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Hypermobility Syndrome (Joint Hypermobility Syndrome)

Hyperflexible joints are common and do not necessarily indicate that an individual has a Tensile Hereditary Connective Tissue Disease. Joint hypermobility decreases with age. Some studies suggest that 10% to 25% of the population may have hyperflexible joints and that 5% of individuals with hypermobility have symptoms. Symptoms caused by increased joint mobility can range from arthralgias to dislocation or injury. Individuals with severe hypermobility and recurrent dislocations may have Ehlers–Danlos syndrome (EDS).

The Beighton score for joint laxity and hypermobility uses a simple 9-point system. A score of 5 or more indicates hypermobility:

  1. Knee extension more than 10 degrees past 180 degrees: 1 point for each knee

  2. Extension of the elbow 10 degrees or more past 180 degrees: 1 point for each elbow

  3. Extension of the thumb to touch the flexor aspect of the forearm: 1 point for each thumb.

  4. Extension of the little (5th) fingers backward so that they are beyond parallel (over 90°) with the posterior forearm: 1 point for each little finger

  5. Forward trunk flexion (knees fully extended) so that the palms of the hands can be placed flat on the ground: 1 point

Brighton diagnostic criteria for benign joint hypermobility syndrome (BJHS):

Major criteria

  1. Beighton score of 4/9 or higher (see Question 5)

  2. Arthralgia for longer than 3 months in four or more joints

Minor criteria

  1. Beighton score of 1, 2, or 3/9

  2. Arthralgia (≥3 months) in one to three joints or back pain (≥3 months), spondylosis, spondylolysis/spondylolisthesis

  3. Dislocation/subluxation in more than one joint, or in one joint on more than one occasion

  4. Three or more soft-tissue lesions (epicondylitis, tenosynovitis, bursitis)

  5. Marfanoid habitus

  6. Abnormal skin: striae, hyperextensibility, thin, papyraceous scarring

  7. Eye signs: drooping eyelids, myopia, or antimongoloid slant

  8. Varicose veins or hernia or uterine/rectal prolaps

Classical EDS cEDS AD Major: COL5A1, COL5A1, Rare: COL1A1 c.934C>T, p.(Arg312Cys) Type V collagen, Type I collagen Major criteria 1. Skin hyperextensibility and atrophic scarring 2. Generalized joint hypermobility (GJH) Minor criteria 1. Easy bruising 2. Soft, doughy skin 3. Skin fragility (or traumatic splitting). Molluscoid pseudotumors 5. Subcutaneous spheroids 6. Hernia (or history thereof) 7. Epicanthal folds 8. Complications of joint hypermobility (e.g., sprains, luxation/ subluxation, pain, flexible flatfoot). Family history of a first degree relative who meets clinical criteria Minimal criteria suggestive for cEDS: Major criterion (1): skin hyperextensibility and atrophic scarring Plus Either major criterion GJH And/or: at least three minor criteria Confirmatory molecular testing is obligatory to reach a final diagnosis.
Classical-like EDS clEDS AR TNXB Tenascin XB Major criteria Skin hyperextensibility, with velvety skin texture and absence of atrophic scarring GJH9 with or without recurrent dislocations (most commonly shoulder and ankle) Easy bruisable skin/spontaneous ecchymoses Minor criteria Foot deformities: broad/plumpfore- foot, brachydactyly with excessive skin; pes planus; hallux valgus; piezogenic papules Edema in the legs in absence of cardiac failure Mild proximal and distal muscle weakness Axonal polyneuropathy Atrophy of muscles in hands and feet Acrogeric hands, mallet finger(s), clinodactyly, brachydactyly Vaginal/uterus/rectal prolapse Minimal criteria suggestive for clEDS: All major criteria AND a family history compatible with autosomal recessive transmission.
Cardiac-valvular cvEDS AR COL1A2 (biallelic mutations that lead to COL1A2 - NMD and absence of pro a2(I) collagen chains) Type I collagen Major criteria 1. Severe progressive cardiac-valvular problems (aortic valve, mitral valve) 2. Skin involvement: skin hyperextensibility, atrophic scars, thin skin, easy bruising 3. Joint hypermobility (generalized or restricted to small joints) Minor criteria 1. Inguinal hernia 2. Pectus deformity (especially excavatum) 3. Joint dislocations 4. Foot deformities: pes planus, pes planovalgus, hallux valgus Minimal criteria suggestive for cvEDS: Major Criterion (1): severe progressive cardiac-valvular problems AND a family history compatible with autosomal recessive inheritance Plus Either: one other major criterion And/or: at least two minor criteria Confirmatory molecular testing is obligatory to reach a final diagnosis.
