Rare Classroom: Hypophosphatasia

Welcome to the Rare Classroom, a new series from Patient Worthy. Rare Classroom is designed for the curious reader who wants to get informed on some of the rarest, most mysterious diseases and conditions. There are thousands of rare diseases out there, but only a very small number of them have viable treatments and regularly make the news. This series is an opportunity to learn the basics about some of the diseases that almost no one hears much about or that we otherwise haven’t been able to report on very often.

Eyes front and ears open. Class is now in session.

The disease that we will be learning about today is:


Sometimes called deficiency of alkaline phosphatase or phosphoethanolaminuria.

What is Hypophosphatasia?

  • Hypophosphatasia (HPP) is a genetic condition that causes abnormal development of the bones and teeth. The severity of HPP can vary widely, from fetal death to fractures that don’t begin until adulthood​
  • It has been estimated that severe forms of hypophosphatasia occur in approximately one per 100,000 live births.
    • The more mild childhood and adult forms are probably somewhat more common. About one out of every 200 individuals in the United States may be a carrier for hypophosphatasia.
  • There is no cure for HPP. Treatment is generally directed towards preventing or correcting the symptoms or complications. ​
  • The signs and symptoms for HPP vary widely in severity ranging from very mild to severe and sometimes life threating. ​
  • Adult patients with HPP suffer of chronic pain, recurrent fractures and other orthopedics problems, with severe disability that have a serious negative impact on all aspects of their life​
  • Pneumonia can result if chest distortion is severe. Recurrent fractures can occur. Teeth may be lost prematurely, have wide pulp (inside) chambers, and thereby be predisposed to cavities.​

How Do You Get It?

  • Hypophosphatasia is caused as a result of a molecular defect in gene encoding TNSALP. ​
  • TNSALP is an ectoenzyme present in the outer surface of osteoblast and chondrocyte cell membranes.
  • Low alkaline phosphatase (ALP) activity is the underlying cause of morbidities and premature mortality in hypophosphatasia.​
    • Low ALK results in impaired bone mineralization, which can lead to premature death, progressive physical disability, and poor quality of life.​​
  • The function of TNSALP is to hydrolyze inorganic pyrophosphate and pyridoxal 5′-phosphate, which is a major form of vitamin B6. ​
  • When this ectoenzyme TNSALP is low, inorganic pyrophosphate gets accumulated extracellularly and inhibits formation of hydroxyapatite resulting in medical condition called rickets in infants and children and osteomalacia in adults.​
  • The severe perinatal and infantile forms of hypophosphatasia are inherited as autosomal recessive conditions. The patient receives one defective gene from each parent. ​
  • Some more mild (childhood or adult) hypophosphatasia cases are also inherited this way. ​
  • Other mild adult and odonto hypophosphatasia cases seem to be inherited in an autosomal dominant pattern (the patient gets just one defective gene, not two, transmitted from one of his/her parents). ​
    • In this form, mild hypophosphatasia can occur from generation-to-generation. ​
  • The perinatal form of hypophosphatasia can often be detected during pregnancy by ultrasound and by measuring ALP activity in chorionic villus samples from amniocentesis. ​
  • Individuals with hypophosphatasia and parents of children with hypophosphatasia are encouraged to seek genetic counseling to explain the likelihood and severity of hypophosphatasia recurring in their families.​

What Are The Symptoms?

  • The most severely affected fail to form a skeleton in the womb and are stillborn.​
  • The most mildly affected patients may show only low levels of ALP in the blood, yet never suffer bone problems. ​
  • In general, patients are categorized as having “perinatal”, “childhood” or “adult” hypophosphatasia depending on the severity of the disease, which in turn is reflected by the age at which bone manifestations are first detected.
  • Odontohypophosphatasia refers to children and adults who have only dental, but not skeletal, problems (premature loss of teeth). ​
  • Overall symptoms can include:
    • Insufficient calcification of the skull and other bones
    • In young patients, skull deformations may appear
      • These deformations can lead to craniosynostosis​ (increase intracranial pressure)
    • Fractures due to soft, weakened bones
    • In young patients, premature loss of baby teeth
    • In young patients, poor feeding and weight gain
    • High calcium in the urine and blood
    • Joint stiffness
    • Joint and muscle pain
    • Delayed walking
    • Abnormal gait
    • Osteomalacia

How Is It Treated?

  • For many years, treatment has been generally directed toward preventing or correcting the symptoms or complications. As of now, there is no cure for hypophosphatasia and treatment is aimed at decreasing morbidity associated with hypophosphatasia.​
  • Routine examination of children to look for increased intracranial pressure is essential.
  • Orthopedic care is also required in adults to take care of the fractures. Routine visit to a dentist is also essential.
  • Procedures such as rodding, especially in adults, can be helpful with painful partial fractures in their thigh bones. Expert dental care and physical therapy are recommended
  • Monitoring levels such as alkaline phosphatase, B6, and calcium (which are/can be outside the limits of normal in hypophosphatasia) should be undertaken and are dependent upon how the patient is being treated.​
  • Some treatments which have been tried for treatment of hypophosphatasia, but with not so positive results, are zinc, magnesium, cortisone, and plasma.​
  • In October 2015, a new treatment was introduced in the form of the targeted enzyme replacement therapy Strensiq (asfotase alfa).
    • Strensiq is a tissue-nonspecific alkaline phosphatase indicated for the treatment of perinatal, infantile, and juvenile-onset hypophosphatasia (HPP), and works by replacing alkaline phosphatase.
    • Since its approval, many families have chosen to begin this therapy
    • Careful consideration and consultation with a physician knowledgeable about this treatment and the disorder hypophosphatasia itself are recommended before starting this therapy. ​​
  • Another approved treatment for hypophosphatasia alfacalcidol (marketed as Lonpryl or Alfacal Plus)
  • The patient-reported survey conducted by Weber et al. among adult patients with HPP, revealed the perception of a high burden of symptoms related to HPP and a diminished quality of life (QoL). ​
  • The overall fracture prevalence was found to be very high in this survey: almost half of the study population sustained between 6 and more than 10 fractures over lifetime.​

Where Can I Learn More???

  • Check out our cornerstone on this disease here.
  • Learn more about this illness from Soft Bones.

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