What is familial hypophosphatemia?

Updated: Aug 10, 2020
  • Author: Horacio B Plotkin, MD, FAAP; Chief Editor: Jatinder Bhatia, MBBS, FAAP  more...
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Several different familial and acquired conditions may lead to hypophosphatemia in children. In familial hypophosphatemia, the kidneys fail to reabsorb sufficient phosphate, leading to low levels of serum phosphate. This is usually evident only after age 6-10 months. Prior to this occurrence, the glomerular filtration rate is low, which sustains an adequate phosphate level. Once renal maturity is reached, phosphate levels are usually less than 3.5mg/dL and are often less than 2.5mg/dL. Levels of 1,25(OH)2 vitamin D are actually normal in these patients, owing to an abnormal response to hypophosphatemia, in which levels of 1,25(OH)2 vitamin D should increase.

Mutations in PHEX and DMP1 result in X-linked hypophosphatemic rickets and autosomal recessive hypophosphatemic rickets, respectively. (Most families of patients with familial hypophosphatemia exhibit X-linked dominant inheritance.) PHEX, a phosphate-regulating gene, codes for a protease, which is an enzyme that catalyzes the hydrolysis of a protein.

Degradation of MEPE and DMP-1 and release of ASARM peptides are chiefly responsible for the hypophosphatemic rickets mineralization defect and changes in osteoblast-osteoclast differentiation.

FGF-23 has been implicated in the renal phosphate wasting in tumor-induced osteomalacia and autosomal dominant hypophosphatemic rickets. Mutations in the gene that codes for the main renal sodium-phosphate cotransporter (NPT2a) have been reported in some patients with familial renal calcium stones and hypophosphatemia due to a decrease in renal phosphate reabsorption. These patients have hypercalciuria and elevated levels of 1,25(OH)2 vitamin D3.

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a metabolic disorder caused by homozygous loss-of-function mutations in the SLC34A3 gene, which encodes the renal type IIc sodium-phosphate cotransporter (NaPi-IIc). The typical presentation is severe rickets, hypophosphatemia, and hypercalciuria. [6]

Autosomal recessive and autosomal dominant inheritance have each been found and have been associated with the same clinical phenotype. In approximately one third of patients, the disease appears to occur as a consequence of a new mutation. Clinical findings are similar to those of nutritional rickets, but without proximal myopathy. These patients usually have high bone density. As hypophosphatemia is usually clinically evident at a later age, infantile skull defects are not apparent. Because calcium levels remain normal, neither tetany nor secondary hyperparathyroidism are present.

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