Mutant Nitric Oxide Gene in NICO (Neuralgia-Inducing Cavitational Osteonecrosis)

Objectives: To determine whether or not the T-786C mutation of the endothelial nitric oxide synthase (eNOS) gene affecting nitric oxide (NO) production is associated with NICO, since it has been found in a high proportion of idiopathic hip osteonecrosis cases. Gene polymorphism associated with reduced NO production is associated with vasoconstriction, platelet aggregation, thrombosis and regulation of bone turnover ...all important to ischemic bone damage. Methods: Blood was collected from 22 biopsy-proven NICO patients (17 females; 5 years average pain duration; no bisphosphonate, estrogen or corticosteroid use; hot spot in quadrant of pain via technetium-99 MDP scintigraphy scan) and processed for real time PCR analysis of mutations affecting NO production (eNOS T-786C, stromelysin 5A6A). Two race/gender matched normal controls were used per case. Results: Homozygosity for the mutant eNOS allele (TT) was present in 6 of 22 (27%) NICO cases compared to 0 of 44 (0%) of controls; heterozygosity (TC) was present in 8 cases (36%) vs 15 controls (34%); and the wild-type normal genotype (CC) was present in 9 patients (36%) vs 29 controls (66%) (p = 0.0008). The mutant eNOS T-786C allele was more common in cases (20/44 [45%]) than in controls (15/88 [17%]), p =0.0005. The specificity of eNOS T-786C genotype (homozygosity vs non-homozygosity) was very high, with all 44 healthy controls (100%) free of eNOS homozygosity. However, the distribution of the stromelysin 5A6A genotype in cases did not differ from controls (p=.13) and specificity was low, only 82%, with 36 of 44 healthy controls free of eNOS homozygosity. Conclusions: While cause-and-effect cannot be proven by our study design, the eNOS T-786C polymorphism affecting NO production is associated with NICO and may, therefore, contribute to the multifactorial pathogenesis of that disease, perhaps allowing medical approaches to treatment through use of L-arginine, the amino-acid precursor of NO.