Complications of GACI
Generalized Arterial Calcification of Infancy causes an abnormal buildup of calcium within the walls of the arteries. This can cause critical blockages which can reduce blood flow to organs potentially resulting in high blood pressure, stroke, or heart attack. It can eventually lead to heart failure and death. Survivors of GACI may go on to develop something called intimal hyperplasia, which is thickening of the innermost layer of a blood vessel.
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. Infants with gastrointestinal complications may present with irritability and/or bloody stool. Fortunately, for patients with GACI who survive the critical period of infancy, the gastrointestinal complications dissipate as the child, and thus the child’s blood vessels, grow in size.
Approximately 30% of patients with GACI present with joint calcifications. These calcifications are frequently seen in the hip, ankle, wrist, shoulder, elbow, and knee along with fingers, toes, and spine. Joint calcifications can cause pain and reduced mobility. There is no specific treatment for joint calcification in patients with GACI. In some patients the calcifications spontaneously regress, while in other cases it has persisted. Currently only one patient is known to have had the joint calcification surgically removed prior to his diagnosis of GACI. If the calcification is causing functional impairment of the affected joint, such as reduced range of motion, it would be prudent to seek the assistance of a physical therapist who may be able to help with mobility and function.
Cervical spine fusion secondary to calcification has also been seen in patients with GACI. Prior to elective endotracheal intubation, patients should be evaluated via a lateral cervical spine x-ray. If cervical spine fusion is present, fiberoptic intubation is recommended.
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. The hearing loss is typically caused by calcification of the arteries supplying the inner ear or stapedovestibular ankylosis (immobility of an ear bone). Patients with GACI should be evaluated by an audiologist periodically to determine if there is hearing loss. Patients who do develop hearing loss have benefitted from the use of hearing aids.
Skin and Eye Complications
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 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 containing the membrane of the retina, that may become calcified and crack.
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. Bisphosphonate therapy has been associated with disrupted dental development or delayed tooth eruption, however patients with GACI who have not been treated with bisphosphonates have also presented with infraocclusion and slow orthodontic movement, suggesting that ENPP1 mutations may be responsible.
Autosomal Recessive Hypophosphatemic Rickets Type 2
Many patients who survive GACI go on to develop a rare form of rickets known as Autosomal Recessive Hypophosphatemic Rickets Type 2 (ARHR2). This 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. Find more information on ARHR2 here.
Although there have been no clinical studies, it seems prudent to avoid the use of warfarin if possible because matrix Gla protein (MGP), a potent anti-mineralization factor, needs to be activated by a vitamin K-dependent enzyme, and warfarin interferes with the vitamin K cycle. Warfarin has also been shown to accelerate ectopic mineralization in mice.