View source for X-linked hypophosphatemia

{{Short description|X-linked dominant disorder that causes rickets}}
{{Use mdy dates|date=February 2024}}
{{Infobox medical condition (new)
| name          = X-linked hypophosphatemia
| image         = X-linked dominant.svg
| caption       = This condition is inherited in an [[X-linked dominant]] manner.
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| pronounce     =
| field         =
| synonyms      = '''X-linked dominant hypophosphatemic rickets''', or '''X-linked Vitamin D-resistant rickets''',<ref name="omim">{{Citation |title=HYPOPHOSPHATEMIC RICKETS, X-LINKED DOMINANT; XLHR |vauthors=Rasmussen SA, McKusick VA |date=23 June 2023 |work=Online Mendelian Inheritance in Man |orig-date=Originally published June 4, 1986 |publisher=Johns Hopkins University}} {{OMIM|307800||none}}</ref>
| symptoms      =
| complications = osteomalacia (adults), rickets (children), fractures, enthesopathy, spinal stenosis, abnormal gait, short stature, tinnitus, hearing loss, dental complications, in rare exceptions Chiari malformation can occur.
| onset         =
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| types         =
| causes        = A genetic mutation of the ''PHEX'' gene results in elevated FGF23 hormone.
| risks         =
| diagnosis     =
| differential  =
| prevention    =
| treatment     =
| medication    = phosphate, vitamin-D or [[burosumab]]
| prognosis     =
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}}

'''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.<ref name="xlhxd" /> ''PHEX'' mutations lead to an elevated circulating (systemic) level of the hormone FGF23 which results in renal phosphate wasting,<ref>{{Cite book |title=Endotext |vauthors=Carpenter TO |date=8 June 2022 |publisher=MDText.com, Inc. |veditors=Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, Dungan K, Hershman JM, Hofland J, Kalra S, Kaltsas G, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, Morley JE, New M, Purnell J, Sahay R, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP |location=South Dartmouth, Massachusetts |chapter=Primary Disorders of Phosphate Metabolism |pmid=25905395 |id=National Library of Medicine Bookshelf ID NBK279172 |display-editors=6}}</ref> and local elevations of the mineralization/calcification-inhibiting protein [[osteopontin]] in the extracellular matrix of bones and teeth.<ref>{{Cite journal |last1=Barros |first1=NM |last2=Hoac |first2=B |last3=Neves |first3=RL |last4=Addison |first4=WN |last5=Assis |first5=DM |last6=Murshed |first6=M |last7=Carmona |first7=AK |last8=McKee |first8=MD |date=March 2013 |title=Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia. |journal=Journal of Bone and Mineral Research |volume=28 |issue=3 |pages=688–99 |doi=10.1002/jbmr.1766 |pmid=22991293 |s2cid=20840491 |doi-access=free}}</ref><ref>{{Cite journal |last1=Boukpessi |first1=T |last2=Hoac |first2=B |last3=Coyac |first3=BR |last4=Leger |first4=T |last5=Garcia |first5=C |last6=Wicart |first6=P |last7=Whyte |first7=MP |last8=Glorieux |first8=FH |last9=Linglart |first9=A |last10=Chaussain |first10=C |last11=McKee |first11=MD |date=February 2017 |title=Osteopontin and the dento-osseous pathobiology of X-linked hypophosphatemia. |journal=Bone |volume=95 |pages=151–161 |doi=10.1016/j.bone.2016.11.019 |pmid=27884786}}</ref>  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.<ref>{{Cite journal |last1=Boukpessi |first1=T. |last2=Hoac |first2=B. |last3=Coyac |first3=B. R. |last4=Leger |first4=T. |last5=Garcia |first5=C. |last6=Wicart |first6=P. |last7=Whyte |first7=M. P. |last8=Glorieux |first8=F. H. |last9=Linglart |first9=A. |last10=Chaussain |first10=C. |last11=McKee |first11=M. D. |year=2017 |title=Osteopontin and the dento-osseous pathobiology of X-linked hypophosphatemia |journal=Bone |volume=95 |pages=151–161 |doi=10.1016/j.bone.2016.11.019 |pmid=27884786}}</ref><ref>{{Cite journal |last1=Barros |first1=N. M. |last2=Hoac |first2=B. |last3=Neves |first3=R. L. |last4=Addison |first4=W. N. |last5=Assis |first5=D. M. |last6=Murshed |first6=M. |last7=Carmona |first7=A. K. |last8=McKee |first8=M. D. |year=2013 |title=Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia |journal=Journal of Bone and Mineral Research |volume=28 |issue=3 |pages=688–699 |doi=10.1002/jbmr.1766 |pmid=22991293 |s2cid=20840491 |doi-access=free}}</ref>

