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

Alison M Boyce; Rachel I Gafni; Carlos R Ferreira

doi:10.1007/s11914-020-00577-4

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.

Authors

Alison M Boyce¹, Rachel I Gafni², Carlos R Ferreira³

Affiliations

¹ Skeletal Diseases and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive Room 218 MSC 4320, Bethesda, MD, 20892, USA. boyceam@mail.nih.gov.
² Skeletal Diseases and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive Room 218 MSC 4320, Bethesda, MD, 20892, USA.
³ Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

Abstract

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

Substances

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

Grants and funding

Z99 DE999999/ImNIH/Intramural NIH HHS/United States