View source for Pseudoxanthoma elasticum

{{Short description|Genetic disease in which elastic fibers in certain tissues harden}}
{{Infobox medical condition (new)
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| synonyms        = Grönblad–Strandberg syndrome;<ref name="Bolognia">{{Cite book |last=Rapini |first=Ronald P. |title=Dermatology: 2-Volume Set |last2=Bolognia |first2=Jean L. |last3=Jorizzo |first3=Joseph L. |publisher=Mosby |year=2007 |isbn=978-1-4160-2999-1 |location=St. Louis |name-list-style=vanc}}</ref> Groenblad-Strandberg syndrome
| image           = Pseudoxanthoma_elasticum_3.JPG
| caption         = Pseudoxanthoma elasticum of the posterior lateral neck.  Note the yellowish slightly raised bumps characteristic of this condition.
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'''Pseudoxanthoma elasticum''' ('''PXE''') is a [[genetic disease]] that causes mineralization of elastic fibers in some tissues. The most common problems arise in the [[human skin|skin]] and [[human eye|eye]]s, and later in [[blood vessel]]s in the form of premature [[atherosclerosis]].<ref>{{Cite journal |vauthors=Li Q, van de Wetering K, Uitto J |date=February 2019 |title=Pseudoxanthoma Elasticum as a Paradigm of Heritable Ectopic Mineralization Disorders: Pathomechanisms and Treatment Development |department=review |journal=The American Journal of Pathology |volume=189 |issue=2 |pages=216–225 |doi=10.1016/j.ajpath.2018.09.014 |pmc=6412714 |pmid=30414410}}</ref><ref name="Chassaing">{{Cite journal |vauthors=Chassaing N, Martin L, Calvas P, Le Bert M, Hovnanian A |date=December 2005 |title=Pseudoxanthoma elasticum: a clinical, pathophysiological and genetic update including 11 novel ABCC6 mutations |department=review |journal=Journal of Medical Genetics |volume=42 |issue=12 |pages=881–92 |doi=10.1136/jmg.2004.030171 |pmc=1735972 |pmid=15894595}}</ref><ref name="Finger">{{Cite journal |vauthors=Finger RP, Charbel Issa P, Ladewig MS, Götting C, Szliska C, Scholl HP, Holz FG |year=2009 |title=Pseudoxanthoma elasticum: genetics, clinical manifestations and therapeutic approaches |department=review |journal=Survey of Ophthalmology |volume=54 |issue=2 |pages=272–85 |doi=10.1016/j.survophthal.2008.12.006 |pmid=19298904}}</ref> PXE is caused by [[Recessive#Autosomal recessive gene|autosomal recessive mutations]] in the ''[[ABCC6]]'' gene on the short arm of [[chromosome 16]] (16p13.1).<ref name=Chassaing/><ref name="Marconi_2015">{{Cite journal |display-authors=6 |vauthors=Marconi B, Bobyr I, Campanati A, Molinelli E, Consales V, Brisigotti V, Scarpelli M, Racchini S, Offidani A |date=August 2015 |title=Pseudoxanthoma elasticum and skin: Clinical manifestations, histopathology, pathomechanism, perspectives of treatment |department=review |journal=Intractable & Rare Diseases Research |volume=4 |issue=3 |pages=113–22 |doi=10.5582/irdr.2015.01014 |pmc=4561240 |pmid=26361562}}</ref><ref name="Germain_2017">{{Cite journal |vauthors=Germain DP |date=May 2017 |title=Pseudoxanthoma elasticum |department=review |journal=Orphanet Journal of Rare Diseases |volume=12 |issue=1 |pages=85 |doi=10.1186/s13023-017-0639-8 |pmc=5424392 |pmid=28486967 |doi-access=free}}</ref>

