Skip to main content

Advertisement

SpringerLink
Log in

Congenital Hyperphosphatemic Conditions Caused by the Deficient Activity of FGF23

  • Review
  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

Congenital diseases that could result in hyperphosphatemia at an early age include hyperphosphatemic familial tumoral calcinosis (HFTC)/hyperostosis-hyperphosphatemia syndrome (HHS) and congenital hypoparathyroidism/pseudohypoparathyroidism due to the insufficient activity of fibroblast growth factor (FGF) 23 and parathyroid hormone. HFTC/HHS is a rare autosomal recessive disease caused by inactivating mutations in the FGF23, UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3), or Klotho (KL) genes, resulting in the excessive cleavage of active intact FGF23 (FGF23, GALNT3) or increased resistance to the action of FGF23 (KL). Massive ectopic calcification, known as tumoral calcinosis (TC), is seen in periarticular soft tissues, typically in the hip, elbow, and shoulder in HFTC/HHS, reducing the range of motion. However, other regions, such as the eye, intestine, vasculature, and testis, are also targets of ectopic calcification. The other symptoms of HFTC/HHS are painful hyperostosis of the lower legs, dental abnormalities, and systemic inflammation. Low phosphate diets, phosphate binders, and phosphaturic reagents such as acetazolamide are the treatment options for HFTC/HHS and have various consequences, which warrant the development of novel therapeutics involving recombinant FGF23.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Chakhtoura M et al (2018) Hyperphosphatemic familial tumoral calcinosis secondary to fibroblast growth factor 23 (FGF23) mutation: a report of two affected families and review of the literature. Osteoporos Int 29(9):1987–2009

    Article  CAS  PubMed  Google Scholar 

  2. Al-Azem H, Khan AA (2012) Hypoparathyroidism. Best Pract Res Clin Endocrinol Metab 26(4):517–522

    Article  CAS  PubMed  Google Scholar 

  3. Kilav R, Silver J, Naveh-Many T (1995) Parathyroid hormone gene expression in hypophosphatemic rats. J Clin Invest 96(1):327–333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Slatopolsky E et al (1996) Phosphorus restriction prevents parathyroid gland growth. High phosphorus directly stimulates PTH secretion in vitro. J Clin Invest 97(11):2534–2540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Pfister MF et al (1998) Parathyroid hormone leads to the lysosomal degradation of the renal type II Na/Pi cotransporter. Proc Natl Acad Sci USA 95(4):1909–1914

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bergwitz C, Jüppner H (2012) FGF23 and syndromes of abnormal renal phosphate handling. Adv Exp Med Biol 728:41–64

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ramnitz MS, Gafni RI, Collins MT (2018) Hyperphosphatemic familial tumoral calcinosis. GeneReviews® [Internet]. University of Washington, Seattle, Seattle, WA , pp 1993–2019

  8. Tiwari V et al (2019) Hyperphosphataemic tumoral calcinosis. Lancet 12;393(10167):168

    Article  Google Scholar 

  9. Shimada T et al (2002) Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Endocrinology 143(8):3179–3182

    Article  CAS  PubMed  Google Scholar 

  10. Shimada T et al (2004) FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 19(3):429–435

    Article  CAS  PubMed  Google Scholar 

  11. Ben-Dov IZ et al (2007) The parathyroid is a target organ for FGF23 in rats. J Clin Invest 117(12):4003–4008

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Imura A et al (2007) alpha-Klotho as a regulator of calcium homeostasis. Science 316(5831):1615–1618

    Article  CAS  PubMed  Google Scholar 

  13. Kawakami K et al (2017) Persistent fibroblast growth factor 23 signalling in the parathyroid glands for secondary hyperparathyroidism in mice with chronic kidney disease. Sci Rep 7:40534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Burnett-Bowie SM et al (2009) Effects of hPTH(1–34) infusion on circulating serum phosphate, 1,25-dihydroxyvitamin D, and FGF23 levels in healthy men. J Bone Miner Res 24(10):1681–1685

    Article  PubMed  PubMed Central  Google Scholar 

  15. Araya K et al (2005) A novel mutation in fibroblast growth factor 23 gene as a cause of tumoral calcinosis. J Clin Endocrinol Metab 90(10):5523–5527

    Article  CAS  PubMed  Google Scholar 

  16. Benet-Pagès A et al (2005) An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia. Hum Mol Genet 14(3):385–390

    Article  PubMed  CAS  Google Scholar 

  17. Topaz O et al (2004) Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis. Nat Genet 36(6):579–581

    Article  CAS  PubMed  Google Scholar 

  18. Ichikawa S et al (2007) A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. J Clin Invest 117(9):2684–2691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Polykandriotis EP et al (2004) A case of familial tumoral calcinosis in a neonate and review of the literature. Arch Orthop Trauma Surg 124(8):563–567

