Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Ehlers-Danlos syndrome, hypermobility Type (EDS type III) [Q79.6]

OMIM numbers: 130020, 600985 (TNXB)

Dr. rer. nat. Karin Mayer

Scientific Background

The hypermobility type of EDS is the most common EDS type with a prevalence of 1:5,000 to 1:20,000. In contrast to the other main types of EDS, clinical symptoms are considered least severe. The pattern of inheritance is autosomal dominant with complete penetrance, however, with an extreme variable clinical expressiveness, so that the hypermobility type of EDS seems to be considerably more frequent than the classical type. A significant major clinical criteria is the hypermobility of joints which, according to Brighton (1973), can be categorized in a nine-point scale, where a total score of at least 5 should be present. Like in the classical type of EDS the skin is soft but, in contrast, is not or only slightly hyper-extensible. Furthermore, characteristic signs of the classical or vascular types of EDS like vulnerability of the skin and tissue, and involvment of the vascular system are missing. A positive family history and gastrointestinal or cardiovascular complications as minor criteria can at best support a clinical diagnosis. Chronic pain is frequently described and is particularly problematic for a lot of patients.

The biochemical and molecular etiology of EDS type III is unknown in most cases. In some patients heterozygous frameshift mutations or genomic deletions in the TNXB gene were identified. The gene product tenascin-X is a glycoprotein which is synthesized in the extracellular matrix of the skin, tendons, muscles, and blood vessels. Patients with translational stopp mutations show reduced serum levels of tenascin-X, so that an haploinsufficiency for tenascin-X is assumed. Heterozygous missense mutations were also found in some patients with hypermobility EDS; however, they showed normal serum levels of tenascin-X but abnormalities in the morphology of the elastic fibers. Homozygous or compound heterozygous mutations in the TNXB gene where initially found in a recessively inherited EDS type; however, in these patients tenascin-X is not detectable any more. The phenotype of patients with heterozygous TNXB mutations resembles that of the recessively inherited type. While in patients with tenascin-X deficiency hyper-extensible skin, hypermobility of joints, and propensity for hematoma formation is characteristic, patients with heterozygous TNXB mutations predominantly only present with hypermobility of the joints. TNXB is currently the only gene known to be affected in EDS type III. The clincial consequence of mutations in the TNXB gene is an altered morphology of the elastic fibers of the skin and a reduced density of dermal collagen without abnormalities in the structure of fibrillar collagen.

The biochemical detection of reduced serum levels of tenascin-X can support the clinical diagnosis.