ESPE Abstracts

We report on a 17-year-old patient with hypoparathyroidism which was noticed during the diagnosis of a first renal colic a year and a half ago. At that time, a prevesical ureter stone on the right could be depicted sonographically, which disappeared spontaneously. Initially calcium levels in serum and urine were reported to be normal. However, a slight hypercalcemia and hypercalciuria as well as high normal vitamin D levels without vitamin D substitution were detected intermittently between age 15.5 and 17 years. In addition, hypophosphaturia was repeatedly measured. The family history was unremarkable. Based on this clinical and laboratory constellations, we initiated a gene panel analysis for hypoparathyroidism. We detected a compound heterozygous mutation in the CYP24A1 gene comprising the variants c.1226T>C (P.Leu409Ser) on one allele and c.1434G>A (P.Trp478ter) on the other allele. Genetic analysis of the parents is underway. The variant c.1226T>C (P.Leu409Ser) is listed in the databases as a pathogenic mutation, while the other variant c.1434G>A (P.Trp478ter) is novel. However, the latter leads to a premature stop codon, which makes a pathogenic effect likely. Homozygous or compound-heterozygous mutations in the CYP24A1 gene are described as the molecular cause of autosomal recessive type 1 hypercalcemia (HCINF1). As a result of mutations of the 1,25(OH)2D-24-hydroxylase cytochrome P450 (CYP24A1) the degradation of 1,25(OH)2D3 into inactive metabolites is impaired. 1,25(OH)2D3 increases bone resorption, renal calcium and phosphorus reabsorption, and intestinal calcium and phosphorus absorption. Elevated calcium levels associated with elevated serum 1,25(OH)2D3 consecutively lead to PTH suppression. The clinical manifestations largely depend on the age at diagnosis. Infants may be asymptomatic or may show insufficient weight gain, vomiting, dehydration, lethargy and hypotonia. In contrast, adults with CYP24A1 mutations most frequently present with nephrocalcinosis and/or nephrolithiasis. As additional features abdominal pain, nausea, constipation, pancreatitis, hypertension and neuropsychiatric symptoms are described. The degree of hypercalcemia and symptoms can vary from mild and intermittent to severe. Patients manifesting in infancy usually present with severe courses. Our patient shows a mild and intermittent hypercalcemia with flank pain, nephrolithiasis and borderline arterial hypertension. She is treated with a urin-alkalizing drug and a sufficient daily drinking volume. Long-term management is focussed on eliminating or minimizing symptoms of hypercalcemia and reducing hypercalciuria, but therapeutical options are limited. Low-calcium and vitamin D diet was started in our patient and is the cornerstone of therapy to minimize the risk of nephrocalcinosis and nephrolithiasis.