Pseudoxanthoma elasticum

Pseudoxanthoma elasticum (PXE) is a progressive systemic disease affecting the elastic connective tissue of the skin, eyes, cardiovascular, and gastrointestinal systems. It is characterized by deposits in the skin that look like xanthomas and are caused by calcification of the elastic fibers of the connective tissue. They first appear on the sides of the neck and later affect the armpits, elbows, wrists, navel, groin and back of the knees. As the disease progresses, they can become papules and, eventually, larger plaques. Irregular stripes, so-called angioid streaks, appear in the retina. More rarely, vascular stenoses occur due to mineralization of the internal elastic lamina of middle arteries and gastrointestinal bleeding.

PXE is inherited in an autosomal recessive manner, with an estimated prevalence of 1:25,000 to 1:100,000. The diagnosis of PXE is made clinically on the basis of skin and eye manifestations and can be confirmed histologically by a biopsy of the affected skin areas.

The molecular cause is pathogenic variants in the ABCC6 gene (formerly known as MRP6) on chromosome 16p13.1, which codes for the ATP-binding cassette protein 6 of subfamily C of multi-drug resistance proteins (MRP). At least one altered ABCC6 allele is detectable in almost all patients with PXE, and variants on both alleles can be detected in up to 90%. A 16.4 kb deletion, which covers exons 23-29, is particularly common. It occurs in 30% of alleles in PXE patients in the USA and in 5% of alleles in PXE patients in Europe. The most common point mutation is p.(Arg1141*). Together with the 16.4 kb deletion, it represents 70% of all pathogenic variants.

References

Kranenburg et al. 2018, Eur J Med Genet 2018 May 22. pii: S1769 / Moitra et al. 2017, Int J Mol Sci 18, 1488 / Germain DP 2017, Orphanet J Rare Dis 12:85 / Pfendner et al. 2007, J Med Genet 44:621