Hypophosphatasia
Overview
Hypophosphatasia (HPP) is a rare, inherited condition that is caused by a genetic change. This change causes defective mineralization of growing bones and teeth that are our hard, mineralized body tissues. HPP has a wide range of symptom severity from very mild to lethal and age symptoms begin from perinatal to adult. This variability has led to the categorization of 7 types of HPP: perinatal (severe), perinatal (benign), infantile, severe childhood, mild childhood, adult, and odontohypophosphatasia (dental only). These types have a wide range of variability within each type, as well.
This page addresses symptoms, genetic components of HPP, diagnostics, management and treatment, genetic counselling considerations, and patient resources for all 7 types. Its important to note that due to the variability of HPP, information on this page must be taken critically and thoughtfully interpreted for the type that is most applicable for the reader. Symptoms and outcomes discussed may be more or less severe than is applicable to reader.
Symptoms
Symptoms of HPP vary depending on the type and can have variability within type and within families. The below symptoms represent what is typically seen in each HPP type but is not exhaustive.
| Type | Age Symptoms Develop | Typical Symptoms |
|---|---|---|
| Perinatal (severe) |
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| Perinatal (benign) |
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| Infantile |
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| Severe Childhood |
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| Mild childhood |
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| Adult |
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| Odontohypophosphatasia (dental-only) |
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Outlook:
Severe perinatal HPP was historically considered a lethal condition. However, use of alkaline phosphatase enzyme replacement therapy has significantly improved outcomes. While most babies do survive, treatment response is not 100% [5].
Untreated infantile HPP mortality was previously cited as 50% [3]. However, the used of alkaline phosphatase enzyme replacement therapy has significantly improved the outlook for infantile HPP [5].
Genetics
HPP is a genetic condition, meaning it is caused by changes in our DNA that can be passed from generation to generation since we get half our DNA from each parent. DNA is a long string of letters (A, T, G, and C) whose sequences determines instructions cells use to carry out various functions. Each function is attributed to a gene. The gene ALPL codes for an alkaline phosphatase (AP), an enzyme that is important for bone and tooth mineralization. Changes in the sequence of A, T, G, and C or complete deletion of ALPL gene leads to changes in how AP functions or loss of AP all together, respectively.
Currently, there are over 400 ALPL gene changes that have been found that cause HPP. Each change is unique to a different type of HPP. Knowing the gene change is important to determine how the condition will progress, best way to manage symptoms and other related family members that may be at chance of developing HPP.
Mode of Inheritance:
Mode of inheritance (MOI) describes how a condition travels through generations. Since we get half our DNA from each parent, we have 2 copies of ALPL gene (one from each parent). HPP MOI patterns are determined by how many copies of a changed ALPL gene are required for a person to develop HPP. There are 2 MOIs for HPP: autosomal recessive and autosomal dominant. Typically, more severe types are autosomal recessive while more mild, older onset types can be either autosomal recessive or autosomal dominant. MOI can be determined by a genetic professional or medical doctor. MOI is important because it can help determine other related family members that may have a chance of developing HPP by analyzing the MOI patterns.
| Mode of Inheritance | Types | Pattern |
|---|---|---|
| Autosomal Recessive (AR) |
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| Autosomal Dominant (AD) |
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An appointment with a genetics professional is important to determine accurate familial and individual chance of developing HPP.
Prevalence:
Prevalence is the reported number of individuals in a population with a given condition.
In Ontario, Canada, the rate of severe, autosomal recessive HPP types (perinatal and infantile) has been estimated as 1 in 100,000 (or 0.0001%) [1]. However, due to a founder effect, the Canadian Mennonite population has an HPP prevalence of 1 in 2,500 (or 0.04%). Rates of adult onset and less severe types of HPP vary based on population but can typically found more commonly than severe HPP [5].
Diagnosis
Diagnosis (identification of HPP by medical doctor) can be a clinical diagnosis (based on signs and symptoms) or molecular diagnosis (based on genetic testing). Typically, a clinical diagnosis occurs first followed by molecular diagnosis to confirm. A molecular diagnosis can be important because it can help determine how the condition will progress, best way to manage symptoms and other related family members that may have a chance of developing HPP.
Clinical Diagnosis:
A clinical diagnosis can be made by medical doctor interpretation of: signs and symptoms (see symptoms), blood test results of different enzymes and analytes, and x-ray images of bones and teeth.
Molecular Diagnosis:
Molecular diagnosis (or genetic testing) is a blood test that is different from the blood test used in a clinical diagnosis. This blood test looks at DNA from cells in the blood. The DNA is analyzed for changes in the sequences of the ALPL gene or loss of the ALPL gene.
Not having genetic testing does not change a persons clinical diagnosis of HPP. The choice to undergo genetic testing is a very personal choice and should be made with informed consent.
Management
Management and treatment of HPP often requires the participation of a large, interdisciplinary team of medical professionals. The below outlines some of the management and treatment options that are possible for each type. Discussion with medical team is essential to determine which option is correct for each patient situation.
Management of symptoms is based on treating symptoms as they appear. Management strategies may include:
- Expectation management and family support
- Respiratory support
- Pain management
- Dental care
- Kidney disease care by a nephrologist
- Seizure care by a neurologist (may include vitamin B6 treatment)
- Endocrinology
- Orthopedic care (bone care)
Enzyme Replacement Therapy:
In Canada, alkaline phosphatase enzyme replacement therapy (ERT) is an approved treatment for perinatal, infantile, and severe childhood-onset HPP in patients of any age [5]. ERT has been shown to improve long term survival, respiratory function, and bone mineralization.
Severe perinatal HPP was historically considered a lethal condition. However, use of ERT have significantly improved outcomes. While most babies do survive, treatment response is not 100% [5].
Resources
Support and education is an important part of health literacy, advocacy and empowerment. Please find the below resources as a starting place for further education and engagement.
- https://rarediseases.org/rare-diseases/hypophosphatasia/
- https://medlineplus.gov/genetics/condition/hypophosphatasia/
- https://softbones.org/
References
- Nunes ME. Hypophosphatasia. 2007 Nov 20 [Updated 2023 Mar 30]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1150/
- https://www.mayoclinic.org/medical-professionals/endocrinology/news/hypophosphatasia-clinical-updates-and-therapeutic-advances/mac-20477637
- Tournis, S., Yavropoulou, M. P., Polyzos, S. A., & Doulgeraki, A. (2021). Hypophosphatasia. Journal of clinical medicine, 10(23), 5676.
- Arch Endocrinol Metab. 2023; 67(5): e000626. Published online 2023 May 29. doi: 10.20945/2359-3997000000626
- Khan, A., Josse, R., Kannu, P. et al. Hypophosphatasia: Canadian update on diagnosis and management. Osteoporos Int 30, 1713–1722 (2019). https://doi.org/10.1007/s00198-019-04921-y