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Generalized arterial calcification of infancy
Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Condition

Generalized arterial calcification of infancy

Generalized arterial calcification of infancy is a rare, life-threatening circulatory disorder characterized by the abnormal accumulation of calcium in the arterial walls, often leading to heart failure in early life.

Overview & Symptoms

Generalized arterial calcification of infancy (GACI) is a disorder affecting the circulatory system that becomes apparent before birth or within the first few months of life. It is characterized by abnormal accumulation of the mineral calcium (calcification) in the walls of the blood vessels that carry blood from the to the rest of the body (the ). This calcification often occurs along with thickening of the lining of the arterial walls (the intima). These changes lead to narrowing (stenosis) and stiffness of the arteries, which forces the heart to work harder to pump blood. As a result, heart failure may develop in affected individuals, with signs and symptoms including difficulty breathing, accumulation of fluid () in the extremities, a bluish appearance of the skin or lips (cyanosis), severe high blood pressure (hypertension), and an enlarged heart (cardiomegaly).

People with GACI may also have calcification in other organs and tissues, particularly around the joints. In addition, they may have hearing loss or softening and weakening of the bones ().

Some individuals with GACI also develop features similar to those of another disorder called pseudoxanthoma elasticum (PXE). PXE is characterized by the accumulation of calcium and other minerals (mineralization) in elastic fibers, which are a component of connective tissue. Connective tissue provides strength and flexibility to structures throughout the body. Features characteristic of PXE that also occur in GACI include yellowish bumps called papules on the underarms and other areas of skin that touch when a joint bends (flexor areas); and abnormalities called angioid streaks affecting tissue at the back of the eye, which can be detected during an eye examination.

As a result of the cardiovascular problems associated with GACI, individuals with this condition often do not survive past infancy, with death typically caused by a heart attack or stroke. However, affected individuals who survive their first six months, known as the critical period, can live into adolescence or early adulthood.

Frequency

The prevalence of GACI has been estimated to be about 1 in 391,000. At least 200 affected individuals have been described in the medical literature.

Causes

In about two-thirds of cases, GACI is caused by mutations in the ENPP1 gene. This gene provides instructions for making a protein that helps break down a molecule called adenosine triphosphate (ATP), specifically when it is found outside the cell (extracellular). Extracellular ATP is quickly broken down into other molecules called adenosine monophosphate (AMP) and pyrophosphate. Pyrophosphate is important in controlling calcification and other mineralization in the body. Mutations in the ENPP1 gene are thought to result in reduced availability of pyrophosphate, leading to excessive calcification in the body and causing the signs and symptoms of GACI.

GACI can also be caused by mutations in the ABCC6 gene. This gene provides instructions for making a protein called MRP6, also known as the ABCC6 protein. This protein is found primarily in the liver and kidneys, with small amounts in other tissues such as the skin, stomach, blood vessels, and eyes.

MRP6 is thought to transport certain substances across the cell membrane; however, the substances have not been identified. Some studies suggest that the MRP6 protein stimulates the release of ATP from cells through an unknown mechanism, allowing it to be broken down into AMP and pyrophosphate and helping to control deposition of calcium and other minerals in the body as described above. Other studies suggest that a substance transported by MRP6 is involved in the breakdown of ATP. This unidentified substance is thought to help prevent mineralization of tissues.

Mutations in the ABCC6 gene lead to an absent or nonfunctional MRP6 protein. It is unclear how a lack of properly functioning MRP6 protein leads to GACI. This shortage may impair the release of ATP from cells. As a result, little pyrophosphate is produced, and calcium accumulates in the blood vessels and other tissues affected by GACI. Alternatively, a lack of functioning MRP6 may impair the transport of a substance that would normally prevent mineralization, leading to the abnormal accumulation of calcium characteristic of GACI.

Some people with GACI do not have mutations in the ENPP1 or ABCC6 gene. In these affected individuals, the cause of the disorder is unknown.

Associated Genes

  • ABCC6
  • ENPP1

Inheritance Pattern

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Other Names for This Condition

  • Arteriopathia calcificans infantum
  • Diffuse arterial calcifying elastopathy of infancy
  • GACI
  • Idiopathic infantile arterial calcification
  • Idiopathic obliterative arteriopathy
  • IIAC
  • Infantile calcifying arteriopathy
  • Medial coronary sclerosis of infancy
  • Occlusive infantile arteriopathy

Frequently Asked Questions

Prenatal diagnosis relies on detailed fetal ultrasound that may show echogenic (bright) arterial walls, especially in the aorta and renal arteries, or signs of hydrops fetalis. If suspicion is high, fetal MRI can provide additional detail. After birth, a plain radiograph often reveals linear arterial calcifications, and confirmatory testing includes genetic sequencing for ENPP1 or ABCC6 mutations and serum alkaline phosphatase levels.
The mainstay of treatment is intravenous bisphosphonates (e.g., etidronate) to inhibit further calcium deposition, started as early as possible. Some centers add oral phosphate supplements and vitamin D restriction to lower calcium‑phosphate product. In ENPP1‑related cases, experimental enzyme‑replacement or monoclonal antibody therapy (e.g., ENPP1‑Fc) may be offered in clinical trials. Aggressive management of heart failure with diuretics, ACE inhibitors, and afterload‑reducing agents is also essential.
Blood pressure control is critical because high pressure worsens arterial narrowing. First‑line agents are oral calcium channel blockers (e.g., amlodipine) or beta‑blockers (e.g., propranolol) titrated to the infant’s weight and renal function. In severe cases, intravenous nitroprusside may be used short‑term under intensive‑care monitoring. Regular echocardiograms guide therapy adjustments.
Most GACI cases are autosomal recessive, meaning both parents carry one pathogenic variant in ENPP1 or ABCC6. Siblings have a 25 % chance of being affected, a 50 % chance of being carriers, and a 25 % chance of being unaffected non‑carriers. Once a pathogenic variant is identified in the proband, targeted carrier testing for parents and predictive testing for siblings (including prenatal or pre‑implantation genetic diagnosis) is recommended.
Source: MedlinePlus, National Library of Medicine

MedlinePlus brings together authoritative health information from the National Library of Medicine (NLM), the National Institutes of Health (NIH), and other government agencies and health-related organizations.

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