Vascular EDS vEDS AD Major: COL3A1, Rare: COL1A1 c.934C>T, p.(Arg312Cys) c.1720C>T, p.(Arg574Cys) c.3227C>T, p.(Arg1093Cys) Type III collagen, Type I collagen Major criteria Family history of vEDS with documented causative variant in COL3A1 Arterial rupture at a young age Spontaneous sigmoid colon perforation in the absence of known diverticular disease or other bowel pathology Uterine rupture during the third trimester in the absence of previous C-section and/or severe peripartum perineum tears Carotid-cavernous sinus fistula (CCSF) formation in the absence of trauma Minor criteria Bruising unrelated to identified trauma and/or in unusual sites such as cheeks and back Thin, translucent skin with increased venous visibility Characteristic facial appearance Spontaneous pneumothorax Acrogeria Talipes equinovarus Congenital hip dislocation Hypermobility of small joints Tendon and muscle rupture Keratoconus Gingival recession and gingival fragility Early onset varicose veins (under age 30 and nulliparous if female) Minimal criteria suggestive for vEDS: A family history of the disorder, arterial rupture or dissection in individuals less than 40 years of age, unexplained sigmoid colon rupture, or spontaneous pneumothorax in the presence of other features consistent with vEDS should all lead to diagnostic studies to determine if the individual has vEDS. Testing for vEDS should also be considered in the presence of a combination of the other “minor” clinical features listed above.
Hypermobile EDS hEDS AD Unknown Unknown The clinical diagnosis of hEDS needs the simultaneous presence of criteria 1 AND 2 AND 3. Criterion 1: Generalized Joint Hypermobility (GJH) Criterion 2: Two or More Among the Following Features (A–C) MUST Be Present (for Example: A and B; A and C; B and C; A and B and C) Feature A 1. Unusually soft or velvety skin 2. Mild skin hyperextensibility 3. Unexplained striae such as striae distensae or rubrae at the back, groins, thighs, breasts and/or abdomen in adolescents, men or prepubertal women without a history of significant gain or loss of body fat or weight 4. Bilateral piezogenic papules of the heel 5. Recurrent or multiple abdominal hernia(s) (e.g., umbilical, inguinal, crural) 6. Atrophic scarring involving at least two sites and without the formation of truly papyraceous and/or hemosideric scars as seen in classical EDS 7. Pelvic floor, rectal, and/or uterine prolapse in children, men or nullipa- rous women without a history of morbid obesity or other known pre- disposing medical condition 8. Dental crowding and high or narrow palate 9. Arachnodactyly, as defined in one or more of the following: (i) positive wrist sign (Steinberg sign) on both sides; (ii) positive thumb sign (Walker sign) on both sides 10. Arm span-to-height >1.05 11. Mitral valve prolapses (MVP) mild or greater based on strict echocardio- graphic criteria 12. Aortic root dilatation with Z-score >+2 Feature B: positive family history Feature C: musculoskeletal complications (must have at least one): Musculoskeletal pain in two or more limbs, recurring daily for at least 3 months Chronic, widespread pain for >3 months Recurrent joint dislocations or frank joint instability, in the absence of trauma (a or b) Three or more atraumatic dislocations in the same joint or two or more atraumatic dislocations in two different joints occurring at different times Medical confirmation of joint instability at two or more sites not related to trauma Criterion 3: All the Following Prerequisites MUST Be Met 1. Absence of unusual skin fragility, which should prompt consideration of other types of EDS 2. Exclusion of other heritable and acquired connective tissue disorders, including autoimmune rheumatologic conditions. In patients with an acquired connective tissue disorder (e.g., lupus, rheumatoid arthritis, etc.), additional diagnosis of hEDS requires meeting both Features A and B of Criterion 2. Feature C of Criterion 2 (chronic pain and/or insta- bility) cannot be counted towards a diagnosis of hEDS in this situation. 3. Exclusion of alternative diagnoses that may also include joint hypermobility by means of hypotonia and/or connec- tive tissue laxity. Alternative diagnoses and diagnostic categories include, but are not limited to, neuromuscular disorders (e.g., myopathic EDS, Bethlem myopathy), other HCTD (e.g., other types of EDS, Loeys–Dietz syndrome, Marfan syndrome), and skeletal dysplasias (e.g., OI). Exclusion of these considerations may be based upon history, physical examination, and/or molecular genetic testing, as indicated.
