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

Abstract

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.

• Authors: Amanda L Tencza, Shoji Ichikawa, Anna Dang, David Kenagy, Edward McCarthy, Michael J Econs, Michael A Levine
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 94 Issue 11 Pg. 4433-8 (Nov 2009) ISSN: 1945-7197 [Electronic] United States
• PMID: 19820004 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• SLC34A3 protein, human
• Sodium-Phosphate Cotransporter Proteins, Type IIc

Topics

• Child
• Exons (genetics)
• Familial Hypophosphatemic Rickets (genetics, pathology)
• Female
• Femur (pathology)
• Heterozygote
• Humans
• Hypercalciuria (genetics)
• Magnetic Resonance Imaging
• Male
• Mutation, Missense
• Nephrolithiasis (genetics)
• Nuclear Family
• Polymerase Chain Reaction
• Sodium-Phosphate Cotransporter Proteins, Type IIc (genetics)
• Tibia (pathology)