Article Title

Primary osteoarthritis in the ankle joint is associated with finger metacarpophalangeal osteoarthritis and the H63D mutation in the HFE gene: Evidence for a hemochromatosis-like polyarticular osteoarthritis phenotype


Background and Aim: Osteoarthritis (OA) can occur in the ankle joint. It also occurs in an appreciable proportion of subjects with hereditary hemochromatosis (HH). Might these conditions have common genetic characteristics? The aim of this study was to test the hypothesis that HFE gene mutations are associated with primary osteoarthritis in the ankle joint.

Methods: Consecutive referred patients who had primary or secondary (posttraumatic) OA of the ankle joint were assessed by a single rheumatologist and had a full physical and joint examination. Plain x-rays of the ankle joint, other clinically involved osteoarthritic joints, iron studies, HFE genotyping, and Hb electrophoresis were performed. The significance of differences was evaluated by 2-tailed Fisher exact test.

Results: Fourteen patients met the inclusion criteria for primary ankle OA and 6 met the criteria for secondary ankle OA. One of the 14 had had a previous subtalar joint fusion and was excluded. Among the remaining 13, 7 had OA in the index and/or middle finger metacarpophalangeal joints (MCP2,3 OA) with radiologic features similar to those found in hemochromatotic arthropathy (HA). Furthermore, 11 of the 13 had at least one HFE mutation, one subject in this group was homozygous for H63D, one was compound heterozygous for C282Y and S65C, and one was compound heterozygous for H63D and S65C. Eight were heterozygous for H63D. The 13 subjects were compared with the 6 secondary ankle OA subjects and with a previously studied population cohort (n = 3011) from the town of Busselton in whom HFE genotyping had been performed. A statistically significant increase in the frequency of HFE gene mutations was observed in the group with primary OA of the ankle joint compared with that with secondary ankle joint OA (P = 0.0095) and compared with the Busselton cohort (P = 0.0008). Furthermore, a statistically significant association between finger MCP joint OA and primary ankle joint OA was observed (P = 0.0436). Iron studies were normal in the 13 primary and 6 secondary ankle OA subjects. None of the subjects with ankle OA had clinical signs of hemochromatosis or abnormal liver function tests.

Conclusions: A strong and statistically significant association was observed between HFE gene mutations and primary OA in the ankle joint. The frequent presence of MCP2,3 OA in these patients suggests the existence of a type 2 polyarticular OA phenotype that closely resembles the arthropathy of HH and which appears to be clinically differentiable from type 1 OA or nodal generalized OA (NGOA). HFE gene mutations may be a marker for the type 2 polyarticular OA phenotype and a clue to OA pathogenesis.

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