signs of central sensitization, including exercise‐induced hypoalgesia (EIH), and fatigue severity in adolescents with HSD/hEDS.MethodsIn this prospective, experimental, case–control study, thirty‐seven adolescents with HSD/hEDS and 47 healthy adolescents (all aged 13–17 years) were included. Pressure pain thresholds (PPTs) were measured at four muscle groups using a pressure algometer. EIH was evaluated by measuring PPTs on two muscle groups immediately after an exercise test on a bicycle ergometer. Participants also completed questionnaires on fatigue and cognitive/emotional factors.ResultsThe study demonstrated significantly lower PPTs in four different muscle groups in adolescents with HSD/hEDS compared to the healthy control group. Both groups achieved a significantly higher PPTs after exercise in the muscle involved in the activity. Adolescents with HSD/hEDS reported higher fatigue levels and more cognitive/emotional difficulties than the control group.ConclusionAdolescents with HSD/hEDS showed generalized hyperalgesia measured through PPTs at different body sites. EIH was partly affected in adolescents with HSD/hEDS, presenting as unchanged pain sensitivity in the remote muscle. Pain should be considered as a phenomenon that is influenced by different biopsychosocial factors, including possible central sensitization, which increase its complexity.Significance statementThis study breaks new ground by showing signs of central sensitization, including diminished EIH, in adolescents with HSD or hEDS. Given that exercise is a key element in pain management, these findings offer valuable insights when developing treatment plans for adolescents with HSD or hEDS.

Headache disorders in patients with Ehlers-Danlos syndromes and hypermobility spectrum disorders

Extra-articular symptoms, including headaches, are frequently encountered in patients with Ehlers-Danlos syndrome (EDS) and hypermobility spectrum disorders (HSD), and may be the presenting complaint. Migraine is reported in up to three quarters of patients with symptomatic joint hypermobility, have a higher headache frequency, and an earlier age of onset compared to the general population. Orthostatic headache is an important presentation, and should raise suspicion of an underlying spinal cerebrospinal fluid leak, dysautonomia, and craniocervical pathology, which are all associated with heritable connective tissue disorders (HCTD) including EDS. Any proposed invasive procedure should be scrupulously balanced against its potential risks, taking into account the type of EDS (e.g., vascular EDS) and its systemic manifestations. This is particularly pertinent when suspecting craniocervical instability since it remains a controversial diagnosis with a limited treatment evidence-base. This article reviews the commonly encountered headache disorders in patients with joint hypermobility-related conditions with a focus on EDS and HSD, describes their diverse presentations, and an overview of the recommended management strategies. It also emphasises the need for increased awareness of comorbid conditions in EDS and HSD among clinicians treating headaches to ensure a patient-tailored approach and facilitate a multidisciplinary approach in managing often complex cases.

Uncovering the alterations in extrinsic foot muscle mechanical properties and foot posture in fibromyalgia: a case-control study.

The aim of the study was to evaluate foot posture and the mechanical properties of extrinsic foot muscles in fibromyalgia. Patients with fibromyalgia (n = 86) and age- and gender-matched controls (n = 41) were included in the study. Foot Posture Index (FPI), Beighton and Brighton criteria were used to evaluate static foot posture, joint hypermobility, and benign joint hypermobility syndrome (BJHS), respectively. Tonus, elasticity, and stiffness of the extrinsic foot muscles including gastrocnemius medialis, tibialis anterior, and peroneus longus were measured by the MyotonPRO® device. Foot function, quality of life, and physical activity level were assessed by the Foot Function Index (FFI), Short Form-36 (SF-36), and the International Physical Activity Questionnaire-Short Form (IPAQ-SF), respectively. The frequency of abnormal foot posture in the fibromyalgia and control groups was 68.6% versus 39%, respectively; and neutral foot posture was approximately twice as prevalent in the control group compared to the fibromyalgia group (p = 0.006). Pronated foot posture was the most common abnormality in fibromyalgia (61.6%) and observed in 85.5% of the patients with joint hypermobility and in 87.1% of those meeting BJHS criteria. The elasticity of peroneus longus at rest and the elasticity of tibialis anterior in the standing position were significantly different between the fibromyalgia group and the control group [1.08 (0.22) vs. 1.02 (0.25), p = 0.037 and 0.92 (0.29) vs. 0.87 (0.24), p = 0.011, respectively]. Regarding the fibromyalgia group, no difference was detected among foot posture groups in terms of myotonometric data. Pronation foot posture is common in fibromyalgia with a much higher frequency in fibromyalgia patients with hypermobility. In daily clinical practice for fibromyalgia, particular attention should be given to foot alignment.