    Article  PubMed  Google Scholar 

  20. Ramnitz MS et al (2016) Phenotypic and genotypic characterization and treatment of a cohort with familial tumoral calcinosis/hyperostosis-hyperphosphatemia syndrome. J Bone Miner Res 31(10):1845–1854

    Article  CAS  PubMed  Google Scholar 

  21. Urakawa I et al (2006) Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444(7120):770–774

    Article  CAS  PubMed  Google Scholar 

  22. Wöhrle S et al (2011) FGF receptors control vitamin D and phosphate homeostasis by mediating renal FGF-23 signaling and regulating FGF-23 expression in bone. J Bone Miner Res 26(10):2486–2497

    Article  PubMed  CAS  Google Scholar 

  23. Wöhrle S et al (2013) Pharmacological inhibition of fibroblast growth factor (FGF) receptor signaling ameliorates FGF23-mediated hypophosphatemic rickets. J Bone Miner Res 28(4):899–911

    Article  PubMed  CAS  Google Scholar 

  24. Wu AL et al (2013) Antibody-mediated activation of FGFR1 induces FGF23 production and hypophosphatemia. PLoS ONE 8(2):e57322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lee JC et al (2015) Identification of a novel FN1-FGFR1 genetic fusion as a frequent event in phosphaturic mesenchymal tumour. J Pathol 235(4):539–545

    Article  CAS  PubMed  Google Scholar 

  26. Takashi Y et al (2019) Activation of unliganded FGF receptor by extracellular phosphate potentiates proteolytic protection of FGF23 by its O-glycosylation. Proc Natl Acad Sci USA 116(23):11418–11427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Frishberg Y et al (2007) Hyperostosis-hyperphosphatemia syndrome: a congenital disorder of O-glycosylation associated with augmented processing of fibroblast growth factor 23. J Bone Miner Res 22(2):235–242

    Article  CAS  PubMed  Google Scholar 

  28. Xiao Z et al (2014) Osteocyte-specific deletion of Fgfr1 suppresses FGF23. PLoS ONE 9(8):e104154

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Bergwitz C et al (2009) Defective O-glycosylation due to a novel homozygous S129P mutation is associated with lack of fibroblast growth factor 23 secretion and tumoral calcinosis. J Clin Endocrinol Metab 94(11):4267–4274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Roberts MS et al (2018) Autoimmune hyperphosphatemic tumoral calcinosis in a patient with FGF23 autoantibodies. J Clin Invest 128(12):5368–5373

    Article  PubMed  PubMed Central  Google Scholar 

  31. Nichols P et al (1990) Parathyroidectomy in chronic renal failure: a nine-year follow-up study. Q J Med 77(283):1175–1193

    Article  CAS  PubMed  Google Scholar 

  32. Pecovnik-Balon B, Kramberger S (1997) Tumoral calcinosis in patients on hemodialysis. Case report and review of the literature. Am J Nephrol 17(1):93–95

    Article  CAS  PubMed  Google Scholar 

  33. Chefetz I et al (2008) Normophosphatemic familial tumoral calcinosis is caused by deleterious mutations in SAMD9, encoding a TNF-alpha responsive protein. J Invest Dermatol 128(6):1423–1429

    Article  CAS  PubMed  Google Scholar 

  34. Zuo QY et al (2019) Clinical and genetic analysis of idiopathic normophosphatemic tumoral calcinosis in 19 patients. J Endocrinol Invest. https://doi.org/10.1007/s40618-019-01097-4

    Article  PubMed  Google Scholar 

  35. King JB (1998) Post-traumatic ectopic calcification in the muscles of athletes: a review. Br J Sports Med 32(4):287–290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Shimada T et al (2004) Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 113(4):561–568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sitara D et al (2004) Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice. Matrix Biol 23(7):421–432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ichikawa S et al (2009) Ablation of the Galnt3 gene leads to low-circulating intact fibroblast growth factor 23 (Fgf23) concentrations and hyperphosphatemia despite increased Fgf23 expression. Endocrinology 150(6):2543–2550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kuro-o M et al (1997) Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390(6655):45–51