Arthrochalasia EDS aEDS AD COL1A1, COL1A2 Type I collagen Major criteria 1. Congenital bilateral hip dislocation 2. Severe GJH, with multiple disloca- tions/subluxations 3. Skin hyperextensibility Minor criteria 1. Muscle hypotonia 2. Kyphoscoliosis 3. Radiologically mild osteopenia 4. Tissue fragility, including atrophic scars 5. Easy bruisable skin Minimal criteria suggestive for aEDS: Major criterion : Congenital bilateral hip dislocation Plus Either major criterion: skin hyperextensibility Or major criterion: severe GJH with multiple dislocations/subluxations and at least two other minor criteria Confirmatory molecular testing is obligatory to reach a final diagnosis
Dermatosparaxis EDS dEDS AR ADAMTS2 ADAMTS-2 Major criteria: Extreme skin fragility with congenital or postnatal skin tears Characteristic craniofacial features, which are evident at birth or early infancy, or evolve later in childhood Redundant, almost lax skin, with excessive skin folds at the wrists and ankles Increased palmar wrinkling Severe bruisability with a risk of subcutaneous hematomas and haemorrhage Umbilical hernia Postnatal growth retardation Short limbs, hand and feet Perinatal complications due to connective tissue fragility Minor criteria Soft and doughy skin texture Skin hyperextensibility Atrophic scars GJH Complications of visceral fragility (e.g., bladder rupture, diaphragmatic rupture, rectal prolapse) Delayed motor development2 Osteopenia Hirsutism Tooth abnormalities Refractive errors (myopia, hypermetropia) Strabismus Minimal criteria suggestive for dEDS: Major criterion: extreme skin fragility – AND major criterion: characteristic craniofacial features Plus Either: one other major criterion And/or: three minor criteria Confirmatory molecular testing is obligatory to reach a final diagnosis.
Kyphoscoliotic EDS kEDS AR PLOD1, FKBP14 LH1 FKBP22 Major criteria 1. Congenital muscle hypotonia 2. Congenital or early onset kyphoscoliosis (progressive or nonprogressive) 3. GJH with dislocations/subluxations (shoulders, hips, and knees in particular) Minor criteria: 1. Skin hyperextensibility 2. Easy bruisable skin 3. Rupture/aneurysm of a mediumsized artery 4. Osteopenia/osteoporosis 5. Blue sclerae 6. Hernia (umbilical or inguinal) 7. Pectus deformity 8. Marfanoid habitus 9. Talipes equinovarus 10. Refractive errors (myopia, hypermetropia) Gene-specific minor criteria 1. PLOD1 1. Skin fragility (easy bruising, friable skin, poor wound healing, widened atrophic scarring) 2 Scleral and ocular fragility/ rupture 3. Microcornea 4. Facial dysmorphology 2. FKBP14 Congenital hearing impairment (sensorineural, conductive, or mixed) Follicular hyperkeratosis Muscle atrophy Bladder diverticula Minimal criteria suggestive for kEDS: – Major criterion (1): congenital muscle hypotonia– AND major criterion (2): congenital or early-onset kyphoscoliosis Plus – Either major criterion (3): GJH– And/or three minor criteria (either general or gene-specific criteria) Confirmatory molecular testing is obligatory to reach a final diagnosis.
Brittle Cornea syndrome BCS AR ZNF469 PRDM5 ZNF469 PRDM5 Major criteria Thin cornea, with or without rupture (central corneal thickness often<400 mm) Early onset progressive keratoconus Early onset progressive keratoglobus Blue sclerae Minor criteria Enucleation or corneal scarring as a result of previous rupture Progressive loss of corneal stromal depth, especially in central cornea High myopia, with normal or moderately increased axial length Retinal detachment Deafness, often with mixed conductive and sensorineural components, progressive, higher frequencies of- ten more severely affected (“slop- ing” pure tone audiogram), Hypercompliant tympanic membranes Developmental dysplasia of the hip Hypotonia in infancy, usually mild if present Scoliosis Arachnodactyly Hypermobility of distal joints Pes planus, hallux valgus Mild contractures of fingers (espe- cially 5th) Soft, velvety skin, translucent skin • Minimal criteria suggestive for kEDS: – Major criterion (1): thin cornea, with or without rupture (central corneal thickness often <100 micrometer)– Either: at least one other major criterion– And/or three other minor criteria Confirmatory molecular testing is obligatory to reach a final diagnosis