Stigmas of dysembryogenesis of undifferentiated connective tissue dysplasia in bronchial asthma

Connective tissue dysplasia is a disturbance of its development during embryogenesis and the postnatal period due to genetically altered fibrillogenesis of the extracellular matrix. Undifferentiated connective tissue dysplasia (UCTD) includes a set of phenotypic characteristics that do not fit into any already known dysplastic syndrome or phenotype. It is this pathology of connective tissue that is widespread and is constantly encountered in the practice of doctors of various profiles, serving as the basis for the formation of various chronic diseases. As for bronchial asthma (BA), it is quite natural that studies have appeared to identify the characteristics of the course of BA with connective tissue dysplasia, primarily in children. It has been shown that asthma in children associated with connective tissue dysplasia has a number of clinical features: an earlier onset of the disease, a higher incidence of concomitant diseases, and a more severe course. The features of the course of bronchial asthma associated with connective tissue dysplasia in adults have been practically not studied. Our very first results from a study of adult patients with BA showed that in patients with a mild course of the disease, up to 3 stigmas of disembryogenesis were recorded, in patients with a moderate course - from 2 to 4, and in patients with a severe course - from 1 to 8 stigmas. Correlation analysis (the data was obtained on a small material, therefore we do not consider it statistically significant) provides a distinct basis for continuing the study. Thus, negative correlations have been identified between the presence of stigmas (myopia, dolichostenomelia, joint hypermobility, wide atrophic scars, varicose veins) and such an important characteristic of the disease as its controllability.

Efficacy of dextrose prolotherapy for temporomandibular joint hypermobility: A systematic review and meta-analysis

ABSTRACT Objective We reviewed the efficacy of dextrose prolotherapy versus placebo and other active interventions, like autologous blood injection (ABI) and botulinum toxin (BTX), in improving the outcomes of temporomandibular joint (TMJ) hypermobility. Methods We searched PubMed, the Cochrane CENTRAL library, Embase, Scopus, and Web of Science databases to identify randomized controlled trials (RCTs) . Maximal mouth opening (MMO), pain, and frequency of dislocations were analyzed. Results Eight RCTs were included. In comparison with placebo, dextrose prolotherapy was associated with significantly reduced pain and MMO. Comparison of dextrose with ABI revealed no significant difference in MMO. Qualitative analysis showed no significant difference in outcomes in patients who received dextrose prolotherapy and BTX. Conclusions Low-quality evidence suggests that dextrose prolotherapy may reduce MMO and improve pain scores compared to placebo in patients with TMJ hypermobility. Low-quality evidence also suggests that there may be minimal difference in outcomes between dextrose vs ABI and BTX.

Postural Orthostatic Tachycardia Syndrome (POTS). Follow – Up of 25 cases

Background: Postural orthostatic tachycardia syndrome (POTS) is a clinical syndrome diagnosed when orthostatic intolerance and tachycardia appear in the standing position. POTS significantly impairs patients' quality of life. Aim: To report the symptoms, anamnestic and clinical elements, findings in the Tilt Test (HUT), evolution and treatment of POTS patients with a follow-up from 8 months to 28 years. Material and Methods: We reviewed from march 1996 to june 2024, 1269 HUT exams in our laboratory. Those reports in which orthostatic postural tachycardia and symptoms compatible with POTS appeared, were selected for analysis. Results: We identified 25 patients (2.6% of all positive Tilt test reports) with compatible signs and symptoms. Most patients complained of orthostatic intolerance, dizziness and frequent fainting. There was a delay of 8 -10 years between the onset of symptoms and the time of diagnosis. Orthostatic tachycardia and symptoms occurred on average after 3.5 and 5.2 minutes, respectively, when staying in the standing position. Our patients had a high frequency of syncope or presyncope in their families (60% frequency) and hypermobility joint syndrome (64% prevalence). 40% of the patients reported relief of their symptoms after being treated (most of them with fludrocortisone). Most patients that reported little or no relief, did not use medications or were treated for a short period. Conclusions: POTS is not common but significantly impairs the quality of life of those who suffer from it. We found a clear association with joint hypermobility syndrome, an excessive venous pooling during standing and a family history of syncope or lipothymia. Best treament is with fludrocortisone alone or in combination with midodrine.

