Disease Profile

Hypophosphatasia

Prevalence ?
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of Onset

All ages

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ICD-10

E83.3

Inheritance

Autosomal dominant ?A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive ?Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked dominant ?X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked recessive ?Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic ?Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor ?Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other Names (AKA)

Phosphoethanol-aminuria; Hypophosphatasia mild; Phosphoethanolaminuria;

Categories

Congenital and Genetic Diseases; Metabolic disorders; Mouth Diseases;

Summary

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. Signs and symptoms may include poor feeding and respiratory problems in infancy; short stature; weak and soft bones; short limbs; other skeletal abnormalities; and hypercalcemia. Complications can be life-threatening. The mildest form of the condition, called odontohypophosphatasia, only affects the teeth.[1] HPP is caused by mutations in the ALPL gene. Perinatal (onset before birth) and infantile HPP are inherited in an autosomal recessive manner. The milder forms, especially adult forms and odontohypophosphatasia, may be inherited in an autosomal recessive or autosomal dominant manner.[2] While treatment has always been symptomatic and supportive, recently an enzyme replacement therapy (ERT) called asfotase alfa has been show to improve bone manifestations people with childhood onset HPP and has been approved by the FDA.[3][4]

Symptoms

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.[1]

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.[1]

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.[1]

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Abnormality of the dentition
Abnormal dentition
Abnormal teeth
Dental abnormality

[ more ]

0000164
Abnormality of the metaphysis
Abnormality of the wide portion of a long bone
0000944
Abnormality of the ribs
Rib abnormalities
0000772
Bowing of the long bones
Bowed long bones
Bowing of long bones

[ more ]

0006487
Craniosynostosis
0001363
Emphysema
0002097
Failure to thrive in infancy
Faltering weight in infancy
Weight faltering in infancy

[ more ]

0001531
Feeding difficulties in infancy
0008872
Large fontanelles
Wide fontanelles
0000239
Narrow chest
Low chest circumference
Narrow shoulders

[ more ]

0000774
Short stature
Decreased body height
Small stature

[ more ]

0004322
Skin dimple over apex of long bone angulation
0001024
30%-79% of people have these symptoms
Anemia
Low number of red blood cells or hemoglobin
0001903
Hypercalcemia
High blood calcium levels
Increased calcium in blood

[ more ]

0003072
Irritability
Irritable
0000737
Muscular hypotonia
Low or weak muscle tone
0001252
Recurrent fractures
Increased fracture rate
Increased fractures
Multiple fractures
Multiple spontaneous fractures
Varying degree of multiple fractures

[ more ]

0002757
Respiratory insufficiency
Respiratory impairment
0002093
Seizure
0001250

Cause

Hypophosphatasia (HPP) is a genetic condition caused by mutations in the ALPL gene. This gene gives the body instructions to make an enzyme called alkaline phosphatase, which is needed for mineralization of the bones and teeth. Mutations in this gene lead to an abnormal version of the enzyme, thus affecting the mineralization process. A shortage of the enzyme also causes other substances to build up in the body. These abnormalities lead to the features of HPP.

ALPL mutations that almost completely eliminate alkaline phosphatase activity generally cause the more severe forms of HPP, while mutations that reduce activity to a lesser extent often cause the milder forms of HPP.[1]

Treatment

Until recently, management of hypophosphatasia (HPP) has mostly been aimed at addressing symptoms of the condition.[5] For example:

  • Hydration, restriction of dietary calcium, vitamin D, and sometimes thiazide diuretics for hypercalcemia
  • Ventilatory support for severely affected infants, some of which need a tracheostomy, which can lead to problems with speech and language development and tolerance of oral feeds
  • Physiotherapy, occupational therapy and chronic pain management for pain and motor difficulty
  • Surgery for fractures that fail to heal

More recently, research has shown positive effects of human recombinant enzyme replacement therapy (ERT), called asfotase alfa, on people who began having symptoms before 6 months of age. There reportedly have been significant improvements in the X-ray appearances of bone tissue, along with improvements in growth, respiratory function, motor development and calcium homeostasis after 6–12 months of treatment. The children in the original study have now received more than three years of treatment, without apparent major side effects, and with continuing improvement in affected systems.[5] Asfotase alfa appears to be a valuable emerging therapy for the treatment of bone manifestations in people with pediatric-onset HPP.[4] In October of 2015 the FDA approved asfotase alfa, sold as Strensiq.[3]

Bone marrow and stem cell transplantation in infancy and childhood have improved the severity of the disease, but have not provided long term improvement.[5]

FDA-Approved Treatments

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition. Learn more orphan products.

Organizations

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

    Social Networking Websites

      Learn More

      These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

      Where to Start

      • Genetics Home Reference (GHR) contains information on Hypophosphatasia. This website is maintained by the National Library of Medicine.
      • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.
      • The MAGIC Foundation has an information page about hypophosphatasia.

        In-Depth Information

        • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
        • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
        • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
        • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
          Orphanet
          Orphanet
        • PubMed is a searchable database of medical literature and lists journal articles that discuss Hypophosphatasia. Click on the link to view a sample search on this topic.

          References

          1. Hypophosphatasia. Genetics Home Reference (GHR). September 2007; https://ghr.nlm.nih.gov/condition=hypophosphatasia.
          2. Etienne Mornet and Mark E Nunes. Hypophosphatasia. GeneReviews. November, 2011; https://www.ncbi.nlm.nih.gov/books/NBK1150/.
          3. Morrow T. Expensive New Biologic Helps Children Fight Hypophosphatasia. Manag Care. December, 2015; 24(12):25-26. https://www.managedcaremag.com/linkout/2015/12/25.
          4. Scott LJ. Asfotase Alfa: A Review in Paediatric-Onset Hypophosphatasia. Drugs. February, 2016; 76(2):255-262.
          5. Bishop N. Clinical management of hypophosphatasia. Clin Cases Miner Bone Metab. May-August 2015; 12(2):170-173.