ESPE Abstracts

Children affected by idiopathic infantile hypercalcemia (IIH) may develop polyuria, polydipsia, failure to thrive, developmental delay and nephrocalcinosis already during the first weeks of life. Elevated levels of activated 1-,25(OH)₂D₃ have been shown to cause the characteristic increase in serum calcium levels in this disorder. Two major underlying genetic causes have been identified so far: in IIH type 1 loss-of-function mutations in CYP24A1 lead to impaired degradation and thus accumulation of activated 1-,25(OH)₂D_3. In the less frequent type 2, loss-of-function mutations in SLC34A1, encoding the renal sodium-phosphate cotransporter 2a (NaPi-IIa), lead to severe renal phosphate wasting. The resulting low levels in serum phosphate entail a decrease in FGF23, resulting in an increase of 1-,25(OH)₂D₃ followed by hypercalcemia and a decrease in parathyroid hormone (PTH), because FGF23 usually reduces 1-,25(OH)₂D₃ serum levels by inhibiting its activation via 1-α-hydroxylase and by inducing its degradation via CYP24A1. We present an infant that developed marked hypercalcemia and was diagnosed with nephrocalcinosis at the age of four weeks. Serum calcium was found to be elevated to a maximum of 3.7 mmol/l (reference 2-2.7 mmol/l), ionized calcium increased to 1.6 mmol/l (refrence1.15-1.35 mmol/l). In the following, phosphate serum levels decreased (min. 0.75 mmol/l) and PTH was suppressed (<0,1 mmol/l, reference 1.3-7.6 mmol/l), however no increase in parathyroid hormone-related peptide was detected (PTHr P <0,5pmol/l). 25-OH-D₃ levels were normal, whereas 1-,25(OH)₂D₃ was significantly elevated (274 ng/l, reference 25-154 ng/l). Tubular reabsorption of phosphate was decreased (75%) and urinary calcium excretion elevated (2.9 mg/mg creatinine, reference < 0,8) with subsequent bilateral nephrocalcinosis °III. Thus, the laboratory findings suggested IIH type 2. Genetic testing revealed two distinct heterozygous variants in SLC34A1, c.1223T>A, p.(Val408Glu) and c.1425_1426del, p.(Cys476Serfs*128). Both variants had been described in the context of IIH before, therefore, hypercalcemia in the present patient was likely to be explained by compound heterozygosity in SLC34A1. Parental segregation analysis was initiated, results are currently pending. Vitamin D prophylaxis was immediately suspended and both intravenous rehydration combined with furosemide and a low-calcium diet were initiated. Later, based on the genetic findings, phosphate supplementation was started at an initial dosage of 0.85 mmol/kg and gradually reduced as normalization of calcium levels could be observed. Therefore, the present case report emphasizes that early genetic testing in infants presenting with clinical symptoms of IIH is crucial in order to prevent complications and provide appropriate treatment.