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''.<ref>{{Cite journal |last1=Reznikov |first1=N. |last2=Hoac |first2=B. |last3=Buss |first3=D. J. |last4=Addison |first4=W. N. |last5=Barros NMT |last6=McKee |first6=M. D. |year=2020 |title=Biological stenciling of mineralization in the skeleton: Local enzymatic removal of inhibitors in the extracellular matrix |journal=Bone |volume=138 |page=115447 |doi=10.1016/j.bone.2020.115447 |pmid=32454257 |s2cid=218909350}}</ref><ref>{{Cite journal |last1=McKee |first1=M. D. |last2=Buss |first2=D. J. |last3=Reznikov |first3=N. |year=2022 |title=Mineral tessellation in bone and the Stenciling Principle for extracellular matrix mineralization |journal=Journal of Structural Biology |volume=214 |issue=1 |page=107823 |doi=10.1016/j.jsb.2021.107823 |pmid=34915130 |s2cid=245187449}}</ref> 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).<ref>{{Cite journal |last1=McKee |first1=MD |last2=Buss |first2=DJ |last3=Reznikov |first3=N |date=December 13, 2021 |title=Mineral tessellation in bone and the stenciling principle for extracellular matrix mineralization. |journal=Journal of Structural Biology |volume=214 |issue=1 |pages=107823 |doi=10.1016/j.jsb.2021.107823 |pmid=34915130 |s2cid=245187449}}</ref><ref>{{Cite journal |last1=McKee |first1=MD |last2=Hoac |first2=B |last3=Addison |first3=WN |last4=Barros |first4=NM |last5=Millán |first5=JL |last6=Chaussain |first6=C |date=October 2013 |title=Extracellular matrix mineralization in periodontal tissues: Noncollagenous matrix proteins, enzymes, and relationship to hypophosphatasia and X-linked hypophosphatemia. |journal=Periodontology 2000 |volume=63 |issue=1 |pages=102–22 |doi=10.1111/prd.12029 |pmc=3766584 |pmid=23931057}}</ref><ref>{{Cite journal |last1=Buss |first1=DJ |last2=Reznikov |first2=N |last3=McKee |first3=MD |date=November 1, 2020 |title=Crossfibrillar mineral tessellation in normal and Hyp mouse bone as revealed by 3D FIB-SEM microscopy. |url=https://escholarship.mcgill.ca/concern/articles/vq27zt432 |journal=Journal of Structural Biology |volume=212 |issue=2 |pages=107603 |doi=10.1016/j.jsb.2020.107603 |pmid=32805412 |s2cid=221164596}}</ref>  The prevalence of the disease is 1 in 20,000.<ref>{{Cite journal |last=Carpenter TO |date=Apr 1997 |title=New perspectives on the biology and treatment of X-linked hypophosphatemic rickets |journal=Pediatr. Clin. North Am. |volume=44 |issue=2 |pages=443–466 |doi=10.1016/S0031-3955(05)70485-5 |pmid=9130929 |doi-access=free}}</ref>

