Hypophosphatasia (HPP) is a rare genetic disorder that affects the development of bones and teeth. The name itself provides a clue to its core feature: hypo- meaning “low,” and -phosphatasia referring to the enzyme alkaline phosphatase. Individuals with HPP have abnormally low levels of this crucial enzyme in their blood.

To understand HPP, it is essential to understand the basics of bone formation. Bone is a living tissue composed of a flexible protein matrix (mostly collagen) that acts as a scaffold. To give this scaffold its strength and rigidity, the body must deposit crystals of calcium and phosphate onto it. This process requires a key enzyme called tissue-nonspecific alkaline phosphatase (TNSALP).

Think building a strong brick wall. The collagen is the stack of bricks, and calcium and phosphate are the raw ingredients for the mortar. The TNSALP enzyme acts as the essential chemical catalyst that allows the mortar to harden and bind the bricks together. In hypophosphatasia, the body’s supply of this catalyst is faulty or missing. Without enough functional TNSALP, the mortar remains soft and weak. The bricks are there, but the wall is fragile, unstable, and prone to crumbling. This is why the bones in HPP are soft (a condition called osteomalacia in adults and rickets in children) and are highly susceptible to fractures and deformities.

This enzyme deficiency also leads to a buildup of the chemicals that TNSALP was supposed to break down. These substances, particularly inorganic pyrophosphate (PPi), pyridoxal 5’-phosphate (PLP, a form of vitamin B6), and phosphoethanolamine (PEA), accumulate to high levels in the blood and urine. Excess PPi further inhibits bone mineralization, worsening the problem.

In my experience, hypophosphatasia often goes undiagnosed, especially in adults, because its symptoms mimic osteoporosis or early dental disease. It’s only after multiple unexplained fractures or early tooth loss that the underlying enzyme defect is discovered.

Hypophosphatasia is caused by mutation in the ALPL gene. This gene contains the precise genetic instructions for making the TNSALP enzyme. When the ALPL gene is mutated, the resulting TNSALP enzyme is either not produced, is produced in insufficient quantities, or is misshapen and cannot function properly.

Without a working TNSALP enzyme, the body cannot effectively mineralize the skeleton. Researchers have identified over 400 different mutations in the ALPL gene. The specific type and location of the mutation often correlate with the wide range of severity seen in HPP.

Genetic testing has changed how we understand HPP. I’ve seen cases where two siblings with the same mutation had very different symptoms, one with mild bone pain and the other with severe skeletal deformities. That variability can make diagnosis tricky.

Hypophosphatasia is inherited and may follow either an autosomal recessive or autosomal dominant pattern, depending on the type and severity.

Autosomal Recessive Inheritance

The most severe forms of HPP, the perinatal and infantile types are inherited in an autosomal recessive pattern.

• This means that for a child to have the severe form of the disease, they must inherit two copies of the mutated ALPL gene, one from each parent.
• Parents are almost always unaffected carriers. A carrier has one normal copy of the gene and one mutated copy. They are generally healthy but may have very mild symptoms, such as low alkaline phosphatase levels on a blood test.
• When two carriers have a child, there is a 25% chance with each pregnancy that the child will inherit two mutated genes and be affected with severe HPP.

Because both parents must carry the same rare faulty gene, the chances of having a child with an autosomal recessive condition are higher in communities where marriage between close relatives, such as first cousins, is a common cultural practice. This is because related individuals have a greater likelihood of carrying the same inherited genetic traits.

Autosomal Dominant Inheritance

The milder forms of HPP, such as the adult and odontohypophosphatasia types, are often inherited in an autosomal dominant pattern.

• In this case, an individual only needs to inherit one copy of the mutated gene from one affected parent to have the condition.
• An affected parent has a 50% chance of passing the condition on to each of their children.

In some cases, HPP can also arise from a new, spontaneous (de novo) mutation in a child with no family history of the disorder. Genetic counseling can help families understand their specific situation and the risk of recurrence.

I always ask about dental history in families with suspected HPP. Premature loss of baby teeth, especially with intact roots is often the first clue, even before bone symptoms begin.

The signs and symptoms vary widely based on onset age and severity of enzyme deficiency. There are six main clinical forms:

• Perinatal (Lethal) HPP: This is the most severe form. It presents before birth with profound skeletal undermineralization visible on prenatal ultrasound. Babies are often stillborn or die shortly after birth from respiratory failure due to an underdeveloped rib cage.
• Infantile HPP: Symptoms appear within the first six months of life. This form is also very severe and can be life-threatening. It is characterized by:
  • Severe skeletal deformities resembling rickets, with soft skull bones and bowed legs.
  • Poor feeding and “failure to thrive.”
  • Respiratory complications due to a soft, pliable rib cage.
  • High blood calcium levels (hypercalcemia), which can lead to kidney damage.
• Childhood HPP: This form presents after six months of age and has a wider range of severity. The hallmark sign is the premature loss of deciduous (baby) teeth, often before the age of 5, with the roots still intact. Other signs include:
  • Short stature and delayed walking.
  • Bone deformities, such as bowed legs or knock-knees.
  • A characteristic “waddling” gait.
  • Bone and joint pain.
• Adult HPP: This form is often diagnosed in middle age. Symptoms can be vague and may include:
  • A history of premature loss of adult teeth.
  • Recurrent, poorly healing stress fractures, especially in the feet (metatarsals).
  • Chronic bone, joint, or muscle pain.
  • Thigh pain due to pseudofractures of the femur.
• Odontohypophosphatasia: This is the mildest form of the disease. It is characterized by abnormal dental health, such as the premature loss of teeth or severe dental cavities, but with no evidence of the bone disease (rickets or osteomalacia) seen in other forms.

