What Is Hypophosphatasia?

Hypophosphatasia (HPP), also known as Rathbun disease, is a rare inborn disorder that affects the development of bones and teeth. In HPP, a genetic mutation impairs the ALPL gene, which regulates mineralization (or “calcification”), a process essential for bone and tooth strength.

The severity of this condition varies. More severe cases, in which skeletal abnormalities are present at birth, are seen in about 1 in 100,000 newborns. Management of this condition ranges from taking nonsteroidal anti-inflammatory drugs (NSAIDs) and using orthotics to injections of the drug Strensiq (asfotase alfa).

Types of Hypophosphatasia

The severity of hypophosphatasia is closely tied to the age of onset of symptoms. There are six major clinical forms that doctors diagnose:

• Perinatal HPP is the most severe form, in which symptoms are seen at birth, and in the womb. In some cases, this can lead to stillbirth.
• Perinatal benign HPP is a milder form of HPP in newborns, with symptoms often improving over time.
• Infantile HPP are cases in which symptoms arise within six months of birth, often associated with difficulty feeding and gaining weight in infancy.
• Childhood HPP ranges a great deal in severity, with symptoms typically arising by age 2 or 3.
• Adult HPP also causes a range of signs and symptoms and can cause bones to be easily fractured.
• Odonto-HPP refers to early loss of baby teeth in infancy, as well as surprise loss of teeth in adults, without skeletal issues.   

Hypophosphatasia Symptoms

There’s a great deal of variation when it comes to how cases of HPP present, with some symptoms associated only with certain forms of the condition. In addition, there are many individual differences when it comes to symptoms of this genetic disorder. Its features in one family member may not resemble those of another.

The symptoms of perinatal HPP, present while in the womb, lead to severe developmental issues, including:

• Short, bowed arms and legs
• Failure to thrive (insufficient feeding)
• Brittle bones
• Lack of muscular development
• Chest deformity
• Stillbirth
• Respiratory failure

Children with infantile and childhood HPP are also more likely to experience skeletal abnormalities, including:

• Craniosynostosis: This is when the bones of the skull fuse together, causing brachycephaly, a deformation of the shape of the head.
• Intracranial hypertension: Craniosynostosis also can cause spikes in the pressure applied by cerebrospinal fluid on the brain, leading to headaches and bulging of the eyes (known as “proptosis”).
• Bone malformation: Weakening and softening of the bones causes bowing of the limbs in a similar fashion to rickets. Some may have widened wrist or ankle joints.  
• Chest deformities: Insufficient development of the ribs, especially in infants, can cause difficulty breathing, respiratory failure, and pneumonia.
• Bone fracture: Since they’re weaker, the bones of infants and children with HPP are prone to breaking.
• Tooth loss: HPP infants and children experience loss of one or more baby teeth before the fifth birthday.
• Affected gait: Developmental delays can affect the ability to walk, with affected children learning to walk later in life and often adopting a distinctive waddling gait.
• Other symptoms: Fever accompanied with pain in the bones, as well as diminished muscle tone, can occur in infants, making them appear limp.

Finally, adults with HPP may experience:

• Unexplained loss of adult teeth
• Calcific periarthritis, joint pain, and inflammation due to high levels of calcium in the blood
• Chrondrocalcinosis, damaging the cartilage, leading to joint pain and motor difficulties
• Pain in the rotator cuff, elbow, and Achilles tendon
• Low bone density
• “Adult rickets,” or osteomalacia, a softening of the bones
• Frequent bone fractures, especially stress fractures and partial fractures

Causes

Being an inherited condition, HPP is caused by mutations in the ALPL gene, which regulates the production of an essential enzyme called tissue-nonspecific alkaline phosphatase (TNSALP). This enzyme, which removes oxygen and phosphorous from other molecules, is essential for mineralization. It plays a critical role in ensuring necessary minerals are deposited into bones and teeth.

Affected individuals produce a nonfunctioning form of TNSALP, which allows compounds called inorganic pyrophosphates to build up in the body. In turn, this inhibits mineralization. The intensity of symptoms is directly related to the amount of TNSALP the body produces, with the most severe cases arising when ALPL mutations completely halt its production.

Diagnosis

As with other developmental disorders, the diagnosis of HPP involves both an assessment of symptoms and other kinds of tests. Approaches include:

• Clinical evaluation: Many cases are first isolated by assessing medical history, as well as any symptoms and outward signs themselves.
• Imaging: X-rays and other kinds of imaging may be employed to assess the scope of damage and find signs of damage or malformation.
• Ultrasound imaging: Cases of perinatal HPP can be discovered via imaging approaches during pregnancy.
• Bone densitometry: This test assesses the density and strength of bones affected by HPP by using specialized X-rays.
• Blood tests: Tests of ALPL in the blood, called ALPL assays, can aid in diagnosis, with low amounts being potential markers of HPP.
• Pyridoxal phosphate (PLP) test: Presence of elevated levels of PLP, the biologically active form of vitamin B6, imply insufficient TNSALP activity.
• Phosphoethanolamine (PEA) test: Low levels of this substance, which indicate low levels of TNSALP in the blood or urine, can also be a sign of HPP.
• Genetic testing: Via blood samples, doctors can also assess directly if there are mutations of the ALPL gene.

