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Ehlers-Danlos Syndromes: Classification and the Hypermobility Spectrum
Introduction
The Ehlers-Danlos syndromes (EDS) are a clinically and genetically heterogeneous group of heritable connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. The 2017 international classification recognizes 13 subtypes, each with distinct clinical criteria and, with one exception, defined molecular bases.
The 2017 International Classification
Major Subtypes
Classical EDS (cEDS) features skin hyperextensibility, atrophic scarring, and generalized joint hypermobility, caused by variants in COL5A1, COL5A2, or rarely COL1A1. Classical-like EDS (clEDS) presents with skin hyperextensibility and easy bruising with generalized joint hypermobility, caused by biallelic TNXB variants following autosomal recessive inheritance. Vascular EDS (vEDS) is the most life-threatening subtype, characterized by arterial, intestinal, and uterine fragility with thin translucent skin, caused by COL3A1 or rarely COL1A1 variants. Hypermobile EDS (hEDS) features generalized joint hypermobility with musculoskeletal complications and is the only subtype without a known molecular basis. Kyphoscoliotic EDS (kEDS) presents with severe muscle hypotonia at birth and progressive scoliosis, caused by PLOD1 or FKBP14 variants. Arthrochalasia EDS (aEDS) features bilateral congenital hip dislocation and severe joint hypermobility, caused by COL1A1 or COL1A2 variants affecting the N-propeptide cleavage site.
Rarer Subtypes
Dermatosparaxis EDS (dEDS) involves extreme skin fragility from ADAMTS2 variants. Cardiac-valvular EDS (cvEDS) causes severe progressive cardiac valvular disease from biallelic COL1A2 variants leading to complete absence of pro-alpha2(I) collagen chains. Brittle cornea syndrome (BCS) involves thin cornea with risk of rupture from ZNF469 or PRDM5 variants. Spondylodysplastic EDS (spEDS) presents with short stature, muscle hypotonia, and skeletal dysplasia from B4GALT7, B3GALT6, or SLC39A13 variants. Musculocontractural EDS (mcEDS) features congenital contractures and craniofacial features from CHST14 or DSE variants. Myopathic EDS (mEDS) involves proximal muscle weakness and joint contractures from COL12A1 variants. Periodontal EDS (pEDS) causes severe early-onset periodontitis from C1R or C1S variants.
| EDS Subtype | Gene(s) | Inheritance | Key Features | Major Complications |
|---|---|---|---|---|
| Classical (cEDS) | COL5A1, COL5A2 | AD | Skin hyperextensibility, atrophic scarring | Wound dehiscence; joint instability |
| Vascular (vEDS) | COL3A1 | AD | Thin translucent skin, arterial/bowel fragility | Arterial rupture; bowel perforation; median lifespan 51 years |
| Hypermobile (hEDS) | Unknown | AD | Joint hypermobility, chronic pain | Disability; POTS; no vascular rupture |
| Kyphoscoliotic (kEDS) | PLOD1, FKBP14 | AR | Neonatal hypotonia, severe kyphoscoliosis | Respiratory failure; ocular fragility |
| Arthrochalasia (aEDS) | COL1A1, COL1A2 | AD | Bilateral congenital hip dislocation | Severe joint hypermobility |
| Classical-like (clEDS) | TNXB | AR | Skin hyperextensibility, easy bruising | Joint hypermobility |
| Cardiac-valvular (cvEDS) | COL1A2 | AR | Progressive valvular disease | Heart failure; valve replacement needed |
| Dermatosparaxis (dEDS) | ADAMTS2 | AR | Extreme skin fragility, sagging redundant skin | Skin tears; bruising |
| Periodontal (pEDS) | C1R, C1S | AD | Severe early-onset periodontitis | Tooth loss; gingival fragility |
Hypermobile EDS and the Hypermobility Spectrum
Diagnostic Criteria for hEDS (2017)
The diagnosis requires meeting all three criteria. Criterion 1 requires generalized joint hypermobility assessed by the Beighton score, with age-specific cutoffs (6 or greater for prepubertal children, 5 or greater for pubertal age to 50, and 4 or greater for those over 50). Criterion 2 requires two or more of three features: Feature A includes systemic manifestations of a generalized connective tissue disorder (5 or more of 12 specified items); Feature B is a positive family history meeting criteria for hEDS; and Feature C encompasses musculoskeletal complications including chronic pain and recurrent dislocations or instability. Criterion 3 requires exclusion of alternative diagnoses including other EDS subtypes, other heritable connective tissue disorders, and autoimmune conditions.