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.<ref>{{OMIM|193100}}</ref> 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.<ref>{{Cite web |title=Hypophosphatemic rickets |url=http://rarediseases.info.nih.gov/GARD/Disease.aspx?PageID=4&DiseaseID=6735 |url-status=dead |archive-url=https://web.archive.org/web/20120612101237/http://rarediseases.info.nih.gov/GARD/Disease.aspx?PageID=4&diseaseID=6735 |archive-date=June 12, 2012 |access-date=October 10, 2012 |website=Genetic and Rare Diseases Information Center |publisher=National Institutes of Health}}</ref>

==Symptoms and signs==
The most common symptoms of XLH affect the bones and teeth, causing pain, abnormalities, and [[osteoarthritis]]. Symptoms and signs can vary between children and adults and can include (but not limited to):

'''Children'''

{{columns-list|colwidth=35em|* [[Rickets]]<ref name="Osteomalacia and Rickets">{{Cite web |title=Osteomalacia and Rickets |url=https://www.lecturio.com/concepts/osteomalacia-and-rickets/ |access-date=August 24, 2021 |website=The Lecturio Medical Concept Library}}</ref>
* [[Dentin]] defects and enamel abnormalities causing [[dental abscess]]es{{cn|date=November 2024}}
* [[Craniostenosis]]<ref>{{Cite web |last1=Silva |first1=Sandra |last2=Jeanty |first2=Philippe |date=June 7, 1999 |title=Cloverleaf skull or kleeblattschadel |url=http://www.thefetus.net/page.php?id=340 |url-status=dead |archive-url=https://web.archive.org/web/20070107153006/http://thefetus.net/page.php?id=340 |archive-date=January 7, 2007 |access-date=February 3, 2007 |website=TheFetus.net |publisher=MacroMedia}}</ref>
* [[Fracture]]s and [[pseudofracture]]s{{cn|date=November 2024}}
* [[Bone pain]]<ref name="Luger, N. Mach 2005">Luger, N. Mach, D. Sevcik, M. Mantyh, P. (2005). Bone cancer pain: From mechanism to model to therapy. ''Journal of Pain and Symptom Management''. 29(5): 32-46.</ref>
* [[Fatigue]]<ref name="Fatigue">{{Cite web |title=Fatigue |url=https://medlineplus.gov/ency/article/003088.htm |access-date=April 30, 2020 |website=MedlinePlus}}</ref>
* [[Delayed growth]]{{cn|date=November 2024}}
* [[Delayed motor development]]{{cn|date=November 2024}}
}}

