In short
Hypophosphatasia is a rare genetic condition that weakens bones and teeth, making them soft and prone to damage. This inherited disorder can appear at any age, from before birth through adulthood, and varies dramatically in its impact—from life-threatening complications in newborns to milder symptoms like stress fractures in middle-aged adults.
Key points
- Hypophosphatasia is caused by mutations in the ALPL gene, resulting in deficient alkaline phosphatase enzyme activity that prevents proper bone and tooth mineralization.
- The condition affects approximately 1 in 100,000 to 1 in 300,000 babies in severe forms, but milder forms are more common, affecting around 1 in 6,000 to 1 in 7,000 people.
- Symptoms vary dramatically from life-threatening respiratory problems in newborns to stress fractures and dental issues in adults, with no two cases being exactly the same.
- Early tooth loss with the root still intact before age five is one of the most recognizable signs of HPP, though this symptom often goes unrecognized.
- Many adults with HPP experience years of misdiagnosis, being told their symptoms are psychosomatic or related to more common conditions like fibromyalgia or depression.
- Enzyme replacement therapy with asfotase alfa, approved in 2015, has been life-changing for many patients, particularly infants who previously faced high mortality rates.
- The Mennonite population in Manitoba, Canada, experiences much higher rates of severe HPP—about 1 in 2,500 births—compared to the general population.
- HPP affects more than just bones and teeth, with patients experiencing muscle weakness, chronic pain, kidney problems, and neuropsychiatric symptoms that significantly impact quality of life.
Understanding Hypophosphatasia
Hypophosphatasia, often shortened to HPP, occurs when a person's body cannot produce enough of an important enzyme called alkaline phosphatase. This enzyme plays a crucial role in helping bones and teeth absorb minerals like calcium and phosphorus through a process called mineralization. When this process fails to work properly, bones become soft and weak, and teeth may fall out earlier than expected. The condition is caused by changes, or mutations, in a gene called ALPL, which provides instructions for making the alkaline phosphatase enzyme.
The condition affects people differently depending on how much alkaline phosphatase enzyme activity remains in the body. Generally, the less enzyme activity present, the more severe the symptoms tend to be. Some people experience only mild dental problems, while others face serious complications affecting their breathing, bones, and overall health.
HPP can be inherited in different ways. When a person receives two mutated genes—one from each parent—the condition tends to be more severe. This is called autosomal recessive inheritance. When someone inherits just one mutated gene, the symptoms are usually milder and appear later in life. This is known as autosomal dominant inheritance.
How Common Is Hypophosphatasia?
Hypophosphatasia is considered a rare disease, though its exact frequency varies depending on the severity of symptoms. The most severe forms affect approximately 1 in 100,000 to 1 in 300,000 babies born each year worldwide. However, milder forms of the condition are more common than previously thought, affecting around 1 in 6,000 to 1 in 7,000 people in the general population.
Certain populations experience HPP at higher rates. The Mennonite community in Manitoba, Canada, for example, has a notably higher frequency of severe forms, with about 1 in 2,500 babies born with the condition. This difference exists because genetic mutations can become more common in populations where people with shared ancestry have children together.
Many experts believe that HPP is actually underdiagnosed, particularly in its milder forms. Adults with symptoms like bone pain, frequent fractures, or early tooth loss may go years without receiving a correct diagnosis. Some are mistakenly diagnosed with other conditions like fibromyalgia, depression, or osteoporosis.
What Causes Hypophosphatasia?
The root cause of hypophosphatasia lies in genetic mutations that affect the ALPL gene. This gene contains the blueprint for making tissue-nonspecific alkaline phosphatase, an enzyme essential for proper bone and tooth development. When mutations occur in this gene, the enzyme either cannot be produced at all or works improperly.
Under normal circumstances, bones and teeth build themselves up by incorporating calcium and phosphorus through mineralization. However, the body also produces chemicals that prevent mineralization from happening in the wrong places, such as in blood vessels. Alkaline phosphatase keeps these mineral-blocking chemicals from affecting bones and teeth, allowing proper mineralization where it is needed.
When the ALPL gene is mutated, the enzyme cannot perform its job effectively. Mineral-blocking chemicals build up in places they should not, preventing minerals from getting into bones and teeth. This makes bones softer and weaker than normal, and teeth become fragile and prone to falling out. More than 400 different mutations in the ALPL gene have been identified in people with HPP, leading to highly variable symptoms even within the same family.