Overlapping conditions in Long COVID at a multisite academic center

BackgroundMany patients experience persistent symptoms after COVID-19, a syndrome referred to as Long COVID (LC). The goal of this study was to identify novel new or worsening comorbidities self-reported in patients with LC.MethodsPatients diagnosed with LC (n = 732) at the Mayo Long COVID Care Clinic in Rochester, Minnesota and Jacksonville, Florida were sent questionnaires to assess the development of new or worsening comorbidities following COVID-19 compared to patients with SARS-CoV-2 that did not develop LC (controls). Both groups were also asked questions screening for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), generalized joint hypermobility (GJH) and orthostatic intolerance. 247 people with LC (33.7%) and 40 controls (50%) responded to the surveys.ResultsIn this study LC patients averaged 53 years of age and were predominantly White (95%) women (75%). The greatest prevalence of new or worsening comorbidities following SARS-CoV-2 infection in patients with LC vs. controls reported in this study were pain (94.4% vs. 0%, p < 0.001), neurological (92.4% vs. 15.4%, p < 0.001), sleep (82.8% vs. 5.3%, p < 0.001), skin (69.8% vs. 0%, p < 0.001), and genitourinary (60.6% vs. 25.0%, p = 0.029) issues. 58% of LC patients screened positive for ME/CFS vs. 0% of controls (p < 0.001), 27% positive for GJH compared to 10% of controls (p = 0.026), and a positive average score of 4.0 on orthostatic intolerance vs. 0 (p < 0.001). The majority of LC patients with ME/CFS were women (77%).ConclusionWe found that comorbidities across 12 surveyed categories were increased in patients following SARS-CoV-2 infection. Our data also support the overlap of LC with ME/CFS, GJH, and orthostatic intolerance. We discuss the pathophysiologic, research, and clinical implications of identifying these conditions with LC.

Study on the balance and gait characteristics of subjects with generalized joint hypermobility residing in high-altitude using wearable devices: a cross-sectional study

PurposeTo investigate the characteristics of balance and gait functions in Generalized Joint Hypermobility (GJH) subjects residing in high-altitude areas.MethodsThis study included 61 university students (28 with GJH and 33 healthy controls) all from the high-altitude region of Linzhi, Tibet Autonomous Region. The Riablo™ wearable intelligent rehabilitation assessment and training system was used to assess static balance (with eyes open and closed) and gait function (during flat walking) in both groups.ResultsCompared to healthy subjects, GJH subjects exhibited significantly impaired balance, indicated by an increased distance of the center of pressure position from the ideal center of gravity(EO: P = 0.007, EC: P = 0.031) and greater amplitude of center of pressure displacements (EO: P = 0.043, EC: P = 0.032). Gait velocity(P = 0.007), stride length(P = 0.012), and swing stance phase of the gait cycle(P = 0.046) were significantly reduced in GJH subjects compared to healthy subjects. A significant increase in the flat-foot phase of the gait cycle(P = 0.022) was observed in GJH subjects compared to healthy subjects.ConclusionThe current study demonstrated that GJH subjects residing in high-altitude areas exhibit impairments in balance and gait, providing a basis for training and prevention strategies tailored for this population. And this study used the wearable intelligent rehabilitation evaluation and training system in high-altitude areas, providing methodological references for scientific research on balance and gait function under non laboratory conditions.Trial registrationControlled Trials No.102772023RT133, Registered 13 October 2023.

