Autosomal recessive hypophosphatemic rickets type 1 (ARHR1)

(OMIM phenotype number #241520)

Autosomal recessive hypophosphatemic rickets (ARHR) is an extremely rare disease, characterized by hypophosphatemia resulting from renal phosphate wasting. It has been described in few families of Middle Eastern and European origins. Clinical manifestations include: growth retardation, lower-extremity deformities, pathologic fractures, dental defects, and, in some patients, also enthesopathy. Patients also show hypophosphatemia, low levels of serum 1,25-dihydroxyvitamin D, whereas serum calcium, parathyroid hormone, urinary calcium excretion are normal, and high circulating levels of FGF23. ARHR is subdivided in two subtypes: Autosomal recessive hypophosphatemic rickets type 1 (ARHR1) and type 2 (ARHR2). ARHR1 is caused by homozygous loss-of-function mutations in the DMP1 (Dentin matrix protein 1) gene. DMP1 is a noncollagenous extracellular protein, highly expressed in osteoblasts and osteocytes, in bone and teeth. It plays critical roles in bone mineralization, phosphate homeostasis and odontogenic differentiation.

Gene

DMP1 gene, 4q22.1 (OMIM gene/locus number #600980)

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, 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.

Fig. Skeletal and dental findings in patient affected by ARHR1, at the age of 53 years. (a, b) Radiographs show mild bowing of her legs and severe kyphosis. (c) A panoramic radiograph shows loss of all her teeth.

Reproduced from J Bone Miner Metab, A novel nonsense mutation in the DMP1 gene in a Japanese family with autosomal recessive hypophosphatemic rickets, 2010;28:585-90, Koshida R, Yamaguchi H, Yamasaki K, et al., with permission of Springer.


References

  1. Mäkitie O, Pereira RC, Kaitila I, et al. Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel DMP1 mutation. J Bone Miner Res. 2010 Oct;25(10):2165-74.
  2. Turan S, Aydin C, Bereket A, et al. Identification of a novel dentin matrix protein-1 (DMP-1) mutation and dental anomalies in a kindred with autosomal recessive hypophosphatemia. Bone. 2010 Feb;46(2):402-9.
  3. Lorenz-Depiereux B, Bastepe M, Benet-Pagès A, et al. Nat Genet. 2006 Nov;38(11):1248-50. DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis.
  4. Koshida R, Yamaguchi H, Yamasaki K et al. J Bone Miner Metab. 2010 Sep;28(5):585-90. A novel nonsense mutation in the DMP1 gene in a Japanese family with autosomal recessive hypophosphatemic rickets.
  5. Masi L, Agnusdei D, Bilezikian J et al. Taxonomy of rare genetic metabolic bone disorders. Osteoporos Int. 2015 Jun 13.
  6. http://www.omim.org