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Disease Overview



Hypophosphatasia (often called HPP) is a rare, inherited condition that affects the way bones and teeth develop and stay strong. It happens because of low activity of an important enzyme in the body called alkaline phosphatase (ALP). Normally, ALP helps calcium and phosphate join together to make healthy, strong bones and teeth. When ALP doesn’t work as it should, bones and teeth may not harden properly. This can lead to weak bones, fractures, and dental problems. Low ALP in HPP can cause symptoms beyond bone and teeth and include muscle weakness, profound fatigue, pain, difficulty walking, neurological, renal, and respiratory problems, among others.


HPP is caused by changes (sometimes called variants or mutations) in a gene called ALPL. This gene gives the body instructions to make ALP. So far, scientists have identified more than 450 different ALPL variants.9 That’s one reason why symptoms can look very different from person to person. Symptoms can appear at any age and may change or worsen over time. Some people mainly have bone problems, while others have more muscle or other health issues. Infants and children may show signs such as weak bones, breathing problems, seizures, or losing baby teeth too early. HPP in babies can be life-threatening. Older children and adults may experience muscle weakness, fatigue, ongoing pain, difficulty walking, and broken bones (or “pseudofractures”).


Because the symptoms vary, many people may suffer from HPP for years before getting the correct diagnosis. HPP can cause serious challenges in everyday activities. For some, it may limit the ability to walk, move around, or complete daily tasks without help. For others, pain, fatigue, or mobility problems may impact quality of life. While everyone’s journey with HPP is different, the impact can be significant. Support and care are important to help manage the condition.


HPP Diagnosis


HPP is rare and often resembles more common conditions, making diagnosis challenging. For individuals with signs and symptoms suggestive of HPP, a thorough clinical assessment and measurement of ALP activity are essential for accurate diagnosis. Elevated ALP substrate levels such as serum pyridoxal 5'-phosphate (PLP or vitamin B6) and urinary phosphoethanolamine (PEA) can provide supportive evidence, although these markers may not be elevated in all cases. Genetic testing to identify ALPL variants can further aid diagnosis, especially when clinical findings are unclear; however, negative or inconclusive results do not rule out HPP.


Severe early-onset disease occurring before six months of age is estimated at about 1 in 300,000 births, while data from the United States in 2023 suggest a diagnosed prevalence of approximately 3 per 100,000 across all ages, with most cases in adults. Misdiagnosis may lead to inappropriate treatments that worsen symptoms. Infants and children may be mistaken for having rickets or osteogenesis imperfecta, and adults for osteoporosis or other musculoskeletal disorders. Careful interpretation of laboratory values is critical to distinguish HPP from these conditions.


Diagnosing HPP involves evaluating a combination of biochemical findings, genetic information, clinical history, and physical or imaging assessments.


Biochemical Findings

  • Low serum ALP activity level; caution: ALP levels vary by age and sex and proper reference ranges must be used in order to recognize low ALP; infants, children, and adolescents have higher ALP levels than adults.
  • Testing for ALP substrates, which are often elevated in HPP:
    • Pyridoxal 5’-phosphate (PLP, a form of vitamin B6)
    • Phosphoethanolamine (PEA)
  • Inorganic pyrophosphate (PPi) may also be elevated, but testing is currently limited to research settings

Genetic Findings

  • Variants in the ALPL gene may support diagnosis, but genetic testing is not required

Clinical History and Symptoms

  • Family history of HPP (eg, siblings or parents with the condition)
  • Skeletal symptoms (eg, fractures)
  • Dental symptoms (eg, premature loss of teeth)
  • Non-skeletal symptoms, which may include:
    • Neurological issues (eg, headaches, anxiety, depression, Vitamin B6-responsive seizures)
    • Kidney problems (eg, kidney stones)
    • Respiratory problems
    • Muscle weakness, fatigue
    • Musculoskeletal pain (eg, bone pain, muscle pain, joint pain, body pain)
    • Rheumatologic symptoms (affecting joints and other parts of the musculoskeletal system, eg, pseudogout, fibromyalgia)

Functional, Radiographic Assessments, Questionnaires

  • Tests that assess physical functioning, such as the 6-minute walk testa or chair rise testb
  • Radiologic exams to identify bone changes if clinically indicated (eg, pseudofractures, fracture healing, chondrocalcinosis)
  • Renal ultrasound (eg, to detect nephrocalcinosis)
  • Eye exam (eg, to detect eye calcifications)
  • Questionnaires: SF-36 (quality of life), BPI-SF (pain), LEFS (Lower Extremity Functional Scale)

aThe 6-minute walk test is a test used in children and adults with HPP that measures how far they can walk on a hard, flat surface for 6 minutes.
bThe chair rise test is a test used in children and adults with HPP that measures the time it takes to stand 5 times without using arm support.


Health Management Strategies


Historically, management of HPP has focused on symptom relief. Several different approaches have been used to help manage the skeletal and non-skeletal manifestations of HPP, including:

  • Pain management
  • Vitamin B6 to control seizures, as the seizures associated with HPP do not respond to conventional antiseizure medications
  • Surgical care
    • Orthopedic surgical intervention may be necessary to treat fractures and pseudofractures (a bone defect that looks like an incomplete fracture on x-ray), especially in adult patients.
    • Craniectomy may be necessary to treat craniosynostosis (a condition where the skull bones in an infant join too soon), which is sometimes observed in children with HPP, which leads to increased intracranial pressure and can lead to neurological complications.
    • Neurosurgical interventions may be necessary in patients with neurological complications such as paralysis or numbness of extremities, papilledema (a condition where the optic nerve that connects the eye and brain swells)
  • Dental care (eg preventative dental care replacement of teeth lost, dentures)
  • Physical therapy
  • Occupational therapy
  • Assistive devices (walker, braces, splints, cane, wheelchair to help with mobility)
  • Home modifications
  • Dietary restrictions, such as lowering dietary phosphate and calcium intake, to improve hyperphosphatemia (high amount of phosphate in the blood) and hypercalcemia (high amount of calcium in the blood)