Risk Factors
The primary risk factor for developing hypophosphatasia is having parents who carry mutations in the ALPL gene. If both parents carry a mutation, their children have a higher chance of inheriting the condition in its more severe form. When only one parent carries the mutation, children may develop milder symptoms or become carriers themselves without showing any signs of the disease.
People with a family history of unexplained bone problems, early tooth loss, or skeletal abnormalities have an increased likelihood of carrying or developing HPP. Those who lost their baby teeth before age five with the root still intact, or who experienced severe dental problems as teenagers, may have undiagnosed hypophosphatasia.
Certain ethnic backgrounds carry higher risks. Individuals of Mennonite descent from Manitoba, Canada, face significantly higher odds of having or carrying mutations associated with severe HPP. Genetic counseling can help people understand their risk and make informed decisions about family planning.
Symptoms and How They Affect Patients
Hypophosphatasia causes a wide range of symptoms that vary dramatically from person to person. Even members of the same biological family with the condition may experience completely different symptoms. The type of symptoms and their severity usually depend on when the condition first appears and how much alkaline phosphatase enzyme activity remains in the body.
Perinatal Hypophosphatasia
The most severe form of HPP appears before or shortly after birth. Healthcare providers can often detect signs during pregnancy through ultrasound imaging. Affected babies may have short, bowed arms and legs that have not developed properly, underdeveloped ribs, and chest deformities. The weakness in the chest and rib structure can lead to serious breathing difficulties. Some pregnancies end in stillbirth, and some babies born with this form may die within days from respiratory failure if left untreated.
A milder perinatal form exists where babies are born with bowed arms and legs that gradually improve after birth. These infants may later develop symptoms ranging from mild dental issues to more significant bone problems.
Infantile Hypophosphatasia
Symptoms of infantile HPP usually become noticeable within the first six months of life. Babies may struggle with weight gain and growth, and their baby teeth may fall out earlier than expected. Parents might notice that their infant has an abnormally shaped head due to premature fusion of skull bones, a condition called craniosynostosis. This can lead to increased pressure inside the skull, causing headaches and eyes that appear to bulge forward.
Affected infants often have soft, misshapen bones that resemble rickets, a condition caused by vitamin D deficiency. Their wrists and ankles may appear wider than normal, and their chest and rib bones may be deformed or fractured. Breathing can become difficult, and episodes of fever accompanied by bone pain are common. Many babies with infantile HPP have poor muscle tone, often described as "floppy infant syndrome," making it hard for them to hold their head up or move normally.
High calcium levels in the blood, called hypercalcemia, can cause vomiting, constipation, fatigue, and poor feeding. In rare cases, affected babies may experience seizures. Some children with infantile HPP see their bone problems improve randomly during early childhood, though treatment is still important to prevent permanent complications like short stature and bone deformities.
Childhood Hypophosphatasia
Children diagnosed with HPP may experience a wide range of symptoms. Some have early loss of baby teeth with roots intact, which is one of the most recognizable signs of the condition. Others develop bone pain, frequent fractures, and difficulty keeping up with their peers during physical activities. Affected children may have delayed motor skill development, meaning they learn to walk, run, and climb later than other children their age.
The bones in their wrists, knees, and ankles may appear wider on X-rays, and they may develop bowed legs. Short stature is common, and some children experience chronic pain that makes it hard to participate in school activities or play with friends. Muscle weakness can make everyday tasks like climbing stairs or getting up from a sitting position challenging.
Adult Hypophosphatasia
Adults with HPP often experience symptoms that are mistaken for other, more common conditions. Persistent bone and joint pain, generalized muscle weakness, and chronic fatigue are frequent complaints. Many adults report a lifetime of subtle symptoms they never connected to a single condition—such as losing adult teeth unexpectedly, experiencing frequent stress fractures in the feet and legs, or having difficulty with activities that require prolonged standing or walking.
One characteristic finding in adults with HPP is the development of pseudofractures, which are incomplete breaks in bones that appear as lines on X-rays. These typically occur in the thighs and feet and can be extremely painful. Without proper diagnosis and treatment, they may fail to heal properly. Some adults develop sudden, serious arthritis or experience calcium deposits in their joints and soft tissues, leading to pain and inflammation.
