X-linked hypophosphatemia

X-linked hypophosphatemia
Other namesX-linked dominant hypophosphatemic rickets, or X-linked Vitamin D-resistant rickets,[1]
This condition is inherited in an X-linked dominant manner.
SpecialtyEndocrinology, pediatrics Edit this on Wikidata
Complicationsosteomalacia (adults), rickets (children), fractures, enthesopathy, spinal stenosis, abnormal gait, short stature, tinnitus, hearing loss, dental complications, in rare exceptions Chiari malformation can occur.
CausesA genetic mutation of the PHEX gene results in elevated FGF23 hormone.
Medicationphosphate, vitamin-D or burosumab

X-linked hypophosphatemia (XLH) is an X-linked dominant form of rickets (or osteomalacia) that differs from most cases of dietary deficiency rickets in that vitamin D supplementation does not cure it. It can cause bone deformity including short stature and genu varum (bow-leggedness). It is associated with a mutation in the PHEX gene sequence (Xp.22) and subsequent inactivity of the PHEX protein.[2] PHEX mutations lead to an elevated circulating (systemic) level of the hormone FGF23 which results in renal phosphate wasting,[3] and local elevations of the mineralization/calcification-inhibiting protein osteopontin in the extracellular matrix of bones and teeth.[4][5] An inactivating mutation in the PHEX gene results in an increase in systemic circulating FGF23, and a decrease in the enzymatic activity of the PHEX enzyme which normally removes (degrades) mineralization-inhibiting osteopontin protein; in XLH, the decreased PHEX enzyme activity leads to an accumulation of inhibitory osteopontin locally in bones and teeth to block mineralization which, along with renal phosphate wasting, both cause osteomalacia and odontomalacia.[6][7]

For both XLH and hypophosphatasia, inhibitor-enzyme pair relationships function to regulate mineralization in the extracellular matrix through a double-negative (inhibiting the inhibitors) activation effect in a manner described as the Stenciling Principle.[8][9] Both these underlying mechanisms (renal phosphate wasting systemically, and mineralization inhibitor accumulation locally) contribute to the pathophysiology of XLH that leads to soft bones and teeth (hypomineralization, osteomalacia/odontomalacia).[10][11][12] The prevalence of the disease is 1 in 20,000.[13]

X-linked hypophosphatemia may be lumped in with autosomal dominant hypophosphatemic rickets under general terms such as hypophosphatemic rickets. Hypophosphatemic rickets are associated with at least nine other genetic mutations.[14] Clinical management of hypophosphatemic rickets may differ depending on the specific mutations associated with an individual case, but treatments are aimed at raising phosphate levels to promote normal bone formation.[15]

  1. ^ Rasmussen SA, McKusick VA (June 23, 2023) [Originally published June 4, 1986], "HYPOPHOSPHATEMIC RICKETS, X-LINKED DOMINANT; XLHR", Online Mendelian Inheritance in Man, Johns Hopkins University 307800
  2. ^ Cite error: The named reference xlhxd was invoked but never defined (see the help page).
  3. ^ Carpenter TO (June 8, 2022). "Primary Disorders of Phosphate Metabolism". In Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, et al. (eds.). Endotext. South Dartmouth, Massachusetts: MDText.com, Inc. PMID 25905395. National Library of Medicine Bookshelf ID NBK279172.
  4. ^ Barros, NM; Hoac, B; Neves, RL; Addison, WN; Assis, DM; Murshed, M; Carmona, AK; McKee, MD (March 2013). "Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia". Journal of Bone and Mineral Research. 28 (3): 688–99. doi:10.1002/jbmr.1766. PMID 22991293. S2CID 20840491.
  5. ^ Boukpessi, T; Hoac, B; Coyac, BR; Leger, T; Garcia, C; Wicart, P; Whyte, MP; Glorieux, FH; Linglart, A; Chaussain, C; McKee, MD (February 2017). "Osteopontin and the dento-osseous pathobiology of X-linked hypophosphatemia". Bone. 95: 151–161. doi:10.1016/j.bone.2016.11.019. PMID 27884786.
  6. ^ Boukpessi, T.; Hoac, B.; Coyac, B. R.; Leger, T.; Garcia, C.; Wicart, P.; Whyte, M. P.; Glorieux, F. H.; Linglart, A.; Chaussain, C.; McKee, M. D. (2017). "Osteopontin and the dento-osseous pathobiology of X-linked hypophosphatemia". Bone. 95: 151–161. doi:10.1016/j.bone.2016.11.019. PMID 27884786.
  7. ^ Barros, N. M.; Hoac, B.; Neves, R. L.; Addison, W. N.; Assis, D. M.; Murshed, M.; Carmona, A. K.; McKee, M. D. (2013). "Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia". Journal of Bone and Mineral Research. 28 (3): 688–699. doi:10.1002/jbmr.1766. PMID 22991293. S2CID 20840491.
  8. ^ Reznikov, N.; Hoac, B.; Buss, D. J.; Addison, W. N.; Barros NMT; McKee, M. D. (2020). "Biological stenciling of mineralization in the skeleton: Local enzymatic removal of inhibitors in the extracellular matrix". Bone. 138: 115447. doi:10.1016/j.bone.2020.115447. PMID 32454257. S2CID 218909350.
  9. ^ McKee, M. D.; Buss, D. J.; Reznikov, N. (2022). "Mineral tessellation in bone and the Stenciling Principle for extracellular matrix mineralization". Journal of Structural Biology. 214 (1): 107823. doi:10.1016/j.jsb.2021.107823. PMID 34915130. S2CID 245187449.
  10. ^ McKee, MD; Buss, DJ; Reznikov, N (December 13, 2021). "Mineral tessellation in bone and the stenciling principle for extracellular matrix mineralization". Journal of Structural Biology. 214 (1): 107823. doi:10.1016/j.jsb.2021.107823. PMID 34915130. S2CID 245187449.
  11. ^ McKee, MD; Hoac, B; Addison, WN; Barros, NM; Millán, JL; Chaussain, C (October 2013). "Extracellular matrix mineralization in periodontal tissues: Noncollagenous matrix proteins, enzymes, and relationship to hypophosphatasia and X-linked hypophosphatemia". Periodontology 2000. 63 (1): 102–22. doi:10.1111/prd.12029. PMC 3766584. PMID 23931057.
  12. ^ Buss, DJ; Reznikov, N; McKee, MD (November 1, 2020). "Crossfibrillar mineral tessellation in normal and Hyp mouse bone as revealed by 3D FIB-SEM microscopy". Journal of Structural Biology. 212 (2): 107603. doi:10.1016/j.jsb.2020.107603. PMID 32805412. S2CID 221164596.
  13. ^ Carpenter TO (April 1997). "New perspectives on the biology and treatment of X-linked hypophosphatemic rickets". Pediatr. Clin. North Am. 44 (2): 443–466. doi:10.1016/S0031-3955(05)70485-5. PMID 9130929.
  14. ^ Online Mendelian Inheritance in Man (OMIM): 193100
  15. ^ "Hypophosphatemic rickets". Genetic and Rare Diseases Information Center. National Institutes of Health. Archived from the original on June 12, 2012. Retrieved October 10, 2012.