'''Adults'''
* [[Osteomalacia]]<ref name="Osteomalacia and Rickets">{{Cite web |title=Osteomalacia and Rickets |url=https://www.lecturio.com/concepts/osteomalacia-and-rickets/ |access-date=August 24, 2021 |website=The Lecturio Medical Concept Library}}</ref>
* Dental abscesses<ref name=":1">{{Cite journal |last1=Linglart |first1=A. |last2=Biosse-Duplan |first2=M. |last3=Briot |first3=K. |last4=Chaussain |first4=C. |last5=Esterle |first5=L. |last6=Guillaume-Czitrom |first6=S. |last7=Kamenicky |first7=P. |last8=Nevoux |first8=J. |last9=Prié |first9=D. |last10=Rothenbuhler |first10=A. |last11=Wicart |first11=P. |last12=Harvengt |first12=P. |year=2014 |title=Therapeutic management of hypophosphatemic rickets from infancy to adulthood |journal=Endocrine Connections |volume=3 |issue=1 |pages=R13–R30 |doi=10.1530/EC-13-0103 |pmc=3959730 |pmid=24550322}}</ref>
* Limited range of movement ([[enthesopathy]])<ref name=":1" /><ref>{{Cite journal |last1=Buss |first1=Daniel J. |last2=Rechav |first2=Katya |last3=Reznikov |first3=Natalie |last4=McKee |first4=Marc D. |date=September 2023 |title=Mineral tessellation in mouse enthesis fibrocartilage, Achilles tendon, and Hyp calcifying enthesopathy: A shared 3D mineralization pattern |url=http://dx.doi.org/10.1016/j.bone.2023.116818 |journal=Bone |volume=174 |pages=116818 |doi=10.1016/j.bone.2023.116818 |issn=8756-3282 |pmid=37295663 |s2cid=259131061|url-access=subscription }}</ref>
* Short stature<ref name=":1" />
* [[Fatigue]]<ref name="Fatigue">{{Cite web |title=Fatigue |url=https://medlineplus.gov/ency/article/003088.htm |access-date=April 30, 2020 |website=MedlinePlus}}</ref>
* Fractures / pseudofracture<ref>{{Cite web |title=Overview of Bone Fractures |url=https://www.lecturio.com/concepts/overview-of-bone-fractures/ |access-date=August 24, 2021 |website=The Lecturio Medical Concept Library}}</ref>
* Bone pain<ref name="Luger, N. Mach 2005">Luger, N. Mach, D. Sevcik, M. Mantyh, P. (2005). Bone cancer pain: From mechanism to model to therapy. ''Journal of Pain and Symptom Management''. 29(5): 32-46.</ref> People often have bowed legs or knock knees in which they usually cannot touch both knees and ankles together at the same time.{{citation needed|date=October 2020}}
* Craniostenosis<ref name=":1" />
* Osteoarthritis<ref>{{Cite web |title=Osteoarthritis |url=https://www.lecturio.com/concepts/osteoarthritis/ |access-date=August 24, 2021 |website=The Lecturio Medical Concept Library}}</ref>
* Spinal stenosis<ref>{{Cite journal |last1=Skrinar |first1=A. |last2=Dvorak-Ewell |first2=M. |last3=Evins |first3=A. |last4=MacIca |first4=C. |last5=Linglart |first5=A. |last6=Imel |first6=E. A. |last7=Theodore-Oklota |first7=C. |last8=San Martin |first8=J. |year=2019 |title=The Lifelong Impact of X-Linked Hypophosphatemia: Results From a Burden of Disease Survey |journal=Journal of the Endocrine Society |volume=3 |issue=7 |pages=1321–1334 |doi=10.1210/js.2018-00365 |pmc=6595532 |pmid=31259293}}</ref>
* Hearing loss<ref name=":1" />
* Depression<ref>{{Cite journal |last1=Hawley |first1=S. |last2=Shaw |first2=N. J. |last3=Delmestri |first3=A. |last4=Prieto-Alhambra |first4=D. |last5=Cooper |first5=C. |last6=Pinedo-Villanueva |first6=R. |last7=Javaid |first7=M. K. |year=2020 |title=Higher prevalence of non-skeletal comorbidity related to X-linked hypophosphataemia: a UK parallel cohort study using CPRD |journal=Rheumatology |volume=60 |issue=9 |pages=4055–4062 |doi=10.1093/rheumatology/keaa859 |pmid=33331900}}</ref>
* Impaired innate immunity<ref name="Beck-Nielsen">{{Cite journal |last1=Beck-Nielsen |first1=Signe Sparre |last2=Mughal |first2=Zulf |last3=Haffner |first3=Dieter |last4=Nilsson |first4=Ola |last5=Levtchenko |first5=Elena |last6=Ariceta |first6=Gema |last7=de Lucas Collantes |first7=Carmen |last8=Schnabel |first8=Dirk |last9=Jandhyala |first9=Ravi |last10=Mäkitie |first10=Outi |date=February 26, 2019 |title=FGF23 and its role in X-linked hypophosphatemia-related morbidity |journal=Orphanet Journal of Rare Diseases |volume=14 |issue=1 |pages=58 |doi=10.1186/s13023-019-1014-8 |issn=1750-1172 |pmc=6390548 |pmid=30808384 |doi-access=free}}</ref>
* Defective mineral tessellation (an ultrastructural mineralization deficiency)<ref>{{Cite journal |last1=Buss |first1=Daniel J. |last2=Reznikov |first2=Natalie |last3=McKee |first3=Marc D. |date=November 2020 |title=Crossfibrillar mineral tessellation in normal and Hyp mouse bone as revealed by 3D FIB-SEM microscopy |url=http://dx.doi.org/10.1016/j.jsb.2020.107603 |journal=Journal of Structural Biology |volume=212 |issue=2 |pages=107603 |doi=10.1016/j.jsb.2020.107603 |issn=1047-8477 |pmid=32805412 |s2cid=221164596}}</ref><ref>{{Cite journal |last1=Buss |first1=Daniel J. |last2=Rechav |first2=Katya |last3=Reznikov |first3=Natalie |last4=McKee |first4=Marc D. |date=September 2023 |title=Mineral tessellation in mouse enthesis fibrocartilage, Achilles tendon, and Hyp calcifying enthesopathy: A shared 3D mineralization pattern |url=http://dx.doi.org/10.1016/j.bone.2023.116818 |journal=Bone |volume=174 |pages=116818 |doi=10.1016/j.bone.2023.116818 |issn=8756-3282 |pmid=37295663 |s2cid=259131061|url-access=subscription }}</ref>

