Autosomal dominant hypophosphatemic rickets (ADHR)

(OMIM phenotype number #193100)

Autosomal dominant hypophosphatemic rickets (ADHR) is a rare genetic disorder of phosphate homeostasis, caused by heterozygous point mutations at amino acid residues 176 or 179 in fibroblast growth factor 23 (FGF23). These mutations disrupt enzymatic cleavage of the protein by a furin-like proprotein convertase, resulting in enhanced FGF23 bioactivity. FGF23, a secreted protein of 251 amino acids, reduces expression of sodium-phosphate co-transporters, NPT2a and NPT2c, on the apical surface of proximal renal tubule cells, resulting in renal phosphate wasting, and 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. FGF23, directly or indirectly, is involved in the pathogenesis of many diseases associated with low phosphate levels, such as tumor-induced osteomalacia (TIO), X-linked hypophosphatemic rickets (XLH), autosomal recessive hypophosphatemic rickets (ARHR), and McCune–Albright syndrome. ADHR is characterized by impaired mineralization of bone, rickets and/or osteomalacia, suppressed levels of calcitriol (1,25-dihydroxyvitamin D3), renal phosphate wasting, and low serum phosphate. This disease is the less common form of hypophosphatemic rickets, and has an incomplete penetrance and variable age of onset. Fluctuations in FGF23 concentration correlate with disease severity. Recent studies have revealed that iron could be one of the factors contributing to the regulation of FGF23 expression. Low iron levels were shown to correlate negatively with FGF23 levels in ADHR patients. In some cases remissions have been described.

Treatments for ADHR include: daily oral administration of phosphate and calcitriol, which prevents secondary hyperparathyroidism. Moreover, it is recommended a frequent monitoring of height, calcium, alkaline phosphatase, parathyroid hormone, and phosphate serum levels, urinary calcium and creatinine. In some cases, corrective surgery of skeletal deformities may be necessary.

Gene

FGF23 gene, 12p13.32 (OMIM gene/locus number #605380).

Phenotype

Fatigue and muscle weakness, short stature, early onset (1–3 years): severe bowing of lower extremities, rickets with enlarged costochondral junctions of the ribs; late onset (puberty): bone pain (no 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 intact FGF23, and normal PTH.
 

Fig. Imaging data of patient affecyed by ADHR. (a) X-ray of ankles and feet shows osteoporosis and two fractures of the second metatarsal bone of both feet (red arrows). (b) Bone scan shows multiple areas (cervical rib, vertebrae, articular genua, and ankle joints) of increased tracer uptake.

Reproduced from J Bone Miner Metab, FGF23 analysis of a Chinese family with autosomal dominant hypophosphatemic rickets, 2004;36:1213-8, Sun Y, Wang O, Xia W, et al., with permission of Springer.


References

  1. Seton M, Jüppner H. Autosomal dominant hypophosphatemic rickets in an 85 year old woman: characterization of her disease from infancy through adulthood. Bone. 2013 Feb;52(2):640-3.
  2. Sun Y, Wang O, Xia W, et al.  FGF23 analysis of a Chinese family with autosomal dominant hypophosphatemic rickets. J Bone Miner Metab. 2012 Jan;30(1):78-84.
  3. Imel EA, Hui SL, Econs MJ. FGF23 concentrations vary with disease status in autosomal dominant hypophosphatemic rickets. J Bone Miner Res. 2007 Apr;22(4):520-6.
  4. Imel EA, Peacock M, Gray AK, et al. Iron modifies plasma FGF23 differently in autosomal dominant hypophosphatemic rickets and healthy humans. J Clin Endocrinol Metab. 2011 Nov;96(11):3541-9. doi: 10.1210/jc.2011-1239. Epub 2011 Aug 31.
  5. Bergwitz C, Jüppner H. FGF23 and syndromes of abnormal renal phosphate handling. Adv Exp Med Biol. 2012;728:41-64.
  6. Masi L, Agnusdei D, Bilezikian J et al. Taxonomy of rare genetic metabolic bone disorders. Osteoporos Int. 2015 Jun 13.
  7. http://www.omim.org