*2.3. PXE and GACI Are Different Clinical Manifestations of a Phenotypic Continuum*

PXE is primarily caused by ABCC6 deficiency, while GACI patients typically present mutations in the *ENPP1* gene. However, some GACI patients only carry *ABCC6* mutations and typical PXE manifestations can be associated with *ENPP1* mutations. The clinical and molecular genetic characterization of PXE and GACI [16,17] has suggested that ABCC6 and NPP1 are functionally related [56] and give rise to overlapping phenotypes with GACI being a severe and acute form of PXE and vice versa [8,16,57].

Calcification of joints and arteries (CALJA, OMIM#211800) is outside of the scope of this review. However, it is worth mentioning briefly because its molecular etiology is intimately related to that of PXE and GACI. CALJA is due to mutated CD73 (encoded by *NT5E*) [10], which is functionally downstream to NPP1 (Figure 1). The disease is characterized by vascular calcification in the lower limbs and periarticular mineralization. CALJA is caused by enhanced PPi degradation [10,11] resulting from reduced adenosine signaling and abnormal activation of tissue non-specific alkaline phosphatase (TNAP/*ALPL*) [11,20] (Figure 1).