== Genetics ==
XLH affects about 1:20,000 individuals and is the most common cause of inherited phosphate wasting.<ref name="Beck-Nielsen" />

It is associated with a mutation in the ''[[PHEX]]'' gene sequence, located on the human [[X chromosome]] at location Xp22.2-p22.1.<ref name=omim/><ref name=xlhxd/><ref>{{Citation |title=PHOSPHATE-REGULATING ENDOPEPTIDASE HOMOLOG, X-LINKED; PHEX |vauthors=Rasmussen SA, Kniffin CL |date=17 October 2023 |work=Online Mendelian Inheritance in Man |orig-date=Originally published July 28, 2005 |publisher=Johns Hopkins University}} {{OMIM|300550||none}}</ref> The PHEX protein regulates another protein called [[fibroblast growth factor 23]] (produced from the FGF23 gene). Fibroblast growth factor 23 normally inhibits the kidneys' ability to reabsorb phosphate into the bloodstream. Gene mutations in PHEX prevent it from correctly regulating fibroblast growth factor 23. The overactivity of FGF-23 reduces vitamin D 1α-hydroxylation and phosphate reabsorption by the kidneys, leading to [[hypophosphatemia]] and the related features of [[rickets]].<ref>{{Cite journal |last1=Perwad |first1=Farzana |last2=Zhang |first2=Martin Y. H. |last3=Tenenhouse |first3=Harriet S. |last4=Portale |first4=Anthony A. |date=November 1, 2007 |title=Fibroblast growth factor 23 impairs phosphorus and vitamin D metabolism in vivo and suppresses 25-hydroxyvitamin D-1alpha-hydroxylase expression in vitro |journal=American Journal of Physiology. Renal Physiology |volume=293 |issue=5 |pages=F1577–1583 |doi=10.1152/ajprenal.00463.2006 |issn=1931-857X |pmid=17699549 |s2cid=20559055}}</ref> Also in XLH, where PHEX enzymatic activity is absent or reduced, osteopontin<ref name="pmid11021631">{{Cite journal |last=Sodek |first=J |display-authors=etal |year=2000 |title=Osteopontin |journal=Critical Reviews in Oral Biology and Medicine |volume=11 |issue=3 |pages=279–303 |doi=10.1177/10454411000110030101 |pmid=11021631 |doi-access=free}}</ref>—a mineralization-inhibiting secreted substrate protein found in the extracellular matrix of bone<ref name="pmid16612083">{{Cite journal |last=McKee |first=MD |display-authors=etal |year=2005 |title=Hierarchies of extracellular matrix and mineral organization in bone of the craniofacial complex and skeleton |journal=Cells Tissues Organs |volume=181 |issue=3–4 |pages=176–188 |doi=10.1159/000091379 |pmid=16612083 |s2cid=40705942}}</ref>—accumulates in bone (and teeth) to contribute to the osteomalacia (and odontomalacia) as shown in the mouse homolog (Hyp) of XLH and in XLH patients.<ref>{{Cite journal |last1=McKee |first1=MD |last2=Hoac |first2=B |last3=Addison |first3=WN |last4=Barros |first4=NM |last5=Millán |first5=JL |last6=Chaussain |first6=C |date=October 2013 |title=Extracellular matrix mineralization in periodontal tissues: Noncollagenous matrix proteins, enzymes, and relationship to hypophosphatasia and X-linked hypophosphatemia |journal=Periodontology 2000 |volume=63 |issue=1 |pages=102–22 |doi=10.1111/prd.12029 |pmc=3766584 |pmid=23931057}}</ref><ref>{{Cite journal |last1=Boukpessi |first1=T |last2=Hoac |first2=B |last3=Coyac |first3=BR |last4=Leger |first4=T |last5=Garcia |first5=C |last6=Wicart |first6=P |last7=Whyte |first7=MP |last8=Glorieux |first8=FH |last9=Linglart |first9=A |last10=Chaussain |first10=C |last11=McKee |first11=MD |date=November 21, 2016 |title=Osteopontin and the dento-osseous pathobiology of X-linked hypophosphatemia |journal=Bone |volume=95 |pages=151–161 |doi=10.1016/j.bone.2016.11.019 |pmid=27884786}}</ref><ref name="pmid22991293">{{Cite journal |last=Barros |first=NMT |display-authors=etal |year=2013 |title=Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia |journal=Journal of Bone and Mineral Research |volume=28 |issue=3 |pages=688–699 |doi=10.1002/jbmr.1766 |pmid=22991293 |doi-access=free}}</ref>

