Hypophosphatemic rickets with hyperparathyroidism (HRH)

(OMIM phenotype number %612089)

Hypophosphatemic rickets with hyperparathyroidism (HRH) is a form of hypophosphatemic rickets with marked parathyroid hyperplasia. It has been demonstrate that HRH is caused by a mutation that results in increased levels of circulating α-Klotho. It has been described a de novo translocation with a breakpoint adjacent to α-Klotho. It encodes a α-glucuronidase, and is implicated in aging and regulation of FGF (Fibroblast Growth Factor) signaling. High plasma α-Klotho levels and α- glucuronidase activity have been described in HRH, and unexpectedly, also high circulating FGF23 level. These findings suggest that the elevated α-Klotho concentration mimics aspects of the normal response to hyperphosphatemia. When phosphate is in excess, FGF23 is secreted from bone and acts on the kidney to promote phosphate excretion into urine and suppress vitamin D synthesis (see also XLHR). Klotho, a single-pass transmembrane protein expressed in renal tubules, is an obligate coreceptor to bind and activate FGF receptors isoforms (FGFR1c, 3c, 4) and significantly increases the affinity of these FGFRs specifically to FGF23.

Gene

KLOTHO gene, 13q13.1 (OMIM gene/locus number 604824).

Phenotype

Kidney stones, rickets, bone pain, and bowing of lower extremities.

Main biochemical alterations

High Ur P, low Pi, low renal TmP/GFR, normal Ca, low-normal Ur Ca, normal 25 OH D; low-normal 1,25(OH)2D, high bone ALP, high PTH (normal intact FGF23). 

References

  1. Brownstein CA, Adler F, Nelson-Williams C, et al. A translocation causing increased alpha-klotho level results in hypophosphatemic rickets and hyperparathyroidism. Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3455-60.
  2. Kuro-o M. Overview of the FGF23-Klotho axis. Pediatr Nephrol. 2010 Apr;25(4):583-90.
  3. Masi L, Agnusdei D, Bilezikian J et al. Taxonomy of rare genetic metabolic bone disorders. Osteoporos Int. 2015 Jun 13.
  4. http://www.omim.org