Hypophosphatasia Symptoms and Causes

Hypophosphatasia (HPP) is an inherited disorder affecting the development of bones and teeth. This happens when the mineralization process is disrupted leading to the signs and symptoms of HPP, including failure to thrive; soft, weak bones; and premature tooth loss.

This article will discuss what HPP is, its symptoms, complications, when to see a doctor, and what causes HPP.

Types of HPP

Mineralization generally deposits calcium and phosphorus to help with bone and tooth development. It is vital for the development of strong bones and rigid teeth. With HPP, the mineralization process becomes disrupted.

The signs and symptoms of HPP can appear anywhere from birth to adulthood. There are six types of HPP, which are named for when they occur:

• Benign prenatal HPP: This type of HPP is rare and characterized by limb shortening and bowing that resolves slowly and spontaneously. These symptoms may later return in middle childhood and adulthood.
• Lethal perinatal HPP: This type of HPP is usually diagnosed at birth or with ultrasound before birth. It presents with skeletal abnormalities in the chest wall and long bones. X-rays usually show signs of hypomineralization (a decrease in mineral content). This type of HPP can be fatal, with high numbers of stillbirths or death shortly after birth.
• Infantile HPP: This type of HPP is diagnosed by the age of 6 months. Its main symptoms are rickets and fractures (broken bones). Rickets is a condition that affects childhood bone development and causes bone pain; poor growth; soft, weak bones; and sometimes, bone deformities. HPP fractures are usually detected by X-rays.
• Childhood HPP: The signs and symptoms of childhood HPP appear after 6 months of age. It is usually diagnosed after a child fails to develop motor skills and doesn’t reach developmental milestones. The most common symptom of childhood HPP is the early loss of baby teeth before age 5.
• Adult HPP: This type is present early in life, but symptoms aren’t notable until adulthood. Symptoms include unspecified musculoskeletal disorders (disorders affecting muscles and bones), slow healing, and frequent fractures of the femur (thigh bone) and metatarsal bones (long bones of the feet). It also causes bone softening, tooth loss, and chronic joint and muscle pain.
• Odontohypophosphatasia: This type of HPP only affects the teeth. Symptoms include abnormal tooth development and premature loss of permanent teeth.

Frequent Symptoms

The most common symptoms of HPP, especially in children and infants, are failure to thrive; weak, soft bones; and premature tooth loss.

Failure to Thrive

Failure to thrive is one of the earliest signs in infants with HPP. Signs of failure to thrive are poor feeding, inadequate weight gain, irritability, and excessive crying.

Weak, Soft Bones

A main feature of HPP is impairment of the body’s ability to deposit calcium and phosphorus into developing bones and teeth. These minerals are responsible for making the bones and teeth strong enough to withstand the effects of daily use.

In infants, skull deformities can occur and lead to craniosynostosis—a birth defect in which the bones in a baby’s skull join together too early. HPP can also cause bones to become soft and weak, leading to fractures.

Premature Tooth Loss

In children, early tooth loss begins between 1 and 2 years of age. The teeth typically fall out on their own.

In addition to premature tooth loss, children with HPP have decreases in the height of the alveolar bone (the thick ridge of bone that contains the tooth sockets) and various malocclusions, such as overbite, underbite, crossbite, overcrowding, spacing, and open bite.

In adults, HPP can lead to periodontal disease, which is the loss of bony support that holds the teeth to the jaw. The increased risk for periodontal disease is due to abnormal tooth-bone attachments.

Rare Symptoms

Less frequent symptoms of HPP are breathing troubles, muscle weakness, musculoskeletal pain, motor skills impairment, and seizures.

Breathing Problems

Perinatal and infantile HPP can cause respiratory failure where there isn’t sufficient oxygen absorbed by the lungs to meet the needs of the body. Respiratory failure is the most common cause of death for infants with HPP.