    Article  CAS  PubMed  Google Scholar 

  40. Martinez S et al (1990) Imaging of tumoral calcinosis: new observations. Radiology 174(1):215–222

    Article  CAS  PubMed  Google Scholar 

  41. Olsen KM, Chew FS (2006) Tumoral calcinosis: pearls, polemics, and alternative possibilities. Radiographics 26(3):871–885

    Article  PubMed  Google Scholar 

  42. Ichikawa S et al (2006) Tumoral calcinosis presenting with eyelid calcifications due to novel missense mutations in the glycosyl transferase domain of the GALNT3 gene. J Clin Endocrinol Metab 91(11):4472–4475

    Article  CAS  PubMed  Google Scholar 

  43. McGrath E, Harney F, Kinsella F (2010) An ocular presentation of familial tumoral calcinosis. BMJ Case Rep 20:2010

    Google Scholar 

  44. Yancovitch A et al (2011) Novel mutations in GALNT3 causing hyperphosphatemic familial tumoral calcinosis. J Bone Miner Metab 29(5):621–625

    Article  PubMed  Google Scholar 

  45. Rafaelsen S et al (2014) Long-term clinical outcome and phenotypic variability in hyperphosphatemic familial tumoral calcinosis and hyperphosphatemic hyperostosis syndrome caused by a novel GALNT3 mutation; case report and review of the literature. BMC Genet 15:98

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Shah A et al (2014) Severe vascular calcification and tumoral calcinosis in a family with hyperphosphatemia: a fibroblast growth factor 23 mutation identified by exome sequencing. Nephrol Dial Transplant 29(12):2235–2243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Dumitrescu CE et al (2009) A case of familial tumoral calcinosis/hyperostosis-hyperphosphatemia syndrome due to a compound heterozygous mutation in GALNT3 demonstrating new phenotypic features. Osteoporos Int 20(7):1273–1278

    Article  CAS  PubMed  Google Scholar 

  48. Ringpfeil F et al (2000) Pseudoxanthoma elasticum: mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter. Proc Natl Acad Sci USA 97(11):6001–6006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Campagnoli MF et al (2006) Familial tumoral calcinosis and testicular microlithiasis associated with a new mutation of GALNT3 in a white family. J Clin Pathol 59(4):440–442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Garringer HJ et al (2007) Two novel GALNT3 mutations in familial tumoral calcinosis. Am J Med Genet A 143A(20):2390–2396

    Article  CAS  PubMed  Google Scholar 

  51. Chefetz I et al (2005) A novel homozygous missense mutation in FGF23 causes Familial Tumoral Calcinosis associated with disseminated visceral calcification. Hum Genet 118(2):261–266

    Article  CAS  PubMed  Google Scholar 

  52. Larsson T et al (2005) A novel recessive mutation in fibroblast growth factor-23 causes familial tumoral calcinosis. J Clin Endocrinol Metab 90(4):2424–2427

    Article  CAS  PubMed  Google Scholar 

  53. Ichikawa S et al (2007) Novel GALNT3 mutations causing hyperostosis-hyperphosphatemia syndrome result in low intact fibroblast growth factor 23 concentrations. J Clin Endocrinol Metab 92(5):1943–1947

    Article  CAS  PubMed  Google Scholar 

  54. Mikati MA, Melhem RE, Najjar SS (1981) The syndrome of hyperostosis and hyperphosphatemia. J Pediatr 99(6):900–904

    Article  CAS  PubMed  Google Scholar 

  55. Ichikawa S et al (2010) Clinical variability of familial tumoral calcinosis caused by novel GALNT3 mutations. Am J Med Genet A 152A(4):896–903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Lammoglia JJ, Mericq V (2009) Familial tumoral calcinosis caused by a novel FGF23 mutation: response to induction of tubular renal acidosis with acetazolamide and the non-calcium phosphate binder sevelamer. Horm Res 71(3):178–184

    Article  CAS  PubMed  Google Scholar 

  57. Slavin RE, Wen J, Barmada A (2012) Tumoral calcinosis—a pathogenetic overview: a histological and ultrastructural study with a report of two new cases, one in infancy. Int J Surg Pathol 20(5):462–473

    Article  PubMed  Google Scholar 

  58. Topaz O et al (2006) A deleterious mutation in SAMD9 causes normophosphatemic familial tumoral calcinosis. Am J Hum Genet 79(4):759–764

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Warner DR et al (1998) A novel mutation in the switch 3 region of Gsalpha in a patient with Albright hereditary osteodystrophy impairs GDP binding and receptor activation. J Biol Chem 273(37):23976–23983

