| Hypermobile EDS (hEDS) | The hypermobile type of EDS is an autosomal-dominant disorder that presents with phenotypic variability. Common signs and symptoms include joint hypermobility, affecting large and small joints; soft, smooth skin that may be slightly elastic, with easy bruising and unexplained striae; piezogenic papules of the heel; chronic musculoskeletal pain (as differentiated from acute due to injury); early-onset osteoarthritis; osteopenia; gastrointestinal issues (dysmotility, bloating, nausea, vomiting, heartburn, constipation); migraine headaches; dysfunction of the nervous system, including pain and postural orthostatic tachycardia syndrome. Rapid labor and delivery, psychological dysfunction, and psychosocial impairments are common. |
- 1.
Generalized joint hypermobility - 2.
Evidence of syndrome features, musculoskeletal complications, and/ or family history - 3.
Exclusion of alternative diagnoses
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| Classical EDS | The classical type of EDS is an autosomal-dominant connective tissue disorder associated with skin hyperextensibility, articular hypermobility, and tissue fragility with peculiar “cigarette-paper” scars. Clinical findings include mild short stature; narrow maxilla; myopia; ectopia lentis; small, irregularly placed teeth; mitral valve prolapse; aortic root dilatation; inguinal or umbilical hernia; spontaneous bowel rupture; bowel diverticula; osteoarthritis; joint hypermobility and dislocations (hip, shoulder, elbow, knee, or clavicle); pes planus; fragile skin; cigarette-paper scars; dystrophic scarring; poor wound healing; molluscoid pseudotumors; skin hyperextensibility; hypotonia in infancy; muscle fatigue and cramps; and premature birth following premature rupture of fetal membranes. |
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| Classical-like EDS type 1 | Classical-like EDS type 1 is either an autosomal-recessive disorder due to mutations in the gene encoding TNXB or a contiguous gene-deletion syndrome that includes TNXB and CYP21A2. Characteristic findings include childhood onset, mitral valve prolapse and quadricuspid aortic valve (deletion syndrome), hiatal hernia and other gastrointestinal issues, urogenital anomalies in the deletion syndrome (ambiguous genitalia, bicornuate uterus, renal agenesis, urethral prolapse), joint hypermobility and subluxations, arthralgia, piezogenic papules and brachydactyly of the feet, leg edema, hyperextensible skin with no scarring, proximal muscle weakness and atrophy, and chronic fatigue. |
Diagnostic criteria Similar to classical form of EDS but lacks skin scarring and has autosomal-recessive inheritance Laboratory genetic (mutation) testing TNXB Contiguous deletion that includes TNXB and CYP21A2 Other laboratory findings Serum, absence of TNX Electromyogram with myopathic pattern Elevated serum 17-hydroxyproges-terone level (seen in patients with contiguous gene defect)
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| Classical-like EDS type 2 | Classical-like EDS type 2 is an autosomal-recessive disorder that falls in the EDS spectrum, associated with joint hypermobility, skin laxity, delayed wound healing, abnormal scarring, and aortic dilation. Clinical findings include joint laxity with dislocations, redundant and hyperextensible skin, poor wound healing with abnormal scarring, piezogenic papules, osteoporosis, micrognathia, ptosis, mitral valve prolapse and aortic dilation, bowel rupture, gut dysmotility, hernias, pes planus, and hallux valgus. |
Diagnostic criteria Similar to classical form of EDS but with autosomal-recessive inheritance Laboratory genetic (mutation) testing AE-Binding Protein 1 (AEBP1) Other laboratory findings Transmission electron microscopy of skin shows irregular disrupted collagen fibrils with moderate variation in collagen size
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| Cardiac-valvular EDS | The cardiac-valvular type of EDS is an ultrarare autosomal-recessive disorder characterized by generalized peripheral joint hypermobility, moderate to severe cardiac valvular disease (particularly the mitral valve), skin hyperextensibility, variable atrophic scarring, easy bruising, lower-eyelid ptosis, inguinal hernias, bilateral flatfeet with hindfoot pronation, genu recurvata, and hypoplasia of the interphalangeal creases. |
Diagnostic criteria Findings of EDS Suspected if patient presents with severe cardiovascular involvement that is progressive Laboratory genetic (mutation) testing Recessively inherited COL1A2 nonsense (null mutations)
