Generalized Arterial Calcification of Infancy

Generalized Arterial Calcification of Infancy

OVERVIEW

Generalized arterial calcification of infancy (GACI) is a rare genetic disorder that affects the circulatory system in addition to other body systems. It occurs in approximately 1:200,000 pregnancies. GACI affects males and females equally and occurs in populations all around the world. It has an autosomal recessive inheritance pattern and usually affects infants during the first 6 months of life. There have been slightly over 200 cases documented since GACI was first described in medical literature in 1899.

Symptoms of GACI include respiratory distress, arterial calcification, gastrointestinal issues, joint calcification, hearing loss, high blood pressure, stroke, reduced or absent pulses, and heart failure. GACI manifests itself differently even within families with the same genetic cause of the disease. No two people with GACI will have identical medical characteristics.

GACI type 1 occurs in 75% of patients, is caused by variants in the ENPP1 gene, and is also called ENPP1 deficiency. Patients with ENPP1 deficiency are at risk of developing autosomal recessive hypophosphatemic rickets type 2 (ARHR2). ARHR2 can cause bone pain, bone deformities (knocked knees, bowed legs), dental problems, calcification of ligaments and short stature. With proper treatment the bones can be strengthened, and side effects minimized.

GACI type 2 occurs in 10% of patients, is caused by variants in the ABCC6 gene, and is also called ABCC6 deficiency. As they get older, patients with ABCC6 deficiency are at risk of developing characteristics similar to pseudoxanthoma elasticum (PXE), involving the elastic tissue of the skin, the eye, cardiovascular and gastrointestinal systems.

Sometimes individuals affected with GACI do not have variants in the ENPP1 or ABCC6 genes, and in those cases the cause of the disorder is unknown.

Currently, there is no curative treatment for GACI and survival rates vary greatly. Treatment with bisphosphonates might lead to increased survival rates. Spontaneous regression of arterial calcifications can occur, and antihypertensive treatment can be tapered off gradually

SYNONYMS

ENPP1 deficiency

ABCC6 deficiency

idiopathic infantile arterial calcification (IIAC)

idiopathic arterial calcification of infancy (IACI)

arterial calcification of infancy

occlusive infantile arterial calcification

occlusive infantile arteriopathy

GACI

SUBDIVISIONS

GACI type 1

GACI type 2

SIGNS & SYMPTOMS

Newborns with GACI may exhibit symptoms such as difficulty breathing, reduced or absent pulses, cardiomyopathy, cardiomegaly or accumulation of fluid in the extremities (edema). They may struggle with heart failure or high blood pressure (hypertension). Newborns with GACI may also present with feeding difficulties, irritability or failure to thrive. On ultrasound or echocardiograph, the condition is characterized by calcification of the arteries or the valves of the heart accompanied by thickening of the lining of the arteries (intima).

Calcification in blood vessels may cause arterial stiffness/hardening, therefore making pulses faint or absent altogether.

Infants with GACI may suffer from gastrointestinal complications such as inflammation of the wall of the small intestine or obstruction due to stenosis. Infants with gastrointestinal complications may present with irritability and/or bloody stool. The gastrointestinal complications tend to go away as the child grows.

In nearly 50% of cases, babies are diagnosed soon after birth due to these symptoms. In other babies, GACI is recognized later, usually around 1-6 months of age after gradual or persisting symptoms.

Joint calcifications are seen in roughly 30% of babies with GACI. These calcifications are frequently seen in the hip, ankle, wrist, shoulder, elbow, knee, foot and sternoclavicular (SC) joint.

Many patients with GACI type 1 go on to develop a rare form of rickets known as autosomal recessive hypophosphatemic rickets type 2 (ARHR2). This can result in bone and joint pain, bone deformities, calcification of ligaments and short stature.

Individuals with GACI are at risk for developing hearing loss. The hearing loss can be conductive, sensorineural, or mixed and can present as early as infancy. The hearing loss might be caused by calcification of the arteries supplying the inner ear, immobility of the ear bone (stapedovestibular ankylosis) and/or abnormal remodeling of small bones (ossicles) in the middle ear.

Older patients with GACI may go on to develop symptoms of pseudoxanthoma elasticum (PXE). PXE is a disorder that causes select elastic tissue in the body to become mineralized due to calcium and other minerals being deposited in the tissue. This can result in changes in the skin and eyes. The changes to the skin frequently present on the neck, underarms, inside of the elbows, the groin and behind the knees. It may resemble a rash or have a cobblestone appearance. Another complication is the possible development of angioid streaks in the eye. Angioid streaks are small breaks in Bruch’s membrane, an elastic tissue between the retina and underlying blood vessels, that may become calcified and crack.

