Generalized arterial calcification of infancy

Other Names: Occlusive infantile arteriopathy; Idiopathic infantile arterial calcification; IIAC; Generalized arterial calcification in infancy

A rare genetic vascular disease characterized by early onset (between in utero to infancy) of extensive calcification and stenosis of the large and medium sized arteries. Presentation is typically with respiratory distress, congestive heart failure and systemic hypertension. 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 heart to the rest of the body (the arteries). 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.

Epidemiology

Approximately 300 cases have been reported worldwide in the medical literature. The prevalence is unknown; however, based on carrier frequency of the recognized pathogenic variants, the frequency of 1/566,000 has been suggested.

Cause

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.

Inheritance

Autosomal recessive inheritance, a 25% chance

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.

Signs and symptoms

Signs and symptoms including difficulty breathing, accumulation of fluid (edema) 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 (rickets).

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.

Diagnosis

Generalized arterial calcification of infancy (GACI) should be suspected in individuals with a combination of the following:

Typical cardiovascular findings including heart failure, respiratory distress, edema, cyanosis, hypertension, and/or cardiomegaly Characteristic imaging findings of widespread arterial calcification and/or narrowing of large- and medium-sized vessels Appearance of typical clinical and histologic skin findings of pseudoxanthoma elasticum (PXE) and/or angioid streaks Development of rickets after infancy Imaging Computed tomography (CT) is the preferred imaging modality to assess for calcifications. Multi-detector computed tomography (MDCT) has been reported to detect not just arterial wall calcification but also intimal thickening causing luminal narrowing , which appears as a target or bull’s eye with a center of high attenuation (the lumen) surrounded by low attenuation (the thickened intima), which is again surrounded by high attenuation (the calcification of the arterial wall).

Echocardiogram: Detect echo brightness of the arteries near the heart, including the coronary and pulmonary arteries, ascending aorta and aortic arch, and large arteries originating from the aortic arch; Detect the presence of left ventricular hypertrophy and/or pericardial effusion.

Ultrasound examination of the abdomen and head can be used to detect echo-bright vessels.

Standard x-rays can sometimes detect arterial calcifications, but with low sensitivity, and many times arterial calcifications are detected only on reexamination of x-rays after the diagnosis of GACI was made postmortem .

Magnetic resonance imaging (MRI) and angiography (MRA) are insensitive to detecting arterial wall calcification, but can detect luminal stenosis , especially when performed with breath-hold and cardiac gating techniques .

Coronary angiography can be normal despite the presence of extensive arterial wall calcifications, likely because widespread involvement of all coronary arteries results in diffuse narrowing without the focal areas of stenosis detectable by angiography .

Molecular Genetic Testing One genetic testing strategy is serial single gene molecular genetic testing based on the order in which pathogenic variants most commonly occur (i.e., ENPP1 followed by ABCC6). Typically sequence analysis would be performed first, followed by deletion/duplication analysis if one or no pathogenic variant is identified.

Treatment

Use of bisphosphonates appears to significantly increase survival. Standard anti-hypertensive therapy is warranted for hypertension. Aspirin therapy is warranted in those with severe coronary stenosis who are at increased risk for coronary thrombosis. Anti-hypertensive therapy is warranted for hypertension. Treatment of hypophosphatemic rickets involves calcitriol and oral phosphate supplements. It seems prudent to avoid the use of warfarin if possible. Where endotracheal intubation is required, lateral cervical spine x-ray is recommended to evaluate for cervical spine fusion, and thereby avoid secondary complications.

Prognosis

Prognosis is poor; most infants die from myocardial infarction within the first year of life, with the greatest number of deaths occurring within the first six months. Nevertheless, long-term survival into the second and third decade has been reported.

NIH genetic and rare disease info

• NIH info on Generalized arterial calcification of infancy

Generalized arterial calcification of infancy is a rare disease.

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