Many adults with HPP also experience non-skeletal symptoms that significantly affect their quality of life. These can include headaches, depression, anxiety, gastrointestinal problems, and neuropsychiatric symptoms. The chronic pain and physical limitations can make it difficult to work, exercise, or maintain social relationships.
Odontohypophosphatasia
This form of HPP affects only the teeth, without causing noticeable skeletal problems. People with odontohypophosphatasia lose their baby teeth before age five, often with the root still intact. They may also experience unexpected loss of adult teeth or have severe dental problems throughout life. This form often goes undiagnosed because the symptoms seem limited to dental issues.
Prevention
Because hypophosphatasia is a genetic condition caused by inherited mutations, there is no way to prevent it from developing in someone who has inherited the affected genes. However, families with a history of HPP or who have had a child with the condition can take steps to understand their risk and make informed decisions.
Genetic counseling provides valuable information for individuals and families affected by HPP. A genetic counselor can explain the inheritance patterns, help people understand the likelihood of passing the condition to future children, and discuss available options. For families who know they carry mutations in the ALPL gene, prenatal testing during pregnancy can detect whether a developing baby has inherited the condition.
For people already diagnosed with HPP, preventing complications involves working closely with a team of healthcare specialists. Regular monitoring can catch problems early, and appropriate treatment can help prevent fractures, improve bone strength, and maintain quality of life. Physical therapy and careful attention to bone health can reduce the risk of serious complications.
Adults diagnosed with HPP should avoid certain medications used to treat osteoporosis, called bisphosphonates, as these can make HPP symptoms worse. It is important for anyone with HPP to inform all their healthcare providers about their diagnosis so that treatment plans can be adjusted appropriately.
How the Body Changes in Hypophosphatasia
Understanding how hypophosphatasia affects the body requires looking at what happens at the cellular and chemical level. The changes go beyond just weak bones—they affect multiple systems throughout the body in complex ways.
In healthy bones, specialized cells called osteoblasts help build new bone tissue by promoting mineralization. Alkaline phosphatase enzyme works by breaking down substances that would otherwise prevent mineralization from happening. One of these substances is inorganic pyrophosphate (PPi), which normally inhibits the formation of calcium phosphate crystals in bones. When alkaline phosphatase levels are too low, pyrophosphate accumulates and blocks proper bone mineralization.
At the same time, other substances that are normally broken down by alkaline phosphatase also build up. Pyridoxal 5'-phosphate (PLP), which is a form of vitamin B6, accumulates to high levels in the blood. In severe cases, particularly in infants, elevated PLP can cause seizures that respond only to vitamin B6 treatment. Another substance called phosphoethanolamine (PEA) also builds up and can be detected in urine.
The skeletal changes in HPP resemble those seen in rickets, a condition caused by vitamin D deficiency. However, in HPP, the problem is not a lack of vitamin D but rather the body's inability to properly use minerals to build bone. On X-rays, bones may appear less dense than normal, with areas that look almost transparent. The growth plates—areas near the ends of long bones where growth occurs in children—may appear widened and irregular.
In teeth, similar problems occur. The structures that anchor teeth in the jaw, including a substance called cementum, fail to mineralize properly. This makes teeth loose and prone to falling out, even when no cavities or gum disease are present. The enamel, which is the hard outer coating of teeth, may also be poorly formed, making teeth more susceptible to damage and decay.
Beyond bones and teeth, alkaline phosphatase deficiency affects other tissues. The accumulation of calcium in soft tissues, including kidneys and blood vessels, can occur. This can lead to kidney stones and problems with kidney function. Some people develop calcium deposits in their joints, causing sudden, painful inflammation similar to conditions like gout.
The muscle weakness commonly seen in HPP may result from both skeletal problems and direct effects on muscle tissue. When bones are weak and painful, people naturally move less, leading to muscle deconditioning. However, research suggests that the metabolic abnormalities in HPP may also directly affect muscle function and strength.
The neurological symptoms in HPP, including seizures in infants and neuropsychiatric problems in adults, likely result from the accumulation of substances that normally would be broken down by alkaline phosphatase. The exact mechanisms are still being studied, but it is clear that the enzyme plays important roles beyond just bone health.
