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• W2034854893 abstract "To the Editor: Ehlers-Danlos syndrome (EDS) is a heterogeneous group of heritable connective-tissue disorders, generally affecting skin, joints, and blood vessels. The most recent classification recognizes six subtypes (Beighton et al. Beighton et al., 1998Beighton P De Paepe A Steinmann B Tsipouras P Wenstrup RJ Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997.Am J Med Genet. 1998; 77: 31-37Crossref PubMed Scopus (1271) Google Scholar), of which the hypermobility type (HT-EDS [formerly EDS type III] [MIM 130020]) is the most common. This type of EDS is similar to benign joint hypermobility syndrome (BJHS), and both are often considered to represent the same hyperlaxity syndrome, since no clear clinical distinction can be made (Grahame Grahame, 1999Grahame R Joint hypermobility and genetic collagen disorders: are they related?.Arch Dis Child. 1999; 80: 188-191Crossref PubMed Scopus (211) Google Scholar). Although various causative genes have been found in all other types of EDS, the genetic basis of HT-EDS or BJHS remains unexplained (Steinmann et al. Steinmann et al., 2002Steinmann B Royce PM Superti-Furga A The Ehlers-Danlos syndrome.in: Royce PM Steinmann B Connective tissue and its heritable disorders. Wiley-Liss, New York2002: 431-523Crossref Google Scholar). One family has been described that has a missense mutation in COL3A1 (Narcisi et al. Narcisi et al., 1994Narcisi P Richards AJ Ferguson SD Pope FM A family with Ehlers-Danlos syndrome type III/articular hypermobility syndrome has a glycine 637 to serine substitution in type III collagen.Hum Mol Genet. 1994; 3: 1617-1620Crossref PubMed Scopus (72) Google Scholar), resulting in a phenotype that resembles HT-EDS, without obvious vascular complications. Mutations in COL3A1 generally result in the severe vascular type of EDS (MIM 130050). To our knowledge, no other cases of COL3A1 mutations in HT-EDS have been reported. Recently, we showed that deficiency of the extracellular-matrix protein tenascin-X (TNX), encoded by the TNXB gene, causes a new type of recessively inherited EDS (Schalkwijk et al. Schalkwijk et al., 2001Schalkwijk J Zweers MC Steijlen PM Dean WB Taylor G Van Vlijmen IM van Haren B Miller WL Bristow J A recessive form of the Ehlers-Danlos syndrome caused by tenascin-X deficiency.N Engl J Med. 2001; 345: 1167-1175Crossref PubMed Scopus (277) Google Scholar). Patients with complete deficiency of TNX showed marked joint hypermobility, skin hyperextensibility, and easy bruising. The absence of atrophic scars and recessive inheritance distinguishes TNX deficiency from the classical type of EDS. In our initial report (Schalkwijk et al. Schalkwijk et al., 2001Schalkwijk J Zweers MC Steijlen PM Dean WB Taylor G Van Vlijmen IM van Haren B Miller WL Bristow J A recessive form of the Ehlers-Danlos syndrome caused by tenascin-X deficiency.N Engl J Med. 2001; 345: 1167-1175Crossref PubMed Scopus (277) Google Scholar), only a few heterozygous family members were available for examination. Here, we have examined all 20 heterozygous family members (individuals from families A–D in table 1) who were available for further study, regardless of clinical symptoms; in all of these individuals, we have found significantly reduced serum TNX levels (56% ± 6% vs. 100% ± 14% in the control population; P<.001, by Student's t test) (fig. 1f), and, in 17 of them, we have confirmed heterozygosity for a truncating TNXB mutation (table 1). Clinical examination revealed generalized joint hypermobility in nine family members (45%), using the Beighton score (Beighton et al. Beighton et al., 1973Beighton P Solomon L Soskolne CL Articular mobility in an African population.Ann Rheum Dis. 1973; 32: 413-418Crossref PubMed Scopus (1073) Google Scholar), for HT-EDS, or the Brighton criteria (Grahame et al. Grahame et al., 2000Grahame R Bird HA Child A The revised (Brighton 1998) criteria for the diagnosis of benign joint hypermobility syndrome (BJHS).J Rheumatol. 