What is the management approach for a patient presenting with blue sclera, low alkaline phosphatase (ALP), and hyperphosphatemia?

Hypophosphatasia: Diagnosis and Management

Immediate Diagnostic Confirmation

The combination of blue sclera, low alkaline phosphatase (ALP), and hyperphosphatemia strongly suggests hypophosphatasia (HPP), a rare genetic disorder of bone mineralization that requires immediate diagnostic confirmation through genetic testing of the ALPL gene and measurement of bone-specific ALP and ALP substrates. 1, 2

This clinical triad is highly unusual and warrants urgent evaluation, as HPP can be misdiagnosed as osteoporosis and inappropriately treated with antiresorptive therapy, which may worsen outcomes including atypical femoral fractures. 3, 4

Diagnostic Workup

Essential Laboratory Tests

• Bone-specific ALP measurement is critical, as total ALP may occasionally be normal in HPP while bone-specific ALP remains low (reference range 5.3-19.5 μg/L). 5
• Serum calcium and phosphate levels should be measured; HPP typically shows phosphate in the lower normal range or mildly elevated, with calcium in the lower normal to mildly elevated range. 1, 6
• Pyridoxal phosphate (vitamin B6) levels are characteristically elevated in HPP due to impaired ALP-mediated degradation; levels above the reference range strongly support the diagnosis. 1, 4, 6
• Urinary phosphoethanolamine (PEA) is elevated in HPP and correlates inversely with ALP levels (r=-0.49, p=0.001). 2, 6
• Parathyroid hormone (PTH) should be measured to exclude secondary hyperparathyroidism. 1
• 25(OH) vitamin D and 1,25(OH)2 vitamin D levels should be assessed to exclude vitamin D deficiency or other metabolic bone disorders. 1

Genetic Testing

• ALPL gene sequencing is the definitive diagnostic test and should be performed to confirm HPP; approximately 50% of adults with unexplained low ALP carry an ALPL mutation. 1, 2, 6
• Genetic counseling should be offered to patients with confirmed HPP, especially for family planning. 1

Clinical Assessment

• Detailed musculoskeletal examination should assess for lower limb deformities, bone pain, joint pain, muscle weakness, and gait abnormalities. 1
• Dental evaluation is essential, as HPP causes premature tooth loss, dental abscesses, and "gray gums" in childhood; patients require twice-yearly dental examinations. 1, 5
• Radiographic evaluation should include skeletal survey looking for pseudofractures, stress fractures, osteomalacia, chondrocalcinosis, and calcific periarthritis. 1, 2
• Neurological examination should assess for complications of craniosynostosis and spinal stenosis. 1

Management Approach

Critical Treatment Considerations

Antiresorptive therapy (bisphosphonates, denosumab) is relatively contraindicated in HPP and may trigger atypical femoral fractures; any such therapy should be discontinued immediately. 3, 4

Enzyme Replacement Therapy

• Asfotase alfa (burosumab) is the specific treatment for HPP and should be considered for patients with confirmed diagnosis and significant symptoms. 1, 5
• The EMA-approved starting dose is 0.4 mg/kg body weight subcutaneously every 2 weeks, with titration in 0.4 mg/kg increments to a maximum of 2.0 mg/kg (maximum 90 mg). 1
• Fasting serum phosphate levels should be monitored every 2 weeks during the first month, every 4 weeks during the following 2 months, then as appropriate to guide dose titration. 1

Monitoring Protocol

• Serum phosphate, calcium, ALP, and PTH should be monitored every 3-6 months. 1
• Urinary calcium-to-creatinine ratio should be checked every 3-6 months to detect hypercalciuria. 1
• 1,25(OH)2 vitamin D levels should be measured every 3-6 months in patients on enzyme replacement therapy. 1
• Renal ultrasonography should be performed every 1-2 years to screen for nephrocalcinosis. 1

Common Pitfalls to Avoid

• Do not assume normal total ALP excludes HPP; bone-specific ALP may be low despite normal total ALP, and genetic testing may still confirm the diagnosis. 5
• Do not initiate phosphate supplementation as would be done for X-linked hypophosphatemia (XLH); HPP presents with normal-to-high phosphate, not hypophosphatemia. 1, 7
• Do not overlook vitamin B6 testing; elevated pyridoxal phosphate is a key diagnostic marker that is frequently missed, with 0% of patients in one study having this test ordered despite low ALP. 4, 6
• Do not prescribe bisphosphonates or denosumab for presumed osteoporosis without first excluding HPP in patients with low ALP, as this can precipitate atypical fractures. 3, 4

Differential Diagnosis Considerations

The hyperphosphatemia in this case is atypical for classic HPP, which usually shows normal or low-normal phosphate levels. 1, 6 Consider:

• Renal insufficiency should be excluded by measuring creatinine and estimated GFR. 1
• Hypoparathyroidism can cause hyperphosphatemia and should be excluded by PTH measurement. 1
• Secondary causes of low ALP including malnutrition, zinc deficiency, magnesium deficiency, hypothyroidism, and certain medications should be investigated. 2