*2.4. Thalassemia*

For the most part, PXE is a monogenic disease caused by mutations in *ABCC6*. However, other than the cases associated with *ENPP1* mutations [17], PXE manifestations can

arise from multifactorial inheritance [58,59], environmental exposure [60–63] or secondary to β-thalassemia and sickle cell anemia [64]. β-thalassemia (MIM 141900) is a monogenic disorder caused by mutations in the β-*globin* gene that leads to the underproduction of β-globin chains. The stoichiometric excess of α-chains unbound to β-globin is unstable and precipitates in red blood cell precursors causing the ineffective erythropoiesis. In the past decade, it has become apparent that a large number of Mediterranean patients affected by β-thalassemia or sickle cell anemia also develop manifestations similar to PXE [64]. β-thalassemia and PXE are distinct genetic disorders, yet, the ectopic mineralization phenotype seen in β-thalassemia and sickle cell patients is clinically and structurally identical to inherited PXE [65–68] and arises independently of *ABCC6* mutations [69]. Based on studies with a mouse model of β-thalassemia (*Hbbth3/+*), it was suggested that the β-thalassemia patients could have a suboptimal endowment of ABCC6 expression in liver (and possibly reduced PPi production), thereby increasing susceptibility to ectopic mineralization in a PXE-like manner. If this is indeed the case, then β-thalassemia and sickle cell patients could benefit from several treatment options developed for the inherited forms of PXE.
