Familial osteoarthritis and Milwaukee shoulder associated with calcium pyrophosphate and apatite crystal deposition

Objective. To characterize and define the phenotypes observed in a large It alo-Argentinean kindred with osteoarthritis, chondrocalcinosis, and Milwauk ee shoulder (MS). Methods. Seventy-five members were evaluated with a history,examination, an d radiographs of shoulders, spine, hands, and knees. Superior subluxation o f the glenohumeral joint was graded using shoulder radiographs and tomograp hy and nuclear magnetic resonance imaging and 3 dimensional computed tomogr aphy was performed on selected members. In 31 family members peripheral blo od DNA was utilized for genetic linkage analysis of several candidate gene loci previously linked to chondrocalcinosis phenotypes, as well as those im plicated in the proper patterning of skeletal elements and cartilage differ entiation. In addition, direct sequence analysis of type II collagen gene ( COL2A1), the gene that codes for the major structural protein of cartilage, was undertaken in 3 affected and 3 unaffected members of the family. Results. MS was seen in one member of the first generation and 6 members of the 2nd generation, while 8 members of the 3rd generation showed an incomp lete form of MS. Isolated superior subluxation of the shoulder was seen in 16 other family members of the 3rd and 4th generations. Osteoarthritis of t he spine and peripheral joints was seen in 31 affected members, while chond rocalcinosis was observed in 6 members of the first generation. Shoulder sy novial fluid from: 2 patients showed the presence of both apatite and calci um pyrophosphate dihydrate crystals. Direct analysis of the COL2A1 gene ind icated no known disease determining mutations in affected members, thus exc luding this gene as a candidate gene in this family. Genetic linkage to sev eral candidate loci, including the chondrocalcinosis loci on chromosomes 5p and 8q, as well as loci for HOX A and C were also excluded. Linkage analys es of other loci for the HOX B and D genes and the PAX 1 and 9 genes were u ninformative in this kindred. Conclusion. This kindred illustrates an unusual type of osteoarthritis with secondary intraarticular and periarticular calcification and MS in the mos t severely affected elderly members. A search for linkage to some potential candidate genes was either excluded or uninformative, Further linkage anal ysis to identify potential candidate genes is in progress.