What is hypophosphatemic rickets?

Updated: May 18, 2020
  • Author: James CM Chan, MD; Chief Editor: Sasigarn A Bowden, MD  more...
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Hypophosphatemic rickets is a form of rickets that is characterized by low serum phosphate levels and resistance to treatment with ultraviolet radiation or vitamin D ingestion. The term rickets evolved from the old English word wrick, which means "to twist." This twisting or bending of the bones has been known to physicians since antiquity and, as with many diseases, was gradually found to encompass more than a single etiology. Clinical laboratory evaluation of rickets begins with assessment of serum calcium, phosphate, and alkaline phosphatase levels. Osteotomy to realign extremely distorted leg curvatures may be necessary for children whose diagnosis was delayed or whose initial treatment was inadequate.

Since the early 20th century, ultraviolet radiation or vitamin D ingestion has been recognized as a cure for nutritional rickets, although certain forms of rachitic disease have remained refractory to this therapy. Study of these refractory cases revealed low serum phosphate concentration as a common factor. Familial occurrence of this condition led to the diagnosis of familial hypophosphatemic rickets. Treatment with vitamin D produced no change in the rachitic state of these patients, even at rather high doses, leading to the term vitamin D–resistant rickets. (See Etiology and Treatment.)

With recent advances in the understanding of the genetic basis of familial hypophosphatemic rickets, the term X-linked hypophosphatemic rickets has become more commonly used. [1] X-linked hypophosphatemia (XLH) is a dominant disorder and accounts for more than 80% of all familial hypophosphatemia. XLH is considered to be a systemic disorder, from mutation of the phosphate-regulating gene homologous to endopeptidases on the X chromosome (PHEX). PHEX stimulates fibroblast growth factor-23 (FGF-23), expressed in bone. [2, 3] FGF-23 requires heparin and Klotho for binding to the proximal tubule to stimulate phosphaturia. Circulating FGF-23 concentrations have been shown to be 5 times higher in XLH patients, resulting in significant phosphaturia. Finally, XLH patients demonstrate a normal or low serum concentration of 1,25-dihydroxyvitamin D3, suggestive of inadequate formation of this vitamin D metabolite.

The remaining 20% of familial hypophosphatemia patients have autosomal dominant hypophosphatemic rickets from gain-of-function autosomal recessive hypophosphatemic rickets and hereditary hypophosphatemic rickets with hypercalciuria. [1]

Impaired growth and rickets of the femur/tibia are characteristics of XLH. Delayed dentition; dental abscesses; deafness; Chiari malformation; extraskeletal calcification of the tendons, ligaments, and joint capsules; and craniosynostosis are occasionally encountered.

Serum phosphate reduction in relation to normal levels was equal for male and female subjects. [4] Females generally had markedly less bone disease than males, suggesting the random inactivation of the affected X chromosome in females, as might be expected from the Lyon hypothesis. [5, 6] However, lowered serum phosphate levels correlated with an equal degree of renal tubular reduction of tubular time of maximal concentration (Tmax) of phosphate in both sexes, pointing to an additional factor in the creation of the bone disease in affected males. (See Etiology and Workup.)

In XLH patients, the severe hypophosphatemia (< 2.5 mg/dL) is associated with elevated serum alkaline phosphatase. However, despite the severe hypophosphatemia, the serum calcium, PTH, andf 25-hydroxyvitamin D concentrations are normal. Even the serum concentration of 1,25 dihydroxyvitamin D is inappropriately normal or low in XLH patients. Bone radiographs show short, squat long bones and coarse, axial skeleton trabeculation, especially in boys. More severe rachitic knees than wrists are also characteristic findings.

Filtered phosphate, not reabsorbed in the proximal tubule, becomes concentrated in the thick descending limb of loop of Henle, due to water retrieval. The thick descending limb becomes rich in mucopolysaccharides, which attracts calcium phosphate. Such crystals, on migration to the papilla get precipitated as stones. [6]

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