Sometimes, adult HPP is linked to severe respiratory insufficiency (inability of the lungs to exchange enough oxygen and carbon dioxide). This is usually related to chest deformities and respiratory complications, such as acute respiratory failure, pulmonary edema (fluid in the lungs), and pneumonia (lung infection).

People with HPP—regardless of age—with respiratory insufficiency will require intubation, mechanical ventilation, and/or oxygen support.

Muscle and Joint Symptoms

HPP is linked to mobility-related muscular and rheumatologic (related to joint inflammation) symptoms due to defective bone mineralization and impaired calcium and phosphate regulation.

This is especially common in adult HPP and includes muscle and joint pain, muscle weakness, recurring stress fractures, osteomalacia (adult form of rickets), and calcium pyrophosphate dihydrate crystal deposition (CPPD) in the cartilage.

Motor Skills Impairment

Motor skills are actions that involve muscle movement in the body. They include gross motor skills, like crawling, running, and jumping, and fine motor skills, such as grasping objects. 

Motor skill impairment and delayed motor development are more common in perinatal, infant, and childhood types of HPP. Perinatal HPP is sometimes linked to total motor skill impairment.

Seizures

Seizures are sudden, uncontrolled electrical disturbances of the brain. They can affect behavior, movement, feelings, or consciousness.

Seizures are the most common neurological (related to nerves and the brain) symptom of HPP. Seizures that begin soon after birth are either linked to lethal perinatal or infantile HPP. Other types of HPP generally do not cause seizures.

Complications/Sub-Group Indications

Some children might have severe complications of HPP early on. A failure to thrive is sometimes considered a complication of HPP in infancy.

Additional complications of HPP in infancy are:

• Respiratory problems: Including an increased risk for pneumonia infections
• Hypercalcemia: High calcium levels in the blood
• Craniosynostosis: May lead to increased intracranial pressure
• Nephrocalcinosis: A disorder that results from too much calcium in the kidneys

Complications of childhood and adult HPP might include:

• Chronic pain of the bones, joints, and muscles
• Loss of secondary teeth prematurely

When to See a Doctor/Go to the Hospital

If you or your child experiences any of the signs and symptoms of HPP, you should reach out to a doctor. You can assist with the diagnosis process by letting the doctor know all the symptoms experienced. Since some types of HPP are inherited, the doctor should be informed about any family history of the condition.

For babies and young children, parents should report the visible symptoms of the condition, including the failure to thrive. If your child is feeding poorly, not gaining weight, and frequently irritable, contact your child’s pediatrician right away.

Causes

HPP is caused by mutations in the ALPL gene—the gene that gives the body instructions to make an enzyme called tissue-nonspecific alkaline phosphatase (TNSALP). Mutations in this gene lead to abnormalities of this enzyme, which affects the mineralization process.

A shortage of TNSALP might cause other substances to build up and lead to other characteristics of HPP.

In some cases, ALPL gene mutations can almost completely stop the activity of TNSALP and lead to the most severe types of HPP. Other mutations that do not eliminate TNSALP cause milder forms of HPP.

You are at risk for HPP if one or both genetic parents carry a mutated ALPL gene. If a person inherits two copies of the mutated gene, they will have a more severe form of HPP. In this case, HPP appears early in life and is inherited in an autosomal recessive inheritance.

Milder types of HPP are either caused by autosomal recessive or autosomal dominant patterns of inheritance.

There are no other causes or known lifestyle risk factors of hypophosphatasia.

Summary

Hypophosphatasia is a rare inherited disorder that affects the development of bones and teeth. It affects infants, children, and adults. The condition can be severe and life-threatening, especially before and just after birth. However, most people experience milder forms of the disease.

A Word From Verywell

If HPP runs in your family and you want to understand the risk of inheritance, genetic testing might be helpful. It can also be done during pregnancy to confirm an HPP diagnosis so you can better plan for after your baby is born. A negative test can bring about some peace of mind.

Genetic testing can be done in rare instances where the signs and symptoms of a health condition do not necessarily point to HPP. It can also help determine the severity and type of HPP.