TY - JOUR
T1 - Hypophosphatemic rickets with hypercalciuria due to mutation in SLC34A3/type IIc sodium-phosphate cotransporter
T2 - Presentation as hypercalciuria and nephrolithiasis
AU - Tencza, Amanda L.
AU - Ichikawa, Shoji
AU - Dang, Anna
AU - Kenagy, David
AU - McCarthy, Edward
AU - Econs, Michael J.
AU - Levine, Michael A.
PY - 2009/11
Y1 - 2009/11
N2 - Context: Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a metabolic disorder due to homozygous loss-of-function mutations in the SLC34A3 gene encoding the renal type IIc sodium-phosphate cotransporter (NaPi-IIc). The typical presentation is severe rickets and hypophosphatemia, and hypercalciuria is often discovered later or overlooked. Objective: We sought to determine the genetic basis for severe hypercalciuria and nephrolithiasis/nephrocalcinosis in an adolescent male with elevated serum levels of calcitriol but normal serum levels of calcium and phosphorus. Design and Setting: We used PCR to analyze the SLC34A3 gene in the proband and members of his family. Results: The proband was a compound heterozygote for two SLC34A3 missense mutations, a novel c.544C→T in exon 6 that results in replacement of arginine at position 182 by tryptophan (R182W) and c.575C→T in exon 7 that results in replacement of serine at position 192 by leucine (S192L). The R182W and S192L alleles were inherited from the mother and father, respectively, both of whom had hypercalciuria. A clinically unaffected brother was heterozygous for S192L. Conclusion: We report a novel mutation in the SLC34A3 gene in a patient with an unusual presentation of HHRH. This report emphasizes that moderate and severe hypercalciuria can be manifestations of heterozygous or homozygous loss-of-function mutations in the SLC34A3 gene, respectively, providing further evidence for a gene dosage effect in determining the phenotype. HHRH may be an underdiagnosed condition that can masquerade as idiopathic hypercalciuria or osteopenia.
AB - Context: Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a metabolic disorder due to homozygous loss-of-function mutations in the SLC34A3 gene encoding the renal type IIc sodium-phosphate cotransporter (NaPi-IIc). The typical presentation is severe rickets and hypophosphatemia, and hypercalciuria is often discovered later or overlooked. Objective: We sought to determine the genetic basis for severe hypercalciuria and nephrolithiasis/nephrocalcinosis in an adolescent male with elevated serum levels of calcitriol but normal serum levels of calcium and phosphorus. Design and Setting: We used PCR to analyze the SLC34A3 gene in the proband and members of his family. Results: The proband was a compound heterozygote for two SLC34A3 missense mutations, a novel c.544C→T in exon 6 that results in replacement of arginine at position 182 by tryptophan (R182W) and c.575C→T in exon 7 that results in replacement of serine at position 192 by leucine (S192L). The R182W and S192L alleles were inherited from the mother and father, respectively, both of whom had hypercalciuria. A clinically unaffected brother was heterozygous for S192L. Conclusion: We report a novel mutation in the SLC34A3 gene in a patient with an unusual presentation of HHRH. This report emphasizes that moderate and severe hypercalciuria can be manifestations of heterozygous or homozygous loss-of-function mutations in the SLC34A3 gene, respectively, providing further evidence for a gene dosage effect in determining the phenotype. HHRH may be an underdiagnosed condition that can masquerade as idiopathic hypercalciuria or osteopenia.
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U2 - 10.1210/jc.2009-1535
DO - 10.1210/jc.2009-1535
M3 - Article
C2 - 19820004
AN - SCOPUS:70449135211
SN - 0021-972X
VL - 94
SP - 4433
EP - 4438
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 11
ER -