hypophosphatasia

What Is Hypophosphatasia (HPP)?

Hypophosphatasia, caused by mutations in the ALPL gene, is an inherited disorder that disrupts a process called mineralization, in which the body deposits minerals like calcium and phosphorus into teeth and bones. Proper mineralization is necessary to make bones strong and rigid and to make teeth strong enough to withstand years of chewing. Symptoms can vary greatly depending upon which mutations an individual carries. Some forms of the disease are severe, while other forms are extremely mild.

The most severe form of HPP appears before birth or in early childhood. In many cases, infants are stillborn because their skeletons fail to form. Other affected infants are born with short limbs, soft skull bones, and an abnormally shaped chest caused by soft, weak ribs. Approximately half of the infants born with the condition die of respiratory failure in the first few weeks of life. Those who survive may have life-threatening complications such as breathing problems, seizures, or high blood-calcium levels, leading to kidney damage.

In a less-severe form, the first sign of the condition is the loss of baby teeth before the age of five. As children grow, they may be below average in height, with bowed legs or knock knees, large wrist and ankle joints, and an abnormally shaped skull. They are more prone to broken bones, bone pain, and arthritis. Children with HPP may also have trouble learning to walk or may develop a waddling gait. Additionally, their teeth may crack or decay more easily than normal.

The mildest form of the disorder is called odontohypophosphatasia and only affects the teeth. Individuals with this form of the condition have abnormal tooth development and lose their teeth early, but do not have skeletal abnormalities.

Usually HPP is inherited in an autosomal recessive manner, meaning both parents must each carry a mutation in the ALPL gene for their children to have a risk of having HPP. In the autosomal recessive form, carriers show no signs and symptoms of the disease. Some mutations in the ALPL gene have been reported to cause an autosomal dominant form of the condition, meaning only 1 copy of the ALPL gene mutation is needed to have symptoms. In the autosomal dominant form, a parent is typically affected or is at risk of developing symptoms. Generally the symptoms in the autosomal dominant form are more mild and do not develop until middle age. The most-common symptoms are early tooth loss and frequent, slow-healing stress fractures in the feet and arthritis. Rarely, more severe symptoms may be seen in childhood.

How Common Is Hypophosphatasia?

Hypophosphatasia affects approximately 1 in 100,000 individuals and is most common in Caucasians. The disease is particularly common in a particular Mennonite population in Ontario, Canada, where it affects 1 in 2,500 individuals.

How Is Hypophosphatasia Treated?

Infants with the most severe form of the condition usually require mechanical help to breathe and may need surgery to release pressure within the skull. Vitamin B6 may relieve seizures. Children and adults with hypophosphatasia should see a dentist every year, beginning at the age of one, to preserve teeth as long as possible. Adults will eventually need false teeth. Aspirin, ibuprofen, and other pain relievers help with bone pain and arthritis. Although preventing bone fractures is difficult, orthotics may help with common fractures in the feet.

Individuals with the condition should not take bisphosphonates, which are drugs commonly prescribed to treat other bone-loss conditions such as osteoporosis. They should also avoid excess vitamin D, which can make calcium build up in the blood.

What Is the Prognosis for an Individual with Hypophosphatasia?

Approximately 50% of infants born with the severe form of the condition will die of respiratory failure in infancy. Exact lifespan for the rest is not known. Individuals with the milder forms of the condition have normal lifespans.