Hypophosphatemic rickets with hypercalciuria due to mutation in SLC34A3/type IIc sodium-phosphate cotransporter: presentation as hypercalciuria and nephrolithiasis.
BACKGROUND
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.


METHODS
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.


CONCLUSIONS
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.
Tencza
Amanda L
AL
Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Ichikawa
Shoji
S
Dang
Anna
A
Kenagy
David
D
McCarthy
Edward
E
Econs
Michael J
MJ
Levine
Michael A
MA
D002648:Child; D005091:Exons / Q000235:genetics; D053098:Familial Hypophosphatemic Rickets / Q000235:genetics* / Q000473:pathology; D005260:Female; D005269:Femur / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D053565:Hypercalciuria / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D020125:Mutation, Missense; D053040:Nephrolithiasis / Q000235:genetics*; D009679:Nuclear Family; D016133:Polymerase Chain Reaction; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc / Q000235:genetics*; D013977:Tibia / Q000473:pathology
C493562:SLC34A3 protein, human; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc