Autosomal recessive hypophosphatemic rickets type 2 (ARHR2)

(OMIM phenotype number #613312)

Autosomal recessive hypophosphatemic rickets (ARHR) is an extremely rare disease, characterized by hypophosphatemia resulting from renal phosphate wasting (See also ARHR1). Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) is caused by homozygous loss-of-function mutation in the ENPP1 gene. ENPP1 encodes a protein called ectonucleotide pyrophosphatase/ phosphodiesterase 1 (NPP1), which is a major generator of extracellular pyrophosphate (PPi). Because PPi inhibits calcification (hydroxyapatite crystal deposition and growth), homozygous inactivating mutations in ENPP1 gene are also responsible for generalized arterial calcification of infancy (see also GACI). In patients with ARHR2, high circulating levels of FGF23 have been described. FGF23 is a secreted protein, which reduces expression of sodium-phosphate co-transporters, NPT2a and NPT2c, resulting in renal phosphate wasting, diminishs the renal 1α-hydroxylase and increases the 24-hydroxylase activity. Moreover, FGF23 acts at the parathyroid gland to decrease parathyroid hormone synthesis and secretion. Currently, it is unclear how mutations in ENPP1 gene results in high FGF23 levels.

Gene

ENPP1 gene, 6q23.2 (OMIM gene/locus number *173335)

Phenotype

Short stature; limited movement of spine and hip, calcification of the ligaments at the bony insertions sites, high bone density at the base of skull, clavicle and rib anomalies, and enthesopathies.

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 intact FGF23, and normal PTH.

Image

Fig. Radiography shows dense ossification of the anterior longitudinal ligament.

Reproduced from Mehta P, Mitchell A, Tysoe C, et al., Novel compound heterozygous mutations in ENPP1 cause hypophosphataemic rickets with anterior spinal ligament ossification, Rheumatology (Oxford) 2012;51:1919-21, by permission of Oxford University Press.

Other resource

www.parathyroid.com

References

  1. Lorenz-Depiereux B, Schnabel D, Tiosano D, et al. Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets. Am J Hum Genet. 2010 Feb 12;86(2):267-72.
  2. Saito T, Shimizu Y, Hori M, et al. A patient with hypophosphatemic rickets and ossification of posterior longitudinal ligament caused by a novel homozygous mutation in ENPP1 gene. Bone. 2011 Oct;49(4):913-6.
  3. Feng JQ, Ward LM, Liu S, et al. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet. 2006 Nov;38(11):1310-5.
  4. Masi L, Agnusdei D, Bilezikian J et al. Taxonomy of rare genetic metabolic bone disorders. Osteoporos Int. 2015 Jun 13.
  5. http://www.omim.org