==Signs and symptoms==

=== Dermatological manifestations ===
Usually, pseudoxanthoma elasticum affects the skin first, often in childhood or early adolescence.<ref>{{Cite journal |vauthors=Naouri M, Boisseau C, Bonicel P, Daudon P, Bonneau D, Chassaing N, Martin L |date=September 2009 |title=Manifestations of pseudoxanthoma elasticum in childhood |journal=The British Journal of Dermatology |volume=161 |issue=3 |pages=635–9 |doi=10.1111/j.1365-2133.2009.09298.x |pmid=19519828 |s2cid=24795259}}</ref> Small, yellowish papular lesions form and cutaneous laxity mainly affect the neck, [[Armpit|axillae]] (armpits), groin, and flexural creases (the inside parts of the elbows and knees).<ref name="Chassaing" /><ref>{{Cite book |last=Neldner |first=Kenneth H. |title=Connective Tissue and Its Heritable Disorders: Molecular, Genetic, and Medical Aspects |last2=Struk |first2=Berthold |date=2003 |publisher=John Wiley & Sons |isbn=9780471221920 |pages=561–583 |chapter=Pseudoxanthoma Elasticum |doi=10.1002/0471221929.ch11 |name-list-style=vanc |s2cid=32736212}}</ref> Skin may become lax and redundant. Many individuals have "oblique mental creases" (horizontal grooves of the chin).<ref>{{Cite journal |vauthors=Lebwohl M, Lebwohl E, Bercovitch L |date=April 2003 |title=Prominent mental (chin) crease: a new sign of pseudoxanthoma elasticum |department=primary |journal=Journal of the American Academy of Dermatology |volume=48 |issue=4 |pages=620–2 |doi=10.1067/mjd.2003.195 |pmid=12664032 |s2cid=4831796}}</ref> The lesions are asymptomatic and have a stochastic pattern of growth and spread.<ref>{{Cite journal |last=Marconi |first=Barbara |last2=Bobyr |first2=Ivan |last3=Campanati |first3=Anna |last4=Molinelli |first4=Elisa |last5=Consales |first5=Veronica |last6=Brisigotti |first6=Valerio |last7=Scarpelli |first7=Marina |last8=Racchini |first8=Stefano |last9=Offidani |first9=Annamaria |date=2015 |title=Pseudoxanthoma elasticum and skin: Clinical manifestations, histopathology, pathomechanism, perspectives of treatment |url=https://www.jstage.jst.go.jp/article/irdr/4/3/4_2015.01014/_article |journal=Intractable & Rare Diseases Research |language=en |volume=4 |issue=3 |pages=113–122 |doi=10.5582/irdr.2015.01014 |issn=2186-361X |pmc=4561240 |pmid=26361562}}</ref>

=== Ocular manifestations ===
PXE first affects the retina through a dimpling of the [[Bruch's membrane|Bruch membrane]] (a thin membrane separating the blood vessel-rich layer from the pigmented layer of the [[retina]]), that is only visible during [[ophthalmologic]] examinations.<ref>{{Cite journal |vauthors=Gliem M, Müller PL, Birtel J, Hendig D, Holz FG, Charbel Issa P |date=June 2016 |title=Frequency, Phenotypic Characteristics and Progression of Atrophy Associated With a Diseased Bruch's Membrane in Pseudoxanthoma Elasticum |department=primary |journal=Investigative Ophthalmology & Visual Science |volume=57 |issue=7 |pages=3323–30 |doi=10.1167/iovs.16-19388 |pmid=27367499 |doi-access=free}}</ref>  This is called [[peau d'orange]] (a French term meaning "skin of the orange"). Eventually the mineralization of the elastic fibers in the Bruch membrane create cracks called [[angioid streaks]] that radiate out from the optic nerve. Angioid streaks themselves do not cause distortion of vision, even if they cross into the foveal area. This symptom is present in almost all PXE patients and is usually noticed a few years after the onset of cutaneous [[wikt:lesion|lesions]]. These cracks may allow small blood vessels that were originally held back by Bruch's membrane to penetrate the retina. These blood vessels sometimes leak, and these [[retinal hemorrhage]]s may lead to the loss of central vision. Vision loss is a major issue in many PXE patients.<ref>{{Cite journal |vauthors=Risseeuw S, Ossewaarde-van Norel J, Klaver CC, Colijn JM, Imhof SM, van Leeuwen R |date=August 2019 |title=Visual Acuity in Pseudoxanthoma Elasticum |department=primary |journal=Retina |volume=39 |issue=8 |pages=1580–1587 |doi=10.1097/IAE.0000000000002173 |pmid=29652691 |s2cid=4893600}}</ref><ref name="Chassaing" /><ref name="Finger" />

