Generalized Arterial Calcification of Infancy: New Insights, Controversies, and Approach to Management

Curr Osteoporos Rep. 2020 Jun;18(3):232-241. doi: 10.1007/s11914-020-00577-4.


Purpose of review: This review summarizes current understanding of generalized arterial calcification of infancy (GACI), emphasizing pathophysiology, clinical presentation, and approaches and controversies in management.

Recent findings: Identification of causative ENPP1 mutations revealed that GACI arises from deficiencies in inorganic pyrophosphate (leading to calcifications) and adenosine monophosphate (leading to intimal proliferation). Identification of genotypic and phenotypic overlap with pseudoxanthoma elasticum and autosomal recessive hypophosphatemic rickets further advanced understanding of GACI as a complex, multisystemic disease. Clinical data is limited to small, retrospective samples; it is therefore unknown whether commonly used medications, such as bisphosphonates and hypophosphatemia treatment, are therapeutic or potentially harmful. ENPP1-Fc replacement represents a promising approach warranting further study. Knowledge gaps in natural history place clinicians at high risk of assigning causality to interventions that are correlated with changes in clinical status. There is thus a critical need for improved natural history studies to develop and test targeted therapies.

Keywords: ABCC6; ENPP1; Fibroblast growth factor 23; Metabolic bone disease.

Publication types

  • Research Support, N.I.H., Intramural
  • Review

MeSH terms

  • Adenosine Monophosphate / metabolism
  • Bone Density Conservation Agents / therapeutic use
  • Calcinosis / genetics
  • Calcinosis / metabolism
  • Calcinosis / physiopathology
  • Calcinosis / therapy
  • Cardiovascular Agents / therapeutic use
  • Chelating Agents / therapeutic use
  • Diphosphates / metabolism
  • Diphosphonates / therapeutic use
  • Familial Hypophosphatemic Rickets / genetics
  • Familial Hypophosphatemic Rickets / metabolism
  • Familial Hypophosphatemic Rickets / physiopathology
  • Genotype
  • Hearing Loss / physiopathology
  • Humans
  • Multidrug Resistance-Associated Proteins / genetics
  • Phenotype
  • Phosphoric Diester Hydrolases / genetics
  • Pseudoxanthoma Elasticum / genetics
  • Pseudoxanthoma Elasticum / metabolism
  • Pseudoxanthoma Elasticum / physiopathology
  • Pyrophosphatases / genetics
  • Thiosulfates / therapeutic use
  • Tooth Diseases / physiopathology
  • Vascular Calcification / genetics
  • Vascular Calcification / metabolism*
  • Vascular Calcification / physiopathology*
  • Vascular Calcification / therapy
  • Vitamin D / therapeutic use


  • ABCC6 protein, human
  • Bone Density Conservation Agents
  • Cardiovascular Agents
  • Chelating Agents
  • Diphosphates
  • Diphosphonates
  • Multidrug Resistance-Associated Proteins
  • Thiosulfates
  • Vitamin D
  • Adenosine Monophosphate
  • diphosphoric acid
  • Phosphoric Diester Hydrolases
  • ectonucleotide pyrophosphatase phosphodiesterase 1
  • Pyrophosphatases
  • sodium thiosulfate

Supplementary concepts

  • Arterial calcification of infancy
  • Hypophosphatemic Rickets, Autosomal Recessive, 2