Hypophosphatasia

The signs and symptoms of hypophosphatasia vary widely and can appear anywhere from before birth to adulthood. The most severe forms of the disorder tend to occur before birth and in early infancy. Hypophosphatasia weakens and softens the bones, causing skeletal abnormalities similar to another childhood bone disorder called rickets. Affected infants are born with short limbs, an abnormally shaped chest, and soft skull bones. Additional complications in infancy include poor feeding and a failure to gain weight, respiratory problems, and high levels of calcium in the blood (hypercalcemia), which can lead to recurrent vomiting and kidney problems. These complications are life-threatening in some cases.^[1]

The forms of hypophosphatasia that appear in childhood or adulthood are typically less severe than those that appear in infancy. Early loss of primary (baby) teeth is one of the first signs of the condition in children. Affected children may have short stature with bowed legs or knock knees, enlarged wrist and ankle joints, and an abnormal skull shape. Adult forms of hypophosphatasia are characterized by a softening of the bones known as osteomalacia. In adults, recurrent fractures in the foot and thigh bones can lead to chronic pain. Affected adults may lose their secondary (adult) teeth prematurely and are at increased risk for joint pain and inflammation.^[1]

The mildest form of this condition, called odontohypophosphatasia, only affects the teeth. People with this disorder typically experience abnormal tooth development and premature tooth loss, but do not have the skeletal abnormalities seen in other forms of hypophosphatasia.^[1]

Hypophosphatasia (HPP) is a genetic condition caused by mutations in the ALPL gene. This gene gives the body instructions to make an enzyme called alkaline phosphatase, which is needed for mineralization of the bones and teeth. Mutations in this gene lead to an abnormal version of the enzyme, thus affecting the mineralization process. A shortage of the enzyme also causes other substances to build up in the body. These abnormalities lead to the features of HPP.

ALPL mutations that almost completely eliminate alkaline phosphatase activity generally cause the more severe forms of HPP, while mutations that reduce activity to a lesser extent often cause the milder forms of HPP.^[1]

Perinatal (onset before birth) and infantile hypophosphatasia (HPP) are inherited in an autosomal recessive manner.^[2] This means that to be affected, a person must have a mutation in both copies of the responsible gene (ALPL) in each cell. Affected people inherit one mutated copy of the gene from each parent, who is referred to as a carrier. Carriers of an autosomal recessive condition typically do not have any signs or symptoms (they are unaffected). When 2 carriers of an autosomal recessive condition have children, each child has a:

• 25% (1 in 4) chance to be affected
• 50% (1 in 2) chance to be an unaffected carrier like each parent
• 25% chance to be unaffected and not be a carrier.

The milder forms, especially adult HPP and odontohypophosphatasia, may be inherited in an autosomal recessive or autosomal dominant manner - depending on the effect the ALPL mutation has on enzyme activity.^[2] In autosomal dominant inheritance, having a mutation in only one copy of the ALPL gene in each cell is enough to cause features of the condition. When a person with a mutation that causes an autosomal dominant HPP has children, each child has a 50% (1 in 2) chance to inherit that mutation.

Most people with autosomal dominant HPP have inherited the mutation from a parent who may or may not have symptoms. Not all people with a mutation that causes autosomal dominant HPP develop symptoms of the condition. While it is possible to have autosomal dominant HPP due to a new mutation that was not inherited (a de novo mutation), this has never been reported in HPP.^[2]

Until recently, management of hypophosphatasia (HPP) has mostly been aimed at addressing symptoms of the condition.^[5] For example:

• Hydration, restriction of dietary calcium, vitamin D, and sometimes thiazide diuretics for hypercalcemia
• Ventilatory support for severely affected infants, some of which need a tracheostomy, which can lead to problems with speech and language development and tolerance of oral feeds
• Physiotherapy, occupational therapy and chronic pain management for pain and motor difficulty
• Surgery for fractures that fail to heal

More recently, research has shown positive effects of human recombinant enzyme replacement therapy (ERT), called asfotase alfa, on people who began having symptoms before 6 months of age. There reportedly have been significant improvements in the X-ray appearances of bone tissue, along with improvements in growth, respiratory function, motor development and calcium homeostasis after 6–12 months of treatment. The children in the original study have now received more than three years of treatment, without apparent major side effects, and with continuing improvement in affected systems.^[5] Asfotase alfa appears to be a valuable emerging therapy for the treatment of bone manifestations in people with pediatric-onset HPP.^[4] In October of 2015 the FDA approved asfotase alfa, sold as Strensiq.^[3]

Bone marrow and stem cell transplantation in infancy and childhood have improved the severity of the disease, but have not provided long term improvement.^[5]