Table 2.

Clinical signs and symptoms of the different EDS types. Major clinical criteria according to the 2017 International EDS Classification are written in bold, minor clinical criteria are written in normal font and additional phenotypic features are written in italics. (G)JH: (generalized) joint hypermobility, MVP: mitral valve prolaps.

EDS Type	Integumentary System	Skeletal System	Neuromuscular	Craniofacial	Ophthalmological	Vascular	Cardiac	Other
cEDS (COL5A1; COL5A2; COL1A1 p.(Arg312Cys))	skin hyperextensibility with atrophic scarring, easy bruising soft doughy skin skin fragility, molluscoid pseudotumours, subcutaneous spheroids, hernia (or history thereof)	GJH, complications of JH	(mild) muscle hypotonia, delayed motor development	epicanthal folds		Rarely aortic root dilatation, rarely arterial dissection/rupture	MVP (non-progressive)
vEDS (COL3A1; COL1A1 p.(Arg312Cys, p.(Arg574Cys), p.(Arg1093Cys)	bruising unrelated to identified trauma and/or in unusual sites, translucent skin, acrogeria	talipes equinovarus, congenital hip dislocation, small joint hypermobility, tendon and muscle rupture		characteristic facial features (large eyes, periorbital pigmentation, small chin, sunken cheeks, thin nose and lips and lobeless ears), gingival recession and gingival fragility	keratoconus	arterial rupture at young age, carotid-cavernous sinus fistula, early-onset varicose veins		spontaneous sigmoid colon perforation, uterine rupture during third trimester of pregnancy, spontaneous pneumothorax
aEDS (COL1A1; COL1A2)	skin hyperextensibility, tissue fragility including atrophic scars, easy bruising, umbilical hernia	congenital bilateral hip dislocation, severe generalized JH with multiple dislocations, kyphoscoliosis, radiologically mild osteopenia, fractures, foot and hand deformities, pectus deformity	muscle hypotonia, delayed motor development	large fontanelle, frontal bossing, hypertelorism, blue sclerae, epicanthal folds, depressed nasal ridge, midface hypoplasia, micrognathia, dentinogenesis imperfecta				pregnancy-related complications (breech, PPROM, polyhydramnios, decreased fetal movements)
dEDS (ADAMTS2)	extreme skin fragility with congenital or postnatal tears, progressively redundant, almost lax skin with excessive skin folds at wrists and ankles, increased palmar wrinkling, severe bruisability with risk of subcutaneous haematoma, umbilical hernia, soft and doughy skin texture, skin hyperextensibility, atrophic scars, hirsutism	postnatal growth retardation with short limbs, GJH, osteopenia, fractures	delayed motor development	large fontanel, puffy eyelids, excessive peri-orbital skin, downslanting palpebral fissures, blue sclerae, hypoplastic chin, tooth abnormalities	refractive errors, strabismus, glaucoma	Intracerebral hemorrhage		perinatal complications related to tissue fragility, complications of visceral fragility, preterm birth (PPROM),
cvEDS (COL1A1; COL1A2)	skin involvement, inguinal hernia	JH, pectus deformity, joint dislocations, foot deformities			blue sclerae, refractive errors		severe progressive cardiac valvular insufficiency
kEDS (PLOD1; FKBP14)	skin hyperextensibility, easy bruising, umbilical or inguinal hernia PLOD1: skin fragility FKBP14: hyperkeratosis follicularis, umbilical skin redundancy	congenital or early-onset kyphoscoliosis, GJH with (sub)luxations, osteopenia/osteoporosis, pectus deformity, marfanoid habitus, talipes equinovarus	congenital muscle hypotonia, delayed motor development FKBP14: muscle atrophy	blue sclerae PLOD1: characteristic craniofacial features: low-set ears, epicanthal folds, down-slanting palpebral fissures, synophrys and high palate	refractive errors PLOD1: microcornea	rupture/aneurysm of medium-sized artery, antenatal/neonatal brain hemorrhage		pregnancy-related complications (breech, PPROM, oligohydramnios, decreased fetal movements) FKBP14: congenital hearing impairment, bladder diverticula, learning disabilities
clEDS-1 (TNXB)	skin hyperextensibility with velvety skin texture and absence of (extensive) atrophic scarring, easily bruisable skin/spontaneous ecchymoses, acrogeric hands	GJH, foot deformities, mallet fingers, clino- or brachydactyly, (sub)luxations	mild proximal and distal muscle weakness, axonal polyneuropathy, atrophy of muscle in hands and feet	narrow/high arched palate		rarely arterial aneurysms	valvular abnormalities	oedema in legs in absence of cardiac failure, vaginal, uterine or rectal prolapse, gastrointestinal complications (perforation, diverticular disease, …), postpartum hemorrhage
clEDS2 (AEBP1)	skin hyperextensibility with atrophic scarring, translucent skin, easy bruising, hernia, aged appearance	GJH, foot deformities, early-onset osteopenia, joint dislocations (mostly hip), arachnodactyly, (kypho)scoliosis, osteopenia		bad tooth quality, dental abnormalities, high narrow palate,		varicose veins, aorta dilatation	MVP	bowel rupture