2000; 27: 1777-1779PubMed Google Scholar), for BJHS (table 1 and fig. 1e). Skin hyperextensibility and easy bruising, frequently seen in the individuals with complete TNX deficiency, were absent. A number of patients with haploinsufficiency had recurring joint dislocations and chronic joint pain, as are seen in HT-EDS and BJHS. Only four family members carrying two normal TNXB alleles were available for study, of whom none had hypermobility. The local medical ethics committee (CMO Regio Arnhem-Nijmegen) approved the study protocol, and informed consent was obtained from all patients.Table 1Clinical and Molecular Findings in Individuals with TNXB Haploinsufficiency/Reduced Serum TNX LevelsIndividualaPedigrees for families A–D are depicted in figure 1. Patients E–J were identified in a cohort with HT-EDS. G2 is a sister of G1 and was identified independently of the screening of the 80 patients with HT-EDS/BJHS. We examined all patients available for study except individuals I and J. (Sex)Year of BirthMutationBeighton ScoreTNX Level (% of Control)Clinical Feature(s)AIII2 (F)1961[GT44906] ins5/952Velvety skin, piezogenic papules, back painAIII3 (M)1964[GT44906] ins4/957Loss of pliancy, Raynaud phenomenonAIII6 (F)1974[GT44906] ins6/959Velvety skin, Raynaud phenomenonAIII7 (F)1977[GT44906] ins5/952StriaeAIII8 (F)1981[GT44906] ins5/950Ankle sprains, knee painAIII9 (F)1984[GT44906] ins5/968Velvety skinBI4 (M)1931Unknown0/956Multiple ankle sprainsBIII1 (F)1976Unknown5/965BIII2 (F)1979Unknown5/962Wheelchair dependent, joint painBIII3 (F)198130-kb del5/962Joint painCI1 (M)1919[AA56063] del0/955CI5 (F)1924[AA56063] delND54CII1 (F)1944[AA56063] del1/946CIII3 (F)1978[AA56063] del3/945Piezogenic papules, lymphedemaCIII4 (F)1980[AA56063] del6/953Velvety skin, multiple (sub)luxationsCIII5 (M)1981[AA56063] del0/957DI1 (M)191930-kb del0/953Velvety skinDI2 (F)193130-kb del0/954Multiple fracturesDII1 (F)196230-kb del2/959DII2 (M)196430-kb del2/961Piezogenic papulesE (F)196130-kb del3/958Chronic joint pain, multiple (sub)luxations, wheelchair dependent, HT-EDS/BJHS according to Brighton criteriaF (F)1970[AA56063] del6/952G1 (F)1972Unknown6/956Luxations, velvety skin, piezogenic papulesG2 (F)1977Unknown6/961Chronic pain, subluxations of multiple jointsH (F)1961Unknown2/964Wheelchair dependent, chronic musculoskeletal pain, shoulder luxations, HT-EDS/BJHS according to Brighton criteriaI (F)1954UnknownND65Diagnosis of HT-EDSJ (F)1974UnknownND54Diagnosis of HT-EDSb ND = not determined.a Pedigrees for families A–D are depicted in figure 1. Patients E–J were identified in a cohort with HT-EDS. G2 is a sister of G1 and was identified independently of the screening of the 80 patients with HT-EDS/BJHS. We examined all patients available for study except individuals I and J. Open table in a new tab b ND = not determined. A striking finding is that 0 of the 6 males with haploinsufficiency fulfilled the clinical criteria for HT-EDS or BJHS, whereas 9 of 14 (64%) females were positive. This finding is in accordance with previous population-based studies that show a female preponderance in joint hypermobility syndromes (Larsson et al. Larsson et al., 1987Larsson LG Baum J Mudholkar GS Hypermobility: features and differential incidence between the sexes.Arthritis Rheum. 1987; 30: 1426-1430Crossref PubMed Scopus (180) Google Scholar; Rikken-Bultman et al. Rikken-Bultman et al., 1997Rikken-Bultman DG Wellink L van Dongen PW Hypermobility in two Dutch school populations.Eur J Obstet Gynecol Reprod Biol. 1997; 73: 189-192Abstract Full Text PDF PubMed Scopus (92) Google Scholar). In a control group of 30 unaffected females of the same age as the females with haploinsufficiency in the present study, we found no individuals with a Beighton score >4. This indicates that the prevalence of generalized joint hypermobility in a population of females with haploinsufficiency is significantly higher than in a control population (P<.001, by χ2 test). No sex differences in serum TNX levels in unaffected individuals and individuals with haploinsufficiency were found (not shown). Because our observations in families carrying previously described TNXB mutations suggested an association between TNXB haploinsufficiency and joint hypermobility, we wondered about the prevalence of TNXB haploinsufficiency in patients with HT-EDS. We measured serum TNX levels (by ELISA) in an unselected cohort of 80 patients with HT-EDS who were recruited through the Dutch organization for patients with EDS. All patients were diagnosed with HT-EDS by a medical specialist, and ∼90% were female. Although the mean serum TNX level was not different in the cohort with HT-EDS overall (99.4%±19.7%) (fig. 1f), six of these patients (7.5% [all female]) had serum TNX levels >2.5 SDs (65%) below the mean for unaffected individuals. On the basis of the normal distribution of serum TNX levels, only 0.6% of individuals would be expected to have such low serum TNX levels, which is significantly less than the frequency found in the population with HT-EDS described in the present study (P<.001, by Fisher's exact test). Clinically, patients with reduced TNX levels showed hypermobile joints, often associated with joint subluxations and chronic musculoskeletal pain (table 1). The clinical findings in these patients differ from those with complete TNX deficiency. Patients with haploinsufficiency do not have skin hyperextensibility and lack the easy bruising seen in patients with TNX deficiency. In addition, TNXB haploinsufficiency is expected to be an autosomal dominant trait, which is in accordance with the observed mode of inheritance of HT-EDS and BJHS. On screening for the presence of a 30-kb deletion described previously (Burch et al. Burch et al., 1997Burch GH Gong Y Liu W Dettman RW Curry CJ Smith L Miller WL Bristow J Tenascin-X deficiency is associated with Ehlers-Danlos syndrome.Nat Genet. 