Drug-resistant epilepsy cases in chromosomal pathology

Two cases of epilepsy in patients with a rare hereditary pathology associated with a chromosomal mutation caused deletion of chromosome 14 are presented. In the first case, this pathology was manifested in the child by generalized tonic-clonic seizures, delayed psycho-verbal development, and facial skull microanomaly. In the second case, it was expressed in tonic epileptic seizures, delayed psycho-verbal development, developmental microanomalies, pyramidal atactic syndrome and hand joint hypermobility. Such clinical observations are of professional and scientific interest, as they relate to a rare neurological pathology, with drug-resistant epilepsy as a leading sign.

Decoding the Genetic Basis of Mast Cell Hypersensitivity and Infection Risk in Hypermobile Ehlers-Danlos Syndrome.

Hypermobile Ehlers-Danlos syndrome (hEDS) is a connective tissue disorder marked by joint hypermobility, skin hyperextensibility, and tissue fragility. Recent studies have linked hEDS with mast cell activation syndrome (MCAS), suggesting a genetic interplay affecting immune regulation and infection susceptibility. This study aims to decode the genetic basis of mast cell hypersensitivity and increased infection risk in hEDS by identifying specific genetic variants associated with these conditions. We conducted whole-genome sequencing (WGS) on 18 hEDS participants and 7 first-degree relatives as controls, focusing on identifying genetic variants associated with mast cell dysregulation. Participants underwent clinical assessments to document hEDS symptoms and mast cell hypersensitivity, with particular attention to past infections and antihistamine response. Our analysis identified specific genetic variants in MT-CYB, HTT, MUC3A, HLA-B and HLA-DRB1, which are implicated in hEDS and MCAS. Protein-protein interaction (PPI) network analysis revealed significant interactions among identified variants, highlighting their involvement in pathways related to antigen processing, mucosal protection, and collagen synthesis. Notably, 61.1% of the hEDS cohort reported recurrent infections compared to 28.5% in controls, and 72.2% had documented mast cell hypersensitivity versus 14.2% in controls. These findings provide a plausible explanation for the complex interplay between connective tissue abnormalities and immune dysregulation in hEDS. The identified genetic variants offer insights into potential therapeutic targets for modulating mast cell activity and improving patient outcomes. Future research should validate these findings in larger cohorts and explore the functional implications of these variants to develop effective treatment strategies for hEDS and related mast cell disorders.

Joint hypermobility in rheumatoid arthritis: A case- control study

Objective: To evaluate the presence of joint hypermobility (JH) in rheumatoid arthritis (RA) patients and the relationship between JH and disease activity, hand functions, and quality of life. Methods: Thirty-four seropositive RA patients and 34 controls were included. Demographic data, body mass index, and state of JH (Beighton scores) of all participants were recorded. Two groups were compared in terms of JH. In RA patients, the Disease Activity Score-28 (DAS-28) was used to evaluate disease activity, the Duruöz Hand Index (DHI) for hand functions, and the Nottingham Health Profile (NHP) for quality of life. A correlation analysis was performed to evaluate the relationship of these data with JH in RA patients. Results: In the RA group, there were no patients with JH. No significant difference was found in the Beighton scores compared to the control group (p=0.383). The Beighton score showed a statistically significant negative correlation with DAS-28, DHI, NHP total, NHP pain, NHP physical activity, and NHP energy level. (p=0.026, p=0.015, p=0.003, p

The Neuroconnective Endophenotype, A New Approach Toward Typing Functional Neurological Disorder: A Case-Control Study.

Functional neurological disorder (FND) is a core neuropsychiatric condition that includes both physical and mental symptoms. Recently, a validated clinical phenotype termed neuroconnective endophenotype (NEP), which includes several physical and psychological characteristics together with joint hypermobility (hypermobility spectrum disorders), was found at a significantly higher frequency among patients with anxiety. The purpose of the present study was to examine the presence of the NEP among patients with FND. The authors conducted a multicenter case-control study comprising 27 FND patients and 27 healthy control participants (matched by sex and age) ages 13 to 58 years. Eight questionnaires were administered. Proportional differences were examined with Student's t tests, one-way analyses of variance, and chi-square tests. Differences between FND patients and control participants were observed. FND patients had higher sensory sensitivity, increased prevalence of hypermobility features (including relevant physical signs and symptoms), greater frequency of polarized behaviors, a greater number of both psychiatric and physical comorbidities, and an increase in the characteristics and sensations typical of anxiety. Particularly striking was the presence of the hypermobility spectrum in more than 75% of FND patients compared with 15% among control participants. FND patients presented higher scores in all five dimensions included in the NEP. Thus, this phenotype, solidifying the original association between anxiety and the hypermobility spectrum, could help to identify an FND subtype when evaluating and managing FND patients, because it provides a new global view of patients' physical and mental symptoms.

