Hypophosphatasia (HPP)

Hypophosphatasia (HPP)

What is hypophosphatasia?

Hypophosphatasia, sometime shortened to HPP, is a rare inherited disorder that affects the development of bones and teeth. In children and adults with hypophosphatasia, the bones and teeth do not absorb enough calcium and phosphorus. This mineralization process is required for healthy bones and teeth. With insufficient mineralization, bones can be soft and easy to fracture and can become deformed. Teeth may not be hard enough to bite and chew some foods. The disorder can also lead to early loss of baby teeth and dental problems later in life.

Signs and symptoms of hypophosphatasia

The signs and symptoms of hypophosphatasia can vary widely, as can the severity of their effects. In general, the younger the age when symptoms occur, the more severe the effects of the disorder, though this is not always the case. Some children with hypophosphatasia have severe health problems, while others have only mild symptoms that improve as they grow into adulthood.
Hypophosphatasia is classified into types based on when the condition is diagnosed.

  • Perinatal hypophosphatasia: In the most severe cases, significant symptoms develop and are detected before birth. The infant may be born with short, bowed arms and legs and underdeveloped ribs. Weakness and deformity in the chest can lead to life-threatening breathing problems.
  • Prenatal and infantile hypophosphatasia: When infants are born with less noticeable signs of HPP or no signs at all, other symptoms within the first six months can be indications of the condition. These may include poor feeding, frequent vomiting, a failure to gain weight, breathing problems or seizures. Soft, weak or deformed bones are another sign. In some infants, the bones of the skull may fuse at the growth seams rather than remaining separate (a condition known as craniosynostosis), leading to pressure on the developing brain.
  • Childhood or juvenile hypophosphatasia: When symptoms first appear in childhood, after 6 months of age, they can include the early loss of baby teeth or a delayed start to walking. Once walking, the child may develop a waddling gait. Skeletal malformations, such as bowed legs or knock knees, can become noticeable as the child begins to walk. The wrists or ankles may become swollen. The bones of the skull may fuse (craniosynostosis) and restrict growth. The child may experience bone and joint pain and muscle weakness.
  • Adult hypophosphatasia: In some cases, no diagnosis is made until a person has reached adulthood, though symptoms may have occurred in childhood. Symptoms in adulthood can include repeated bone fractures, swelling in joints and the premature loss of adult teeth.
  • Odontohypophosphatasia: In the least severe form of the condition, only the teeth are affected and not the bones. Early loss of baby teeth may be the only symptom, or adult teeth may develop abnormally.

Causes of hypophosphatasia

Hypophosphatasia is caused by mutations in the ALPL gene, which directs the production of an enzyme — tissue nonspecific alkaline phosphatase (TNSALP) — that is required for healthy mineralization of bones and teeth. With ineffective or insufficient TNSALP in the body, calcium and phosphate are unable to move from the blood to the bones and teeth. These and other minerals build up in the blood and urine while bones and teeth become weakened and underdeveloped.

Genetics

HPP can occur due to mutations (changes) in one or both copies of the ALPL gene

  • The more severe forms of the disorder, including perinatal, prenatal and infantile hypophosphatasia, are typically autosomal recessive conditions, in which the affected child has two nonworking copies of the ALPL gene. In some cases, the child inherits a nonworking copy from each parent. In other cases, one or both mutations may be new mutations that first occurred in the child, which is also called occurring de novo.
  • Milder forms of the disorder, including adult hypophosphatasia and odontohypophosphatasia, are usually an autosomal dominant condition, in which the affected child has one nonworking copy of the ALPL gene. In some cases, the child inherits the nonworking copy from a parent. In other cases, the mutation can be new mutations that first occurred in the child. 
  • Childhood HPP may be inherited in either an autosomal recessive or autosomal dominant pattern.
  • Parents who carry one nonworking copy of the ALPL may or may not have any symptoms of HPP.

How is hypophosphatasia diagnosed?

If hypophosphatasia or another type of rickets is suspected, your healthcare provider will:

  • Take a complete medical history to understand the occurrence of symptoms.
  • Perform a physical exam.
  • Ask about any history of similar or related symptoms in other family members.
  • Do blood and urine tests to check for raised or reduced levels of certain compounds and enzymes. Low blood levels of alkaline phosphatase (ALP) and high blood levels of pyridoxal 5'-phosphate (PLP, also known as vitamin B6) are characteristic of hypophosphatasia, as are high urine levels of phosphate compounds.

In infants and young children, X-rays or other imaging studies may be done to examine the appearance of the bones and determine bone density. Genetic testing can support, but is not required for, a diagnosis of hypophosphatasia. Genetic testing can be valuable in understanding the inheritance pattern of the disorder.

Treatment for hypophosphatasia

Whether or not a child needs treatment for HPP, and what type of treatment is needed, will depend on how severe the disease is.

Enzyme replacement therapy with asfotase alfa (Strensiq®) has been the primary treatment for severe forms of hypophosphatasia in children since 2015, when it was approved for this use by the Food and Drug Administration (FDA). Given by injection, usually once a week, asfotase alfa replaces missing or ineffective TNSALP and enables healthy mineralization of the bones and teeth.

Other treatments can address specific symptoms and complications. These treatments may include:

  • Non-steroidal anti-inflammatory drugs (NSAIDs) for relief of bone and joint pain
  • Vitamin B6 to help to control seizures in severely affected infants
  • Breathing and feeding support for severely affected infants
  • Physical and occupational therapy
  • Dental care to preserve teeth or replace lost teeth with dentures, bridges or dental implants
  • Surgery to separate fused skull bones or a shunt to relieve the pressure fusing may cause
  • Orthopedic surgery repair fractured bones or correct misaligned joints
  • Dietary changes to limit the amount of calcium and vitamin D intake

Genetic counseling may be helpful for children diagnosed with hypophosphatasia and their families. Understanding how the disorder is inherited and what testing is available can help families make informed decisions as they consider having more children.

Follow-up care

Ongoing care, coordinated by a primary care physician or specialist who is knowledgeable about hypophosphatasia is essential to the long-term health and well-being of children with HPP. Because the disorder can affect different body functions, coordinated care by a team of appropriate specialists is needed.

Treatment of hypophosphatasia at Children’s Hospital of Philadelphia (CHOP) is managed by the Center for Bone Health, which provides comprehensive, coordinated care in collaboration with other pediatric specialties, as needed.

Depending on the patient’s diagnosis and condition, coordinated care might include specialists in:

  • Orthopedics
  • Endocrinology
  • Pain management
  • Dental care
  • Physical and occupational therapy
  • Nutrition
  • Genetics