How Your Clinician Gathers 2 Major or 1 Major and 2 Minor Diagnostic Criteria

Below is an overview of how your clinician gathers the required criteria—either two major criteria or one major plus two minor criteria—to make an adult hypophosphatasia diagnosis. Use this as your “Adult Hypophosphatasia diagnosis checklist” to guide discussions with your care team.

Why a Clear Diagnostic Approach Matters

Adult hypophosphatasia (HPP) is a rare metabolic bone disease caused by low activity of the enzyme tissue-nonspecific alkaline phosphatase (TNSALP). Symptoms can be subtle or overlap with more common conditions, so a systematic checklist helps avoid delays or misdiagnoses.

Diagnostic Criteria Overview

Most experts agree you need:

• Two major criteria
  OR
• One major plus two minor criteria

Major criteria focus on key biochemical and radiographic findings. Minor criteria capture less specific but still supportive clinical features.

Major Criteria

1. Persistently low serum alkaline phosphatase (ALP)
   • Below the lower limit of normal on at least two occasions, measured by an accredited lab.
2. Elevated biochemical markers of TNSALP deficiency
   • High serum pyridoxal-5′-phosphate (PLP, active vitamin B6)
   • Or elevated urine phosphoethanolamine (PEA)
3. Characteristic radiographic or histologic bone changes
   • Pseudofractures (Looser zones) in long bones
   • Fractures that fail to heal or healing poorly
   • Bone biopsy showing osteomalacia

Minor Criteria

1. History of premature loss of deciduous (baby) teeth without obvious cause
2. Chronic musculoskeletal pain (bones, joints, or muscles)
3. Recurrent or delayed fracture healing
4. Low bone mineral density on DEXA scan
5. Muscle weakness, particularly core or proximal muscles
6. Family history of hypophosphatasia or unexplained fractures

How Your Clinician Gathers These Criteria

1. Detailed Medical History

   • Ask about childhood tooth loss, fracture history, bone pain onset and severity.
   • Note any family members with bone disease, early tooth loss or fractures.

2. Physical Examination

   • Check for bone tenderness, muscle strength (especially hips and shoulders), gait abnormalities.
   • Inspect oral health for loose or missing teeth.

3. Laboratory Testing

   • Serum ALP: Confirm a persistently low result (major criterion).
   • Serum PLP and/or urine PEA: Look for elevations that confirm TNSALP deficiency (major criterion).
   • Calcium, phosphate, parathyroid hormone: Rule out other metabolic bone diseases.

4. Imaging Studies

   • X-rays of symptomatic bones: Identify pseudofractures, osteomalacia changes (major criterion).
   • DEXA scan: Measure bone mineral density (minor criterion).
   • Occasionally bone scintigraphy (bone scan) to locate stress fractures.

5. Dental Evaluation

   • Panoramic X-ray of the jaw: Assess tooth development and bone around roots.
   • Review history of premature tooth loss (minor criterion).

6. Genetic Testing (Optional but Supportive)

   • ALPL gene sequencing can confirm a diagnosis, especially if criteria are borderline.
   • Helps with family counseling and identifying mild or atypical cases.

Putting It All Together: Adult Hypophosphatasia Diagnosis Checklist

Use this summary to track which criteria your clinician has documented:

Major Criteria

• Two separate low serum ALP results
• Elevated PLP or PEA
• Radiographic/histologic evidence of osteomalacia or pseudofractures

Minor Criteria

• Premature deciduous tooth loss
• Chronic bone/joint/muscle pain
• Delayed or recurrent fracture healing
• Low bone mineral density on DEXA
• Muscle weakness
• Family history of HPP or unexplained fractures

Diagnosis requires:

• Any two major criteria
  OR
• One major plus two minor criteria

Next Steps & Resources

If you suspect adult hypophosphatasia based on this checklist, consider a
free, online symptom check, using the doctor approved Ubie Symptom Checker
to gather your symptom profile before your appointment.

When to Speak to a Doctor

This checklist is for educational purposes. Always speak to a doctor if you experience:

• Severe or worsening bone pain
• New or non-healing fractures
• Muscle weakness that limits daily activities
• Any symptom that feels life threatening

A timely evaluation can help confirm the diagnosis and guide appropriate treatment—whether enzyme replacement, pain management, or physical therapy.

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By following this “Adult Hypophosphatasia diagnosis checklist,” you and your clinician can work together efficiently to confirm or rule out HPP and begin the right management plan.