Ehlers Danlos Syndrome

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Ehlers-Danlos syndromes (EDS) are a heterogenous group of hereditary connective tissue disorders. The predominant features are joint hypermobility, abnormal skin texture and repair, and tissue and vascular fragility. The 2017 classification system presented 13 EDS types due to pathogenic variants in 19 different genes. The most common types are hypermobile, classical, and vascular. The others are much rarer with mostly undetermined frequencies in the general population.

Classical EDS

Caused by collagen type V disorder (mainly) or collagen type 1A1 or 1A2 disorder (rarely). Disorder of collagen primary structure and collagen processing.

Inheritance: Autosomal dominant
90% COL5A1 or COL5A2 mutation, Rarely COL1A1 or COL1A2 mutation
Major Criteria	Minor Criteria
1.     Skin hyperextensibility and atrophic scarring	1.     Easy bruising
2.     Generalized joint hypermobility (GJH)	2.     Soft, doughy skin
	3.     Skin fragility (or traumatic splitting)
	4.     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)
	9.     Family history of a first degree relative who meets clinical criteria

Minimal criteria suggestive for Classical EDS: Major criterion (1):skin hyperextensibility and atrophic scarring Plus – Either major criterion (2): GJH – And/or: at least three minor criteria. Confirmatory molecular testing is obligatory to reach a final diagnosis.

Classical-like EDS

clEDS resembles classical EDS but is distinguished by its autosomal recessive pattern of inheritance and the lack of atrophic scarring.

It is caused by homozygous or compound heterozygous null alleles in TNXB. TNXB is a gene that encodes tenascin-X which is a large extracellular matrix glycoprotein. It has a corresponding pseudogene called TNXA which is 97% identical to TNXB at its 3' end (exons 32-44) with the only difference being exon 35.

Due to the pseudogene molecular studies are very difficult and hence many authors believe that TNXB-clEDS is underdiagnosed in most laboratories. Making matters more difficult is that chimeric TNXA/TNXB forms can occur from misalignment events during meiosis which is not detected by NGS. There have been 12 different TNXB variants associated with TNXB-clEDS described.

NGS sequencing is only effective for the non-homologous region. NGS also can't detect rarer deletions and duplications. A multi-step testing approach is needed which comprises NGS for the non-homologous region (exon 1-31), Sanger sequencing for the TNXA/TNXB homologous segment (exons 32-44), and quantitative analysis for rearrangements.

An alternative method of testing is Tenascin-X serum concentration measurement, however this doesn't appear to be available through LabPlus.

Haploinsufficiency (i.e. only one abnormal gene) can cause a phenotype similar to hEDS in females but apparently not males that includes chronic joint pain and dislocations. However skin hyper-extensibility and easy bruising is absent. Haploinsufficiency is expected to be an autosomal dominant trait.

Inheritance: Autosomal Recessive
biallelic TNXB mutation
Major Criteria	Minor Criteria
1. Skin hyperextensibility, with velvety skin texture and absence of atrophic scarring	1. Foot deformities: broad / plump forefoot, brachydactyly with excessive skin; pes planus; hallux valgus; piezogenic papules
2. GJH with or without recurrent dislocations (most commonly shoulder and ankle)	2. Edema in the legs in absence of cardiac failure
3. Easy bruisable skin / spontaneous ecchymoses	3. Mild proximal and distal muscle weakness
	4. Axonal polyneuropathy
	5. Atrophy of muscles in hands and feet
	6. Acrogeric hands, mallet finger(s), clinodactyly, brachydactyly
	7. Vaginal/uterus/rectal prolapse

Minimal criteria suggestive for classical-like EDS: – All three major criteria AND a family history compatible with autosomal recessive transmission. Confirmatory molecular testing is obligatory to reach a final diagnosis.

Cardiac-valvular EDS

Caused by a complete lack of the proa2-chain of type I collagen. Disorder of collagen primary structure and collagen processing.

Inheritance: Autosomal recessive
biallelic COL1A2 mutations
Major Criteria	Minor Criteria
1. Severe progressive cardiac-valvular problems (aortic valve, mitral valve)	1. Inguinal hernia
2. Skin involvement: skin hyperextensibility,11 atrophic scars, thin skin, easy bruising	2. Pectus deformity (especially excavatum)
3. Joint hypermobility (generalized or restricted to small joints)	3. Joint dislocations
	4. Foot deformities: pes planus, pes planovalgus, hallux valgus

Minimal criteria suggestive for Cardiac-valvular EDS: – 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

Caused by a collagen type III disorder. Disorder of collagen primary structure and collagen processing.