The disorder is inherited in an [[X-linked dominant]] manner.<ref name=omim/><ref name="xlhxd">{{Cite journal |last1=Saito |first1=T. |last2=Nishii |first2=Y. |last3=Yasuda |first3=T. |last4=Ito |first4=N. |last5=Suzuki |first5=H. |last6=Igarashi |first6=T. |last7=Fukumoto |first7=S. |last8=Fujita |first8=T. |date=Oct 2009 |title=Familial hypophosphatemic rickets caused by a large deletion in PHEX gene |journal=European Journal of Endocrinology |volume=161 |issue=4 |pages=647–651 |doi=10.1530/EJE-09-0261 |pmid=19581284 |doi-access=free}}</ref> This means the defective gene responsible for the disorder (PHEX) is located on the X chromosome, and only one copy of the defective gene is sufficient to cause the disorder when inherited from a parent who has the disorder. Males are normally [[Zygosity#Hemizygous|hemizygous]] for the X chromosome, having only one copy. As a result, X-linked dominant disorders usually show higher [[expressivity (genetics)|expressivity]] in males than females.{{citation needed|date=October 2020}}

As the X chromosome is one of the [[sex chromosome]]s (the other being the [[Y chromosome]]), X-linked inheritance is determined by the [[sex]] of the parent carrying a specific gene and can often seem complex. This is because, typically, [[female]]s have two copies of the X-chromosome and [[male]]s have only one copy. The difference between [[Dominance (genetics)#Dominant trait|dominant]] and [[Dominance (genetics)#Dominant and recessive genetic diseases in humans|recessive]] inheritance patterns also plays a role in determining the chances of a child inheriting an X-linked disorder from their parentage.{{citation needed|date=September 2021}}

==Diagnosis==
The clinical laboratory evaluation of rickets begins with assessing serum calcium, phosphate, and alkaline phosphatase levels. In hypophosphatemic rickets, calcium levels may be within or slightly below the reference range; alkaline phosphatase levels will be significantly above the reference range.Biochemically, XLH is recognized by [[hypophosphatemia]].<ref name="nature">{{Cite journal |last1=Haffner |first1=Dieter |last2=Emma |first2=Francesco |last3=Eastwood |first3=Deborah M. |last4=Duplan |first4=Martin Biosse |last5=Bacchetta |first5=Justine |last6=Schnabel |first6=Dirk |last7=Wicart |first7=Philippe |last8=Bockenhauer |first8=Detlef |last9=Santos |first9=Fernando |last10=Levtchenko |first10=Elena |last11=Harvengt |first11=Pol |last12=Kirchhoff |first12=Martha |last13=Di Rocco |first13=Federico |last14=Chaussain |first14=Catherine |last15=Brandi |first15=Maria Louisa |date=July 2019 |title=Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia |journal=Nature Reviews Nephrology |language=en |volume=15 |issue=7 |pages=435–455 |doi=10.1038/s41581-019-0152-5 |issn=1759-507X |pmc=7136170 |pmid=31068690}}</ref>

