What is the diagnostic approach for Hypophosphatasia (HPP)?

Diagnostic Approach for Hypophosphatasia (HPP)

Suspect HPP in any patient with persistently low serum alkaline phosphatase (ALP) below age-specific reference ranges, particularly when accompanied by fractures, bone pain, dental abnormalities, or skeletal deformities, and confirm diagnosis through genetic testing for ALPL gene variants. 1, 2

Clinical Presentation by Age Group

Children and Adolescents

• Look for rickets-like skeletal changes, impaired growth velocity, skeletal deformities, premature loss of deciduous teeth, and dental abscesses 3
• Assess for low-impact fractures, skeletal pain, joint pain, or weakness with family history of similar symptoms 3
• Physical examination should focus on skeletal deformities, dental abnormalities, and growth parameters (height, weight) 3

Adults

• Evaluate for musculoskeletal pain (present in 41% at diagnosis), history of fractures (54% of patients), particularly atypical locations including subtrochanteric femur fractures, metatarsal stress fractures, and hip/femoral neck fractures 4
• Screen for chondrocalcinosis and pyrophosphate arthropathy (more common in women), early osteoarthritis, pseudofractures, and dental abnormalities 4
• Consider HPP in patients with higher than normal or normal lumbar spine bone mineral density (BMD) who present with minimal trauma fractures or non-healing fractures 5

Initial Biochemical Work-Up

Essential Laboratory Tests

• Serum alkaline phosphatase (ALP): The hallmark finding is persistently low ALP below age-specific reference ranges; interpret carefully in adolescents who typically have higher values due to active bone growth 3, 1
• Serum calcium, phosphate, and creatinine 3
• Parathyroid hormone (PTH) to exclude secondary causes 3
• 25(OH) vitamin D and 1,25(OH)₂ vitamin D levels to rule out vitamin D deficiency 3

Confirmatory Biomarkers

• Pyridoxal 5'-phosphate (PLP): Elevated in HPP (median 68 μg/L vs normal 5-50 μg/L); all tested patients in one series had elevated levels 4
• Urine phosphoethanolamine (PEA): Elevated in 94% of adult HPP patients 4
• These substrates accumulate due to deficient tissue-nonspecific alkaline phosphatase (TNAP) activity 1

Renal Phosphate Assessment

• Calculate tubular maximum reabsorption of phosphate per glomerular filtration rate (TmP/GFR) to assess renal phosphate handling and exclude other phosphate disorders 3

Radiographic Evaluation

• Obtain radiographs of long bones, spine, and skull to assess for rickets-like changes, osteomalacia, osteopenia, or pseudofractures 3
• Look for characteristic findings including undermineralized bone, fractures in atypical locations, and skeletal deformities 1
• In adults, assess for chondrocalcinosis on joint radiographs 4

Differential Diagnosis Considerations

Key Distinctions

• Exclude X-linked hypophosphatemia (XLH): XLH presents with elevated (not low) ALP, hypophosphatemia with renal phosphate wasting, and non-suppressed FGF23 levels 3
• Rule out osteoporosis: HPP may present with normal or high lumbar spine BMD despite fractures, unlike typical osteoporosis 5
• Exclude vitamin D deficiency and secondary hyperparathyroidism: Check vitamin D and PTH levels 3

Important Clinical Pitfalls

• Do not assume osteoporosis based solely on fracture history; HPP can present with normal or elevated BMD at the lumbar spine 5
• Avoid bisphosphonate therapy in HPP patients, as these drugs are contraindicated and may worsen bone mineralization 1
• Low ALP may be overlooked or dismissed as a laboratory error; persistently low values warrant investigation 2

Genetic Testing for Definitive Diagnosis

• Confirm diagnosis with genetic testing for ALPL gene variants on chromosome 1, which encodes tissue-nonspecific alkaline phosphatase 1, 2, 6
• Genetic testing distinguishes HPP from other bone disorders and guides treatment decisions 2
• HPP demonstrates autosomal recessive or dominant inheritance patterns with variable penetrance and expression 6
• Variants of uncertain significance (VUS) may complicate interpretation; clinical correlation with biochemical and radiographic findings is essential 6

Diagnostic Algorithm Summary

1. Screen: Identify persistently low ALP in patients with suggestive clinical features (fractures, bone pain, dental issues)
2. Confirm biochemically: Measure PLP and urine PEA (elevated in HPP)
3. Exclude alternatives: Check calcium, phosphate, PTH, vitamin D, and TmP/GFR to rule out other metabolic bone diseases
4. Image: Obtain skeletal radiographs to assess for characteristic bone changes
5. Definitive diagnosis: Perform ALPL genetic testing 1, 2

Special Considerations

• Symptomatic HPP patients typically have lower median minimum ALP and PLP levels with higher median urine PEA compared to asymptomatic individuals 4
• Gender may influence clinical expression, with women more commonly experiencing metatarsal fractures and chondrocalcinosis 4
• Some patients may have persistently low ALP without identifiable ALPL variants, requiring clinical judgment and consideration of other genetic factors 6