title: Late-onset hereditary hypophosphatemic rickets with hypercalciuria (HHRH) due to mutation of SLC34A3/NPT2c.
abstract: To identify a genetic basis for markedly reduced bone density and multiple fractures in an adult patient with hypophosphatemia and hypercalciuria.
  
  
  
  A 54-year-old Vietnamese man, his unaffected two daughters and wife.
  
  
  
  We performed biochemical studies and sequenced the SLC34A3 gene using genomic DNA from peripheral blood mononuclear cells.
  
  
  
  Biochemical evaluation of the proband revealed hypophosphatemia with increased renal phosphate wasting, hypercalciuria, low serum parathyroid hormone (PTH) and an elevated serum 1,25(OH)2D level. Mutation analysis of SLC34A3 gene revealed that the patient was a compound heterozygote for two nonsynonymous nucleotide substitutions: a novel c.571G>A (p.G191S) damaging mutation and the previously reported c.200G>A (p.R67H) polymorphism, consistent with the clinical diagnosis of late-onset hereditary hypophosphatemic rickets with hypercalciuria (HHRH). His wife and older daughter both carried the p.R67H polymorphism, while his younger daughter was compound heterozygous for p.R67H and p.G191S.
  
  
  
  HHRH is an uncommon autosomal recessive disease that generally manifests in childhood as rickets or nephrolithiasis, but an adult onset phenotype may occur in heterozygous carriers of SLC34A3 mutations. The severe presentation of this proband in adulthood with marked nephrolithiasis, multiple fractures and low bone density emphasizes the importance of measuring the serum phosphorus level in patients with suspected but unexplained osteoporosis and/or recurrent renal stones. The recognition of late-onset HHRH facilitates timely institution of appropriate therapy.
authors.affiliation: Division of Endocrinology Diabetes and Metabolism, Cooper Medical School of Rowan University, Camden, NJ 08103, USA.
authors.forename: Gauri
authors.initials: G
authors.lastname: Dhir
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Li
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address: levinem@chop.edu.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Levine
mesh_terms: D017668:Age of Onset; D001842:Bone and Bones / Q000473:pathology; D003720:Densitometry; D053098:Familial Hypophosphatemic Rickets / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D053565:Hypercalciuria / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D013902:Radiography, Thoracic; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc / Q000235:genetics*
chemical_list: C493562:SLC34A3 protein, human; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc
keywords: HHRH; Hypophosphatemia; Nephrocalcinosis; Osteoporosis, osteomalacia; SLC34A3