Additionally, patients with PXE are at a greater risk of developing optic nerve head (ONH) drusen, which are calcified lesions within the optic nerve. Careful monitoring should be considered to prevent further complication, such as retinal artery occlusion and optic neuropathy.<ref>{{Citation |last=Ahmed |first=Harris |title=Optic Disc Drusen |date=2024 |work=StatPearls |url=http://www.ncbi.nlm.nih.gov/books/NBK580547/ |access-date=2024-03-07 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=35593854 |last2=Khazaeni |first2=Leila}}</ref>

=== Cardiovascular manifestations ===
PXE is caused by mineralization in connective tissues in mainly the skin, eyes, and blood vessels.<ref name=":4">{{Cite journal |last=Germain |first=Dominique P. |date=2017-05-10 |title=Pseudoxanthoma elasticum |journal=Orphanet Journal of Rare Diseases |volume=12 |issue=1 |pages=85 |doi=10.1186/s13023-017-0639-8 |issn=1750-1172 |pmc=5424392 |pmid=28486967 |doi-access=free}}</ref> As a result of mineralized buildup in the vascular wall, patients may be at a greater risk for [[intermittent claudication]], a condition in which cramping pain in the leg is induced by exercise,<ref>{{Cite journal |display-authors=6 |vauthors=Lefthériotis G, Abraham P, Le Corre Y, Le Saux O, Henrion D, Ducluzeau PH, Prunier F, Martin L |date=November 2011 |title=Relationship between ankle brachial index and arterial remodeling in pseudoxanthoma elasticum |department=primary |journal=Journal of Vascular Surgery |volume=54 |issue=5 |pages=1390–4 |doi=10.1016/j.jvs.2011.04.041 |pmc=5529101 |pmid=21723076}}</ref> and peripheral artery disease.<ref name=":4" /> Occlusions in cerebral arteries can lead to reduced or blocked blood flow, resulting in serious complications including [[transient ischemic attack]] (TIA) and [[stroke]]. Similarly, blockages in the coronary circulatory system, also called [[coronary artery disease]] may develop, leading to [[angina pectoris|angina]] and [[myocardial infarction]] (heart attack).<ref>{{Cite journal |vauthors=Kranenburg G, de Jong PA, Mali WP, Attrach M, Visseren FL, Spiering W |date=January 2017 |title=Prevalence and severity of arterial calcifications in pseudoxanthoma elasticum (PXE) compared to hospital controls. Novel insights into the vascular phenotype of PXE |department=primary |journal=Atherosclerosis |volume=256 |pages=7–14 |doi=10.1016/j.atherosclerosis.2016.11.012 |pmid=27940376}}</ref> Cerebral ischemia in PXE is caused by small vessel occlusive disease.{{cn|date=October 2024}}

=== Other manifestations ===
Although not much is known about potential gastroenterological manifestations, [[gastrointestinal bleeding]] is a rare symptom and usually involved bleeding from the [[stomach]].{{cn|date=October 2024}}

Other rare neurological complications may include intracranial aneurysms, subarachnoid and intracerebral hemorrhages.<ref>{{Cite journal |display-authors=6 |vauthors=Kauw F, Kranenburg G, Kappelle LJ, Hendrikse J, Koek HL, Visseren FL, Mali WP, de Jong PA, Spiering W |date=February 2017 |title=Cerebral disease in a nationwide Dutch pseudoxanthoma elasticum cohort with a systematic review of the literature |department=review |journal=Journal of the Neurological Sciences |volume=373 |pages=167–172 |doi=10.1016/j.jns.2016.12.053 |pmid=28131180 |s2cid=206292331}}</ref>

==Genetics==
[[Image:autorecessive.svg|thumb|right|Pseudoxanthoma elasticum has an [[autosomal recessive]] pattern of inheritance.]]