Spondylodysplastic EDS spEDS AR B4GALT7 B3GALT6 SLC39A13 b4GalT7 b3GalT6 ZIP13 Major criteria Short stature (progressive in childhood) Muscle hypotonia (ranging from severe congenital, to mild later- onset) Bowing of limbs Minor criteria Skin hyperextensibility soft, doughy skin, thin translucent skin Pes planus Delayed motor development Osteopenia Delayed cognitive development Gene-specific minor criteria B4GALT7 – Radioulnar synostosis – Bilateral elbow contractures or limited elbow movement – GJH – Single transverse palmar crease – Characteristic craniofacial features – Characteristic radiographic findings – Severe hypermetropia – Clouded cornea B3GALT6 – Kyphoscoliosis (congenital or early onset, progressive) – Joint hypermobility, generalized or restricted to distal joints, with joint dislocations – Joint contractures (congenital or progressive) (especially hands) – Peculiar fingers (slender, tapered, arachnodactyly, spatulate, with broad distal phalanges) – Talipes equinovarus – Characteristic craniofacial features – Tooth teeth discoloration, dysplastic Characteristic radiographic findings – Osteoporosis with multiple spon- taneous fractures – Ascending aortic aneurysm – Lung hypoplasia, restrictive lung disease SLC39A13: – Protuberant eyes with bluish sclerae – Hands with finely wrinkled palms – Atrophy of the thenar muscles, and tapering fingers – Hypermobility of distal joints – Characteristic radiologic findings Minimal criteria suggestive for spEDS: – Major criterion (1): short stature – AND major criterion (2): muscle hypotonia Plus – Characteristic radiographic abnormalities and at least three other minor criteria (general or type-specific) Confirmatory molecular testing is obligatory to reach a final diagnosis
Musculocontractural EDS mcEDS AR CHST14 DSE D4ST1 DSE Major criteria 1. Congenital multiple contractures, characteristically adduction-flexion contractures and/or talipes equino- varus (clubfoot) 2. Characteristic craniofacial features, which are evident at birth or in early infancy 3. Characteristic cutaneous features in- cluding skin hyperextensibility, easy bruisability, skin fragility with atrophic scars, increased palmar wrinkling Minor criteria 1. Recurrent/chronic dislocations 2. Pectus deformities (flat, excavated) 3. Spinal deformities (scoliosis, kyphoscoliosis) 4. Peculiar fingers (tapering, slender, cylindrical) 5. Progressive talipes deformities (val- gus, planus, cavum) 6. Large subcutaneous hematomas 7. Chronic constipation 8. Colonic diverticula 9. Pneumothorax/ pneumohemothorax 10. Nephrolithiasis/cystolithiasis 11. Hydronephrosis 12. Cryptorchidism in males 13. Strabismus 14. Refractive errors (myopia, astigmatism) 15. Glaucoma/elevated intraocular pressure Minimal criteria suggestive for mcEDS: • – At birth or in early childhood: Major criterion (1): Congenital multiple contractures AND (2) characteristic craniofacial features • – In adolescence and in adulthood: Major criterion (1): Congenital mul- tiple contractures AND (3) charac- teristic cutaneous features Confirmatory molecular testing is obligatory to reach a final diagnosis.
Myopathic EDS mEDS AD or AR COL12A1 Type XII collagen Major criteria 1. Congenital muscle hypotonia, and/ or muscle atrophy, that improves with age 2. Proximal joint contractures (knee, hip, and elbow) 3. Hypermobility of distal joints Minor criteria 1. Soft, doughy skin 2. Atrophic scarring 3. Motor developmental delay 4. Myopathy on muscle biopsy Minimal clinical criteria suggestive for mEDS: – Major criterion (1): congenital muscle hypotonia that improves with age Plus – Either: one other major criterion – And/or: three minor criteria Confirmatory molecular testing is obligatory to reach a final diagnosis.
Periodontal EDS pEDS AD C1R C1S C1r C1s • Major criteria • – Severe and intractable periodontitis of early onset (childhood or adolescence) • – Lack of attached gingiva • – Pretibial plaques • – Family history of a first-degree relative who meets clinical criteria • Minor criteria • – Easy bruising • – Joint hypermobility, mostly distal joints • – Skin hyperextensibility and fragility, abnormal scarring (wide or atrophic) • – Increased rate of infections • – Hernias • – Marfanoid facial features • – Acrogeria • – Prominent vasculature • Minimal criteria suggestive for pEDS: • – Major criterion (1): severe and intractable periodontitis of early onset (childhood or adolescence) • – OR major criterion (2): lack of attached gingiva Plus – At least two other major criteria and one minor criterion Confirmatory molecular testing is obligatory to reach a final diagnosis.
Clinical EDS subtype Abbreviation inheritance pattern Genetic basis Protein
AD, autosomal dominant
AR, autosomal recessive



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