Hypophosphatasia

Hypophosphatasia is a rare genetic condition that causes bones and teeth to become soft and weak, affecting people in very different ways depending on when symptoms first appear and how severe they are.

Table of contents

• What is hypophosphatasia?
• Medical identification codes
• Other names
• Types of hypophosphatasia
• What causes hypophosphatasia?
• Signs and symptoms
• How is hypophosphatasia diagnosed?
• Treatment options
• How common is it?

What is hypophosphatasia?

Hypophosphatasia (HPP) is a rare genetic condition that affects how bones and teeth develop and stay strong. The condition makes bones and teeth soft and weak by interfering with a process called mineralization, which is when minerals like calcium and phosphorus are absorbed into bones and teeth to make them hard and sturdy^[1][2].

HPP is considered a type of metabolic bone disease, meaning it affects how the body processes minerals needed for healthy bones^[1]. The condition ranges widely in how serious it is. In mild cases, it mainly increases the risk of broken bones in adulthood. In the most severe cases, it can cause stillbirth or death shortly after birth^[1][3].

No two cases of HPP are exactly the same, even within the same family. The symptoms and their severity depend mainly on when they first appear and how much the body’s enzyme activity is affected^[1][3].

Medical identification codes

E83.3

Other names

Rathbun disease, Rathbun’s syndrome, phosphoethanolaminuria, deficiency of alkaline phosphatase

Types of hypophosphatasia

There are seven major forms of hypophosphatasia. These types are based on when symptoms begin and how severe they are. Generally, the earlier symptoms appear, the more serious the condition tends to be, though this is not always the case^[1][6].

Perinatal severe hypophosphatasia is the most serious form. Healthcare providers can usually see signs before birth using ultrasound during pregnancy. Babies may have short, bowed arms and legs that are underdeveloped, along with poorly formed ribs and chest deformities. Some pregnancies end in stillbirth. Babies born with this form may die within days from breathing failure due to chest weakness^[1][3].

Perinatal benign hypophosphatasia shows bowed arms and legs at birth that healthcare providers can see on ultrasound during pregnancy. However, unlike the severe form, the bone problems gradually improve after birth. Symptoms that develop later can range from those seen in infantile HPP to only dental problems^[1].

Infantile hypophosphatasia usually becomes noticeable within the first six months of a baby’s life. Babies may have trouble gaining weight and growing properly. They may lose baby teeth early, have soft and misshapen bones similar to rickets, experience breathing difficulties, and have weak muscle tone that makes them seem “floppy”^[1][2]. In some cases, the bone problems improve on their own during early childhood, but treatment is still important to prevent permanent complications like short stature and misshapen bones^[1].

Childhood hypophosphatasia can be mild or severe. Children may experience delayed walking, bone pain, muscle weakness, and early loss of baby teeth with the root still intact. Some children have frequent bone fractures, especially in their feet, while others may have only mild symptoms^[1][2].

Adult hypophosphatasia typically causes bone pain, joint problems, and frequent fractures, especially in the feet and legs. Adults may experience stress fractures, severe muscle and joint pain, headaches, fatigue, and dental problems. Many adults with HPP remember having symptoms during childhood but never received a diagnosis^[1][11].

Odontohypophosphatasia only affects teeth and leads to early loss of baby teeth, usually before age 5, with the root still intact. This form does not cause skeletal problems and often goes undiagnosed^[1][2].

Pseudohypophosphatasia is an extremely rare form where people have normal levels of the enzyme alkaline phosphatase but still have symptoms similar to the infantile form^[1].

What causes hypophosphatasia?

HPP is caused by changes, called mutations, in the ALPL gene. This gene normally produces an enzyme called alkaline phosphatase (ALP) that helps bones and teeth absorb minerals properly^[2][5].

Your body has chemicals that prevent too much mineralization in places where it shouldn’t happen, like in blood vessels. The ALP enzyme keeps these mineral-blocking chemicals from affecting bones and teeth, allowing minerals to strengthen them where needed^[2].

When the ALPL gene is mutated, the enzyme cannot do its job properly. Mineral-blocking chemicals build up where they shouldn’t, keeping minerals from getting into bones and making them softer than normal^[2][5].

The condition can be inherited in different ways. People with two gene mutations—one from each parent—tend to have more severe disease. Those with one mutation usually have a milder version that appears later in life^[2][19]. More than 400 different mutations in the ALPL gene have been identified in patients with HPP^[6][15].

Signs and symptoms

Hypophosphatasia causes many different symptoms throughout the body. Which symptoms someone experiences depends mainly on which type of HPP they have^[1][2].

Common symptoms across different ages include soft, weak, or deformed bones that break easily. Babies and young children may have bowed arms and legs, wider than normal wrist and ankle bones, problems with chest and rib bones, and breathing difficulties. They may also experience poor muscle tone that makes them seem floppy, trouble gaining weight and growing, and early loss of baby teeth with the root still intact^[1][2].

