Placing joint hypermobility in context: traits, disorders and syndromes

Abstract

Background: Joint hypermobility (JHM) is a common physical trait. It may occur alone or in combination with musculoskeletal (MSK) pain, outside or within more complex phenotypes. Hypermobility spectrum disorders (HSD) are diagnosed in individuals with JHM and related MSK pain, when an alternative diagnosis cannot be identified. Conversely, the Ehlers-Danlos syndrome (EDS) encompasses a group of rare hereditary connective tissue disorders featuring JHM along with other pleiotropic manifestations. The 2017 EDS Classification identifies 13 different subtypes. Hypermobile EDS (HEDS) is the only EDS variant still lacking a confirmatory test.

Sources of data: Literature was reviewed searching for the most relevant papers related to key arguments. Particular attention was focused on papers published after the 2017 Classification.

Areas of agreement: Definition, epidemiology, assessment tools and patterns of JHM are presented. The morbid nature of the 2017 EDS Classification and of the 'spectrum' is also illustrated.

Areas of controversy: We discuss current limitations and disagreements concerning the 'spectrum', HSD and HEDS.

Growing points: In the clinical context, elucidation of the pathophysiology of pain related to JHM should develop in parallel with the analysis of pleiotropic manifestations of syndromes with JHM.

Areas timely for developing research: Future challenges concerning classification, nosology, diagnosis and management of JHM, EDS and related disorders are discussed.

Keywords: Beighton score; Ehlers-Danlos syndrome; hypermobility spectrum disorders; international classification; joint hypermobility.

Fig. 1

(A) Prevalence of joint hypermobility worldwide. An overview of the prevalence of joint hypermobility in various populations and countries. (B) BS. When possible, the ROM should be measured with an orthopedic goniometer. Adapted from: https://www.ehlers-danlos.com/. The cut-off for generalized joint hypermobility is 5 and 6 for adults and children, respectively (ref. no. 18). (C) Decision tree for individuals with joint hypermobility within the ‘spectrum’. ^*Historical joint hypermobility/HSD needs a positive 5PQ. ^**In children, the BS cut-off for generalized joint hypermobility is increased by 1 (= 6). 5PQ, five-point questionnaire. BS, Beighton score. GJH, generalized joint hypermobility. G-HSD, generalized hypermobility spectrum disorder. hEDS, hypermobile Ehlers-Danlos syndrome. HJH, historical joint hypermobility. H-HSD, historical hypermobility spectrum disorder. LJH, localized joint hypermobility. L-HSD, localized hypermobility spectrum disorder. PJH, peripheral joint hypermobility. P-HSD, peripheral hypermobility spectrum disorder.

Fig. 2

(A) Conceptualization of ‘the Spectrum’ and progression into the 2017 Classification of EDS and Related Disorders. ‘The Spectrum’ is a theoretical concept incorporating all phenotypes of JHM related to its association with MSK features and outside the pleiotropic nature of monogenic syndromes. On one end, there are the various forms of non-syndromic, asymptomatic JHM (ns/aJHM). On the other end, they progressively intermingle with symptomatic and more complex, though still molecularly undefined, phenotypes, whose extreme is represented by the hEDS. In the clinical context, the presence of JHM-related MSK symptoms, mainly pain, separates ns/aJHM from the HSD. At the same time, the 2017 criteria for hEDS distinguish the latter from HSD. hEDS is the only EDS type that remains without known molecular basis. Therefore, its diagnosis is established exclusively by the application of clinical criteria. Conversely, the diagnosis of all other EDS types needs confimation by positive molecular testing or, in selected cases only, alternative investigations. (B) Epidemiological overview of key terms in the field of JHM and EDS. In the blue triangle, MSK pain, JHM and EDS are identified as separate entities which may coexist in specific clinical scenarios. The combination of MSK pain and JHM more commonly occurs in the context of HSD. This circumstance should be distinguished from MSK pain which independently occurs in combination with JHM (see ‘C’), as well as from EDS and, in particular, hEDS which commonly features both MSK pain and JHM. The percentages indicate trait/condition frequencies in the general population. ^***Value presumed in the absence of any robust epidemiological study according to the current view in the field of JHM and EDS. (C) phenotypical relationships between MSK pain and JHM. MSK pain may present in combination with various degrees/forms of JHM. Nevertheless, observing MSK pain and JHM in the same individual does not always imply a causal relationship. Therefore, JHM-related MSK pain should be distinguished from the chance co-occurrence of MSK pain and JHM. Among the clinical forms of JHM-related MSK pain, HSD is currently recognized as the commonest one. More rarely, JHM-related MSK pain is observed in the context of genetic syndromes, among which EDS and, in particular, hEDS are the most frequent diagnoses.

Fig. 3

Simplified representation of the pathogenetic processes leading from JHM to a repetitive cycle causing chronic MSK pain and worsening disability in JHM-related MSK pain.