Hypermobility Spectrum Disorders (HSD)
Patients with symptomatic joint hypermobility who do not meet full hEDS criteria are classified within the hypermobility spectrum disorders. Subtypes include generalized HSD (G-HSD), localized HSD, peripheral HSD, and historical HSD. Clinical management is essentially identical to hEDS. HSD should not be considered a lesser diagnosis, as morbidity can be equivalent.
Vascular EDS: A Critical Subtype
Vascular EDS carries a median life expectancy of 51 years without intervention. Major complications include arterial dissection or rupture, bowel perforation, and uterine rupture during pregnancy. Celiprolol has demonstrated reduced arterial events in a randomized trial. Pregnancy carries significant maternal risk (up to 12% maternal mortality per pregnancy in older literature). Minimally invasive diagnostic approaches are preferred, and elective surgery should be avoided when possible. Screening for vascular complications via CT angiography or MR angiography from head to pelvis at baseline is recommended.
Genetic Testing Strategy
Targeted gene panel or single-gene testing is appropriate when a specific subtype is clinically suspected. Collagen biochemistry from dermal fibroblast culture is considered for suspected cEDS or vEDS when molecular testing is inconclusive. For suspected hEDS, genetic testing is performed primarily to exclude other subtypes since no causative gene has yet been identified. MLPA or exon-level CNV analysis for TNXB is important due to pseudogene complications.
Multidisciplinary Management
Physical therapy is the cornerstone of management, focusing on joint stabilization, proprioceptive training, and graded exercise. Pain management requires a multimodal approach with caution regarding opioids; low-dose naltrexone and TENS are considered. Cardiovascular monitoring includes echocardiography for valvular assessment and vascular imaging for vEDS. Orthopedic care involves joint stabilization procedures with awareness of tissue healing challenges. Psychological support is essential given the high prevalence of anxiety, depression, and functional impairment. Autonomic dysfunction, particularly postural orthostatic tachycardia syndrome (POTS), should be screened for as a common comorbidity. GI management addresses functional GI disorders, gastroparesis, and mast cell activation considerations.
Clinical Pearls
Vascular EDS requires a high index of suspicion; family history of early death from arterial rupture or unexplained bowel perforation should prompt COL3A1 testing. hEDS remains a clinical diagnosis, and a negative genetic panel does not exclude it but should prompt consideration of alternative diagnoses. The Beighton score alone is insufficient for diagnosis and must be contextualized with age, symptom burden, and exclusion criteria. Hypermobility Spectrum Disorders deserve the same clinical attention and multidisciplinary management as hEDS.
References
- Malfait F, Francomano C, Byers P, et al. The 2017 international classification of the Ehlers-Danlos syndromes. American Journal of Medical Genetics Part C. 2017;175(1):8-26.
- Castori M, Tinkle B, Levy H, et al. A framework for the classification of joint hypermobility and related conditions. American Journal of Medical Genetics Part C. 2017;175(1):148-157.
- Byers PH, Belmont J, Black J, et al. Diagnosis, natural history, and management in vascular Ehlers-Danlos syndrome. American Journal of Medical Genetics Part C. 2017;175(1):40-47.
- Ong KT, Perdu J, De Backer J, et al. Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial. Lancet. 2010;376(9751):1476-1484.