Carefully evaluate serum phosphate levels in the first year of life, because the concentration reference range for infants (5.0–7.5&nbsp;mg/dL) is high compared with that for adults (2.7–4.5&nbsp;mg/dL).{{citation needed|date=October 2020}}

Serum parathyroid hormone levels are within the reference range or slightly elevated. [[calcitriol]] (1,25-(OH)<sub>2</sub> vitamin D<sub>3</sub>) levels are low or within the lower reference range. Most importantly, urinary loss of phosphate is above the reference range.{{citation needed|date=September 2021}}

The renal tubular reabsorption of phosphate (TRP) in X-linked hypophosphatemia is 60%; normal TRP exceeds 90% at the same reduced plasma phosphate concentration. The TRP is calculated with the following formula:{{citation needed|date=September 2021}}

: 1 − [Phosphate Clearance (C<sub>P<sub>i</sub></sub>) / Creatinine Clearance (C<sub>cr</sub>)] × 100

== Treatment ==
Conventional therapy consisted of medications including [[human growth hormone]], [[calcitriol]], and oral [[phosphate]],<ref name="pmid20157195">{{Cite journal |last1=Imel |first1=E. A. |last2=DiMeglio, L. A. |last3=Hui, S. L. |last4=Carpenter, T. O. |last5=Econs, M. J. |date=February 15, 2010 |title=Treatment of X-Linked Hypophosphatemia with Calcitriol and Phosphate Increases Circulating Fibroblast Growth Factor 23 Concentrations |journal=Journal of Clinical Endocrinology & Metabolism |volume=95 |issue=4 |pages=1846–1850 |doi=10.1210/jc.2009-1671 |pmc=2853995 |pmid=20157195}}</ref><ref name="pmid6252463">{{Cite journal |last1=Glorieux |first1=F. H. |last2=Marie, P. J. |last3=Pettifor, J. M. |last4=Delvin, E. E. |date=October 30, 1980 |title=Bone response to phosphate salts, ergocalciferol, and calcitriol in hypophosphatemic vitamin D-resistant rickets |journal=The New England Journal of Medicine |volume=303 |issue=18 |pages=1023–1031 |doi=10.1056/NEJM198010303031802 |pmid=6252463}}</ref> and calcitriol;<ref name="pmid20157195" /><ref name="pmid6252463" /> Unwanted effects of this therapy have included [[secondary hyperparathyroidism]], [[nephrocalcinosis]], kidney stones, and cardiovascular abnormalities.{{cn|date=November 2024}}

