Hypophosphatasia

What is the hypophosphatasia?

Hypophosphatasia (HPP) is a rare genetic (inherited) condition that affects how your bones and teeth develop. Specifically, it makes them soft and weak by affecting how they mineralize (calcify). HPP is a type of metabolic bone disease.

HPP ranges widely in severity. At its most mild, it significantly increases your risk of stress fractures in middle age. At its most severe, it can result in stillbirth or death shortly after birth.

Types of hypophosphatasia

There are seven major forms of hypophosphatasia based on the age at which symptoms begin and their severity. The types of HPP from most to least severe include:

• Perinatal (before birth) severe hypophosphatasia
• Perinatal benign hypophosphatasia
• Infantile (after birth) hypophosphatasia
• Childhood hypophosphatasia (mild or severe)
• Adult hypophosphatasia
• Odontohypophosphatasia (this only affects your teeth and leads to early loss of baby — or deciduous — teeth)
• Pseudohypophosphatasia (an extremely rare form of HPP in which you have normal levels of alkaline phosphatase but have symptoms common to those of the infantile form)

How common is hypophosphatasia?

Hypophosphatasia is rare in the general population. Severe forms affect 1 in 100,000 to 1 in 300,000 babies born each year. But mild forms of the condition (like adult HPP) are more common. They affect around 1 in 6,000 to 1 in 7,000 people.

Of note, HPP is more frequent in the Mennonite population in Manitoba, Canada. About 1 in 2,500 babies in this population have severe forms of the condition.

What are the symptoms of hypophosphatasia?

Hypophosphatasia causes lots of different symptoms. No two cases are the same — even cases within the same biological family. Which symptoms you experience usually depends on which type of HPP you have.

Symptoms of perinatal HPP

Healthcare providers can usually see signs of perinatal HPP in fetuses via ultrasound during pregnancy. They include:

• Short, bowed arms and legs that are underdeveloped (under-mineralized)
• Underdeveloped ribs
• Chest deformity (flail chest)

Some pregnancies end in stillbirth. Some babies born with perinatal HPP may die after several days from respiratory failure due to chest weakness.

Symptoms of perinatal benign HPP

At birth, infants with perinatal benign HPP have bowed arms and legs. Healthcare providers can typically see this with ultrasound during the pregnancy.

The bone malformations improve gradually after birth. The symptoms that later develop can range from those of infantile HPP to odontohypophosphatasia.

Symptoms of infantile HPP

Symptoms of infantile HPP usually become noticeable within the first six months of a baby’s life. They may include:

• Issues with weight gain and growth
• Early loss of baby teeth
• Abnormal skull bone fusion (craniosynostosis), which can lead to a misshapen head (brachycephaly)
• Increased pressure in their skull (intracranial hypertension), which can cause headaches and bulging eyes (proptosis)
• Soft and misshapen bones that resemble rickets
• Widened bones in their wrists and ankles
• Misshapen chest and rib bones and fractures (breaks) in these bones
• Breathing difficulties
• Episodes of fever with bone pain
• Lack of muscle tone (hypotonia), which people sometimes call “floppy infant syndrome”
• Hypercalcemia, which can cause vomiting, constipation, fatigue and poor feeding
• Seizures (this is rare)

In some cases, the bone mineralization issues in infantile HPP can improve randomly during early childhood. But it’s still important to get treatment to avoid permanent complications like a short stature and misshapen bones.

Symptoms of childhood HPP

Childhood HPP can range from mild to severe. Symptoms can include:

• Low bone mineral density for their age with unexplained fractures (most common signs of the mild form)
• Craniosynostosis with intracranial hypertension
• Misshapen bones that become apparent at 2 to 3 years
• Bone and joint pain
• Losing baby (deciduous) teeth prematurely. This typically means one or more baby teeth fall out before the age of 5
• Weakness with a delay in walking (not taking first steps by 18 months of age)
• Waddling gait (walking pattern)

In some cases, childhood HPP can spontaneously improve in young adulthood. But complications can return during middle age or late adulthood.

Symptoms of adult HPP

Adult HPP has wide-ranging symptoms, which may include:

• Softened bones (osteomalacia)
• Bone pain
• Loss of adult teeth (some people with adult HPP have a history of rickets during childhood or premature baby teeth loss)
• Bone fractures, especially stress fractures in the metatarsal bones in your feet or pseudofractures (Looser zones) in your femur
• Repeated fractures, which can cause chronic pain and weakness
• Joint inflammation and/or pain due to calcific periarthritis
• Sudden, severe arthritis (chondrocalcinosis or pseudogout)

Symptoms of odontohypophosphatasia

Odontohypophosphatasia only affects your teeth — not your skeletal bones. The main signs are losing your baby teeth prematurely — in infancy or early childhood. Some people experience unexpected adult tooth loss in adulthood.

