Pseudoxanthoma Elasticum as a Paradigm of Heritable Ectopic Mineralization Disorders: Pathomechanisms and Treatment Development

Am J Pathol. 2019 Feb;189(2):216-225. doi: 10.1016/j.ajpath.2018.09.014. Epub 2018 Nov 7.


Ectopic mineralization is a global problem and leading cause of morbidity and mortality. The pathomechanisms of ectopic mineralization are poorly understood. Recent studies on heritable ectopic mineralization disorders with defined gene defects have been helpful in elucidation of the mechanisms of ectopic mineralization in general. The prototype of such disorders is pseudoxanthoma elasticum (PXE), a late-onset, slowly progressing disorder with multisystem clinical manifestations. Other conditions include generalized arterial calcification of infancy (GACI), characterized by severe, early-onset mineralization of the cardiovascular system, often with early postnatal demise. In addition, arterial calcification due to CD73 deficiency (ACDC) occurs late in life, mostly affecting arteries in the lower extremities in elderly individuals. These three conditions, PXE, GACI, and ACDC, caused by mutations in ABCC6, ENPP1, and NT5E, respectively, are characterized by reduced levels of inorganic pyrophosphate (PPi) in plasma. Because PPi is a powerful antimineralization factor, it has been postulated that reduced PPi is a major determinant for ectopic mineralization in these conditions. These and related observations on complementary mechanisms of ectopic mineralization have resulted in development of potential treatment modalities for PXE, including administration of bisphosphonates, stable PPi analogs with antimineralization activity. It is conceivable that efficient treatments may soon become available for heritable ectopic mineralization disorders with application to common calcification disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • 5'-Nucleotidase / deficiency*
  • Diphosphates / blood
  • Diphosphonates / therapeutic use*
  • GPI-Linked Proteins / deficiency
  • Humans
  • Multidrug Resistance-Associated Proteins / genetics
  • Multidrug Resistance-Associated Proteins / metabolism
  • Phosphoric Diester Hydrolases / genetics
  • Phosphoric Diester Hydrolases / metabolism
  • Pseudoxanthoma Elasticum* / blood
  • Pseudoxanthoma Elasticum* / drug therapy
  • Pseudoxanthoma Elasticum* / genetics
  • Pseudoxanthoma Elasticum* / pathology
  • Pyrophosphatases / genetics
  • Pyrophosphatases / metabolism
  • Vascular Calcification* / blood
  • Vascular Calcification* / drug therapy
  • Vascular Calcification* / genetics
  • Vascular Calcification* / pathology


  • ABCC6 protein, human
  • Diphosphates
  • Diphosphonates
  • GPI-Linked Proteins
  • Multidrug Resistance-Associated Proteins
  • diphosphoric acid
  • 5'-Nucleotidase
  • NT5E protein, human
  • Phosphoric Diester Hydrolases
  • ectonucleotide pyrophosphatase phosphodiesterase 1
  • Pyrophosphatases

Supplementary concepts

  • Arterial calcification of infancy