80% of clinical cases of pseudoxanthoma elasticum have detectable mutations in the ''ABCC6'' gene.<ref name=":0">{{Cite journal |author-link2=Mark G. Lebwohl |vauthors=Ringpfeil F, Lebwohl MG, Christiano AM, Uitto J |date=May 2000 |title=Pseudoxanthoma elasticum: mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter |department=primary |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=97 |issue=11 |pages=6001–6 |bibcode=2000PNAS...97.6001R |doi=10.1073/pnas.100041297 |pmc=18548 |pmid=10811882 |doi-access=free}}</ref><ref name=":1">{{Cite journal |display-authors=6 |vauthors=Bergen AA, Plomp AS, Schuurman EJ, Terry S, Breuning M, Dauwerse H, Swart J, Kool M, van Soest S, Baas F, ten Brink JB, de Jong PT |date=June 2000 |title=Mutations in ABCC6 cause pseudoxanthoma elasticum |department=primary |journal=Nature Genetics |volume=25 |issue=2 |pages=228–31 |doi=10.1038/76109 |pmid=10835643 |s2cid=510024}}</ref><ref name="LeSaux">{{Cite journal |display-authors=6 |vauthors=Le Saux O, Urban Z, Tschuch C, Csiszar K, Bacchelli B, Quaglino D, Pasquali-Ronchetti I, Pope FM, Richards A, Terry S, Bercovitch L, de Paepe A, Boyd CD |date=June 2000 |title=Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum |department=primary |journal=Nature Genetics |volume=25 |issue=2 |pages=223–7 |doi=10.1038/76102 |pmid=10835642 |s2cid=8883528|hdl=11380/304934 |hdl-access=free }}</ref><ref name=":2">{{Cite journal |display-authors=6 |vauthors=Struk B, Cai L, Zäch S, Ji W, Chung J, Lumsden A, Stumm M, Huber M, Schaen L, Kim CA, Goldsmith LA, Viljoen D, Figuera LE, Fuchs W, Munier F, Ramesar R, Hohl D, Richards R, Neldner KH, Lindpaintner K |year=2000 |title=Mutations of the gene encoding the transmembrane transporter protein ABC-C6 cause pseudoxanthoma elasticum |department=primary |journal=Journal of Molecular Medicine |volume=78 |issue=5 |pages=282–6 |doi=10.1007/s001090000114 |pmid=10954200 |s2cid=8062022}}</ref> Mutations in almost all parts of the gene have been described, of all types (missense, nonsense, splice alteration, insertion, small deletion or large deletion). Although there have been reports of [[Dominance relationship|autosomal dominant]] inheritance, the inheritance is typically autosomal recessive (both parents need to be carriers, and there is a 25% chance that a child will inherit ''both'' abnormal copies of the gene and therefore develop the condition).<ref name=Chassaing/>

