What is generalized arterial calcification of infancy (GACI)?

Generalized arterial calcification of infancy (GACI) is a rare, genetic disease that affects the circulatory system in general, and the large and medium sized arteries in particular, throughout the body. The disease causes an abnormal buildup of calcium in the walls of the blood vessels, including those that carry blood from the heart to the rest of the body. Though sometimes diagnosed before birth, while a baby is in utero, GACI is more often diagnosed after birth.

GACI usually occurs during fetal development. Certain genetic defects cause the body to have low levels of pyrophosphate in the blood. Pyrophosphate is an enzyme that prevents the buildup of calcium deposits in blood vessels and arteries. Without enough of this substance, calcium begins to build up (called calcification), which narrows vessels and arteries and restricts blood flow.

This hardening of the arteries and vessels often causes newborns with GACI to show clinical signs of hypertension, heart disease, and kidney disease at birth. Infants with the disease are also at risk for stroke, heart attacks, and kidney failure early in life.

The prevalence of GACI is estimated to be about 1 in 391,000.

Signs and symptoms of GACI

Most babies are diagnosed with GACI after they are born. The initial indication of GACI is high blood pressure or kidney failure. Physicians may order X-rays for newborns with these conditions to look for calcification in arteries.

Heart failure may also develop in these infants and they may experience:

• Difficulty breathing
• Accumulation of fluid (edema) in the extremities
• A bluish appearance of the skin or lips (cyanosis)
• An enlarged heart (cardiomegaly)

Other signs and symptoms may occur in older individuals and include:

• Calcification in others areas of the body, including the joints
• Hearing loss
• Softening or weakening of the bones (rickets)
• Yellowish bumps called papules on the underarms and other areas of skin that touch when a joint bends
• Angioid streaks, which affect the tissue at the back of the eye and can be detected during an eye examination

Many of the symptoms of GACI are similar to another genetic disorder called pseudoxanthoma elasticum (PXE). It’s important that you work with your child’s healthcare team to determine an accurate diagnosis.

Causes of GACI

GACI is a genetic condition. There are two forms of GACI and they have many features in common in infants and young children. As children with these conditions grow up, though, the diseases produce different symptoms.

Both forms of GACI are autosomal recessive, which means that an affected baby has inherited two defective genes, one from each unaffected but carrier parent.

• Type 1, the more common form, affects two thirds of patients and is caused by mutations in the ENPP1 gene. This gene encodes an enzyme that is necessary to make pyrophosphate. In the absence of this enzyme, pyrophosphate levels are low, and calcification in the arteries develops. Type 1 often results in death during the first six months of life. Babies who survive are at risk of developing an unusual form of rickets: A loss of phosphate in the urine leads to low levels of phosphate in the blood, which weakens the bones.
• Type 2, which was co-discovered by CHOP researchers, is caused by mutations in the ABCC6 gene. Mutations in this gene are also associated with low serum levels of pyrophosphate, although the mechanism is unknown. Most children and adults who have mutations in ABCC6 do not develop GACI. Instead, the mutations lead to a condition called pseudoxanthoma elasticum (PXE). This condition affects the elastic tissue of the skin, the eye, and the cardiovascular and gastrointestinal systems. Calcifications typically occur in older children and adults.

Both parents must carry the recessive gene for GACI in order to pass the disease on to a child. Although carriers don’t show any symptoms, if both parents have the recessive gene, there is a 25 percent chance each child conceived will have the disease.

Testing and diagnosis of GACI

Nearly half of all babies with GACI are diagnosed early, generally soon after birth and in some cases before birth by fetal ultrasound. After birth, affected babies may show signs of heart failure, high blood pressure, respiratory distress, edema or fluid collections, or an enlarged heart.

In other babies, GACI is recognized later, within the first three to six months of life, with symptoms ranging from respiratory distress and cyanosis to heart failure and hypertension. In some babies, feeding problems, irritability and failure to thrive are the presenting features.

If a baby is born with heart failure, high blood pressure or kidney disease, standard X-rays, computerized axial tomography (CT scan), or MRI may be recommended to determine if there is calcification or stenosis (narrowing) in the arteries.

Today, fetal therapy is recognized as one of the most promising fields in pediatric medicine. Type 1 GACI can often be diagnosed in utero by fetal ultrasound during the third trimester, which may allow physicians to begin treating the condition before birth.