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  Oct 24, 2018

Hypophosphatasia Diagnosis

Hypophosphatasia 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 (mineralization) is impaired, leaving the bones susceptible to fracture and deformity and increasing the risk of tooth loss.

The condition is caused by mutations in the ALPL gene, which codes for an enzyme called alkaline phosphatase (ALP). This enzyme metabolizes several substrates and ALPLmutation 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 and it is the accumulation of PPi that is responsible for the defective mineralization seen in hypophosphatasia.

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

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


Hypophosphatasia is a rare condition and determining whether a patient has this disease is not always easy because it shares signs and symptoms with other more common diseases. Hypophosphatasia can affect many different tissues and structures in the body and symptoms vary significantly between patients.

The first step in diagnosing hypophosphatasia is 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 hypophosphatasia include the following:

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

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

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

ALP activity

In suspected cases of hypophosphatasia, 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 hypophosphatasia. Due to its specific association with hypophosphatasia 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 hypophosphatasia.

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 aged between 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 hypophosphatasia 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 hypophosphatasia must not take calcium, phosphate or vitamin D supplements because they cannot process these minerals properly. This can lead to stunted growth, calcium deposition in the kidneys and bone lesions.

If a diagnosis of hypophosphatasia is confirmed, a doctor may prescribe medication to help manage pain in the bones, joints and muscles. They may also recommend individualized dental care to help maintain bone and gum health and consult an orthopedic surgeon to discuss whether surgery may be an option to help stabilize soft and weak bones.

Genetic testing

Genetic testing for ALPL gene mutation is not required to diagnose hypophosphatasia, 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.