Proprioception and its relationship with range of motion in hypermobile and normal mobile children.

To investigate differences in proprioception using four proprioceptive tests in children with and without hypermobility. Additionally, it was tested if the results on one proprioceptive test predict the results on the other tests. Of the children (8-11years), 100 were classified as normal mobile (Beighton score 0-4) and 50 as hypermobile (Beighton score 5-9). To test proprioception, in the upper extremity the unilateral and bilateral joint position reproduction tasks were used and for the lower extremity the loaded and unloaded wedges task. No differences were found in any of the proprioception tests between the two groups. Estimating the height of the wedges was easier in the loaded position (mean penalty in standing and sitting position, 4.78 and 6.19, respectively). Recalling the elbow position in the same arm resulted in smaller errors compared to tasks reproducing the position with the contralateral arm. Of the four angles used (110°, 90°, 70°, 50°), the position recall in the 90° angle had the smallest position error (1.8°). Correlations between the proprioception tests were weak (Loaded and Unloaded (r 0. 28); Uni and Bilateral (r 0.39), Upper and Lower extremity not significant). No indication of poorer proprioception was found in children with hypermobile joints compared to their normal mobile peers. Loading gives extra information that leads to fewer errors in the wedges task performed while standing, but this effect is independent of joint mobility. Proprioception test outcomes are dependent on the test used; upper extremity results do not predict lower extremity outcomes or vice versa.

The Effect of Attention Focus Instructions on Strength and Balance in Subjects With Generalized Joint Hypermobility

ABSTRACT This study aims to examine the effects of different attention focuses on muscle strength and balance performance in individuals with Generalized Joint Hypermobility (GJH). This randomized crossover trial included 32 individuals with GJH whose Beighton score was greater than 5. Subjects performed each task under external attentional focus, internal attentional focus, and neutral attentional focus condition. Knee extensor muscle strength was measured using the Isokinetic Dynamometer. Postural stability was evaluated using the Biodex Balance System, while dynamic balance was assessed using the Y Balance Test. The main effects of attentional focus on the outcomes were analyzed using repeated measures ANOVA and post-hoc corrections with a 95% confidence interval. Subjects produced significantly higher quadriceps peak torque during external focus instruction and internal focus instruction compared to neutral condition (p = .006). Postural stability performance were found to be better during external attention focus compared to the internal focus of attention and the neutral group (p = .008). In addition, an increase in Y balance composite score was observed during external condition compared to internal condition and neutral condition (p < .001). Whether internal or external, the use of attentional focus may be beneficial for optimal force production during training in individuals with GJH. External attention focus enabled better postural stability and dynamic balance performances.

Biallelic and monoallelic variants in EFEMP1 can cause a severe and distinct subtype of heritable connective tissue disorder.