Patients with GACI frequently present with dental issues such as teeth that don’t fully erupt (infraocclusion), over-retained primary teeth, ankylosis, slow orthodontic movement and excessive build-up of normal cementum on the roots of the teeth.

CAUSES

In 2003 it was discovered that variants in the ENPP1 gene were the cause of approximately 75% of cases of GACI. The ENPP1 gene provides the instructions for making a protein that helps to break down a molecule called adenosine triphosphate (ATP), when it is found outside the cell (extracellular). Extracellular ATP is broken down into adenosine monophosphate (AMP) and pyrophosphate (PPi). Variants in the ENPP1 gene result in low levels of pyrophosphate. Pyrophosphate is important in controlling calcification and other mineralization in the body. Low pyrophosphate levels allow calcification to develop in the arteries. Low AMP levels lead to narrowing of the blood vessels, with restriction of blood flow.

In 2008, variants in the ABCC6 gene were identified as a cause of GACI in approximately 10% of patients. The ABCC6 gene provides instructions for making a protein called MRP6 (ABCC6 protein). Variants in the ABCC6 gene lead to non-functional or absent MRP6 protein. Although not proven, some researchers think that the lack of MRP6 protein impedes the release of ATP from cells and as a result pyrophosphate production is limited.

There are rare cases where patients with GACI do not have variants in either the ENPP1 or ABCC6 gene. Therefore, it is thought that there may still be at least one other unknown gene that could be responsible for causing GACI in patients, or that variants in one of the two known genes were missed by the sequencing technology.

GACI is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.

AFFECTED POPULATIONS

GACI affects males and females equally and occurs in populations all across the world. There have been slightly over 200 cases documented since GACI was first described in the medical literature in 1899. It is estimated to occur in approximately 1 out of every 200,000 pregnancies with the carrier rate being 1:223. Survival statistics vary greatly but are currently estimated at around 50%.

GACI usually affects infants during the first 6 months of life, but mild cases may go undiagnosed until later in life, when other complications of the condition lead to a diagnosis.

DISORDERS WITH SIMILAR SYMPTOMS

Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) is a very rare disease typically caused by variants in the ENPP1 gene. It is also a component of ENPP1 deficiency. Patients with ARHR2 suffer from low phosphate levels in the blood (hypophosphatemia) as a result of renal phosphate wasting. The correct balance of phosphate is essential for the normal formation of teeth and bones. The frequency of the disease is unknown. (For more information on this condition, search for “ARHR2” in the Rare Disease Database.)

Pseudoxanthoma elasticum (PXE) is an inherited disorder caused by variants in the ABCC6 gene that affects connective tissue in some parts of the body. Elastic tissue in the body becomes mineralized; that is, calcium is deposited in the tissue. This can result in changes in the skin, eyes, cardiovascular system, and gastrointestinal system. Clinicians first recognized PXE more than 100 years ago. Researchers have made a number of significant advances in the past few years. (For more information on this condition, search for “PXE” in the Rare Disease Database.)

DIAGNOSIS

GACI should always be considered in infants and children presenting with hypertension, cardiac failure or sudden death. Ultrasonography can aid in the diagnosis. The preferred imaging modality to assess calcifications extension is whole-body computed tomography (CT) scan combined with CT angiography.

Prenatal diagnosis has been reported and an ultrasound may reveal polyhydramnios (excess amniotic fluid), pericardial effusion (fluid around the heart) or echogenicity (brightness) of the major arteries, abnormal cardiac contractility, hydrops or hyperechoic kidneys.

To confirm a GACI diagnosis the baby (and parents) may be genetically tested for variants in the ENPP1 or ABCC6 genes. Prenatal genetic testing for GACI can be confirmed through an amniocentesis or chorionic villus sampling (CVS) if the specific gene variants in the parents have been determined.

Medical Monitoring

Newborn babies with GACI are closely observed and are usually hospitalized in the neonatal intensive care unit (NICU).

Ongoing monitoring of GACI includes ultrasounds, echocardiograms, electrocardiogram (EKG/ECG’s), CT scans, X-rays, regular blood pressure measurements, checking pulses in all extremities, frequent lab and urine tests and hearing tests.

 Type Of Doctor Department : Physician or Geneticist