THU461 Severe Hypercalcemia Associated With Perinatal Hypophosphatasia While Receiving Enzyme Replacement Therapy

Abstract

Abstract Disclosure: M. Salama: None. P.J. Tebben: None. Introduction: Hypophosphatasia (HPP) is characterized by defective bone mineralization due to reduced function of tissue non-specific alkaline phosphatase (TNSALP) from pathogenic ALPL gene variants. Initial presentation varies according to the clinical phenotype. Hypercalcemia is more common in the perinatal and infantile forms and may be mitigated or prevented with enzyme replacement therapy asfotase alfa (AA). Here, we report a patient who developed severe hypercalcemia while receiving AA and describe our management strategy. Case: A now three-year-old girl with perinatal hypophosphatasia presented with severe hypercalcemia at 9 months of age. Her prenatal ultrasound was suggestive of a skeletal dysplasia. She was diagnosed with HPP shortly after birth and initiated AA on day two of life. She had normal calcium of 10.5 mg/dl at diagnosis. Phosphorus 9.3 mg/dl, total alkaline phosphatase <5 U/L, pyridoxal 5-phosphata (PLP) 974 mcg/L and phosphoethanolamine (PEA) 1084 nmoL/mg. Calcium dropped to 6.8 mg/dL after starting AA for which calcium supplementation was transiently utilized. At nine months of age, she developed severe hypercalcemia (15.8 mg/dl). Her phosphorus was 5.5 mg/dl, PLP 14 mcg/l and 25 hydroxyvitamin D 28 ng/ml. Parathyroid hormone and calcitriol were appropriately suppressed at <6.0 pg/ml and <8.0 pg/mL respectively. She was receiving 2 mg/kg of Asfotase three times weekly. Initial management included intravenous fluids and a reduction in dietary calcium intake by 50%. Within 2 days, calcium came down to upper normal for age at 11 mg/dL. AA dose was increased to 3 mg/kg three times weekly due to hypercalcemia and mildly worsening radiographs. Hypercalcemia recurred and initially responded to IV fluids and further dietary calcium reduction (low calcium formula (2.9 mg/ 5 fl oz)). Despite these measures, she required a third hospital admission when calcitonin 4 IU/kg every 12 hours was added to her restricted dietary calcium intake and AA therapy. On this regimen, her calcium normalized without recurrence of severe hypercalcemia. Over the subsequent eight months, calcium intake was slowly increased, and calcitonin tapered and discontinued with maintenance of calcium within the normal range. Conclusion: Hypercalcemia is common in infants with untreated, severe HPP and is likely mitigated for most when treated with AA. This case highlights the importance of monitoring calcium concentrations and intake in infants with HPP. Although calcitonin is generally not considered a long-term therapy for hypercalcemia, bisphosphonates may worsen the bone disease of HPP and should be avoided. This case demonstrates the utility of calcitonin therapy added to low calcium intake and maximal AA dosing to treat severe, persistent hypercalcemia in an infant with perinatal HPP. Presentation: Thursday, June 15, 2023