In February 2018 the European Medicines Agency first licensed a monoclonal antibody directed against FGF23, the first drug targeting the underlying cause for this condition,<ref>{{Cite journal |last1=Carpenter |first1=TO |last2=Whyte MP |last3=Imel EA |last4=Boot AM |last5=Högler W |last6=Linglart A |last7=Padidela R |last8=Van't Hoff W |last9=Mao M |last10=Chen CY |last11=Skrinar A |last12=Kakkis E |last13=San Martin J |last14=Portale AA |date=May 24, 2018 |title=Burosumab Therapy in Children with X-Linked Hypophosphatemia |url=https://digitalcommons.wustl.edu/open_access_pubs/6845 |journal=The New England Journal of Medicine |type=Submitted manuscript |volume=378 |issue=21 |pages=1987–1998 |doi=10.1056/NEJMoa1714641 |pmid=29791829 |s2cid=44135503 |hdl-access=free |hdl=1805/18603}}</ref> called [[burosumab]].<ref>{{Cite web |date=September 17, 2018 |title=EMA authorisation details |url=https://www.ema.europa.eu/en/medicines/human/EPAR/crysvita#authorisation-details-section}}</ref> It was then licensed by the US Food and Drug Administration in June 2018<ref>{{Cite news |title=FDA press release |url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-therapy-rare-disease-causes-low-phosphate-blood-levels-bone-softening|archive-url=https://web.archive.org/web/20200618215939/https://www.fda.gov/news-events/press-announcements/fda-approves-first-therapy-rare-disease-causes-low-phosphate-blood-levels-bone-softening|url-status=dead|archive-date=June 18, 2020}}</ref> Burosumab is shown to target the major symptoms of XLH by decreasing elevated alkaline phosphatase and normalizing severe hypophosphatemia, leading to substantial improvement of rickets in child and adolescent patients.<ref>{{Cite journal |last1=Ewert |first1=Annika |last2=Rehberg |first2=Mirko |last3=Schlingmann |first3=Karl Peter |last4=Hiort |first4=Olaf |last5=John-Kroegel |first5=Ulrike |last6=Metzing |first6=Oliver |last7=Wühl |first7=Elke |last8=Schaefer |first8=Franz |last9=Kemper |first9=Markus J |last10=Derichs |first10=Ute |last11=Richter-Unruh |first11=Annette |last12=Patzer |first12=Ludwig |last13=Albers |first13=Norbert |last14=Dunstheimer |first14=Desiree |last15=Haberland |first15=Holger |date=2023-04-25 |title=Effects of Burosumab Treatment on Mineral Metabolism in Children and Adolescents With X-linked Hypophosphatemia |url=https://academic.oup.com/jcem/article/108/10/e998/7142566 |journal=The Journal of Clinical Endocrinology & Metabolism |volume=108 |issue=10 |pages=e998–e1006 |doi=10.1210/clinem/dgad223 |pmid=37097907 |issn=0021-972X|url-access=subscription }}</ref>

The leg deformity can be treated with [[Ilizarov frame]]s and [[Computer-assisted orthopedic surgery|CAOS]].<ref name=":0" />
In the event of severe bowing, an [[osteotomy]] can be performed to correct the leg shape.<ref name=":0">{{Cite web |title=X-linked hypophosphatemia {{!}} Genetic and Rare Diseases Information Center (GARD) – an NCATS Program |url=https://rarediseases.info.nih.gov/diseases/12943/x-linked-hypophosphatemia |access-date=October 21, 2018 |website=rarediseases.info.nih.gov |language=en}}</ref>

== Society and culture ==
[https://xlhalliance.org International XLH Alliance] – an alliance of international patient groups for individuals affected by XLH and related disorders.

[[Jennyfer Marques Parinos]] is a [[Table tennis at the Paralympics|Paralympic]] bronze medalist from Brazil who has XLH. She competes under a class 9 disability.

== See also ==
* [[Autosomal dominant hypophosphatemic rickets]]
* [[Hypophosphatemia]]
* [[Tumor-induced osteomalacia]]

==References==
{{Reflist}}

== External links ==
* {{Chorus|00754}}
* {{RareDiseases|6735|Hypophosphatemic rickets; XLH; Hypophosphatemia, vitamin D-resistant rickets}}
{{Inborn errors of metal metabolism}}
{{X-linked disorders}}
{{Medical resources
|   DiseasesDB     = 6513
|   ICD10          = {{ICD10|E|83|3|e|70}}
|   ICD9           = {{ICD9|275.3}}
|   ICDO           =
|   OMIM           = 307800
|   MedlinePlus    =
|   eMedicineSubj  = ped
|   eMedicineTopic = 1128
|   eMedicine_mult = {{eMedicine2|article|922305}}  MeshName       =
|   MeshID         = D053098
|   Orphanet       = 89936
}}
{{Authority control}}

[[Category:Vitamin D]]
[[Category:X-linked dominant disorders]]
[[Category:Metabolic disorders]]
[[Category:Rare diseases]]