Inheritance: Autosomal dominant
Heterozygous mutation in the COL3A1 gene Rarely specific heterozygous arginine-to-cysteine substitution mutations in COL1A1
Major Criteria	Minor Criteria
1. Family history of vascular EDS with documented causative variant in COL3A1	1. Bruising unrelated to identified trauma and/or in unusual sites such as cheeks and back
2. Arterial rupture at a young age	2. Thin, translucent skin with increased venous visibility
3. Spontaneous sigmoid colon perforation in the absence of known diverticular disease or other bowel pathology	3. Characteristic facial appearance
4. Uterine rupture during the third trimester in the absence of previous C-section and/or severe peripartum perineum tears	4. Spontaneous pneumothorax
5. Carotid-cavernous sinus fistula formation in the absence of trauma	5. Acrogeria
	6. Talipes equinovarus
	7. Congenital hip dislocation
	8. Hypermobility of small joints
	9. Tendon and muscle rupture
	10. Keratoconus
	11. Gingival recession and gingival fragility
	12. Early onset varicose veins (under age 30 and nulliparous if female)

Minimal criteria suggestive for vascular EDS: 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 vascular EDS should all lead to diagnostic studies to determine if the individual has vascular EDS. Testing for vascular EDS should also be considered in the presence of a combination of the other “minor” clinical features listed above.

Hypermobile EDS

Main article: Hypermobile Ehlers Danlos Syndrome

Molecular basis unknown. Likely genetic heterogeneity.

Inheritance: Autosomal dominant
Criterion	Features
1. Generalized joint hypermobility	Beighton score >6 for pre-pubertal children and adolescents, >5 for pubertal men and women up to the age of 50, and >4 for those >50 years of age
2: Two or More Among the 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 nulliparous women without a history of morbid obesity or other known predisposing 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 prolapse (MVP) mild or greater based on strict echocardiographic criteria 12. Aortic root dilatation with Z-score
	Feature B: Positive family history, with one or more first degree relatives
	Feature C: 1. Musculoskeletal pain in two or more limbs, recurring daily for at least 3 months 2. Chronic, widespread pain for >3 months 3. Recurrent joint dislocations or frank joint instability, in the absence of trauma (a or b) a. Three or more atraumatic dislocations in the same joint or two or more atraumatic dislocations in two different joints occurring at different times b. Medical confirmation of joint instability at two or more sites not related to trauma.
3. All the pre-requisites must be met	1. Absence of unusual skin fragility, which should prompt consideration of other types of EDS 2. 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 hypermobility EDS requires meeting both Features A and B of Criterion 2. Feature C of Criterion 2 (chronic pain and/or instability) 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 connective 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

Caused by heterozygous mutations in either COL1A1 or COL1A2, that cause entire or partial loss of exon 6 of the respective gene. Disorder of collagen primary structure and collagen processing.

Inheritance: Autosomal dominant
COL1A1 or COL1A2 mutation
Major Criteria	Minor Criteria
1. Congenital bilateral hip dislocation	1. Muscle hypotonia
2. Severe GJH, with multiple dislocations / subluxations	2. Kyphoscoliosis
3. Skin hyperextensibility	3. Radiologically mild osteopenia
	4. Tissue fragility, including atrophic scars
	5. Easy bruisable skin

Minimal criteria suggestive of arthrochalasia EDS: - Major criterion (1) Plus – Either major criterion (3) Or major criterion (2) and at least two other minor criteria.  

Confirmatory molecular testing is obligatory to reach a final diagnosis.

Dermatosparaxis EDS

Caused by biallelic mutations in ADAMTS2, the gene encoding ADAMTS-2, the main procollagen I N-proteinase. Disorder of collagen primary structure and collagen processing.