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| Vascular EDS (vEDS) | The vascular form of EDS is an autosomal-dominant disorder defined by the major complications of arterial and bowel rupture, and uterine rupture during pregnancy. Clinical features include short stature; thin lips; lobeless ears; keratoconus; pinched-appearing, thin nose; periodontal disease and early loss of teeth; mitral valve prolapse; intracranial aneurysms; spontaneous pneumothorax and hemoptysis; inguinal hernias; spontaneous rupture of bowel; uterine rupture during pregnancy; uterine and bladder prolapse; joint laxity of the distal phalanges with acroosteolysis; hip dislocations; clubfeet; fragile skin with paper-thin scars and prominent vascular markings, poor wound healing, molluscoid pseudotumors and acrogeria; and scalp alopecia. Death often occurs before the fifth decade. |
Diagnostic criteria Suspected if patient, particularly younger than age 40, presents with one of the following: arterial aneurysms, dissection, or rupture; intestinal rupture; uterine rupture during pregnancy; family history of vEDS Laboratory genetic (mutation) testing COL3A1
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| Arthrochalasia EDS | The arthrochalasia type of EDS, formerly EDS type 7A and 7B, is an autosomal-dominant disorder that is distinguished from other types of EDS by the markedly increased frequency of congenital hip dislocation and extreme joint laxity with recurrent joint subluxations and minimal skin involvement. Clinical findings include mild to moderate short stature; midface hypoplasia; severe joint dislocations with recurrent joint subluxations; early-onset osteoarthritis; osteopenia with increased risk for fractures; kyphoscoliosis and scoliosis; congenital hip dislocations; thin, hyperextensible, atrophic scars; hypotonia with gross-motor developmental delay. |
Diagnostic criteria Severe joint hypermobility, congenital hip dislocation, facial dysmorphism, osteopenia, kyphoscoliosis Laboratory genetic (mutation) testing COL1A1 COL1A2
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| Dermatosparaxis EDS | Dermatosparaxis EDS is an autosomal-recessive disorder of connective tissue resulting from deficiency of procollagen peptidase. Characteristic findings include extreme skin fragility with congenital and postnatal skin tears, soft and doughy skin with hyperextensibility and atrophic scars, excessive skin at joints with increased palmar creases, and severe bruisability with risk for hematomas and hemorrhage. Facial findings include delayed closure of the anterior fontanel, blue sclera, epicanthal folds, blepharochalasis, prominent lips, hypodontia, and discolored teeth. Other findings include umbilical and inguinal hernias, short stature, joint laxity, osteopenia, delayed motor milestones, organ system abnormalities due to visceral fragility (diaphragmatic and bladder rupture, rectal prolapse), and prematurity. |
Diagnostic criteria Autosomal-recessive inheritance Minimal criteria for diagnosis include extreme skin fragility and characteristic facial findings Laboratory genetic (mutation) testing ADAMTS2 Other laboratory findings Collagen fibrils demonstrate hieroglyphic pattern
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| Kyphoscoliotic EDS type 1 | Kyphoscoliotic EDS type 1 is an autosomal-recessive disorder resultant from mutations in the gene PLOD1. Characteristic findings include marfanoid habitus, keratoconus, microcornea, myopia, retinal detachment, ocular rupture, glaucoma, blindness, tooth crowding, gastrointestinal hemorrhage, bladder prolapse, joint laxity with dislocations, osteoporosis, congenital scoliosis and progressive kyphosis, arachnodactyly, pes planus, talipes equinovarus, thin skin, moderate scarring, molluscoid pseudotumors, decreased fetal movements, and premature rupture of membranes. Risks include rupture of medium-size arteries, cardiac failure, decreased pulmonary function, recurrent pneumonias, and respiratory insufficiency secondary to chest deformity. |
Diagnostic criteria Autosomal-recessive inheritance Major criteria: Congenital muscular hypotonia (progressive or early-onset kyphoscoliosis) Generalized joint hypermobility with dislocations/subluxations (shoulders, hips, and knees in particular) Laboratory genetic (mutation) testing PLOD1 Other laboratory findings Increased ratio of deoxypyridinoline to pyridinoline crosslinks in urine measured by high-performance liquid chromatography
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| Kyphoscoliotic EDS type 2 | Kyphoscoliotic EDS type 2 is an autosomal-recessive disorder caused by mutations in the gene encoding FKBP14. Characteristic findings include hearing loss, myopia, occasional cleft palate, tricuspid valve insufficiency, aortic rupture and arterial dissection, subdural hygroma, insufficiency of cardiac valves, restrictive lung disease due to severe scoliosis, hernias, bladder diverticulum, progressive kyphoscoliosis, hypermobility of large and small joints, pes planus, equinovarus, hyperelastic skin, easy bruising, follicular hyperkeratosis, muscular atrophy, and myopathy. |
Diagnostic criteria Autosomal-recessive inheritance Major criteria: Congenital muscular hypotonia Congenital or early-onset kyphoscoliosis Generalized joint hypermobility Laboratory genetic (mutation) testing FKBP14 Other laboratory findings Normal pyridinoline excretion in urine Electromyography: myopathic pattern in adulthood
