Article

Hypophosphatemic rickets with hypercalciuria due to mutation in SLC34A3/NaPi-IIc can be masked by vitamin D deficiency and can be associated with renal calcifications.

Department of Pediatrics and Adolescent Medicine, Division of Pediatric Endocrinology and Diabetology, University of Lübeck, Lübeck, Germany.
Experimental and Clinical Endocrinology &amp Diabetes (impact factor: 1.69). 02/2009; 117(2):49-56. DOI:10.1055/s-2008-1076716 pp.49-56
Source: PubMed

ABSTRACT Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is caused by mutations in SLC34A3, the gene encoding the renal sodium-phosphate co-transporter NaPi-IIc. Despite increased urinary calcium excretion, HHRH is typically not associated with kidney stones prior to treatment. However, here we describe two sisters, who displayed nephrolithiasis or nephrocalcinosis upon presentation. The index patient, II-4, presented with short stature, bone pain, and knee X-rays suggestive of mild rickets at age 8.5 years. Laboratory evaluation showed hypophosphatemia, elevated 1,25(OH) (2) vitamin D levels, and hypercalciuria, later also developing vitamin D deficiency. Her sister, II-6, had a low normal serum phosphorous level, biochemically vitamin D deficiency and no evidence for osteomalacia, but had undergone left nephro-ureterectomy at age 17 because of ureteral stricture secondary to renal calculi. Nucleotide sequence analysis of DNA from II-4 and II-6 revealed a homozygous missense mutation c.586G>A (p.G196R) in SLC34A3/NaPi-IIc. Ultrasonographic examinations prior to treatment showed grade I nephrocalcinosis for II-4, while II-6 had grade I-II nephrocalcinosis in her remaining kidney. Four siblings and the mother were heterozygous carriers of the mutation, but showed no biochemical abnormalities. With oral phosphate supplements, hypophosphatemia and hypercalciuria improved in both homozygous individuals. Renal calcifications that are presumably due to increased urinary calcium excretion can be the presenting finding in homozygous carriers of G196R in SLC34A3/NaPi-IIc, and some or all laboratory features of HHRH may be masked by vitamin D deficiency.

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  • Article: Hypophosphatemic rickets with hypercalciuria due to mutation in SLC34A3/type IIc sodium-phosphate cotransporter: presentation as hypercalciuria and nephrolithiasis.
    Amanda L Tencza, Shoji Ichikawa, Anna Dang, David Kenagy, Edward McCarthy, Michael J Econs, Michael A Levine
    [show abstract] [hide abstract]
    ABSTRACT: 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. 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. We used PCR to analyze the SLC34A3 gene in the proband and members of his family. 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. 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.
    The Journal of clinical endocrinology and metabolism 10/2009; 94(11):4433-8. · 6.50 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

biochemically vitamin D deficiency
 
gene encoding
 
Hereditary hypophosphatemic rickets
 
homozygous individuals
 
homozygous missense mutation c.586G>A
 
hypophosphatemia
 
knee X-rays suggestive
 
Laboratory evaluation
 
low normal serum phosphorous level
 
mild rickets
 
Nucleotide sequence analysis
 
oral phosphate supplements
 
remaining kidney
 
Renal calcifications
 
renal calculi
 
renal sodium-phosphate co-transporter NaPi-IIc
 
short stature
 
ureteral stricture secondary
 
urinary calcium excretion
 
vitamin D deficiency