Rodney Grahame

Dysautonomia in the joint hypermobility syndrome

PURPOSE Extraarticular manifestations of the joint hypermobility syndrome may include the peripheral nervous system. The purpose of this study was to investigate autonomic function in patients with this syndrome. METHODS Forty-eight patients with the joint hypermobility syndrome who fulfilled the 1998 Brighton criteria and 30 healthy control subjects answered a clinical questionnaire designed to evaluate the frequency of complaints related to the autonomic nervous system. Next, 27 patients and 21 controls underwent autonomic evaluation: orthostatic testing, cardiovascular vagal and sympathetic functions, catecholamine levels, and adrenoreceptor responsiveness. RESULTS Symptoms related to the autonomic nervous system, such as syncope and presyncope, palpitations, chest discomfort, fatigue, and heat intolerance, were significantly more common among patients. Orthostatic hypotension, postural orthostatic tachycardia syndrome, and uncategorized orthostatic intolerance were found in 78% (21/27) of patients compared with in 10% (2/21) of controls. Patients with the syndrome had a greater mean (+/- SD) drop in systolic blood pressure during hyperventilation than did controls (-11 +/- 7 mm Hg vs. -5 +/- 5 mm Hg, P = 0.02) and a greater increase in systolic blood pressure after a cold pressor test (19 +/- 10 mm Hg vs. 11 +/- 13 mm Hg, P = 0.06). Patients with the syndrome also had evidence of alpha-adrenergic (as assessed by administration of phenylephrine) and beta-adrenergic hyperresponsiveness (as assessed by administration of isoproterenol). CONCLUSION The autonomic nervous system-related symptoms of the patients have a pathophysiological basis, which suggests that dysautonomia is an extraarticular manifestation in the joint hypermobility syndrome.

Joint hypermobility and genetic collagen disorders: are they related?

The HDCTs constitute a heterogeneous group of rare genetically determined diseases, the best known of which are Ehlers-Danlos and Marfan syndromes and osteogenesis imperfecta. Hypermobility is a feature common to them all, but it is also a feature that is highly prevalent in the population at large. Symptomatic hypermobile subjects (whose symptoms are attributable to their hypermobility) are said to be suffering from the benign joint hypermobility syndrome, which has many features that overlap with the HDCTs. It is not yet known whether there is a variety of hypermobility (symptomatic or otherwise) that is not part of a connective tissue disorder.

The lack of clinical distinction between the hypermobility type of Ehlers-Danlos syndrome and the joint hypermobility syndrome (a.k.a. hypermobility syndrome)

The Lack of Clinical Distinction Between the Hypermobility Type of Ehlers–Danlos Syndrome and the Joint Hypermobility Syndrome (a.k.a. Hypermobility Syndrome) Brad T. Tinkle,* Howard A. Bird, Rodney Grahame, Mark Lavallee, Howard P. Levy, and David Sillence Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio University of Leeds, West Yorkshire, United Kingdom University College Hospital, London, United Kingdom Memorial Sports Medicine Institute, South Bend, Indiana Johns Hopkins University, Baltimore, Maryland Connective Tissue Dysplasia Management Service, The Children’s Hospital at Westmead, Westmead, New South Wales, Australia

Postural tachycardia syndrome—current experience and concepts

Postural tachycardia syndrome (PoTS) is a poorly understood but important cause of orthostatic intolerance resulting from cardiovascular autonomic dysfunction. PoTS is distinct from the syndromes of autonomic failure usually associated with orthostatic hypotension, such as pure autonomic failure and multiple system atrophy. Individuals affected by PoTS are mainly young (aged between 15 years and 40 years) and predominantly female. The symptoms—palpitations, dizziness and occasionally syncope—mainly occur when the patient is standing upright, and are often relieved by sitting or lying flat. Common stimuli in daily life, such as modest exertion, food ingestion and heat, are now recognized to be capable of exacerbating the symptoms. Onset of the syndrome can be linked to infection, trauma, surgery or stress. PoTS can be associated with various other disorders; in particular, joint hypermobility syndrome (also known as Ehlers–Danlos syndrome hypermobility type, formerly termed Ehlers–Danlos syndrome type III). This Review describes the characteristics and neuroepidemiology of PoTS, and outlines possible pathophysiological mechanisms of this syndrome, as well as current and investigational treatments.

The 2017 international classification of the Ehlers-Danlos syndromes.