What causes hypophosphatasia?

Genetic variants (changes) cause hypophosphatasia — specifically, variants in the ALPL gene. Normally, this gene provides instructions for your body to make an enzyme called tissue-nonspecific alkaline phosphatase (TNSALP). This enzyme is necessary for your bones and teeth to mineralize (harden). Variants that affect how the ALPL gene produces TNSALP mean that it can’t do its job properly (or at all).

Bone mineralization is the process by which the bone matrix becomes filled with calcium phosphate nanocrystals (the “hard” substances in your bones). Bone matrix is made of proteins like collagen mixed with calcium, phosphate and other minerals.

Genetic variants that almost completely block the function of TNSALP usually result in the more severe forms of hypophosphatasia. Other variants, which reduce but don’t totally block the activity of TNSALP, often cause milder forms of the condition.

How is hypophosphatasia inherited?

You inherit the severe forms of hypophosphatasia, like perinatal hypophosphatasia, in an autosomal recessive pattern. This means that both biological parents need to pass an altered ALPL gene on to their child. In most cases, biological parents don’t experience HPP symptoms and don’t know they carry the gene variant that causes it.

Milder forms of hypophosphatasia can have either an autosomal recessive or an autosomal dominant pattern. The latter pattern means that only one biological parent needs to have an altered ALPL gene to pass it on to their child.

How is hypophosphatasia diagnosed?

Healthcare providers use physical exams, imaging tests and laboratory tests to diagnose hypophosphatasia. Providers who are familiar with the condition typically spot it quickly. But it may take longer for providers who are unfamiliar with HPP to diagnose it.

Tests that can help lead to an HPP diagnosis include:

• Alkaline phosphatase (ALP) blood tests. ALP is an enzyme that plays a role in bone mineral density. People with HPP typically have low ALP levels for their age. Other conditions can cause low ALP levels, so this test can’t confirm the diagnosis.
• Pyridoxal 5ʹ-phosphate (PLP) blood test. PLP is a form of vitamin B6. People with HPP usually have high levels of PLP.
• X-rays. In severe forms of HPP, X-rays can show bone malformations characteristic of the condition. There are other causes of bone issues, so your child’s provider may not recognize it as HPP right away.
• Genetic testing. This can detect variants in the ALPL gene that cause HPP. However, not all laboratories offer this test.

How is hypophosphatasia treated?

There’s no cure for hypophosphatasia. But a medication injection called asfotase alfa (Strensiq®) is the main treatment that can help manage it. It’s a subcutaneous (under the skin) injection that works as a TNSALP enzyme replacement therapy. Children and adults who develop symptoms in childhood can use the medication.

Studies show that asfotase alfa can improve breathing function, calcium levels, bone health and survival in children with the infantile and early childhood (juvenile) type of HPP.

Other treatments for HPP mainly help to manage specific symptoms and complications. Your child may need a team of experts for their care, including:

• Pediatricians
• Orthopedists
• Pediatric endocrinologists
• Pediatric neurosurgeons
• Nephrologists
• Periodontists
• Pain management specialists
• Physical therapists
• Occupational therapists

Examples of supportive treatments include:

• Respiratory support for breathing difficulties
• Helmet therapy or surgery for craniosynostosis
• A shunt or skull surgery for intracranial hypertension
• Vitamin B6 for seizures due to HPP
• Regular dental care starting at an early age to assess tooth issues
• Dietary calcium restriction, certain diuretics and calcitonin injections for hypercalcemia
• Nonsteroidal anti-inflammatory drugs (NSAIDs) for bone and joint pain
• Bone fracture treatments, like casts and splints, or surgery (internal fixation) to repair broken bones

Can I prevent hypophosphatasia?

You can’t prevent hypophosphatasia because it’s a genetic condition.

Talk to your healthcare provider about genetic counselingif you’re concerned about the risk of passing on hypophosphatasia or other genetic conditions to your biological children.

What can I expect if my child has hypophosphatasia?

It’s important to remember that no two people with hypophosphatasia are affected in the same way. It’s impossible to predict how the condition will affect your child as they grow. The best way you can prepare is to talk to healthcare providers who specialize in researching and treating HPP, if possible. They’ll tell you which symptoms or changes to look out for and what the future might hold.

How do I take care of my child with hypophosphatasia?

If your child has HPP, it’s important to advocate for them to ensure they get the best medical care. Some healthcare providers you come across may not be familiar with this rare condition. Advocating for care can help your child have the best possible quality of life.

You and your family may also want to consider joining a support group to meet others who can relate to your experiences.

When should my child see their healthcare provider?

If your child has hypophosphatasia, they’ll need to see their team of healthcare providers regularly to receive treatment and monitor their symptoms.