Variants in EFEMP1, encoding Fibulin-3, were previously reported as a rare cause of heritable connective tissue disorder (HCTD) with recurrent hernias and joint hypermobility. We report three new cases with biallelic or monoallelic EFEMP1 variants and severe hernia phenotypes. Two male siblings of 10 and 13 years old presented with marfanoid habitus, recurrent inguinal and umbilical hernias, generalized joint hypermobility, and scoliosis. Parents and halfsiblings reported joint hypermobility and umbilical hernias. The eldest boy died at age 16 from incarcerated gastrointestinal herniation complicated by gastric and bowel necrosis with perforation. Autopsy revealed widespread intestinal diverticula. Immunohistochemistry of skin and fascia tissue did not reveal any abnormalities, including normal staining of elastic fibers. Both siblings harbored compound heterozygous likely pathogenic EFEMP1 variants (c.1320 + 2T > A, p.? and c.698G > A, p.Gly233Asp). An unrelated 58-year-old male had marfanoid features, high myopia, recurrent diaphragmatic and inguinal hernias, and chronic gastrointestinal dilatation with severe malabsorption. Both his dizygotic twin-brother and mother had recurrent hernias and high myopia. This man died at 59 years of age, and autopsy showed extensive diaphragmatic herniation, bowel diverticula, and pulmonary emphysema. A heterozygous EFEMP1 splice-variant (c.81 + 1G > A, p.?) was identified, causing exon skipping leading to a start-loss. Targeted genome reanalysis nor RNA-sequencing revealed a second variant at the other allele. The reported individuals expand the clinical and pathological phenotypes of EFEMP1-related disease, a distinct entity within the spectrum of HCTD. The severe and recurrent hernias, gastrointestinal dilatation, and diverticulosis result in an increased risk for life-threatening complications, demanding early recognition and close monitoring.

7655 Genetic Mysteries Unveiled: Unusual Mutation Unraveled In Hypophosphatasia

Abstract Disclosure: A. Sharma: None. P. Katikaneni: None. S. Tanveer: None. K. Selk: None. Introduction: Hypophosphatasia (HPP), an inherited dental-osseous metabolic illness, is caused by inactivating mutations in the gene encoding the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP), which leads to a decrease in TNSALP enzymatic activity. Patients with HPP typically experience dental and skeletal mineralization issues as their most common symptoms; musculoskeletal abnormalities, numerous fractures, tiredness, and migraines are less common clinical presentations. Case Report: Our 75-year-old male patient initially presented 1.5 years prior following a spontaneous T12 vertebral fracture. A bone biopsy was performed and did not reveal evidence of malignancy. Testing for SPEP/UPEP was not consistent with myeloma, and thyroid testing was also unrevealing. His alkaline phosphatase level was consistently &amp;lt;40 IU/L since 1999. An evaluation was done for low alkaline phosphatase and secondary reasons for bone loss. This testing did not reveal vitamin D deficiency, parathyroid disease, hypophosphatemia, laboratory evidence of celiac disease, hypogonadism, or hypomagnesemia. A vitamin b6 level was markedly elevated at 119 ng/mL (ref range 2.1-21.7) while not on supplementation. He had noticed multiple fractures as a child, but he had written them off as minor injuries. He could clearly remember breaking his right wrist and clavicle. As an adult, he had rib fractures and a foot fracture. He was unable to recollect losing his primary teeth. Almost all his teeth are crowns or implants despite taking exceptional care of them. He did not have joint hypermobility. Genetic testing revealed the patient was heterozygous for an ALPL gene variant, c.876_882delinsT. It was a variant of undetermined significance at that time. His daughter also was found to have a low alkaline phosphatase and the same genetic test result. She also has experienced dental carries and joint pain. Our patient initiated teriparatide due to the need for more urgent therapy for extensive spinal surgery. He was later transitioned to asfotase alfa therapy and has not had any further fractures at the time of this report. Discussion: Hypophosphatasia is a rare inborn disorder due to mutations in the tissue nonspecific alkaline phosphatase gene ALPL and is characterized by low ALP levels. Affected individuals will also have elevated vitamin b6 levels and urinary phosphoethanolamine (PEA) levels. Early diagnosis of HPP is necessary to prevent bone fracture pain and improve quality of life. Inaccurate assessments can miss diagnoses of parents and other family members and even lead to lost opportunities to treat a patient with a substantial illness burden. This case highlights the mutation c.876_882delinsT as a likely pathologic variant in the ALPL gene. It also supports that patients with HPP can also respond to teriparatide treatment. Presentation: 6/2/2024