The Ehlers–Danlos syndromes (EDS) are a clinically and genetically heterogeneous group of heritable connective tissue disorders (HCTDs) characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Over the past two decades, the Villefranche Nosology, which delineated six subtypes, has been widely used as the standard for clinical diagnosis of EDS. For most of these subtypes, mutations had been identified in collagen‐encoding genes, or in genes encoding collagen‐modifying enzymes. Since its publication in 1998, a whole spectrum of novel EDS subtypes has been described, and mutations have been identified in an array of novel genes. The International EDS Consortium proposes a revised EDS classification, which recognizes 13 subtypes. For each of the subtypes, we propose a set of clinical criteria that are suggestive for the diagnosis. However, in view of the vast genetic heterogeneity and phenotypic variability of the EDS subtypes, and the clinical overlap between EDS subtypes, but also with other HCTDs, the definite diagnosis of all EDS subtypes, except for the hypermobile type, relies on molecular confirmation with identification of (a) causative genetic variant(s). We also revised the clinical criteria for hypermobile EDS in order to allow for a better distinction from other joint hypermobility disorders. To satisfy research needs, we also propose a pathogenetic scheme, that regroups EDS subtypes for which the causative proteins function within the same pathway. We hope that the revised International EDS Classification will serve as a new standard for the diagnosis of EDS and will provide a framework for future research purposes.

Unexplained gastrointestinal symptoms and joint hypermobility: is connective tissue the missing link?

Background  Unexplained gastrointestinal (GI) symptoms and joint hypermobility (JHM) are common in the general population, the latter described as benign joint hypermobility syndrome (BJHS) when associated with musculo‐skeletal symptoms. Despite overlapping clinical features, the prevalence of JHM or BJHS in patients with functional gastrointestinal disorders has not been examined.

Joint hypermobility syndrome

Joint hypermobility syndrome (JHS), previously known as benign joint hypermobility syndrome (BJHS), is a heritable disorder of connective tissue that comprises symptomatic hypermobility predisposing to arthralgia, soft tissue injury, and joint instability.1 It is indistinguishable from the hypermobility type of Ehlers-Danlos syndrome.2 Complications may include autonomic dysfunction, proprioceptive impairment, premature osteoarthritis, intestinal dysmotility, and laxity in other tissues causing hernias or uterine or rectal prolapse. Symptoms are often minimal or mild, but 168 out of 700 patients with joint hypermobility syndrome (24%) attending the UCH Hypermobility Clinic already had an established chronic pain syndrome at the time of their first outpatient attendance. These patients were experiencing serious pain, disability, and impairment of the quality of life, some patients becoming chairbound or even bedbound.3 #### Case scenario A 30 year old project manager, who is new to your general practice, presents with right anterior knee pain after slipping and landing on his knee three months ago. Imaging shows no abnormality, but he describes a long history of recurrent shoulder subluxation, and many soft tissue problems and joint pains, often after similarly trivial trauma, and he states that imaging and blood tests “for arthritis” have always been normal. You note that he has no signs of inflammation but that he is hypermobile according to the Beighton score (see box 1), and looking up the Brighton criteria, which includes and extends the older Beighton score (see box 2), you mention he fulfils the criteria for joint hypermobility syndrome, and he expresses relief there is an explanation for his symptoms. #### Box 1 Nine-point Beighton score for joint hypermobility syndrome4 One point is gained for each side of the body for the first four manoeuvres listed below, such that the hypermobility score is a maximum of 9 if all are positive.

Hypermobility: an important but often neglected area within rheumatology.

Hypermobility-related disorders are frequently encountered in clinical practice, but are too often dismissed as trivial. In this Viewpoint, Prof. Grahame discusses why the current perception of these disorders is inadequate, and highlights recent advances in the field as well as challenges and opportunities for future research and therapy.

Joint hypermobility and rectal evacuatory dysfunction: an etiological link in abnormal connective tissue?

Background  Previous studies report an association between joint hypermobility (JHM), as a clinical feature of underlying connective tissue (CT) disorder, and pelvic organ prolapse. However, its association with rectal evacuatory dysfunction (RED) has not been evaluated. To investigate the prevalence of JHM in the general population and in patients with symptoms of RED referred for anorectal physiological investigation.

Chronic arthritis associated with the presence of intrasynovial rubella virus.

In this report we present 21 instances in which live rubella virus was isolated from synovial fluid obtained from 6 cases of inflammatory oligoarthritis or polyarthritis over a period of 2 years in the absence of firm clinical evidence of rubella. In 3 cases (cases 1, 2, 6,) a persistent oligoarthritis predominantly affecting the knee joints occurred in 2 adult women and one man, lasting to date 27, 29, and 18 months respectively, and in one of these cases virions were found in cells of the synovial membrane. In case 3 a boy of 9 presented with an illness indistinguishable from the systemic variety of juvenile chronic arthritis (Stills disease). In case 4 a young man with persistent monoarthritis was found to have ankylosing spondylitis, and in case 5 a progressive erosive polyarthritis developed 5 years after an attack of rubella complicated by rubella arthritis. The virus was identified by a variety of virological techniques and infection confirmed by immunofluorescence and (in one case) electron microscopy.