Conclusions
CALJA is an extremely rare genetic disorder of isolated calcification that is characterized by late-onset calcification of the arteries and joints of the extremities. Mutation of the NT5E gene that encodes CD73 have been implicated in CALJA.1 CD73 is a membrane-bound ecto-5’-nucleotidase catalyzing the conversion of AMP to adenosine.1 The enzymic activity of CD73 plays an important role in the inhibition of inflammation, atherosclerosis, and ectopic tissue calcification. In patients with this genetic disorder, ischemic symptoms (including intermittent claudication and chronic limb-threatening ischemia) are common due to heavily calcified stenotic or occluded arteries.
Inflammation plays a key role in the pathogenesis of AS regardless of the presence of anatomical abnormalities. The deletion of the CD73 gene in mice resulted in almost complete loss of the pathway that degrades AMP to adenosine at a vascular surface, leading to the development of aortic valve dysfunction.7 The NT5E gene mutation may also contribute to the pathogenesis of calcific aortic valve disease and is associated with an increased risk of AS.
We described the cases of two Japanese sisters aged 81 and 74 years, both of whom underwent AVR for AS and were diagnosed with CALJA and NT5E gene mutation. These are the first two reported cases of patients with the NT5E mutation who underwent surgical AVR for AS. The severity of AS in these patients was similar to that of genetically normal patients with AS despite the high-risk nature of aortic valve calcification.
Because the symptoms of the NT5E mutation have a late onset, other factors may also contribute to the severity and timing of CALJA. There may be undiagnosed patients with the NT5E mutation and CALJA, and the incidence of homozygous variants of NT5E may be underestimated. Genetic experts, vascular specialists, and cardiovascular surgeons should consider the possibility of NT5E mutations in patients who require AVR for AS and distal arterial bypass surgery for limb ischemia.