    Article  CAS  PubMed  Google Scholar 

  60. Shore EM et al (2006) A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet 38(5):525–527

    Article  CAS  PubMed  Google Scholar 

  61. Eytan O et al (2013) Cole disease results from mutations in ENPP1. Am J Hum Genet 93(4):752–757

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Weiss MJ et al (1988) A missense mutation in the human liver/bone/kidney alkaline phosphatase gene causing a lethal form of hypophosphatasia. Proc Natl Acad Sci USA 85(20):7666–7669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Chuck AJ et al (1989) Crystal deposition in hypophosphatasia: a reappraisal. Ann Rheum Dis 48(7):571–576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Tandon S et al (2017) Multiple asymptomatic juxta-articular nodules mimicking tuberous-xanthoma-a unusual presentation of tophaceous gout. J Cutan Aesthet Surg 10(4):223–225

    Article  PubMed  PubMed Central  Google Scholar 

  65. Maderal AD, Viera MH, Alonso-Llamazares J (2014) Systemic lupus erythematosus with dystrophic calcifications. Int J Dermatol 53(1):e74–75

    Article  PubMed  Google Scholar 

  66. Nakamura T et al (2016) Dystrophic calcinosis with both a huge calcified mass in the cervical spine and calcification in the chest wall in a patient with rheumatoid overlap syndrome. Clin Rheumatol 35(5):1403–1409

    Article  PubMed  Google Scholar 

  67. Dima A, Balanescu P, Baicus C (2014) Pharmacological treatment in calcinosis cutis associated with connective-tissue diseases. Rom J Intern Med 52(2):55–67

    PubMed  Google Scholar 

  68. Kim TK et al (2014) Synovial osteochondromatosis in the subacromial bursa mimicking calcific tendinitis: sonographic diagnosis. J Clin Ultrasound 42(4):237–240

    Article  PubMed  Google Scholar 

  69. Baheti AD et al (2015) Imaging features of primary and metastatic extremity synovial sarcoma: a single institute experience of 78 patients. Br J Radiol 88(1046):20140608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Lufkin EG et al (1980) Phosphorus excretion in tumoral calcinosis: response to parathyroid hormone and acetazolamide. J Clin Endocrinol Metab 50(4):648–653

    Article  CAS  PubMed  Google Scholar 

  71. Finer G et al (2014) Hyperphosphatemic familial tumoral calcinosis: response to acetazolamide and postulated mechanisms. Am J Med Genet A 164A(6):1545–1549

    Article  PubMed  CAS  Google Scholar 

  72. Yamaguchi T et al (1995) Successful treatment of hyperphosphatemic tumoral calcinosis with long-term acetazolamide. Bone 16(4 Suppl):247S–250S

    Article  CAS  PubMed  Google Scholar 

  73. Garringer HJ et al (2006) The role of mutant UDP-N-acetyl-alpha-D-galactosamine-polypeptide N-acetylgalactosaminyltransferase 3 in regulating serum intact fibroblast growth factor 23 and matrix extracellular phosphoglycoprotein in heritable tumoral calcinosis. J Clin Endocrinol Metab 91(10):4037–4042

    Article  CAS  PubMed  Google Scholar 

  74. Leibrock CB et al (2016) Acetazolamide sensitive tissue calcification and aging of klotho-hypomorphic mice. J Mol Med (Berl) 94(1):95–106

    Article  CAS  Google Scholar 

  75. Favia G et al (2014) Hyperphosphatemic familial tumoral calcinosis: odontostomatologic management and pathological features. Am J Case Rep 15:569–575

    Article  PubMed  PubMed Central  Google Scholar 

  76. Jost J et al (2016) Topical sodium thiosulfate: a treatment for calcifications in hyperphosphatemic familial tumoral calcinosis? J Clin Endocrinol Metab 101(7):2810–2815

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science. We also want to thank Prof. Yaacov Frishberg from Shaare Zedek Medical Center in Israel for providing us a roentgenographic image of an affected patient.

Funding

Funding was provided by Ministry of Health, Labour and Welfare (Grant Nos. 18K09018 and 19H03676).

Author information

Authors and Affiliations

  1. Division of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo, Japan

    Nobuaki Ito

  2. Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan

    Seiji Fukumoto

Authors
  1. Nobuaki Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Seiji Fukumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nobuaki Ito.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ito, N., Fukumoto, S. Congenital Hyperphosphatemic Conditions Caused by the Deficient Activity of FGF23. Calcif Tissue Int 108, 104–115 (2021). https://doi.org/10.1007/s00223-020-00659-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00223-020-00659-6

Keywords

Search

Navigation