Dysautonomia is a recognized manifestation in patients with joint hypermobility (JH) disorders. Symptoms can be highly debilitating and commonly include physical deconditioning and poor aerobic fitness. In this study, the prevalence of dysautonomia, range of associated symptoms, patient-reported physical activity levels, and echocardiographic features were assessed retrospectively in a cohort of 144 patients (94% female) with hypermobile Ehlers-Danlos syndrome (hEDS) or hypermobility spectrum disorder (HSD). Echocardiographic parameters of left ventricular size and function were compared between patients with and without dysautonomia as well as to reported values from healthy controls. Dysautonomia was identified in 65% of female and 44% of male subjects and was associated with a high burden of symptomatology, most commonly exercise intolerance (78%). Exercise capacity was limited by dysautonomia, often postural symptoms, in half of all patients. We observed a reduction in physical activity following the onset or significant flare of hEDS/HSD, most strikingly noting the proportion of dysautonomic patients with sedentary lifestyle, which increased from 44% to 85%. JH-related dysautonomia was associated with smaller cardiac chamber sizes, consistent with the previous reports in positional orthostatic tachycardia syndrome. Dysautonomia is prevalent in patients with hEDS/HSD, and exercise intolerance is a key feature and leads to drastic decline in physical activity. Unfavorable cardiac geometry may underlie dysautonomia symptoms and may be due to cardiac atrophy in the setting of aerobic deconditioning.

Hypermobile EDS should be suspected in adult probands (individuals who have reached biologic maturity) with the following clinical features [Malfait et al 2017]:
* Joint instability including subluxations and dislocations

* Musculoskeletal pain

* Soft, hyperextensible skin, with atypical stretchmarks and/or scarring

* Dental crowding and a high or narrow-arched palate

* Abdominal hernias

* Pelvic organ prolapse

* A marfanoid body habitus

* Mitral valve prolapse and/or aortic root dilatation

* Family history consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.
In addition, hEDS is associated with clinical manifestations that are not included in the published diagnostic criteria including [Hakim et al 2021]:
* Chronic fatigue

* Easy bruising

* Functional bowel disorders (gastroesophageal reflux, gastritis, early satiety, delayed gastric emptying, irritable bowel syndrome, constipation)

* Additional cardiovascular manifestations (autonomic dysfunction, Raynaud phenomenon, acrocyanosis)

* Reduced efficacy of local anesthetics

* Laryngeal and breathing disorders including apnea

* Neurologic complications (migraine, Chiari I malformation, cerebrospinal fluid leaks, craniocervical instability and associated cord and nerve root pathology, tethered cord, entrapment and peripheral neuropathy, small fiber neuropathy)

* Mast cell activation disorders and immune deficiency including primary immune deficiency

* Anxiety disorders

* Autism and attention-deficit/hyperactivity disorder

* Urogynecologic manifestations (dysmenorrhea, menorrhagia, interstitial cystitis, urinary incontinence, pelvic organ prolapse)

Hypermobile Ehlers-Danlos syndrome (hEDS) is characterized by generalized joint hypermobility, joint instability, pain, soft and hyperextensible skin with atrophic scars and easy bruising, dental crowding, abdominal hernias, pelvic organ prolapse, marfanoid body habitus, mitral valve prolapse, and aortic root dilatation. Subluxations, dislocations, and soft tissue injury are common; they may occur spontaneously or with minimal trauma and can be acutely painful. Degenerative joint and chronic soft tissue disorders may arise due to repeated injury. Chronic pain, distinct from that associated with acute injury, is common and often neuropathic in nature. Chronic fatigue, functional bowel disorders, cardiovascular autonomic dysfunction, swallow and phonation disorders, sleep disorders including apnea, migraine, entrapment and peripheral neuropathies, inflammation from mast cell activation disorders, anxiety disorders, and urogynecologic disorders are common. Mitral valve prolapse and aortic root dilatation, when present, are typically of a mild degree with no increased risk of cardiac complications.

Background: Hypermobility 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.

Objective: The aim of this study was to investigate signs of central sensitization, including exercise-induced hypoalgesia (EIH), and fatigue severity in adolescents with HSD/hEDS.

Methods: In 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.

Results: The 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.

Conclusion: Adolescents 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 Statement: This 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.