What is Hypophosphatasia?
Hypophosphatasia (HPP), caused by harmful genetic changes (mutations) in the ALPL gene, is an inherited disorder that disrupts the body's ability to deposit 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 arms and legs; an abnormally shaped chest caused by soft, weak ribs; and soft skull bones. 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 less-severe forms, the first sign of the condition is loss of baby teeth before the age of five. As children grow, they may be below average height, and they may have abnormal curvature in their legs, large ankle and wrist joints, and an abnormally shaped skull (craniosynostosis). 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 it affects only the teeth. Individuals with this form of the condition have atypical tooth development and lose their teeth early, but they do not experience skeletal abnormalities.
Additional considerations for carriers
Usually HPP is inherited in an autosomal-recessive manner, meaning both parents must carry a mutation in ALPL for their children to be at risk of developing HPP. In the autosomal-recessive form, carriers may experience no symptoms, or they may show mild symptoms. However, some mutations in ALPL cause an autosomal-dominant form of the condition, meaning symptoms will occur with only one ALPL mutation. In the autosomal-dominant form, a parent is affected or is at risk of developing symptoms. Generally, the symptoms in the autosomal-dominant form are milder and do not develop until middle age. The most common symptoms are early tooth loss; frequent, slow-healing stress fractures in the feet; and arthritis. Rarely, more severe symptoms develop in childhood.
How common is Hypophosphatasia?
The incidence of HPP is estimated between 1 in 100,000 to 1 in 200,000 births. The exact incidence is difficult to determine because most estimates are based on the more severe forms of disease and are, therefore, likely to be underestimates. The disease is particularly common in the Canadian Mennonite population where it affects an estimated 1 in 2,500 individuals.
How is Hypophosphatasia treated?
Enzyme replacement therapy can be used to treat individuals with the most severe and childhood forms of HPP. Individuals treated with enzyme replacement therapy have had improved survival rates and showed improvements in bone health and growth. However, the long-term effects of this treatment are not known.
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 HPP 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 lifespans for the remaining 50% is not known. Individuals with the milder forms of the condition have normal lifespans.