1997; 17: 104-108Crossref PubMed Scopus (259) Google Scholar; Schalkwijk et al. Schalkwijk et al., 2001Schalkwijk J Zweers MC Steijlen PM Dean WB Taylor G Van Vlijmen IM van Haren B Miller WL Bristow J A recessive form of the Ehlers-Danlos syndrome caused by tenascin-X deficiency.N Engl J Med. 2001; 345: 1167-1175Crossref PubMed Scopus (277) Google Scholar), we found that this deletion was present in one of these six patients. The 30-kb deletion creates a fusion gene of TNXB and XA, a partial duplicate of TNXB. The XA gene has an internal deletion that truncates its ORF, rendering XA and the fusion gene nonfunctional (Gitelman et al. Gitelman et al., 1992Gitelman SE Bristow J Miller WL Mechanism and consequences of the duplication of the human C4/P450c21/gene X locus.Mol Cell Biol. 1992; 12 (erratum 12:3313–3314): 2124-2134Crossref PubMed Scopus (97) Google Scholar). The deleted allele also lacks CYP21, so this individual is also a carrier for congenital adrenal hyperplasia. Subsequently, we PCR amplified and directly sequenced the coding regions and the intron-exon boundaries of TNXB in the other five patients presumed to have haploinsufficiency (for primers used, see Schalkwijk et al. Schalkwijk et al., 2001Schalkwijk J Zweers MC Steijlen PM Dean WB Taylor G Van Vlijmen IM van Haren B Miller WL Bristow J A recessive form of the Ehlers-Danlos syndrome caused by tenascin-X deficiency.N Engl J Med. 2001; 345: 1167-1175Crossref PubMed Scopus (277) Google Scholar). One patient (individual F in table 1) was heterozygous for a 2-bp deletion, [AA56063] del, in exon 8, resulting in a premature stop codon at the position of amino acid 1231. In the other four patients, we were unable to identify mutations in TNXB. These patients may have mutations, in regulatory sequences or in exons of the TNXB gene, that have not yet been identified, or they may represent the extreme in normal variation of TNX expression. In conclusion, in the present study, we have reported a genetic defect associated with HT-EDS or BJHS. On the basis of the observed phenotype in patients with complete TNX deficiency and the high prevalence of generalized joint hypermobility in heterozygous females, this is likely to be a causative relationship. Reduced TNX expression could disturb deposition of collagen (Mao et al. Mao et al., 2002Mao JR Taylor G Dean WB Wagner DR Afzal V Lotz JC Rubin EM Bristow J Tenascin-X deficiency mimics Ehlers-Danlos syndrome in mice through alteration of collagen deposition.Nat Genet. 2002; 30: 421-425Crossref PubMed Scopus (185) Google Scholar) and the elastic fiber network (Burch et al. Burch et al., 1997Burch GH Gong Y Liu W Dettman RW Curry CJ Smith L Miller WL Bristow J Tenascin-X deficiency is associated with Ehlers-Danlos syndrome.Nat Genet. 1997; 17: 104-108Crossref PubMed Scopus (259) Google Scholar), as has been shown for complete TNX deficiency, resulting in increased laxity of ligaments and tendons. TNXB haploinsufficiency is dominantly inherited and appears to produce clinical findings primarily in women, consistent with clinical descriptions of HT-EDS. Although we identified inactivating TNX mutations in only 2.5% of this cohort with HT-EDS, 7.5% had serum TNX levels low enough to affect collagen metabolism. The present study demonstrates that TNXB haploinsufficiency is associated with HT-EDS and suggests that locus heterogeneity exists for this disorder, as it does for other types of EDS (Byers Byers, 1994Byers PH Ehlers-Danlos syndrome: recent advances and current understanding of the clinical and genetic heterogeneity.J Invest Dermatol. 1994; : 47S-52SCrossref PubMed Scopus (110) Google Scholar). This work was supported, in part, by Public Health Services grant HL60875 (to J.B.)." @default.
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• W2034854893 date "2003-07-01" @default.
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• W2034854893 title "Haploinsufficiency of TNXB Is Associated with Hypermobility Type of Ehlers-Danlos Syndrome" @default.
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