Inheritance: Autosomal recessive
biallelic mutations in ADAMTS2
Major Criteria	Minor Criteria
1. Extreme skin fragility with congenital or postnatal skin tears	1. Soft and doughy skin texture
2. Characteristic craniofacial features, which are evident at birth or early infancy, or evolve later in childhood	2. Skin hyperextensibility
3. Redundant, almost lax skin, with excessive skin folds at the wrists and ankles	3. Atrophic scars
4. Increased palmar wrinkling	4. GJH
5. Severe bruisability with a risk of subcutaneous hematomas and haemorrhage	5. Complications of visceral fragility (e.g., bladder rupture, diaphragmatic rupture, rectal prolapse)
6. Umbilical hernia	6. Delayed motor development
7. Postnatal growth retardation	7. Osteopenia
8. Short limbs, hand and feet	8. Hirsutism
9. Perinatal complications due to connective tissue fragility	9. Tooth abnormalities
	10. Refractive errors (myopia, astigmatism)
	11. Strabismus

Minimal criteria suggestive for dermatospraxais EDS: – Major criterion (1): extreme skin fragility – AND major criterion (2): 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

Most patients with kyphoscoliotic EDS harbor biallelic mutations in PLOD1, the gene encoding the collagen modifying enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1 or LH1 [lysylhydroxylase1]). More rarely biallelic mutations of FKBP14. This encodes FKBP22, a member of the F506 binding family of peptidyl-prolyl cistrans isomerases. Disorder of collagen folding and collagen cross-linking.

Inheritance: Autosomal recessive
biallelic mutations in PLOD1 (most common) biallelic mutations of FKBP14 (rarer)
Major Criteria	Minor Criteria
1. Congenital muscle hypotonia.	1. Skin hyperextensibility
2. Congenital or early onset kyphoscoliosis (progressive or non-progressive)	2. Easy bruisable skin
3.     GJH with dislocations/subluxations (shoulders, hips, and knees in particular)	3. Rupture/aneurysm of a medium sized 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)

Minimal criteria suggestive for kyphoscoliotic EDS: – 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.

NB: LH1 plays an important role as a post-translational modifying enzyme in collagen biosynthesis through

(i)              hydroxylation of helical lysyl residues in—Xaa-Lys-Gly-collagen sequences to hydroxy-lysyl residues which serve as sites of attachment for carbohydrate units (either galactose or glucosyl-galactose) and

(ii)             (ii) in the formation of intra- and intermolecular collagen cross-links. LH1 deficiency results in under hydroxylation of lysyl residues and under glycosylation of hydroxylysyl residues in collagens and, hence, impaired crosslink formation with consequent mechanical instability of the affected tissue.

Brittle cornea syndrome

Caused by biallelic mutations in either ZNF469, encoding ZNF469, a zinc finger protein of unknown function, or PRDM5, encoding a DNA binding transcription factor of the PR/ SET protein family that lacks the intrinsic histon methyltransferase activity. At least one family with a clinical BCS phenotype did not harbour mutations in these genes, suggesting that at least one other gene might be associated with BCS.

Inheritance: Autosomal recessive
biallelic mutations in ZNF469 or biallelic mutations of PRDM5
Major Criteria	Minor Criteria
1. Thin cornea, with or without rupture (central corneal thickness often <400mm)	1. Enucleation o rcorneal scarring because of previous rupture
2. Early onset progressive keratoconus	2. Progressive loss of corneal stromal depth, especially in central cornea
3. Early onset progressive keratoglobus	3. High myopia, with normal or moderately increased axial length
4. Blue sclerae	4. Retinal detachment
	5. Deafness,often with mixed conductive and sensorineural components, progressive, higher frequencies often more severely affected (“sloping” pure tone audiogram)
	6. Hypercompliant tympanic membranes
	7. Developmental dysplasia of the hip
	8. Hypotonia in infancy, usually mild if present
	9. Scoliosis
	10. Arachnodactyly
	11. Hypermobility of distal joints
	12. Pes planus, hallux valgus
	13. Mild contractures of fingers (especially 5th)
	14. Soft, velvety skin, translucent skin

Minimal criteria suggestive for Brittle Cornea Syndrome: – Major criterion (1): thin cornea, with or without rupture (central corneal thickness often <100 micrometer) Plus – Either: at least one other major criterion – And/or three other minor criteria.

Spondylodysplastic EDS

Caused by biallelic mutations in B4GALT7 or in B3GALT6 or in SLC39A13. Disorder of g;ycosaminoglycan biosynthesis.