Some infants experience abnormal skull bone fusion, called craniosynostosis, which can lead to a misshapen head and increased pressure inside the skull. This can cause headaches and bulging eyes. In rare cases, babies may have seizures^[1][3].

Children may have delayed motor development, meaning they take longer to reach milestones like walking. They often experience painful bones and joints, difficulty walking, and problems keeping up physically with other children their age^[2][19].

Adults commonly experience bone and joint pain, frequent fractures especially in the feet and legs, muscle weakness, fatigue, and unexpected tooth loss. Many adults also report headaches, body aches, joint swelling, depression, and dental issues^[2][11].

Some people with HPP may have high levels of calcium in the blood, called hypercalcemia, which can cause vomiting, constipation, weakness, and kidney problems. The condition can also cause calcium deposits in tissues, leading to painful kidney stones or inflammatory arthritis^[1][11].

Many people with HPP need assistive devices like walkers or wheelchairs to help them move around^[5][26].

How is hypophosphatasia diagnosed?

Diagnosing HPP requires combining several pieces of information. Doctors look at symptoms, test results, imaging studies, and genetic testing^[2][3].

The most important laboratory finding is persistently low alkaline phosphatase (ALP) activity in the blood for a person’s age and sex. This is a hallmark feature of HPP^[3][5]. However, laboratory results sometimes only flag ALP levels as abnormal if they are too high, so doctors need to specifically look for low levels^[11].

Doctors also measure elevated levels of ALP substrates—substances that build up when the enzyme is not working properly. These include pyridoxal 5′-phosphate (PLP), inorganic pyrophosphate (PPi), and phosphoethanolamine (PEA) in urine^[3][12].

Imaging studies like X-rays, CT scans, or ultrasounds can show signs of poor bone mineralization, rickets-like features, or bone deformities. In babies, ultrasound during pregnancy may reveal skeletal problems before birth^[1][14].

Genetic testing confirms the diagnosis by identifying mutations in the ALPL gene. This testing can also help predict how severe the condition might be and whether other family members are at risk^[3][5].

Taking a thorough health history is also important. Doctors may ask seemingly unusual questions that can point to HPP, such as whether the person lost teeth with the root intact as a child or had serious dental problems as a teenager^[11].

HPP is often misdiagnosed because it is rare and its symptoms can look like other more common conditions such as osteoporosis, osteopenia, or fibromyalgia^[4][11]. Many patients go years without a correct diagnosis^[11][21].

Treatment options

Treatment for hypophosphatasia must be tailored to each person’s specific needs and involves multiple approaches^[12].

The main treatment for HPP is enzyme replacement therapy (ERT) using a medication called asfotase alfa (Strensiq). This drug was approved by the FDA in 2015 and is the first treatment specifically for HPP^[5][13]. It replaces the missing alkaline phosphatase enzyme that people with HPP lack.

Studies have shown that asfotase alfa can be life-changing for patients. It has improved survival rates dramatically—97% of patients receiving the drug were alive at age 1 year compared with only 42% of untreated patients. The treatment also improves bone mineralization, respiratory function, growth, and functional outcomes in severely affected children^[13][15].

The medication is given by injection under the skin, typically three to six times per week. While it is not something that works overnight, many patients see dramatic improvements over six months to a year. It has allowed many people to go back to work and live normal lives^[11][20].

Supportive care is also important and may include pain management with medications, physical therapy to improve mobility and strength, orthopedic care for bone problems and fractures, dental care for tooth problems, and respiratory support for breathing difficulties when needed^[3][12].

Some patients may need surgery to address skeletal abnormalities, correct bone deformities, or manage fractures. In cases of craniosynostosis, neurosurgical intervention may be necessary^[3][24].

Orthotic devices, mobility aids, or adaptive equipment can provide support and enhance mobility for people with HPP^[24].

It is very important that patients with HPP avoid bisphosphonates and other antiresorptive medications commonly used to treat osteoporosis. These drugs can make HPP worse by further lowering ALP levels^[13][16].

Because HPP affects many body systems, care should involve a team of specialists including endocrinologists, orthopedists, dentists, geneticists, neurologists, and physical therapists^[3][12].

How common is it?

Hypophosphatasia is rare in the general population. Severe forms affect approximately 1 in 100,000 to 1 in 300,000 babies born each year^[1][6].

However, mild forms of the condition, such as adult HPP, are more common and affect around 1 in 6,000 to 1 in 7,000 people^[1].

HPP is more frequent in certain populations. In the Mennonite population in Manitoba, Canada, about 1 in 2,500 babies have severe forms of the condition^[1][4].

Because HPP is often misdiagnosed or undiagnosed, especially in its milder forms, the actual number of people affected may be higher than current estimates suggest^[2][11].