6556 Does Autoimmune Hashimoto’s Hypothyroidism Mask the Diagnosis of Ehlers-Danlos-Syndrome?

Abstract Disclosure: S. Azmat: None. U. Rafat: None. J.L. Gilden: None. Does Autoimmune Hashimoto’s Hypothyroidism Mask the Diagnosis of Ehlers-Danlos Syndrome? Background: Hypothyroidism is well-known to be associated with muscle weakness and fatigue. There are other etiologies for decreased muscle tone such as Ehlers-Danlos syndrome (EDS) which is group of connective tissue disorders characterized by joint hypermobility, skin hyperextensibility and tissue fragility. Other rheumatological and cardiac conditions associated with this syndrome can pose diagnostic challenges. We present case of 32-year-old female presenting with facial muscle weakness and newly diagnosed Hashimoto’s hypothyroidism. We highlight importance of keeping EDS as another differential in patients with muscle weakness allowing for accurate, prompt diagnosis and treatment to be done in timely manner. Case Description: A 32-year-old female professional musician was referred to Endocrine for mouth muscles weakness and decreasing ability to play her French Horn wind instrument with vocal dystonia and the question of whether these were symptoms of hypothyroidism. She was noted to have mild thyroid enlargement and abnormal thyroid function tests with positive thyroid antibodies. Initial TSH was 7.506 uIU/mL(0.55-4.78), free T4 0.9 ng/dL (0.76-1.46), peroxidase antibody = 96,061U/mL (0-60) and thyroglobulin of 134.9 U/mL (0-60). She also reported low energy, intermittent difficulty swallowing and decreased muscle strength. There was no prior personal and family history of hypo/hyperthyroidism or any other disorders. VS were normal, physical exam showe d no thyromegaly, reflexes revealed objective decrease but normal muscle strength. The skin was noted to be hyperextensible with passive hyperextension of fifth metacarpophalangeal joint beyond 90 degrees, thumb to flexor aspect of forearm and elbows bilaterally with positive Beighton criteria for EDS. She later admitted to intermittent palpitations and easy bruising. Subsequent lab tests were negative ANA, anti-mitochondrial, PCEL and striated muscles antibodies. Additionally she had normal IGA, PTH, AM cortisol- ACTH, vitamin B12 levels with negative 21 hydroxylases antibodies and celiac titers. She was started on levothyroxine 25 mcg and recommended for Cardiology evaluation and genetic testing. Physiotherapy was started. Upon six months follow-up she clinically felt better with improved muscle strength, swallowing and energy level. Repeat lab testing showed improved TSH of 2.67 uIU/mL(0.55-4.78) with free T4 of 1.0 ng/dL (0.76-1.46). Conclusion: This case demonstrates that although muscle weakness can be symptom of hypothyroidism one must evaluate all patients for other possible causes. We highlight importance of keeping EDS as a differential especially in female patients with muscle weakness. Though history and physical exam is crucial allowing for prompt diagnosis and treatment for other conditions. Presentation: 6/1/2024

7030 Molecular Analysis Of Congenital Adrenal Hyperplasia-X Syndrome And Development Of A Pilot Panel For Analyzing Structural Variations With Long-Read Sequencing

Abstract Disclosure: J. Kim: None. S. Park: None. J. Yoon: None. D. Kim: None. S. Hwang: None. G. Kim: None. J. Kim: None. J. Choi: None. H. Yoo: None. Purpose: Genomic recombination events between the CYP21A2 and CYP21A1P genes are frequent due to their high sequence homology. Deletions in both the CYP21A2 and TNXB genes result in a chimeric TNXA/TNXB gene, leading to congenital adrenal hyperplasia (CAH)-X syndrome, characterized by a hypermobile form of Ehlers-Danlos syndrome. The aim of study was to determine the frequency of CAH-X syndrome and to develop a pilot panel for structural variation analysis using long-read sequencing technology. Methods: Among the 165 unrelated families with confirmed genetic mutations in the CYP21A2 gene, 44 probands had large deletions in one or both alleles. Long-range PCR was performed in 12 patients out of 44 probands using a forward primer for the 5’-UTR of the CYP21A2 and CYP21A1P and a reverse primer specific for exon 32 of TNXB. The amplified PCR products were then subjected to Sanger sequencing. We constructed a custom panel of 140 kb containing the RCCX modules arranged as STK19-C4A-CYP21A1P-TNXA-STK19B-C4B-CYP21A2-TNXB. In 4 patients with deletions in both the CYP21A2 and TNXB genes, long-read sequencing was performed using the custom panel on the PacBio Sequel II platform. Results: Out of 12 probands, eight harbored TNXA/TNXB chimeras. One patient was homozygous for CAH-X CH1 with a 120 bp deletion in exon 35 and had a Beighton score of 6 for joint hypermobility and multiple diverticula in the ascending colon. Two patients were heterozygous for CAH-X CH1, while three were heterozygous for the CAH-X CH2 with an intact exon 35 and the c.P4058W in exon 40. Two patients carried heterozygous mutations p.S4175N in exon 43, which is an unclassified type. Using long-read sequencing with a custom panel, missense mutations and TNXA/TNXB chimeras were detected in four patients previously identified by conventional direct sequencing and MLPA. Conclusions: This study identified 8 patients with CAH-X syndrome carrying four different TNXA/TNXB chimeras by long-range PCR. Long-read sequencing emerged as a comprehensive and efficient method for the molecular analysis of CAH, especially for the identification of structural variations. Biallelic deletion of TNXB was associated with severe clinical manifestations. Therefore, screening for CAH-X is essential for clinical management and prevention of the long-term consequences of CAH-X syndrome. Presentation: 6/1/2024

