Re‐writing the natural history of pain and related symptoms in the joint hypermobility syndrome/Ehlers–Danlos syndrome, hypermobility type
Abstract
Joint hypermobility syndrome (JHS) and Ehlers-Danlos syndrome, hypermobility type (EDS-HT) are two clinically overlapping connective tissue disorders characterized by chronic/recurrent pain, joint instability complications, and minor skin changes. Fatigue and headache are also common, although are not yet considered diagnostic criteria. JHS/EDS-HT is a unexpectedly common condition that remains underdiagnosed by most clinicians and pain specialists. This results in interventions limited to symptomatic and non-satisfactory treatments, lacking reasonable pathophysiologic rationale. In this manuscript the fragmented knowledge on pain, fatigue, and headache in JHS/EDS is presented with review of the available published information and a description of the clinical course by symptoms, on the basis of authors' experience. Pathogenic mechanisms are suggested through comparisons with other functional somatic syndromes (e.g., chronic fatigue syndrome, fibromyalgia, and functional gastrointestinal disorders). The re-writing of the natural history of JHS/EDS-HT is aimed to raise awareness among clinical geneticists and specialists treating chronic pain conditions about pain and other complications of JHS/EDS-HT. Symptoms' clustering by disease stage is proposed to investigate both the molecular causes and the symptoms management of JHS/EDS-HT in future studies.
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Biomechanical overloading and chronic soft tissue injury likely lead to soft tissue injury manifesting as localized joint arthralgias (nociceptive pain) and, in some, over time, diffuse musculoskeletal pain (central sensitization).
“This likely leads to soft tissue injury manifesting as localized joint arthralgias (nociceptive pain) and in some, over time, diffuse musculoskeletal pain (central sensitization).[2,8,24,25]”
From Hypermobility spectrum disorders: A review (2023) · cites this paper as [24]
Three possible phases of disease progression in JHS/hEDS were proposed: hypermobility, pain, and stiffness.
“At that time, three possible different phases of disease progression were proposed: hypermobility (first phase), pain (second phase) and stiffness (third phase).”
From Severity classes in adults with hypermobile Ehlers–Danlos syndrome/hypermobility spectrum disorders: a pilot study of 105 Italian patients (2019) · cites this paper as [24]
Heterogeneity in disease expression in JHS/hEDS was proposed by our group years ago.
“Heterogeneity in terms of disease expression was put forward years ago by our group, when we approached the natural history of what was previously called JHS/hEDS [23,24].”
From Severity classes in adults with hypermobile Ehlers–Danlos syndrome/hypermobility spectrum disorders: a pilot study of 105 Italian patients (2019) · cites this paper as [24]
Not all individuals with JHS/hEDS have a disease course that invariably progresses to the pain and stiffness phases.
“Although the first phase is observed in or self-described by most patients, not all individuals seem to have a disease course invariably progressing to the pain and stiffness phases.”
From Severity classes in adults with hypermobile Ehlers–Danlos syndrome/hypermobility spectrum disorders: a pilot study of 105 Italian patients (2019) · cites this paper as [24]
Fibronectin and possibly other ECM fragments might act as DAMPs in hEDS and HSD cells, likely contributing to an in vitro inflammation-like phenotype that could relate to chronic pain.
“Fragments of FN and possibly of other ECM proteins might act as DAMPs in hEDS and HSD cells, likely contributing to the generation of the in vitro inflammation-like phenotype, which could be related to the chronic pain observed in hEDS and HSD patients [49].”
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References 108 · Cited by 159
- Authors
- Castori, M., Morlino, S., Celletti, C., Ghibellini, G., Bruschini, M., Grammatico, P., Blundo, C., & Camerota, F.
- Affiliations
- Azienda Ospedaliera San Camillo-Forlanini (IT)
- Policlinico Umberto I (IT)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Castori, Marco
- Venue
- American Journal of Medical Genetics Part A
- Publisher
- Wiley
- Published
- 2013-11-06
- Volume
- 161
- Issue
- 12
- Pages
- 2989-3004
- ISSN
- 1552-4825 (ISSN-L)
- 1552-4833
- OpenAlex
- W2064116071
- Cited by
- 159
- References
- 108
- Citations by year
- 2026: 3 · 2025: 13 · 2024: 10 · 2023: 15 · 2022: 19 · 2021: 12 · 2020: 14 · 2019: 13 · 2018: 12 · 2017: 9 · 2016: 14 · 2015: 15 · 2014: 9 · 2013: 1
- FWCI
- 1.60
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Medical Genetics Part A (publishedVersion)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Health Sciences › Medicine › Psychiatry and Mental health › Fibromyalgia and Chronic Fatigue Syndrome Research
- Health Sciences › Medicine › Pharmacology › Musculoskeletal pain and rehabilitation
- Keywords
- joint hypermobility syndrome, Ehlers-Danlos syndrome hypermobility type, chronic pain, fatigue, headache, natural history (disease), connective tissue diseases, functional somatic syndromes, fibromyalgia, chronic fatigue syndrome, functional gastrointestinal disorders, symptom clustering, disease stage, underdiagnosis
- MeSH terms
- Ehlers-Danlos Syndrome, Fatigue, Headache, Humans, Joint Instability, Pain
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