Osteonecrosis of the femoral head (ONFH), occurring in children or adults, rarely shows familial aggregation. Recent reports from Taiwan and Japan, however, indicate that an inherited form of ONFH is associated with mutation of the type II collagen gene (COL2A1). These patients had not been exposed to known environmental risk factors, such as steroid medications, yet they presented with typical clinical and radiographic features of ONFH. Unlike other genetic disorders due to COL2A1 mutations, these ONFH cases have normal skeletal development before disease onset. The clinical manifestation of COL2A1-associated ONFH varies between pedigrees, and it appears that age of onset has a major effect on disease phenotype, reflecting different degrees of bone regeneration concurrent with bone damage in the hip joint. Although the inherited form of ONFH is rare, it provides an opportunity to study the natural history and pathogenetic mechanism of ONFH. Genetic approach for investigating ONFH is reviewed here, highlighting our current understanding of the many possible causes of ONFH, and at the end, casting a realistic projection on how genetics can advance the development for managing this debilitating disease.
