Ehlers-Danlos Syndrome Test Guide

 

The Collagen Diagnostic Laboratory offers diagnostic testing for EDS type I and II (classical EDS), EDS type IV (vascular EDS), EDS type VI (kyphoscoliotic EDS), EDS types VIIa and VIIb (arthrochalasia), and EDS type VIII (periodontal EDS). There is presently no laboratory test available for individuals with the most common form of EDS – EDS type III (hypermobility EDS). It remains a clinical diagnosis.

Step 1: DNA Sequencing

Approach to genetic testing for Ehlers-Danlos syndrome begins with genomic DNA sequencing of selected genes.  A summary of the testing approach is outlined in the table:

CLASSIFICATIONCLINICAL FEATURESINHERITANCEGENE(S)AVAILABLE CLINICAL TESTING
Classical Type (EDS types I)Soft, velvety, hyperextensible skin; easy bruising; "cigarette paper" scarsDominantCOL5A1 and COL5A2Classical EDS
EDS Panel
Comprehensive EDS Panel
Classical type (EDS type II)Similar to EDS type I but less severe. Soft, hyperextensible skin; joint hypermobility; bruising; normal scar formationDominant (rare recessives)COL5A1 and COL5A2Classical EDS
Hypermobility Type (EDS type III) or Tenascin Deficient TypeMarked large and small joint hypermobility, joint pain, easy bruising, easy bleeding, normal scarsDominantTNXB (<5%)(Not available through CDL)
Vascular Type (EDS type IV)Thin, translucent skin with visible veins; marked bruising; skin and joints have normal extensibility; arterial, bowel and uterine ruptureDominantCOL3A1Vascular, type IV
Ocular-scoliotic (Kyphoscoliosis) Type (EDS type VI)Progressive kyphoscoliosis, joint hypermobility, smooth, hyperelastic and fragile skin, muscular hypotonia and scleral fragility and rupture of the globeRecessivePLOD1Ocular-scoliotic, type VI
Arthrochalasia Type (EDS type VIIA and VIIB)Congenital hip dislocation; very soft, fragile, bruisable skin, marked joint hypermobility, blue sclerae, small jaw, hypertrichosisDominantCOL1A1, COL1A2Arthrochalasia, type VII A/B (Exon 6 COL1A1/2 )
Dermatosparaxis Type (EDS type VIIC)Soft and very thin, fragile skin (tearing of the skin), stretchy skin, easy bruising, joint hypermobilityRecessiveADAMTS2Dermatosparaxis, Type VIIC
Cardiac-Valvular FormJoint hypermobility, skin hyperextensibility, cardiac valvular defectsRecessiveCOL1A2Comprehensive EDS Panel
Periodontal (EDS type VIII)Periodontitis, gingival recession, early tooth loss, easy bruising, skin hyperpigmentation, atrophic scars, joint hypermobility, thin skinDominantC1S, C1RPeridontal, Type VIII
Musculocontractural TypeCraniofacial dysmorphism, congenital contractures of thumbs and fingers, clubfeet, severe kyphoscoliosis, hypotonia, thin skin, easy bruising, atrophic scarring, joint hypermobilityRecessiveCHST14Comprehensive EDS Panel
EDS with progressive kyphoscoliosis, myopathy, and hearing lossSevere muscle hypotonia at birth, progressive scoliosis, joint hypermobility, elastic skin, myopathy, hearing lossRecessiveFKBP14FKBP14-Related EDS
Occipital horn (EDS type XI)Easy bruising, hyperelastic skin, hernias, bladder diverticula, joint hypermobility, varicosities, multiple skeletal abnormalitiesX-Linked RecessiveATP7AComprehensive EDS Panel
Periventricular heterotopia variant (PVNH4)Epilepsy, cardiac defects, joint hypermobilityX-Linked DominantFLNAComprehensive EDS Panel
Spondylocheirdysplastic formShort stature, blue sclerae, thin and hyperelastic skin, muscle atrophyRecessiveSLC39A13Comprehensive EDS Panel

Modified from Byers 2000 in The Metabolic & Molecular Bases of Inherited Disease

Step 2: Optional Splicing Studies

Studies of RNA extracted from cultured fibroblasts are available in instances when it is necessary to expand testing for a full interpretation of an identified variant potentially affecting splicing.  Laboratory directors and staff with work with Investigators and clinicians to plan the appropriate protein/RNA study before requesting a skin biopsy.

Clinical Considerations:

1. Possible diagnosis of classical EDS (type I and II):The classic type of Ehlers-Danlos syndrome (EDS types I & II) is an autosomal dominant disorder characterized by skin hyperextensibility, increased skin fragility, joint hypermobility, and abnormal wound healing. Recent studies indicate that as many as 90% of individuals with EDS classic type have underlying pathogenic variants in COL5A1 or COL5A2, the genes that encode type V collagen.

2. Possible diagnosis of vascular EDS (type IV): The vast majority of probands in families with this form of EDS are identified on the basis of a major complication either bowel perforation or vascular aneurysm or rupture. The International Ehlers-Danlos Foundation Advisory Board set the following guidelines for determination of the clinical diagnosis of EDS type IV. DNA-based testing is recommended for those who meet these guidelines. Note, however, that individuals with nonsense mutations of COL3A1 are less likely to have similar physical characteristics. The clinical diagnosis of EDS type IV is highly suspected when two major diagnostic criteria are present:

Major clinical diagnostic criteria:

  • Intestinal rupture
  • Arterial rupture
  • Uterine rupture during pregnancy
  • Family history of the vascular type of EDS

Minor diagnostic criteria alone are not sufficient to warrant the diagnosis unless identified in an individual with a major criteria.