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| Brittle cornea syndrome type 1 | Brittle cornea syndrome type 1, one of the EDS, is an autosomal-recessive disorder due to mutations in the gene ZNF469. Characteristic findings include marfanoid habitus, macrocephaly, hearing loss, myopia, brittle cornea (extreme thinning of the cornea, with risk of tearing or rupture leading to blindness), keratoconus, keratoglobus, blue sclera, dentinogenesis imperfecta, mitral valve prolapse, joint laxity, hip dislocations and dysplasia, scoliosis, skin scarring, molluscoid pseudotumor, excessively wrinkled skin (particularly palms and soles), and red hair. |
Diagnostic criteria Corneal topography, anterior segment optical coherence tomography, corneal pachymetry Ocular manifestations with extraocular findings of deafness, developmental hip dysplasia, and joint hypermobility Laboratory genetic (mutation) testing ZFN469 Other laboratory findings Normal lysyl hydroxylase activity Normal dermal hydroxylysine content
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| Brittle cornea syndrome type 2 | Brittle cornea syndrome type 2, one of the EDS, is an autosomal-recessive disorder due to mutations in the gene PDRM5. Characteristic findings include hearing loss due to hypercompliant tympanic membranes, myopia, brittle cornea with corneal thinning and risk of rupture, blue sclera, keratoconus, megalocornea, sclerocornea, cornea plana, keratoglobus, hernias, small-joint hypermobility, increased fracture incidence, hip dysplasia, myalgias, skin hyperelasticity, and poor wound healing. |
Diagnostic criteria Corneal topography, anterior segment optical coherence tomography, corneal pachymetry Ocular manifestations with extraocular findings of deafness, developmental hip dysplasia, and joint hypermobility Laboratory genetic (mutation) testing PDRM5
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| Spondylodysplastic EDS 1 type | Spondylodysplastic EDS type 1 is an autosomal-recessive disorder caused by mutations in the B4GALT7 gene. Characteristic findings include dysmorphic features, sparse hair, blue sclera, occasional pectus excavatum, large-joint laxity, kyphoscoliosis, spatulate fingers, talipes equinovarus, hypotonia, hyperextensible skin, cutis laxa, mild developmental delay (occasional), and multiple radiographic abnormalities. |
Diagnostic criteria Progressive short stature Poor muscle tone Bowing of lower extremities Characteristic facial features Radiographic findings Laboratory genetic (mutation) testing B3GALT7 Other laboratory findings Galactosyltransferase I deficiency in fibroblasts
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| Spondylodysplastic EDS type 2 | Spondylodysplastic EDS type 2 is an autosomal-recessive disorder caused by mutations in the B3GALT6 gene. Characteristic findings include dysmorphic features, sparse hair, blue sclera, occasional pectus excavatum, large-joint laxity, kyphoscoliosis, spatulate fingers, talipes equinovarus, hypotonia, hyperextensible skin, cutis laxa, and multiple radiographic abnormalities. |
Diagnostic criteria Progressive short stature Poor muscle tone Bowing of lower extremities Characteristic facial features Radiographic findings Laboratory genetic (mutation) testing B3GALT6
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| Spondylodysplastic EDS type 3 | Spondylodysplastic EDS type 3 is an autosomal-recessive disorder caused by mutations in the zinc transporter gene SLC39A13. The disorder is characterized by moderate short stature; protuberant eyes; high-arched palate with bifid uvula; hypodontia; sparse hair; joint laxity; finger contractures; fine-wrinkled palms; hypothenar muscle atrophy; inability to adduct thumbs; short fingers; pes planus; thin, hyperelastic skin; abnormal scars with poor healing; delayed wound healing; muscle weakness; osteopenia; mild intellectual disability; and radiographic abnormalities. |
Diagnostic criteria Progressive short stature Poor muscle tone Bowing of lower extremities Characteristic facial features Radiographic findings Laboratory genetic (mutation) testing SLC39A13 Other laboratory findings Lysyl pyridinoline/hydroxylysyl pyridinoline (LP/HP) ratio approximately 1 (nl LP/HP: 0.2 + 0.03)
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| Musculocontractural EDS type 1 | Musculocontractural EDS type 1 is an autosomal-recessive disorder caused by mutations in the CHST14 gene. Characteristic findings include wasted body build; dysmorphic facies with prominent ears; hearing impairment; blue sclera; strabismus; myopia; glaucoma; microcornea; retinal detachment; anterior chamber abnormality; cleft palate; cardiac valvular anomalies; atrial septal defect; hemopneumothorax; pectus excavatum; hernias; constipation; duodenal obstruction; hydronephrosis; recurrent cystitis; congenital contractures that include adducted thumbs and distal arthrogryposis; joint laxity and dislocations; tendon abnormalities; scoliosis; progressive talipes valgus and planus; hyperextensible, fragile, transparent skin with atrophic scarring; delayed wound healing; hyperalgesia; recurrent subcutaneous infections; low muscle mass and gross motor delay; and developmental delay in some. |
