Ehlers Danlos Syndrome
The diagnosis of Ehlers Danlos syndrome classic type is established by family history and clinical examination. Diagnostic criteria were developed in 1997 by a medical advisory group from the Ehlers Danlos Foundation in the USA and the Ehlers Danlos Support Group in the UK.
The combination of the first three major diagnostic criteria has high specificity for classic Ehlers Danlos. The presence of one or more minor criteria contributes to the diagnosis of Ehlers Danlos syndrome, but is not sufficient to establish the diagnosis.
Major diagnostic criteria for the classic type of Ehlers Danlos Syndrome:
- Skin hyperextensibility should be tested at a site not subjected to mechanical forces or scarring, such as the volar surface of the forearm. It is measured by pulling up the skin until resistance is felt.
- Widened atrophic scars is a manifestation of tissue fragility
- Joint hypermobility affects both large and small joints, and is usually noted when a child begings to walk. It depends on age, gender, family and ethnicity.
- Positive Family History
Minor diagnostic criteria for the classic type of EDS:
- Smooth, velvety skin
- Molluscoid pseudotumors which are fleshy protuberances associated with scars over pressure points such as the elbows and knees
- Subcutaneous spheroids which are small, cyst-like, hard shot-like nodules, freely moveable in the subcutis over the bony prominences of the legs and arms.
- Complications of joint hypermobility such as sprains, dislocations & subluxations
- Muscle hypotonia
- Easy bruising
- Manifestations of tissue extensibility and fragility such as hiatal hernia and anal prolapse
- Surgical complications such as postoperative hernias
Ehlers Danlos syndrome, classic type, is inherited in an autosomal dominant manner. It is estimated that approximately 50% of affected individuals have inherited the disease-causing mutation from an affected parent, and approximately 50% of affected individuals have a de novo disease-causing mutation. Each child of an affected individual has a 50% chance of inheriting the mutation. Prenatal testing for pregnancies at increased risk may be possible for families in which the disease-causing mutation has been identified in an affected family member.
The diagnosis of Ehlers Danlos syndrome, classic type is established by family history and clinical examination. Quantitative and qualitative studies of type V collagen chains are usually not useful in confirming a diagnosis. At least 50% of individuals with classic Ehlers Danlos syndrome have an identifiable mutation in COL5A1 (46%) or COL5A2 (4%), the genes encoding type V collagen; however, this number may be an underestimate, since no prospective molecular studies of COL5A1 and COL5A2 have been performed in a clinically well-defined group.
Molecular testing can be used to establish the diagnosis in a proband, but it is complicated by the large number of exons in the coding sequences and the wide distribution of mutations. When a clinical diagnosis of classic EDS is suspected, it is recommended to begin with gene sequencing of the COL5A1 gene since most individuals with classic EDS harbor a unique mutation in this gene, which introduces a premature termination codon and nonsense-mediated decay of mRNA. When no COL5A1 mutation is found, sequence analysis of COL5A2 should be performed. If sequence analysis of both COL5A1 and COL5A2 genes does not identify a causal variant in a person with the phenotype of classic Ehlers Danlos syndrome, it may be necessary to obtain a skin biopsy for COL5A1 null allele test and biochemical testing.
The COL5A1 null allele test determines if the individual is heterozygous for one of several COL5A1 polymorphic exonic markers in gDNA and then establishes at the cDNA level whether both alleles are expressed. If only one of the two COL5A1 alleles is present in cDNA, it is assumed that the absent allele is null.
