What Causes HPP
HPP is caused by mutation(s) in the ALPL gene. This gene provides instructions for the body to make an enzyme called tissue-nonspecific ALP. ALP is normally abundant in bones. People with HPP have low ALP activity, which can be measured with a blood test.
ALP supports important functions in the body, including breaking down a substance called inorganic pyrophosphate (PPi) into phosphate. Phosphate combines with calcium for mineralization (hardening) of bones and teeth. When PPi builds up in the body because it is not broken down, it interferes with hardening of bones and leads to bones becoming soft and potentially deformed or fractured. This “soft bone” condition is known as rickets (in growing bones) or osteomalacia (in bones that are no longer growing). Poor mineralization can also lead to loosely anchored teeth or a buildup of calcium in the kidneys or joints. In more severe cases, such as in infants, blood calcium levels can increase and lead to serious complications.
ALP also helps break down a form of vitamin B6 known as pyridoxal-5′-phosphate (PLP). It converts PLP into another molecule (pyridoxal) that can enter the brain to support the action of nerve messengers (neurotransmitters). The lack of breakdown of PLP can lead to vitamin B6–dependent seizures in infants with a severe form of HPP. Other complications of this vitamin B6 imbalance are not yet well understood, but may include nerve pain, headaches, or mental fatigue.
Genetics of HPP
People with HPP have one or two alterations in the ALPL gene, known as mutations. In Canada, doctors specializing in HPP can order a genetic test to check for these mutations to confirm HPP diagnosis. Many different types of mutations in the ALPL gene have been identified, and researchers continue to track them in a database (https://alplmutationdatabase.jku.at/table/). As of 2026, about 500 types of ALPL mutations have been reported. Because there are so many possible mutations, HPP can appear differently from one person to another.
Some mutations almost completely stop the ALPL gene from working, while in milder forms of HPP, the gene still works somewhat but not fully. Severe forms of HPP tend to occur when a child inherits two non-working copies of the gene, one from each parent. This is called autosomal recessive inheritance. In these cases, both parents usually carry a mutated gene but do not have symptoms of HPP. These severe forms typically appear before or soon after birth.
Milder forms of HPP can be inherited in either an autosomal recessive (two altered copies) or autosomal dominant (one altered copy) fashion. Autosomal dominant inheritance means a person can develop HPP after inheriting just one altered gene from a single parent who also has HPP symptoms.
Who is Affected
Overall, HPP is a rare disease. The most severe forms are estimated to occur in Canada in about 1 in 100,000 newborns. This estimated rate is higher than in some other regions, such as Europe (about 1 in 300,000) and Japan (about 1 in 300,000 to 500,000 births). In the Canadian Mennonite population, severe HPP is much more common, affecting an estimated 1 in 2,500 newborns.
Milder forms of HPP are estimated to be more common than severe forms, but it is harder to measure how often they occur. Estimates vary, ranging from about 1 in 500 to 1 in 36,000 people.
Symptoms of HPP can vary greatly from person to person, from very mild to life-threatening. The condition can appear anywhere from before birth to adulthood. When symptoms start before or shortly after birth, HPP is usually more severe than when they appear later in life.
Symptoms
Doctors classify HPP into six types based on when symptoms become apparent. The symptoms and their severity vary across these six types:
1. Perinatal HPP
This is the most severe type of HPP seen before or at birth. The skull and other bones are not fully hardened, and the limbs are short and bowed. Bones can break easily.
Some newborns develop life-threatening complications, especially lung problems. This happens because the chest bones may not form properly, leading to a misshapen or sometimes collapsed chest (thoracodystrophy) that limits lung development and breathing. Chest shape problems and broken bones can also increase the risk of lung infections.
Another serious issue is vitamin B6–related seizures, caused by problems with breaking down vitamin B6. Poor bone mineralization can also lead to high calcium levels in the blood, which may cause poor feeding, vomiting, or constipation.
2. Infantile HPP
Infantile HPP appears after birth, usually within the first 6 months of life. It is somewhat less severe than the perinatal form, but it can still have serious complications in some babies.
Babies often look normal at birth and begin to show symptoms within the first 6 months. Soft bones (rickets) can develop, leading to short, bowed limbs and bone fractures. Breathing problems and serious lung issues may also occur (like in perinatal HPP) because of abnormal chest shape.
The skull bones may close too early (craniosynostosis), which can prevent the skull from growing properly with the brain. This may cause an abnormal head shape, increased pressure in the head, and in some cases downward pushing of the brain.
Babies may also have low muscle tone and delays in movement. High calcium levels are common and can lead to poor feeding, vomiting, and kidney problems (nephrocalcinosis and renal compromise). Other signs include irritability and poor weight gain and growth. Rarely, babies may have vitamin B6–related seizures, as seen in perinatal HPP.
3. Childhood HPP
Childhood HPP usually appears after 6 months of age, and its severity can vary. Some children may have a more severe form with features like infantile HPP, while in others the condition may improve on its own by early adulthood.
One of the first signs is often early loss of baby (primary) teeth, usually before 5 years of age. The teeth may fall out with the root still attached.
Soft bones (rickets) can be seen on X-rays and may sometimes be noticeable without imaging. Children may have short stature, bowed legs or knock knees, or enlarged wrists, knees, or ankles. They may also have muscle weakness, delays in gross motor skills like walking, and bone or joint pain.
Some children, who are more severely affected, may develop early closure of the skull bones (craniosynostosis), which can increase pressure in the head, similar to what is seen in infants with HPP. However, unlike in infants, the childhood form of HPP usually does not cause vitamin B6–related seizures or high blood calcium levels.
4. Adult HPP
Adult HPP is a chronic condition that usually appears in middle age. Soft bones (osteomalacia) tend to cause stress fractures in the feet and thighs, which may heal slowly and be painful. Adults may also experience atypical fractures of the thigh bone.
Adults with HPP tend to lose their adult (secondary) teeth early, sometimes with the root still intact, and may remember losing their baby teeth the same way. Muscle pain, weakness, and fatigue also tend to occur.
Calcium deposits (calcium pyrophosphate crystals) tend to build up in the joints, causing pain and swelling. Kidney problems may develop from these deposits and high calcium in the blood. Adults also tend to experience less specific symptoms like digestive issues, nerve pain, or brain fog.
5. Odonto HPP
This is the mildest form of HPP, which can appear at any age, affecting only the teeth and not the bones. Individuals with odonto HPP tend to have abnormal tooth development and may lose their teeth early, sometimes with the root still attached.
6. Benign or Mild Prenatal HPP
This is the mildest form of HPP, which can appear at any age, affecting only the teeth and not the bones. Individuals with odonto HPP tend to have abnormal tooth development and may lose their teeth early, sometimes with the root still attached.