PXE is an inherited connective tissue disorder that is characterized by progressive accumulation of calcium (calcification) and other minerals in elastic fibers in the skin, retina, and arteries, leading to degeneration of elastic fibers in these body regions and the characteristic features of PXE. The skin manifestations are the most prevalent characteristic of PXE. The diagnosis of PXE is suspected in individuals with characteristic skin and ocular findings and is confirmed by histologic findings on biopsy of lesional skin that shows fragmented and clustered calcified elastic tissues in the middle and lower dermis. Additionally, beta-thalassemia must be considered in the differential diagnosis of PXE because of the occurrence of elastic tissue abnormalities in the skin resembling PXE and angioid streaks in beta-thalassemia and sickling syndromes. Notably, these manifestations occur later in life than in patients with PXE, and their prevalence increases with advancing age. There is yet no definitive therapy for PXE. Management focuses on prevention, screening, and monitoring of complications. Most patients live a normal life span.

To date, more than 188 PXE-causing mutations have been identified in the ABCC6 gene, occurring in nearly all 31 exons of the ABCC6 gene. The majority of identified mutations are missense or nonsense mutations, with a smaller number of splicing mutations or insertions.

PXE was first described to be a sporadic disease, followed by reports of autosomal dominant and recessive inheritance. However, autosomal recessive is the inheritance pattern in PXE in the overwhelming majority of families. Also, pseudo-dominance has been described in two families.

The autosomal recessive pattern of inheritance of PXE is caused in the overwhelming majority of cases by homozygous or compound heterozygous mutations in the ABCC6 gene on chromosome 16p13.1. Individuals carrying heterozygous mutations in this gene express limited manifestations of the PXE phenotype (autosomal dominant PXE). ABCC6 is part of the subclass C of the ATP-binding cassette transporter (ABC), which is an active transmembrane transporter. This gene is predominantly expressed in the liver and kidneys. Interestingly, tissues that are primarily affected by PXE (skin, vessel walls, Bruch's membrane) express only low concentrations of ABCC6. It is poorly understood how ABCC6 mutations cause the characteristic features of PXE disease, particularly the calcification of elastic fibers, which are component of connective tissue. It suggested that lack of functional ABCC6 protein in the liver and kidney may disrupt the transport of particular substances into the blood for distribution to other parts of the body. Without these substances, normal activities in connective tissue, such as the assembly of elastic fibers, may be impaired. Another possibility is that impairment the transportation may reduce levels of substances that normally inhibit calcification of elastic fibers. As a result, calcium may accumulate in elastic fibers of tissues affected by PXE, such as the skin. Additionally, oxidative stress has been reported to play an important role in the pathogenesis of PXE.

 A 16.4 kb deletion involving ABCC6 23-29 is a recurrent mutation found in multiple populations with varying frequency. This mutation represents about 28% of alleles in the US, making it the most common mutation in the US, and about 5% of alleles in Europe. In South African families of Afrikaaners, R1339C mutation represents more than half of the mutations detected, with a common haplotype indicating a founder effect. Lack of mutation detection in some patients could be explained by exonic deletion, splice site mutations distant from the coding sequence, or mutations in the gene regulating sequences. Obviously, the presence of other systemic diseases, such as beta-thalassemia and sickle cell anemia mimicking PXE, must be excluded.