Complications of ENPP1 Deficiency

Mutations in the ENPP1 gene, also known as ENPP1 Deficiency, can cause an inability to regulate pyrophosphate levels in the blood.  This disorder can manifest as either Generalized Arterial Calcification of Infancy (GACI) Type 1 or Autosomal Recessive Hypophosphatemic Rickets Type 2 (ARHR2).  The following is a list of complications that can be caused by ENPP1 Deficiency.  To read more about GACI, click here.  To read more about ARHR2, click here.

It is important to note that ENPP1 Deficiency and ABCC6 Deficiency are part of a closely related spectrum of diseases and there may be some crossover when it comes to the complications associated with each specific gene. 

Cardiovascular Complications

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 the thickening of the innermost layer of the blood vessels.

Gastrointestinal Complications

Infants with GACI may suffer from gastrointestinal complications such as ulcerating inflammation of the wall of the small intestine or obstruction due to stenosis (narrowing of the blood vessels).  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.

Hypophosphatemic Rickets

Autosomal Recessive Hypophosphatemic Rickets Type 2 occurs as a result of ENPP1 mutations.  This can cause bone and joint pain, bone deformities, dental problems, calcification of ligaments, and short stature.  To read more about ARHR2, click here.

Joint Complications

Approximately 30% of patients who develop 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 ENPP1 Deficiency.  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 ENPP1 Deficiency.  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 ENPP1 Deficiency.  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.

Auditory Complications

Individuals with ENPP1 Deficiency are at risk for developing hearing loss.  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).  Patients with ENPP1 Deficiency 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.

Dental Complications

Recent research has shown that patients with ENPP1 Deficiency 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 ENPP1 Deficiency who have not been treated with bisphosphonates have also presented with infraocclusion and slow orthodontic movement, suggesting that the ENPP1 mutations may be responsible.

Skin and Eye Complications

Some patients with ENPP1 Deficiency go on to develop some features characteristic 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 eyes. Angioid streaks are small breaks in Bruch’s Membrane, an elastic tissue containing the membrane of the retina, that may become calcified and crack.

Medical Interactions

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.