Inheritance: Autosomal recessive
biallelic mutations in B4GALT7 or biallelic mutations of B3GALT6 or bialleic mutations in SLC39A13
Major Criteria	Minor Criteria
1. Short stature (progressive in childhood)	1. Skin hyperextensibility, soft, doughy skin, thin translucent skin
2. Muscle hypotonia (ranging from severe congenital, to mild later onset)	2. Pes planus
3. Bowing of limbs	3. Delayed motor development
	4. Osteopenia
	5. Delayed cognitive development
Gene specific criteria (B4GALT7)
Radioulnar synostosis
Bilateral elbow contractures or limited elbow movement
Single transverse palmar crease
Characteristic craniofacial features
Characteristic radiographic findings - radioulnar synostosis, metaphyseal flaring, osteopenia, radial head subluxation or dislocation, and short clavicles with broad medial ends
Severe hypermetropia
Clouded cornea
Gene specific criteria (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
Tooth discoloration
Characteristic craniofacial features
Characteristic radiographic findings
Osteoporosis with multiple spontaneous fractures
Ascending aortic aneurysm
Lung hypoplasia, restrictive lung
Gene specific criteria (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 spondylodysplastic EDS: – 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.

Musculocontractual EDS

Caused by biallelic mutations in CHST14, encoding D4ST1, a single-exon gene encoding carbohydrate sulfotransferase 14 or dermatan 4O-sulfotransferase 1, an enzyme involved in the biosynthesis of the GAG dermatan sulfate. It catalyzes 4-Osulfation of N-acetylgalactosamine (GalNAc) in the sequence “L-iduronic acid (IdoA)-GalNAc,” immediately after epimerization of D-glucuronic acid (GlcA) to IdoA by dermatan sulfate epimerase (DSE).

Inheritance: Autosomal recessive
Biallelic mutations in CHST14
Major Criteria	Minor Criteria
1. Congenital multiple contractures, characteristically adduction-flexion contractures and/or talipes equinovarus (clubfoot)	1. Recurrent/chronic dislocations
2. Characteristic craniofacial features, which are evident at birth or in early infancy	2. Pectus deformities (flat, excavated)
3. Characteristic cutaneous features including skin hyperextensibility, easy bruisability, skin fragility with atrophic scars, increased palmar wrinkling	3. Spinal deformities (scoliosis, kyphoscoliosis)
	4. Peculiar fingers (tapering, slender, cylindrical)
	5. Progressive talipes deformities (valgus, 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 musculocontractual EDS: – 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 multiple contractures AND (3) characteristic cutaneous features. Confirmatory molecular testing is obligatory to reach a final diagnosis.

Myopathic EDS

Caused by heterozygous or biallelic mutations in COL12A1, encoding type XII collagen. The clinical phenotype highly overlaps with collagen type VI-related myopathies, that is, Bethlem Myopathy, and Ullrich Congenital Muscular Dystrophy.

Inheritance: Autosomal dominant or recessive
Heterogenous or biallelic mutations in COL12A1
Major Criteria	Minor Criteria
1. Congenital muscle hypotonia, and/ or muscle atrophy, that improves with age	1. Soft, doughy skin
2. Proximal joint contractures (knee, hip, and elbow)	2. Atrophic scarring
3. Hypermobility of distal joints	3. Motor developmental delay
	4. Myopathy on muscle biopsy

Minimal clinical criteria suggestive for myopathic EDS: – 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

Caused by heterozygous gain of-function mutations in C1R or C1S, encoding subunits C1r and C1s of the first component of the classical complement pathway.

Inheritance: Autosomal dominant
Mutations in the genes C1S or C1R
Major Criteria	Minor Criteria
1. Severe and intractable periodontitis of early onset (childhood or adolescence)	1. Easy bruising
2. Lack of attached gingiva	2. Peripheral joint hypermobility
3. Pretibial plaques	3. Skin hyperextensibility and fragility, abnormal scarring (wide or atrophic)
4. Family history of a first-degree relative who meets clinical criteria	4. Increased rate of infections
	1.      Hernias
	2.      Marfinoid facial features
	3.      Acrogeria
	4.      Prominent vasculature

Minimal criteria suggestive for periodontal EDS:

– 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

Resources

• Special Issue in American Journal of Medical Genetics December 2021
• Special Issue in American Journal of Medical Genetics March 2017
• EDS types and 2017 diagnostic criteria
• Media:EDS_classifications_2017_-_malfait2017.pdf
• 2017 EDS International Classification
• 2017 EDS Classification for Non-Experts
• Ehlers-Danlos Syndrome (EDS) Algorithm and Resources for Primary Care - Mountain States GeneticsMountain States Genetics
• The Ehlers-Danlos syndromes (EDS) GP Toolkit

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