Generalized Arterial Calcification of Infancy (GACI) is a rare genetic disease that primarily affects the circulatory system. GACI causes an abnormal buildup of calcium within the walls of the arteries. This can cause critical blockages which can reduce blood flow to organs which in turn can cause stroke, heart attack, and death. GACI was first described in 1899 and there have been roughly 200 cases reported in medical literature since then. GACI usually occurs during fetal development due to a genetic mutation in either the ENPP1 or ABCC6 genes, though there are some cases of unknown origin. A patient diagnosed with GACI Type 1 is considered to have ENPP1 Deficiency while a patient diagnosed with GACI Type 2 is considered to have ABCC6 Deficiency. Prior to the discovery of the genetic causes of GACI (ENPP1 in 2003 and ABCC6 in 2008), it was known as, and is sometimes still referred to as, Idiopathic Infantile Arterial Calcification (IIAC), Idiopathic Arterial Calcification of Infancy (IACI), Occlusive Infantile Arterial Calcification, and Occlusive Infantile Arteriopathy.
These genetic deficiencies cause the body to have low levels of pyrophosphate in the blood. Pyrophosphate is a metabolite that regulates calcification in the body. Without this proper regulation, calcium is able to build up in the walls of the blood vessels. This can cause narrowing of the vessels and restricts blood flow.
GACI is sometimes diagnosed before birth, in utero, but it is more commonly diagnosed after birth. Newborns with GACI may exhibit symptoms such as difficulty breathing, reduced or absent pulses, cardiomyopathy, or accumulation of fluid in the extremities. They may struggle with heart failure or high blood pressure. Newborns with GACI may also present with feeding difficulties, irritability, or failure to thrive. In nearly 50% of cases, babies are diagnosed soon after birth due to these symptoms. In other babies, GACI is recognized later, usually around 3-6 months of age after gradual or persisting symptoms. In some cases, prenatal diagnosis is possible. An ultrasound may reveal polyhydramnios (excess amniotic fluid), pericardial effusion (fluid around the heart), or echogenicity (brightness) of the major arteries. Also, if there is a family history of GACI or both parents are known carriers, chorionic villi sampling or amniocentesis testing can help provide early diagnosis.
High blood pressure also known as hypertension can be evident at birth or develop in patients with GACI. Calcification in the arteries can lead to vascular disease, narrowing of the arteries, and restricted blood flow causing a patient’s blood pressure to increase. High blood pressure can further damage the arteries by making them vulnerable to plaque build-up associated with atherosclerosis. High blood pressure can also lead to congestive heart failure.
Absent or faint pulses may also be evident at birth or develop in patients with GACI. Calcification in blood vessels may cause arterial stiffness/hardening, therefore making pulses faint or absent altogether. Pulses are not only checked on wrists, arms, and neck but all extremities of the body as it can indicate how widespread the calcification is throughout the body.
Infants with GACI may suffer from gastrointestinal complications such as ulcerating inflammation of the wall of the small intestine or obstruction due to stenosis. These complications are thought to arise from insufficient blood flow to the gastrointestinal tract as a consequence of early vascular compromise.
Joint calcifications are seen in roughly 30% of babies with GACI. These calcifications are frequently seen in the hip, ankle, wrist, shoulder, elbow, and knee along with fingers, toes, and spine. Cervical spine fusion has also been reported in a handful of patients.
Individuals with GACI are at risk for developing hearing loss. In GACI, the hearing loss can be conductive, sensorineural, or mixed, and can present as early as infancy. Hearing loss is typically caused by calcification of the arteries supplying the inner ear or stapedovestibular ankylosis (immobility of an ear bone).
Some patients with GACI go on to develop symptoms of PXE (Pseudoxanthoma Elasticum). 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, eyes, cardiovascular system, and gastrointestinal system.
Recent research has shown that patients with GACI frequently present with dental issues such as infraocclusion, over-retained primary teeth, ankylosis, slow orthodontic movement, and excessive buildup of normal cementum on the roots of the teeth.
Many patients who survive GACI go on to develop a rare form of rickets known as Autosomal Recessive Hypophosphatemic Rickets Type 2 (ARHR2), and is usually associated with the ENPP1 gene. This can result in bone and joint pain, bone deformities, dental problems, calcification of ligaments, and short stature.
GACI affects males and females equally and occurs in populations all across the world. It is estimated to occur in approximately 1 out of every 200,000 births with the carrier rate being 1:223. Survival statistics vary greatly but can be estimated to be around 50%.
There is a great deal of variation in how this disease affects different people. Even siblings with the exact same genetic mutations have been reported to have markedly different clinical courses. Patients with GACI are usually followed by a team of specialists which may include: cardiology, endocrinology, nephrology, orthopedics, physical therapy, dental, audiology, and ophthalmology.