  • Thin, translucent skin (especially noticeable on the chest/abdomen)
  • Easy bruising (spontaneous or with minimal trauma)
  • Characteristic facial appearance (thin lips and philtrum, small chin, thin nose, large eyes)
  • Acrogeria (an aged appearance to the extremities, particularly the hands)
  • Hypermobility of small joints
  • Tendon/muscle rupture
  • Early-onset varicose veins
  • Arteriovenous carotid-cavernous sinus fistula
  • Pneumothorax/pneumohemothorax
  • Chronic joint subluxations/dislocations
  • Congenital dislocation of the hips
  • Talipes equinovarus (clubfoot)
  • Gingival recession

3. Possible diagnosis of EDS type VII A or B: Typically identified in infancy, those reported with EDS VII have had bilateral congenital dislocated hips, significant joint laxity, soft stretchy skin and small mandible.

4. Possible diagnosis of EDS type VI: Ehlers-Danlos syndrome (EDS), the kyphoscoliotic form, (EDS type VI) presents as congenital hypotonia with generalized joint laxity, easy bruising, progressive scoliosis and ocular fragililty. An increased risk for arterial rupture is recognized. The PLOD1 gene encodes enzyme lysyl hydroxylase 1; recessive mutations result in diminished enzyme activity and the described phenotype. Measurement of urinary deoxypyridinoine to pyridinoline croxxlinks is also a highly sensitive and specific test of lysyl-hydroxylase activity. (available elsewhere)

5. Possible diagnosis of EDS type VIII: Clinical features of EDS VIII such as hyperextensible joints, atrophic scarring, and easy bruising can often overlap with other forms of EDS. However, the presence of early-onset severe periodontal inflammation (often leading to premature tooth loss) can distinguish this form of EDS from the other types.

6. Testing of Relatives: In each instance, if a mutation is identified, testing of at-risk relatives is available by directed sequencing of the appropriate gene segment. See GeneReviews.org for discussion of factors to consider in testing relatives.

 

References:

EDS type I/II – Classical type

Symoens S et al.  Comprehensive molecular analysis demonstrates type V collagen mutations in over 90% of patients with classic EDS and allows to refine diagnostic criteria. Hum Mutat 2012 Oct;33(10):1485-93

De Paepe A et al. Mutations in the COL5A1 gene are causal in the Ehlers-Danlos syndromes I and II. Am J Hum Genet. 1997 Mar;60(3):547-54.

Schwarze U et al. Null alleles of the COL5A1 gene of type V collagen are a cause of the classical forms of Ehlers-Danlos syndrome (types I and II). Am J Hum Genet. 2000 Jun;66(6):1757-65.

Wenstrup RJ et al. COL5A1 haploinsufficiency is a common molecular mechanism underlying the classical form of EDS. Am J Hum Genet 2000 Jun;66(6):1766-76.

 

EDS type I/II – Classical Form – Tenascin X deficiency

Schalkwijk J et al. A recessive form of the Ehlers-Danlos syndrome caused by tenascin-X deficiency. N Engl J Med. 2001 Oct 18;345(16):1167-75.

 

EDS type IV- Vascular type

Pepin MG et al.  Survival is affected by mutation type and molecular mechanism in vascular Ehlers-Danlos syndrome (EDS type IV). Genet Med. 2014 Dec;16(12):881-8

Murray M et al.  Pregnancy-related deaths and complications in women with vascular Ehlers-Danlos syndrome. Genet Med. 2014 Dec;16(12):874-80.

Pepin MG and Byers PH.   Gene Reviews:  Ehlers-Danlos syndrome type IV last edited May 3, 2011.

EDS type VI – Lysyl Hydroxylase Deficiency

Wenstrup RJ et al. Ehlers-Danlos syndrome type VI: clinical manifestations of collagen lysyl hydroxylase deficiency. J Pediatr. 1989 Sep;115(3):405-9.

Yeowell HN et al. Mutational analysis of the lysyl hydroxylase 1 gene (PLOD) in six unrelated patients with Ehlers-Danlos syndrome type VI: prenatal exclusion of this disorder in one family. Hum Mutat. 2000 Jul;16(1):90.

Pasquali M et al. Abnormal formation of collagen cross-links in skin fibroblasts cultured from patients with Ehlers-Danlos syndrome type VI. Proc Assoc Am Physicians. 1997 Jan;109(1):33-41.

EDS type VIIA and B Arthrochalasia

Giunta C et al. Ehlers-Danlos syndrome type VII: clinical features and molecular defects. J Bone Joint Surg Am. 1999 Feb;81(2):225-38. Review.

Byers PH et al. Ehlers-Danlos syndrome type VIIA and VIIB result from splice-junction mutations or genomic deletions that involve exon 6 in the COL1A1 and COL1A2 genes of type I collagen. Am J Med Genet. 1997 Oct 3;72(1):94-105.

 

EDS type VIIC – Dermatospraxis

Smith LT et al. Human dermatosparaxis: a form of Ehlers-Danlos syndrome that results from failure to remove the amino-terminal propeptide of type I procollagen. Am J Hum Genet. 1992 Aug;51(2):235-44.

Colige A et al. Human Ehlers-Danlos syndrome type VII C and bovine dermatosparaxis are caused by mutations in the procollagen I N-proteinase gene. Am J Hum Genet 1999 Aug;65(2):308-17.

Nusgens BV et al. Evidence for a relationship between Ehlers-Danlos type VII C in humans and bovine dermatosparaxis. Nat Genet. 1992 Jun;1(3):214-7.