When adults present with recurrent foot fractures and dental issues, I’ve learned to think beyond osteoporosis. HPP is often hiding behind a history of vague bone pain and overlooked dental findings.

Diagnosing HPP requires a combination of clinical suspicion, lab testing, and genetic analysis.

The diagnostic process involves several key steps:

1. Serum Alkaline Phosphatase (ALP) Test: The biochemical hallmark and the most important initial clue for HPP is a consistently low level of the TNSALP enzyme in the blood.  It is crucial for doctors to recognize that a low ALP level, not just a high one, can be a sign of a significant medical condition.
2. Measuring TNSALP Substrates: To confirm the enzyme is not working properly, blood and urine tests are done to measure the levels of the substances it is supposed to break down. High levels of vitamin B6 (in the form of PLP) in the blood and phosphoethanolamine (PEA) in the urine are highly suggestive of HPP.
3. Imaging Studies: X-rays are performed to look for the characteristic signs of defective mineralization, such as rickets in children or stress fractures and pseudofractures in adults.
4. Genetic Testing: The diagnosis is definitively confirmed by molecular genetic testing. A blood sample can be sent for sequencing of the ALPL gene to identify the causative mutations.

The biggest red flag for me is when ALP is abnormally low, especially when most bone diseases show elevated ALP. That lab clue, combined with dental or fracture history, almost always points to HPP.

There is no universal cure for HPP, but treatments aim to manage symptoms and improve quality of life. Management is lifelong and focused on managing symptoms, improving bone health.

1. Enzyme Replacement Therapy (ERT)

The single greatest breakthrough in the treatment of HPP is an enzyme replacement therapy called asfotase alfa (Strensiq®).

• Mechanism: Asfotase alfa is a bioengineered form of the human TNSALP enzyme. It is given as an injection under the skin several times a week. The medication circulates in the body and replaces the function of the missing or faulty enzyme, allowing for proper bone mineralization.
• Impact: This therapy has been shown to be life-saving and has dramatically improved the skeletal deformities, respiratory function, and survival of infants with the most severe forms of HPP (NORD, 2023). It is also used to treat childhood and adult forms of the disease.
• Considerations: ERT is a highly specialized and extremely expensive medication. Access can be a significant challenge for families depending on their country’s healthcare system and resources.

2. Supportive and Symptom-Based Management

This is a critical part of care for all individuals with HPP, especially for those with milder disease or for whom ERT may not be an option.

• Dental Care: Meticulous and regular dental care from a knowledgeable dentist are crucial.
• Orthopedic Care: Management of fractures, and sometimes surgery (e.g., placing rods in long bones) to improve strength and prevent recurrent fractures.
• Physical and Occupational Therapy: To improve strength, mobility, and function.
• Pain Management: Using NSAIDs or other painkillers.
• Things to Avoid: It is generally recommended that individuals with HPP avoid bisphosphonates, a common treatment for osteoporosis, as they can worsen the mineralization defect.

For younger patients, ERT can be life-changing, helping stabilize bones and even reverse some damage. But for adults, management focuses more on lifestyle support and avoiding the wrong medications.

Hypophosphatasia is a rare and complex inherited disease that disrupts the very foundation of skeletal health. It exists on a vast continuum, from a devastating condition in infancy to a subtle problem affecting only the teeth in adulthood. The key to its diagnosis is recognizing the importance of low alkaline phosphatase in the blood. While the journey for patients and families is lifelong and often challenging, the outlook has been fundamentally changed by the development of enzyme replacement therapy, which offers a life-saving treatment for the most severely affected. What I always tell patients and families is this: while there’s no cure for HPP, knowledge is power. With early diagnosis and the right care team, most people can manage symptoms effectively and maintain a fulfilling quality of life

National Institutes of Health, Genetic and Rare Diseases Information Center (GARD). (2021). Hypophosphatasia. Retrieved from https://rarediseases.info.nih.gov/diseases/6738/hypophosphatasia

National Organization for Rare Disorders (NORD). (2023). Hypophosphatasia. Retrieved from https://rarediseases.org/rare-diseases/hypophosphatasia/

Soft Bones: The US Hypophosphatasia Foundation. (n.d.). What is HPP? Retrieved from https://www.softbones.org/