What is the approach to managing a child with hypophosphatasia (low alkaline phosphatase) and hypercalcemia (elevated calcium)?

Management of Low Alkaline Phosphatase and Elevated Calcium in a Child

This presentation is highly suggestive of hypophosphatasia, and the immediate priority is to STOP any calcium and vitamin D supplementation, as these can worsen hypercalcemia and cause life-threatening complications including nephrocalcinosis and renal failure. 1, 2, 3

Immediate Actions

• Discontinue all calcium and vitamin D supplements immediately – these are contraindicated in hypophosphatasia and can precipitate severe hypercalcemia, hypercalciuria, and nephrocalcinosis 3, 4
• Initiate aggressive hydration with intravenous fluids to maintain urine output around 2 L/day to manage hypercalcemia 5
• Consider calcitonin (4-8 units/kg/dose every 8-12 hours) for acute symptomatic hypercalcemia 6
• Switch to low-calcium formula if the child is formula-fed 6, 4

Diagnostic Confirmation

Essential laboratory workup to confirm hypophosphatasia:

• Serum alkaline phosphatase – characteristically LOW (the hallmark finding) 7, 1, 2
• Serum calcium and phosphate – typically elevated or high-normal (unlike typical rickets) 1, 3
• PTH level – will be suppressed due to hypercalcemia 6, 3
• 25-hydroxyvitamin D – should be normal or elevated (rules out nutritional rickets) 7, 3
• Pyridoxal-5'-phosphate (PLP) and phosphoethanolamine (PEA) – elevated levels are specific markers for hypophosphatasia 1, 2
• Urine calcium/creatinine ratio – assess for hypercalciuria 8
• Renal function (BUN, creatinine) – monitor for renal impairment from hypercalcemia 7, 6

Imaging studies:

• Renal ultrasonography – evaluate for nephrocalcinosis, which is a serious complication 8, 3
• Skeletal radiographs – assess for hypomineralization, bone deformities, or rachitic changes 7, 1
• Skull imaging – evaluate for craniosynostosis if clinically indicated 1, 2

Genetic testing:

• ALPL gene sequencing – confirms diagnosis and identifies specific mutations 2, 3

Clinical Assessment

Evaluate for severity indicators that predict poor prognosis:

• Respiratory status – respiratory insufficiency and rib fractures indicate severe disease 1, 2
• Seizures – may result from vitamin B6 deficiency due to elevated PLP 1, 4
• Growth parameters – assess for failure to thrive and growth retardation 7, 1
• Skeletal manifestations – bone pain, deformities, or fractures 7, 2
• Dental examination – premature tooth loss is common (odontohypophosphatasia) 7, 1
• Neurological assessment – evaluate for developmental delays and hypotonia 2

Ongoing Management

Hypercalcemia management:

• Maintain adequate hydration throughout treatment to prevent dehydration and renal complications 8
• Avoid overhydration in patients with cardiac concerns 5
• Monitor calcium levels every 4-6 months until 2 years of age, then every 2 years thereafter 8
• Vitamin B6 supplementation may be needed if seizures occur due to PLP accumulation 1, 4

Nutritional considerations:

• Restrict dietary calcium to age-appropriate levels only – do NOT over-restrict without medical supervision 8
• Avoid multivitamin preparations containing vitamin D in early childhood 8
• Use low-calcium milk formulations if hypercalcemia persists 4

Monitoring schedule:

• Every 3-6 months: height, weight, BMI, blood pressure, ALP, calcium, phosphate, creatinine, PTH, 25(OH) vitamin D 7
• Dental visits twice yearly after tooth eruption 7
• Serial renal imaging if nephrocalcinosis is present 8

Definitive Treatment

Enzyme replacement therapy:

• Asfotase alfa is a novel enzyme replacement therapy specifically targeted to mineralized tissues, showing extremely encouraging results particularly for severe infantile forms of hypophosphatasia 1, 2
• This represents the only disease-modifying treatment currently available 1, 2

Specialist Referrals

Multidisciplinary care is essential:

• Pediatric endocrinologist – for management of metabolic bone disease and hypercalcemia 8
• Pediatric nephrologist – if persistent hypercalcemia, hypercalciuria, or nephrocalcinosis develops 8
• Genetics consultation – for genetic counseling and ALPL gene testing 2, 3
• Dental specialist – for regular monitoring and management of dental complications 7, 1

Critical Pitfall to Avoid

The most dangerous error is misdiagnosing hypophosphatasia as nutritional rickets and treating with calcium and vitamin D supplementation – this can precipitate severe hypercalcemia, acute renal failure, and nephrocalcinosis, potentially causing permanent kidney damage or death 3. The key distinguishing feature is that hypophosphatasia presents with LOW alkaline phosphatase (unlike nutritional rickets where ALP is elevated), along with elevated or high-normal calcium and phosphate levels 1, 2, 3.

Recovery timeline: After discontinuing inappropriate calcium/vitamin D therapy, normalization of alkaline phosphatase typically precedes normalization of calcium (by approximately 55 days) and PTH (by approximately 85 days) 6.