The Collagen Diagnostic Laboratory offers diagnostic testing for EDS type IV (vascular EDS), EDS type VI (kyphoscoliotic EDS) and EDS VII (arthrochalasia). Testing for EDS types I and II (classical EDS) is available elsewhere. There is presently no laboratory test available for individuals with the most common form of EDS - EDS type III or Hypermobility EDS. It remains a clinical diagnosis.
Step 1: DNA Sequencing
Protein electrophoresis of collagens extracted from cultured fibroblasts (collagen screening) and DNA sequencing are available for both disorders. Based on test sensitivity, convenience and cost, directed sequencing of exon 6 in COL1A1 and COL1A2 is recommended as the first step for EDS type VII testing. Genomic sequencing of COL3A1 is recommended first for EDS type IV testing and genomic sequencing of PLOD1 is the first step for EDS type VI testing.
Step 2: Optional Collagen Screening
Collagen screening to evaluate the protein consequence may be needed for clarification or confirmation in evaluation of EDS type IV and VII.
Clinical Considerations:
1. Possible diagnosis of 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
2. 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.
3. 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; the 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)
4. 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.
| Clinical Classification of the Ehlers-Danlos Syndromes | ||||
| Classification | Clinical Features | Inheritance | Gene | Testing |
|---|---|---|---|---|
| Classical type (EDS type I) | Soft, velvety, hyperextensible skin; easy bruising; "cigarette paper" scars | Dominant | COL5A1 and COL5A2 | COL5A1 and COL5A2 sequencing studies (not available in CDL) |
| Classical type (EDS type II) | Similar to EDS type I but less severe. Soft, hyperextensible skin; joint hypermobility; bruising; normal scar formation | Dominant (rare recessives) | COL5A1 and COL5A2 | COL5A1 and COL5A2 sequencing studies (not available in CDL) |
| Hypermobility type (EDS type III) | Soft skin, no scarring; marked large and small joint hypermobility | Dominant | Not known | Research only |
| Vascular type (EDS type IV) | Thin, translucent skin with visible veins; marked bruising; skin and joints have normal extensibility; arterial, bowel and uterine rupture. | Dominant | COL3A1 | 1. COL3A1 sequencing studies. 2. Collagen screening of cultured fibroblasts to define protein consequence. |
| Ocular-scoliotic type (EDS type VI) | Soft, velvety, hyperextensible skin; hypermobile joints, scoliosis; ocular fragility and keratoconus | Recessive | PLOD1 | PLOD1 sequencing studies or urinary pyridinoline cross-links screening. |
| Arthrochalasia type (EDS type VII) | Congenital hip dislocation; very soft, fragile, bruisable skin, marked joint hypermobility, blue sclerae, small jaw, hypertrichosis | Dominant or recessive | COL1A1 exon 6 (type A), COL1A2 exon 6 (type B), PNP1 (type C) | Targeted sequencing of COL1A1/2 exon 6 for types A and B; Collagen screening for types A, B, and C |
| Periodontal (EDS type VIII) | Generalized periodontitis; skin similar to EDS type II | Dominant | Not known | Research only |
Modified from Byers 2000 in The Metabolic & Molecular Bases of Inherited Disease
References:
EDS type I/II - Classical type
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 and Byers PH Genetests (www.genetests.org)
Pepin M et al.Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J Med. 2000 Mar 9;342(10):673-80.
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.