A patient with hypophosphatemia, a femoral fracture, and recurrent kidney stones: report of a novel mutation in SLC34A3.
OBJECTIVE
To determine if there was a genetic contribution to our patient's unusual clinical presentation of nephrolithiasis and nonhealing stress fracture.


METHODS
We describe a 31-year-old man who had rickets as a child and developed a femur insufficiency fracture and recurrent nephrolithiasis as an adult after moving to the United States from India. The patient's clinical course and results from radiographic and biochemical analyses are described. Analysis of the SLC34A3 gene was performed using genomic DNA samples from the patient and his family members.


RESULTS
Before referral to the Yale Bone Center, the patient was treated with calcitriol, ergocalciferol, and phosphate. Changing therapy to phosphate alone led to clinical improvement. Genetic analysis revealed that the patient is a compound heterozygote for mutations in the SLC34A3 gene. On 1 allele, he has a previously described missense mutation in exon 7: c.575C>T (p.Ser192Leu). The other allele carries a novel nonsense mutation in exon 3: c.145C>T (p.Gln49X). One unaffected sibling is a carrier of the missense mutation and 1 sister with a history of flank pain is a carrier of the novel mutation.


CONCLUSIONS
Hereditary hypophosphatemic rickets with hypercalciuria is a rare metabolic disorder associated with mutations in SLC34A3, the gene that encodes the renal sodium phosphate cotransporter NaPi-IIc. Although hypercalciuria is a distinguishing feature of the disease, nephrolithiasis is rarely described. The patient's atypical clinical presentation illustrates that both environmental and genetic factors potentially affect phenotypic expression of SLC34A3 mutations.
Page
Kathleen
K
Section of Endocrinology, Department of Medicine, Yale School of Medicine, New Haven, CT 06520-8020, USA. kathleen.page@yale.edu
Bergwitz
Clemens
C
Jaureguiberry
Graciana
G
Harinarayan
Chittari V
CV
Insogna
Karl
K
D000328:Adult; D005265:Femoral Neck Fractures / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D017674:Hypophosphatemia / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D007669:Kidney Calculi / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009154:Mutation; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc / Q000235:genetics*
C493562:SLC34A3 protein, human; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc