Hypophosphatasia Diagnosis

Hypophosphatasia (HPP) is a rare, inherited metabolic disorder that causes the bones and teeth to become soft and weak. In this condition, the deposition of calcium and phosphorus into bones and teeth, a process otherwise known as mineralization, is impaired, leaving the bones susceptible to fracture and deformity and increasing the risk of tooth loss.

Genetic causes

HPP  is caused by mutations in the ALPL gene, which codes for an enzyme called alkaline phosphatase (ALP). This enzyme metabolizes several substrates; therefore, ALPL mutation results in the production of ALP that is not capable of breaking them down.

These substrates, which include inorganic pyrophosphate (PPi), pyridoxal 5’-phosphate (PLP), and phosphoethanolamine (PEA) then accumulate to abnormal levels in the body. It is the accumulation of PPi that is responsible for the defective mineralization seen in HPP.


There are six forms of HPP, with clinical presentation varying widely between the different types. One form, perinatal lethal HPP is so severe that it can lead to stillbirth, whereas ordontohypophosphatasia is a mild form that only affects the teeth.

The six different forms of HPP include:

  • Perinatal lethal HPP
  • Prenatal benign HPP
  • Infantile HPP
  • Childhood HPP
  • Adult HPP
  • Ordontohypophosphatasia


HPP is a rare condition. Therefore, the determination of whether a patient has this disease is not always easy, as hypophosphatasia shares signs and symptoms with other more common diseases. HPP can affect many different tissues and structures in the body and symptoms vary significantly between patients.

The first step in diagnosing HPP involves the assessment of the visible signs and symptoms of the condition. If a bone mineralizing disorder is suspected, HPP can be differentiated by checking the level of ALP and the substrates it metabolizes.

Signs and symptoms

Clinical hallmarks of HPP include:

  • Skeletal: Rickets, fractures that fail to heal, osteomalacia, osteopenia, craniosynostosis, and/or osteoporosis.
  • Dental: Periodontal disease and/or the premature loss of teeth.
  • Muscular: Chronic pain, weakness, and/or missed or delayed motor milestones.
  • Respiratory: Pulmonary insufficiency and/or respiratory failure.
  • Renal: Hypercalciuria, nephrocalcinosis, and/or severe renal damage.
  • Neurologic: Increased intracranial pressure and/or seizures.
  • Rheumatologic: Osteoarthropathy, chondrocalcinosis, and/or pseudogout.

As the signs and symptoms of HPP overlap with many other more common conditions, it is often misdiagnosed. Some examples of the conditions HPP may be misdiagnosed as include:

  • Nutritional rickets
  • Osteoarthritis
  • Osteogenesis imperfecta
  • Osteopenia/osteoporosis
  • Dentinogenesis imperfecta
  • Chondrodysplasia with bone mineralization defects
  • Periodontal disease
  • Hypophosphatemia

ALP activity

In suspected cases of HPP, the patient’s age-adjusted ALP activity is checked to ensure an accurate diagnosis. Elevated levels of PLP, PPI, and urinary PEA are also biochemical hallmarks of HPP.

Due to its specific association with HPP and its routine use as a clinical assay, elevated PLP is the most commonly used marker for diagnosing the condition, along with low ALP activity. Generally, the lower the ALP level and the higher the PLP level, the more severe the form of HPP.

A widely available, routine blood test can be used to check whether ALP is low. Patients with this condition usually have a level of ALP activity that is below the age-adjusted lower limit of normal. The lowest limit of normal ALP activity is higher among infants, children, and adolescents than among adults. Patients between the ages of 1 and 15 years may have ALP activity that is four times as high as that found in adults.

Early and accurate diagnosis

It is critical that HPP is diagnosed accurately and early on in the course of the condition. A delay in diagnosis can lead to life-threatening and debilitating complications. A misdiagnosis can lead to poor management of the condition and contribute to clinical symptoms.

In cases of misdiagnosis, medications may be prescribed that exacerbate symptoms. For example, patients with HPP must not take calcium, phosphate, or vitamin D supplements, as they cannot process these minerals properly. This can lead to stunted growth, as well as calcium deposition in the kidneys and bone lesions.

If a diagnosis of HPP is confirmed, a doctor may prescribe medications to help manage pain in the bones, joints, and muscles. Clinicians may also recommend individualized dental care to help maintain bone and gum health. Additionally, consultation with an orthopedic surgeon may be needed to discuss whether surgery is an option to help stabilize soft and weak bones.

Genetic testing

Genetic testing for ALPL gene mutation is not required to diagnose HPP, although it may be helpful for establishing less severe forms of the condition where laboratory findings have been inconclusive. Genetic testing may also be used to inform parents of the condition’s inheritance pattern in cases where future pregnancies are being considered.


Further Reading

Last Updated: May 18, 2023

Sally Robertson

Written by

Sally Robertson

Sally first developed an interest in medical communications when she took on the role of Journal Development Editor for BioMed Central (BMC), after having graduated with a degree in biomedical science from Greenwich University.


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