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Genetic and Rare Diseases Information Center (GARD)

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Hypophosphatasia


Other Names for this Disease
  • Hypophosphatasia mild
  • Phosphoethanol-aminuria
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Overview



What is hypophosphatasia?

What are the symptoms of hypophosphatasia?

What causes hypophosphatasia?

How is hypophosphatasia treated?


What is hypophosphatasia?

Hypophosphatasia is a genetic condition in which the activity of an enzyme called alkaline phosphatase is deficient.[1][2]  This enzyme plays an essential role in mineralization - when minerals such as calcium and phosphorus are deposited in developing bones and teeth.  Low activity of this enzyme which characterizes hypophosphatasia also leads to rickets, osteomalacia, or both.  The severity of the symptoms of hypophosphatasia varies widely, from fetal loss during pregnancy to cases in which pathologic fractures first present only in adulthood.[1]  Hypophosphatasia is caused by a mutation in a gene - called the ALPL gene - that provides instructions for making the alkaline phosphatase enzyme.[3] A cure or proven medical therapy for hypophosphatasia has not yet been found.[4] Treatment is generally directed towards preventing or correcting the symptoms or complications.
Last updated: 11/4/2009

What are the symptoms of hypophosphatasia?

The signs and symptoms of hypophosphatasia vary widely and can appear anywhere from before birth to adulthood. The most severe forms of the disorder tend to occur before birth and in early infancy. Hypophosphatasia weakens and softens the bones, causing skeletal abnormalities similar to another childhood bone disorder called rickets. Affected infants are born with short limbs, an abnormally shaped chest, and soft skull bones. Additional complications in infancy include poor feeding and a failure to gain weight, respiratory problems, and high levels of calcium in the blood (hypercalcemia), which can lead to recurrent vomiting and kidney problems. These complications are life-threatening in some cases.[3]

The forms of hypophosphatasia that appear in childhood or adulthood are typically less severe than those that appear in infancy. Early loss of primary (baby) teeth is one of the first signs of the condition in children. Affected children may have short stature with bowed legs or knock knees, enlarged wrist and ankle joints, and an abnormal skull shape. Adult forms of hypophosphatasia are characterized by a softening of the bones known as osteomalacia. In adults, recurrent fractures in the foot and thigh bones can lead to chronic pain. Affected adults may lose their secondary (adult) teeth prematurely and are at increased risk for joint pain and inflammation.[3]

The mildest form of this condition, called odontohypophosphatasia, only affects the teeth. People with this disorder typically experience abnormal tooth development and premature tooth loss, but do not have the skeletal abnormalities seen in other forms of hypophosphatasia.[3]

Last updated: 7/17/2013

What causes hypophosphatasia?

Mutations in the ALPL gene cause hypophosphatasia.[3]

The ALPL gene provides instructions for making an enzyme called alkaline phosphatase. This enzyme plays an essential role in mineralization of the skeleton and teeth. Mutations in the ALPL gene lead to the production of an abnormal version of alkaline phosphatase that cannot participate effectively in the mineralization process. A shortage of alkaline phosphatase allows several other substances (phosphoethanolamine, pyridoxal 5'-phosphate (a form of vitamin B6) and inorganic pyrophosphate), which are normally processed by the enzyme, to build up abnormally in the body. Researchers believe that a buildup of one of these compounds, inorganic pyrophosphate (PPi), underlies the defective mineralization of bones and teeth in people with hypophosphatasia.[4][3][5]

ALPL mutations that almost completely eliminate the activity of alkaline phosphatase usually result in the more severe forms of hypophosphatasia. Other mutations, which reduce but do not eliminate the activity of the enzyme, are often responsible for milder forms of the condition.[3]

The perinatal and infantile forms of hypophosphatasia are inherited as autosomal recessive conditions. In these cases, 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 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.[4]

Individuals with hypophosphatasia and parents of children with hypophosphatasia are encouraged to meet with a genetic professional to learn more about the likelihood and severity of hypophosphatasia recurring in their families.

Last updated: 7/17/2013

How is hypophosphatasia treated?

As yet, there is no cure for hypophosphatasia and no proven medical therapy. Treatment is generally directed towards preventing or correcting the symptoms or complications. Expert dental care and physical therapy are recommended. An orthopedic procedure called "rodding" may be especially helpful for adults with painful partial fractures in their thigh bones.[4]

Some medications are being evaluated. Preliminary results of one study suggest that dietary phosphate restriction could be helpful in the management of hypophosphatasia. In another study teriparatide (the recombinant human parathyroid hormone PTH 1–34) was successfully used to improve and resolve metatarsal stress fractures in adult hypophosphatasia. Enzyme replacement therapy by using a substitutive enzyme targeting mineralized tissue may be the most promising challenge of the next few years.[6]

Infusion of normal alkaline phosphatase has provided only temporary improvement, but prolonged response has been observed after transplantation of marrow cells which express the normal enzymes.[5]

The Research Portfolio Online Reporting Tool (RePORT) provides access to reports, data, and analyses of research activities at the National Institutes of Health (NIH), including information on NIH expenditures and the results of NIH-supported research. You can find studies involving hypophosphatasia by searching this database. In particular, there is a study titled, "Molecular Pathogenesis and Treatment of Hypophosphatasia" that may be of interest to you. To find this and additional studies, click on the link below and enter "hypophosphatasia" in the "Terms Search" box. Then click "Submit Query".
Link: http://projectreporter.nih.gov/reporter.cfm
Last updated: 7/17/2013

References
  1. Plotkin H, Anadiotis GA. Hypophosphatasia. eMedicine Journal . October 20, 2006; http://www.emedicine.com/ped/topic1126.htm. Accessed 2/22/2008.
  2. Behrman RE, Kliegman RM, Jenson HB . Chapter 694--Hypophosphatasia. Nelson Textbook of Pediatrics, 17th edition. Philadelphia, PA: Saunders; 2004; 2344.
  3. Hypophosphatasia. Genetics Home Reference (GHR). 2008; http://ghr.nlm.nih.gov/condition=hypophosphatasia. Accessed 2/22/2008.
  4. Michael P. Whyte. M.D.. Hypophosphatasia. The Magic Foundation. December 5, 2007; http://www.magicfoundation.org/www/docs/175. Accessed 2/19/2008.
  5. Kronenberg HM, Melmed S, Polonsky, KS, Larsen PR. Williams Textbook of Endocrinology, 11th edition. Philadelphia, PA : Saunders Elsevier; 2008;
  6. Etienne Mornet. Hypophosphatasia. Orphanet J Rare Dis. 2007;