We describe a hereditary chondropathy characterized by extreme cartilage friability and cartilage-bone debonding, which has not previously been described in the literature. We also describe initial studies into the molecular basis of this disorder. Affected family members had multiple shoulder, hip, and knee arthropathies, beginning in the pre-teen years and continuing into adulthood. Various diagnoses had been suggested, including spondyloepiphyseal dysplasia, multiple epiphyseal dysplasia, Legg-Calvé-Perthes disease, and Osgood-Schlatter disease. The affected proband father, his 3 affected children, and unaffected family members provided blood samples, which were examined for single-nucleotide polymorphisms (SNPs) in the chromosome 2 region that included the Frizzled-related protein gene, a soluble Wnt protein signaling antagonist that influences bone and cartilage development. All affected individuals showed clear similarities, including effusions, large loose bodies, and bubbling and delamination of the cartilage with exposure of subchondral bone. All affected individuals exhibited radiographic changes in the hip, showing femoral head flattening and secondary degenerative arthritis, accompanied by abnormalities in the physical properties of the cartilage that were evident upon arthroscopic examination. Two SNPs were identified in subjects with the hereditary cartilage debonding syndrome. Examination of the siblings and parents of the proband demonstrated, however, that both SNPs were present in the unaffected mother and in 2 of 4 unaffected siblings of the proband. The clinical findings reported here represent a newly defined clinical syndrome characterized by marked cartilage friability and osteochondral debonding. Because the SNPs are present in the general population, and because unaffected members of this family carry the SNPs, these polymorphisms alone are insufficient to result in the observed phenotype.