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| Musculocontractural EDS type 2 | Musculocontractural EDS type 2 is an autosomal-recessive disorder caused by mutations in the DSE gene. Characteristic findings include hypotonic facies with prominent and abnormally shaped ears, hypertelorism, blue sclera, mitral valve prolapse and regurgitation, mixomatous degeneration of mitral valve, eventration of abdominal wall after surgery, hernia, uterine and bladder prolapse in females, arachnodactyly, camptodactyly, talipes equinovarus, delayed wound healing with atrophic scars, recurrent large subcutaneous hematomas, postecchymotic calcifications, generalized muscle weakness, pain, and occasional cerebral atrophy. |
Diagnostic criteria Clinical findings Laboratory genetic (mutation) testing DSE Other laboratory findings Adulthood, abnormal muscle fiber pattern in histology
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| Myopathic EDS | The myopathic type of EDS, also known as Bethlem myopathy-2, is an autosomal-dominant disorder due to mutations in the gene that encodes type XII collagen (COL12A1) and recessive mutations in the gene COL6A1. Characteristic findings include muscle weakness present in childhood that improves with age but is followed by some deterioration, distal hyperlaxity and flexion contractures, joint hypermobility, and hypertrophic scars. |
Diagnostic criteria Clinical findings Laboratory genetic (mutation) testing COL12A1 (autosomal-dominant) COL6A1 (autosomal-recessive) Other laboratory findings Increased serum creatine kinase Fibroblasts show a reduction of and disorganization in type XII collagen in the extracellular matrix
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| Periodontal EDS type 1 | Periodontal EDS type 1 is an autosomal-dominant disorder caused by heterozygous mutations in the C1R gene, with the defining feature of severe periodontal inflammation. Characteristic findings include significant gingivitis with gum inflammatory destruction of dental attachments and premature loss of teeth; tall stature; acrogeric facies; cerebral and aortic aneurysm; scoliosis; joint laxity; hypermobility; and thin, atrophic skin with easy tearing and bruisability, pretibial hyperpigmentation, and pretibial plaques. |
Diagnostic criteria Early-onset severe periodontitis Generalized lack of attached gingiva Pretibial plaques Family history in a first-degree relative Laboratory genetic (mutation) testing C1R Other laboratory findings Electron microscopy: Abnormally enlarged endoplasmic reticulum cisterna Abnormal variation in collagen fibril diameter
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| Periodontal EDS type 2 | Periodontal EDS type 2 is an autosomal-dominant disorder caused by heterozygous mutation in the C1S gene. Characteristic findings include aggressive periodontitis with gingival recession, tooth loss, hernias, prominent subcutaneous vasculature, irritable bowel and gastrointestinal symptoms, scoliosis, spinal osteoarthritis, joint hypermobility and pain, skin fragility, pretibial hyperpigmentation, abnormal scarring, and increased incidence of cancer. |
Diagnostic criteria Early-onset severe periodontitis Generalized lack of attached gingiva Pretibial plaques Family history in a first-degree relative Laboratory genetic (mutation) testing C1S
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| Hypermobility spectrum disorders (HSD) | Hypermobility spectrum disorders are a wide spectrum of related disorders with joint hypermobility (JH) of unknown molecular etiology. HSD is used as a diagnosis after other well-defined types of EDS, including hEDS, are excluded. Joint hypermobility is defined as the ability of a joint or group of joints to move passively or actively beyond normal physiologic limits. It can be an isolated finding in some individuals. There are four types of JH: generalized (joint) HSD (G-HSD), peripheral (joint) HSD, localized (joint) HSD, and historical (joint) HSD. Individuals with HSD are predisposed to joint trauma, including dislocations, subluxations, and damage to joint tissues; increased occasional and recurrent musculoskeletal pain; decreased muscle mass; and decreased proprioception. G-HSD can be also associated with extra-articular complications that include anxiety disorders, orthostatic tachycardia, a variety of functional gastrointestinal disorders, and pelvic and bladder dysfunction often similar to what is seen in hEDS. |
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