Course:MEDG550/Student Activities/Hypophosphatasia

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Overview

Bone bowing: a common symptom of HPP

Hypophosphatasia (HPP) is a rare, inherited condition. In HPP, bones and teeth do not grow how we would expect, so they are softer and easier to break. There are seven different types of HPP, based on when symptoms start and how serious the condition is. These types are:

  • Perinatal (severe)
  • Perinatal (benign)
  • Infantile
  • Severe childhood
  • Mild childhood
  • Adult
  • Odontohypophosphatasia (dental only)

Even within each type, people may experience different symptoms[1].

This page addresses symptoms, genetics, diagnosis, management, and genetic counselling for all seven types of HPP. It also provides resources that may be helpful to patients and families. It’s important to note that because of how variable the condition can be, all of the information listed may not apply to each person. Talking to your doctor and healthcare team is always recommended.

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 does not include everything.

Type Age Symptoms Develop Typical Symptoms
Perinatal (severe)
  • in utero (during pregnancy)
  • at birth
  • Bone changes on prenatal ultrasound
  • Bone bowing
  • excess amniotic fluid in pregnancy
  • incomplete lung development
  • prenatal bone fractures
  • seizures
Perinatal (benign)
  • in utero (during pregnancy)
  • at birth
  • Bone bowing on prenatal ultrasound and after birth
Infantile
  • before 6 months old
  • appear healthy at birth
  • rickets
  • reduced growth
  • muscle weakness
  • respiratory failure
  • premature tooth loss
  • failure to thrive
  • delayed developmental milestones
  • fusion of skull bones causing brain complications
Severe Childhood
  • after 6 months old and before 18 years old
  • short stature
  • bone deformations
  • bone pain
  • bone breaks/fractures
  • delayed walking
  • misshapen skull
Mild childhood
  • after 6 months old and before 18 years old
  • high rate of fractures
  • early tooth loss
Adult
  • after 18 years old
  • high rate of stress fractures
  • increased dental cavities
  • early tooth loss
  • osteoporosis
Odontohypophosphatasia (dental-only)
  • Variable age
  • high rate of dental cavities and tooth loss
  • loss of bone around teeth

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%[2].

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[2].

Genetics

Why is HPP a Genetic Condition?

Dominant inheritance.jpg

HPP is a genetic condition, meaning it’s caused by changes in our DNA that can be passed from generation to generation. DNA is like a recipe book with all of the instructions our body needs to grow and develop. These instructions are called “genes”. Like in a recipe book, we can have spelling changes in our genes (for example, a typo or a missing paragraph), which can affect the instructions and impact our health. These spelling changes are called “genetic variants”. In HPP, the genetic variants that cause the condition are found in the ALPL gene[1].

How do Genetic Variants in ALPL Cause HPP?

The ALPL gene provides instructions that are important in bone and tooth mineralization. Mineralization is a process where specific ingredients (called minerals) are added into the bone to make them hard and strong. When there is a genetic variant in the ALPL gene, bones and teeth may not harden like we would expect, which causes HPP[4].

Recessive Inheritance.jpg

How is HPP Passed Down?[1]

Everyone has 2 copies of the ALPL gene (one from each parent). In HPP, there are two different ways the condition can be inherited. These two different possibilities are called:

  • Autosomal dominant inheritance pattern: people with HPP only have a genetic variant in one of their ALPL genes.
  • Autosomal recessive inheritance pattern: people with HPP have a genetic variant in both of their ALPL genes.

A person with HPP will either have one or the other possibility.

It’s important to determine which one they have, because it can help determine which family members might be at risk of also developing HPP.

  • In families with the autosomal dominant form (see the top photo), each child of an affected person will have a 50% chance of having HPP.
  • In families with the autosomal recessive form (see the bottom photo), neither parent will have symptoms, but each child will have a 25% chance of having HPP.

Knowing how the condition is passed down in a family can also give us information on how serious the symptoms might be. Typically, more severe types are autosomal recessive.

Mode of Inheritance Types Pattern
Autosomal Recessive (AR)
  • perinatal severe
  • perinatal benign
  • infantile
  • severe childhood
  • mild childhood
  • adult
  • odonto-HPP
  • AR needs both copies of ALPL gene to have disease-causing change for someone to develop HPP
Autosomal Dominant (AD)
  • perinatal benign
  • very rarely infantile
  • severe childhood
  • mild childhood
  • adult
  • odonto-HPP
  • AD only needs 1 copy of ALPL gene to have disease-causing change for someone to develop HPP

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[2].

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[2]. 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%.

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.

  1. https://rarediseases.org/rare-diseases/hypophosphatasia/
  2. https://medlineplus.gov/genetics/condition/hypophosphatasia/
  3. https://softbones.org/

References

  1. ↑ Jump up to: 1.0 1.1 1.2 1.3 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; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1150/
  2. ↑ Jump up to: 2.0 2.1 2.2 2.3 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
  3. ↑ Tournis, S., Yavropoulou, M. P., Polyzos, S. A., & Doulgeraki, A. (2021). Hypophosphatasia. Journal of clinical medicine, 10(23), 5676.
  4. ↑ Whyte, M. P. (2016). Hypophosphatasia—Aetiology, nosology, pathogenesis, diagnosis and treatment. Nature Reviews Endocrinology, 12(4), 233–246. https://doi.org/10.1038/nrendo.2016.14

5. https://www.mayoclinic.org/medical-professionals/endocrinology/news/hypophosphatasia-clinical-updates-and-therapeutic-advances/mac-20477637

6. Arch Endocrinol Metab. 2023; 67(5): e000626. Published online 2023 May 29. doi: 10.20945/2359-3997000000626

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