Treatment

Since HPP can take many forms and ranges in severity, treatment of the condition is typically multidisciplinary and always tailored to the individual case. Typically, a team of pediatricians, orthopedic surgeons, pedodontists (specialists in children’s dental care), and other specialists work together to manage care. While there is no outright cure, a number of approaches are used to take it on:

• Respiratory support: In severe perinatal cases causing breathing difficulties, the newborn may require ventilation and intubation, pharmacological treatment, and even life support.
• Dietary interventions: Some cases of HPP cause hypercalcemia, in which there are high levels of calcium in the blood, so intake of this mineral should be restricted and hydration emphasized. Vitamin B6 may be given to infants to prevent seizures associated with severe skull deformities, while vitamin D3 supplementation should be avoided.  
• Physical therapy: If there is difficulty with motor function, physical or occupational therapy may be needed. This therapy, along with others, can also help with chronic pain problems.
• Surgery: When perinatal and infantile HPP cause severe cerebrospinal pressure on the brain, as in cases of craniosynostosis, surgery or shunting (making holes in the skull to ease pressure) may be indicated. Surgeries can also help take on some bone deformities associated with this condition.
• Rodding and orthopedics: Physical therapy is a regular component of treatment. In cases of repeated bone fracture, specialized metal rods may be used to support the bones. Orthopedic devices, such as foot orthotics, can help with fractures there.  
• Dental care: Those with odontohypophosphatasia, or cases affecting the teeth, may require more frequent appointments with dentists and dental specialists.

Further, several pharmaceutical approaches may be taken:

• Strensiq (asfotase alfa) injection: For perinatal, infantile, and childhood HPP, subcutaneous (under the skin) injections of Strensiq were approved by the Food and Drug Administration (FDA) in 2015 for use in the United States. This therapy replenishes TNSALP levels in the bones, strengthening them.
• Nonsteroidal anti-inflammatory drugs (NSAIDs): To ease pain and inflammation in the bones and joints associated with HPP, NSAIDs such as aspirin, naproxen, or ibuprofen, among others, may be indicated. Due to the risk of side effects, this use is carefully monitored.
• Calcitonin: Application of this hormone, also used to treat osteoarthritis, prevents bone “resorption,” which is when bone material is digested by the body. This reduces blood calcium levels, which cause many of the issues associated with HPP.   

In addition, since HPP is an inherited condition, genetic counseling with families may be employed when cases emerge.

Prognosis

While dependent on the severity of HPP, the prognosis for perinatal and severe infantile HPP cases can be very poor. Prior to the development of current therapies, an estimated 58% to 100% of cases led to death within the first year. Those who survive infancy may have persistent health problems and diminished quality of life.

That said, the outlook is improving. Dedicated treatments can certainly yield positive results for more severe cases, and there are many approaches that help take on the impact of living with HPP.  Also, those with severe HPP are entitled to protections and accommodations in workspaces, schools, and public areas as part of the Americans with Disabilities Act.    

Coping

No doubt, there are many challenges associated with living with HPP, and this often lifelong condition can severely impact mental health. Furthermore, families of those with the condition will inevitably also feel an impact. Strategies that could prove invaluable for taking on the condition include:

• Seeking counseling: For patients and families with perinatal or infantile HPP, counseling is recommended to address associated emotional and personal difficulties. Therapy can also help those with the condition face social stigmas associated with physical disability.
• Finding community: Advocacy organizations, such as Soft Bones, provide helpful information and services for those with rare and genetic disorders like HPP. Online forums and social media communities can also be helpful platforms for sharing experiences and emotions.
• Communicating: The value of having someone to talk to and confide in—a friend or a family member—cannot be understated. It helps, too, to split up the tasks of care for someone with HPP among those you trust and create your own care team.
• Exercising: Incorporating exercise into daily life helps reduce stress levels and improves sleep quality, among other health benefits. Activities like meditation and yoga can also help improve mental health.

A Word From Verywell

Since there is no single treatment—and since no two cases are alike—management of HPP is an always-evolving process. While that road may be challenging, remember that it’s one not traveled alone. Alongside dedicated specialists, you have the support of family and friends and a growing community of patients worldwide.

With advances in the understanding of HPP come advancements in its management. On top of existing therapies for the condition are newer ones showing promise. While there’s still more work ahead, it’s important to remember how far we’ve come.