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Joint hypermobility is a common finding, differing strongly between sexes and among races.1 Joint hypermobility is not a disease in itself, but it can be part of heritable connective tissue disorders, such as Marfan syndrome, Ehlers-Danlos syndrome (EDS), and benign joint hypermobility syndrome (BJHS).2 Although Marfan syndrome and most types of EDS are clinically relatively easy to distinguish by their cardinal features, it is often less easy to differentiate between the hypermobility type of EDS (HT-EDS, formerly type III) and BJHS. Recently, Grahame et al proposed a validated set of diagnostic criteria for BJHS3: the revised Brighton 1998 criteria. Its major criteria are a Beighton score of 4/9 or greater and arthralgia, but the diagnosis can also be based on the presence of minor criteria, including abnormal skin and joint (sub)luxations. HT-EDS can be identified by the Villefranche criteria; the major criteria of this classification include a Beighton score of 5/9 or greater and skin involvement.4 Clearly, there is considerable overlap in the clinical features of BJHS and HT-EDS.
Little is known about the genetic basis of HT-EDS or BJHS. Recently, we have shown that haploinsufficiency for the extracellular matrix protein tenascin-X is associated with HT-EDS.5 Tenascin-X is abundantly expressed in almost all connective tissues, and a 140 kDa fragment is present in serum. The level of serum tenascin-X probably reflects the rate of tenascin-X synthesis in the connective tissues, because subjects who are heterozygous for a tenascin-X null allele express about half of the normal level in their serum.6 Clinically, tenascin-X haploinsufficient subjects show generalised joint hypermobility, arthralgia, and about 40% of them have abnormal skin.
In this study, we investigated whether haploinsufficiency for tenascin-X also occurs in subjects who are diagnosed with BJHS. In collaboration with the Dutch BJHS patient organisation, we collected serum samples from 54 patients (53 female) diagnosed with BJHS by a medical specialist, most of whom were rheumatologists. We measured tenascin-X serum levels in these patients, and found that the mean (SD) level in the BJHS cohort group did not differ from that in the control group (97.6 (25.8)% v 100 (14.1)%, respectively). Of these patients, 14 (26%) had a tenascin-X serum level below the 5th centile of the controls (crude odds ratio 6.4, 95% confidence interval 2.5 to 16.3). Furthermore, four of these patients (7%, all female) had serum tenascin-X levels more than 2.5 standard deviations of control (65%) below the mean for normal subjects. Only 0.6% of subjects would be expected to have such low tenascin-X serum values based on the normal distribution, which is significantly less than the prevalence found in this BJHS group (p<0.05, Fisher’s exact test). Interestingly, the percentage of reduced tenascin-X serum levels in BJHS is similar to the percentage we described in HT-EDS. None of the previously identified truncating tenascin-X mutations were present in any of the patients. It is likely that these patients may have other mutations of tenascin-X or they may represent the extreme in normal variation of tenascin-X expression. Only two patients were available for clinical examination. Both patients had hypermobile joints, often associated with joint subluxations, and chronic musculoskeletal pain.
We have shown that reduced tenascin-X serum levels are present in 5–10% of the patients diagnosed with BJHS or HT-EDS.5 These findings and the considerable overlap of the clinical symptoms suggest that no meaningful distinction can be made between these conditions. Both BJHS and HT-EDS are likely to be genetically heterogeneous and, clearly, the search for candidate genes has only just begun.
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