mEDS (COL12A1)	soft, doughy skin, atrophic scars, hypertrophic scars	proximal joint contractures, (general/distal) JH, congenital hip dislocation, congenital (kypho)scoliosis, pectus deformity	congenital muscle hypotonia and/or muscle atrophy, motor developmental delay, myopathy on muscle biopsy
BCS (ZNF469; PRDM5)	soft, velvety and/or translucent skin, mild skin hyperextensibility, easy bruising, hernia	developmental dysplasia of hip, scoliosis, arachnodactyly, hypermobility of distal joints, pes planus, hallux valgus, mild finger contractures, fractures, osteopenia/osteoporosis	hypotonia in infancy (usually mild)	blue sclerae, frontal bossing, high palate, depressed nasal bridge and/or prominent chin	thin cornea with/without rupture, early-onset progressive keratoconus and/or keratoglobus, enucleation or corneal scarring because of previous rupture, progressive loss of corneal stromal depth, high myopia, retinal detachment		MVP (non-progressive)	deafness (often mixed conductive and sensorineural), hypercompliant tympanic membranes
mcEDS (CHST14; DSE)	skin hyperextensibility, easy bruising, skin fragility with atrophic scars, increased palmar wrinkling, large subcutaneous hematomas, hernia	Recurrent/chronic dislocations, pectus deformities, spinal deformities, peculiar fingers, progressive talipes deformities, mild postnatal growth restriction, marfanoid habitus	congenital multiple contractures (typically adduction/flexion contractures and talipes equinovarus), hypotonia, motor developmental delay, ventricular abnormalities on brain imaging, tethered spinal cord	large fontanelle, short downslanting palpebral fissures, blue sclerae, hypertelorism, short nose with hypoplastic columella, low-set and rotated ears, long philtrum with thin upper lip vermillion, small mouth and hypoplastic chin, crowded teeth	strabismus, refractive errors, glaucoma, retinal detachment		congenital heart defects (typically ASD), valve abnormalities, aortic root dilatation	chronic constipation, colonic diverticulae, pneumo(haemo)thorax, nephrolithiasis/cystolithiasis, hydronephrosis, cryptorchidism in males, hearing impairment, constipation, diverticula, poor breast development in females
spEDS (B3GALT6; B4GALT7; SLC39A13)	skin hyperextensibility, soft and doughy, thin and translucent skin B4GALT7: single transverse palmar crease SLC39A13: hands with finely wrinkled palms	short stature (progressive in childhood), bowing of limbs, pes planus, osteopenia, (characteristic X-ray findings of) skeletal dysplasia, JH B4GALT7: radioulnar synostosis B3GALT6: kyphoscoliosis (congenital or early-onset), JH (generalized or restricted to distal joints), peculiar fingers, osteoporosis with spontaneous fractures SLC39A13: tapering fingers, hypermobility of distal joints	muscle hypotonia (ranging from severe congenital to mild later-onset), delayed motor development B4GALT7: bilateral elbow contractures B3GALT6: joint contractures (congenital or progressive) SLC39A13: atrophy of thenar muscles	B4GALT7: triangular face, wide-spaced eyes, proptosis, narrow mouth, low-set ears, sparse scalp hair, abnormal dentition, flat face, wide forehead, blue sclerae and cleft palate/bifid uvula B3GALT6: midfacial hypoplasia, frontal bossing, proptosis, or prominent eyes, blue sclerae, downslanting palpebral fissures, depressed nasal bridge, long upper lip, low-set ears, micrognathia, abnormal dentition, cleft palate, sparse hair, tooth discoloration, dysplastic teeth SLC39A13: protuberant eyes with bluish sclerae, hypodontia of one or few teeth	B4GALT7: clouded cornea, refractive errors B3GALT6: hypermetropia, rarely corneal clouding SLC39A13: refractive errors	Rarely aortic aneurysm SLC39A13: varicose veins	B3GALT6: MVP, congenital heart defects	cognitive impairment B3GALT6: lung hypoplasia, restrictive lung disease
pEDS (C1R; C1S)	pretibial plaques, easy bruising, skin hyperextensibility and fragility, wide or atrophic scarring, hernias, acrogeria, skin translucency	JH (mostly distal), kypho (scoliosis)		Severe and intractable early-onset periodontitis, lack of attached gingiva, marfanoid facial features		prominent vasculature, rarely arterial dissection/rupture		family history of first-degree relative who meets clinical criteria, increased infection rate
hEDS (genetic defect unknown)	unusually soft or velvety skin, mild skin hyperextensibility, unexplained striae, bilateral piezogenic papules, hernia, mild atrophic scarring,	GJH, arachnodactyly, arm span to height ratio ≥1.05,		dental crowding and high or narrow palate		aortic root dilatation with z score > +2	MVP	pelvic floor, rectal and/or uterine prolapse, positive family history of hEDS