9266 Molecular Analysis Of Congenital Adrenal Hyperplasia-X Syndrome And Development Of A Pilot Panel For Analyzing Structural Variations With Long-Read Sequencing

Abstract Disclosure: J. Kim: None. S. Park: None. J. Yoon: None. D. Kim: None. S. Hwang: None. G. Kim: None. J. Kim: None. J. Choi: None. H. Yoo: None. Purpose: Genomic recombination events between the CYP21A2 and CYP21A1P genes are frequent due to their high sequence homology. Deletions in both the CYP21A2 and TNXB genes result in a chimeric TNXA/TNXB gene, leading to congenital adrenal hyperplasia (CAH)-X syndrome, characterized by a hypermobile form of Ehlers-Danlos syndrome. The aim of study was to determine the frequency of CAH-X syndrome and to develop a pilot panel for structural variation analysis using long-read sequencing technology. Methods: Among the 165 unrelated families with confirmed genetic mutations in the CYP21A2 gene, 44 probands had large deletions in one or both alleles. Long-range PCR was performed in 12 patients out of 44 probands using a forward primer for the 5’-UTR of the CYP21A2 and CYP21A1P and a reverse primer specific for exon 32 of TNXB. The amplified PCR products were then subjected to Sanger sequencing. We constructed a custom panel of 140 kb containing the RCCX modules arranged as STK19-C4A-CYP21A1P-TNXA-STK19B-C4B-CYP21A2-TNXB. In 4 patients with deletions in both the CYP21A2 and TNXB genes, long-read sequencing was performed using the custom panel on the PacBio Sequel II platform. Results: Out of 12 probands, eight harbored TNXA/TNXB chimeras. One patient was homozygous for CAH-X CH1 with a 120 bp deletion in exon 35 and had a Beighton score of 6 for joint hypermobility and multiple diverticula in the ascending colon. Two patients were heterozygous for CAH-X CH1, while three were heterozygous for the CAH-X CH2 with an intact exon 35 and the c.P4058W in exon 40. Two patients carried heterozygous mutations p.S4175N in exon 43, which is an unclassified type. Using long-read sequencing with a custom panel, missense mutations and TNXA/TNXB chimeras were detected in four patients previously identified by conventional direct sequencing and MLPA. Conclusions: This study identified 8 patients with CAH-X syndrome carrying four different TNXA/TNXB chimeras by long-range PCR. Long-read sequencing emerged as a comprehensive and efficient method for the molecular analysis of CAH, especially for the identification of structural variations. Biallelic deletion of TNXB was associated with severe clinical manifestations. Therefore, screening for CAH-X is essential for clinical management and prevention of the long-term consequences of CAH-X syndrome. Presentation: 6/1/2024

High-load strength training compared with standard care treatment in young adults with joint hypermobility and knee pain: study protocol for a randomised controlled trial (the HIPEr-Knee study)

IntroductionPatients with generalised joint hypermobility, including knee hypermobility (GJHk), often experience knee pain and are typically managed with low-intensity strength training and/or proprioceptive training as part of standard care. However,...