Strong genetic linkage was found with mutations in the ''[[ABCC6]]'' gene, which codes for the ABCC6 protein, which is a membrane transporter from the large [[ATP-binding cassette transporter genes|ATP-binding cassette transporter]] family. The protein is expressed in most organs, but mainly in the [[liver]] and [[kidney]]. ABCC6 mediates ATP release in the liver. This is the main source of circulating pyrophosphate (PPi), and individuals affected by PXE have strongly reduced plasma PPi levels, explaining their mineralization disorder.<ref name=":3">{{Cite journal |display-authors=6 |vauthors=Jansen RS, Duijst S, Mahakena S, Sommer D, Szeri F, Váradi A, Plomp A, Bergen AA, Oude Elferink RP, Borst P, van de Wetering K |date=September 2014 |title=ABCC6-mediated ATP secretion by the liver is the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic circulation-brief report |department=primary |journal=Arteriosclerosis, Thrombosis, and Vascular Biology |volume=34 |issue=9 |pages=1985–9 |doi=10.1161/ATVBAHA.114.304017 |pmc=6743317 |pmid=24969777}}</ref> One study suggested that mutations causing total absence of an ABCC6 protein caused a more severe disease,<ref>{{Cite journal |vauthors=Schulz V, Hendig D, Szliska C, Götting C, Kleesiek K |date=June 2005 |title=Novel mutations in the ABCC6 gene of German patients with pseudoxanthoma elasticum |department=primary |journal=Human Biology |volume=77 |issue=3 |pages=367–84 |doi=10.1353/hub.2005.0054 |pmid=16392638 |s2cid=44925940}}</ref> but this could not be confirmed in a subsequent case series.<ref>{{Cite journal |display-authors=6 |vauthors=Pfendner EG, Vanakker OM, Terry SF, Vourthis S, McAndrew PE, McClain MR, Fratta S, Marais AS, Hariri S, Coucke PJ, Ramsay M, Viljoen D, Terry PF, De Paepe A, Uitto J, Bercovitch LG |date=October 2007 |title=Mutation detection in the ABCC6 gene and genotype-phenotype analysis in a large international case series affected by pseudoxanthoma elasticum |department=primary |journal=Journal of Medical Genetics |volume=44 |issue=10 |pages=621–8 |doi=10.1136/jmg.2007.051094 |pmc=2597973 |pmid=17617515}}</ref> Given the variations in age of onset and severity it is likely that other unknown risk factors (genetic, environmental, and lifestyle) may be involved.<ref name=Chassaing/>

Premature [[atherosclerosis]] is also associated with mutations in the ''[[ABCC6]]'' gene, even in those without PXE.<ref name="pmid12176944">{{Cite journal |display-authors=6 |vauthors=Trip MD, Smulders YM, Wegman JJ, Hu X, Boer JM, ten Brink JB, Zwinderman AH, Kastelein JJ, Feskens EJ, Bergen AA |date=August 2002 |title=Frequent mutation in the ABCC6 gene (R1141X) is associated with a strong increase in the prevalence of coronary artery disease |department=primary |journal=Circulation |volume=106 |issue=7 |pages=773–5 |doi=10.1161/01.CIR.0000028420.27813.C0 |pmid=12176944 |s2cid=2107131}}</ref> A syndrome almost indistinguishable from hereditary PXE has been described in patients with [[hemoglobinopathy|hemoglobinopathies]] ([[sickle-cell disease]] and [[thalassemia]]) through a poorly understood mechanism.<ref name=Chassaing/> In addition, there appears to be another PXE-like syndrome with a similar phenotype but as a result of problems with another gene, [[gamma-glutamyl carboxylase]].<ref name="pmid17110937">{{Cite journal |display-authors=6 |vauthors=Vanakker OM, Martin L, Gheduzzi D, Leroy BP, Loeys BL, Guerci VI, Matthys D, Terry SF, Coucke PJ, Pasquali-Ronchetti I, De Paepe A |date=March 2007 |title=Pseudoxanthoma elasticum-like phenotype with cutis laxa and multiple coagulation factor deficiency represents a separate genetic entity |department=primary |journal=The Journal of Investigative Dermatology |volume=127 |issue=3 |pages=581–7 |doi=10.1038/sj.jid.5700610 |pmid=17110937 |doi-access=free|hdl=11380/23189 |hdl-access=free }}</ref> Mutations in ''ABCC6'' can also cause generalized arterial calcification of infancy.<ref>{{Cite journal |display-authors=6 |vauthors=Li Q, Brodsky JL, Conlin LK, Pawel B, Glatz AC, Gafni RI, Schurgers L, Uitto J, Hakonarson H, Deardorff MA, Levine MA |date=March 2014 |title=Mutations in the ABCC6 gene as a cause of generalized arterial calcification of infancy: genotypic overlap with pseudoxanthoma elasticum |department=primary |journal=The Journal of Investigative Dermatology |volume=134 |issue=3 |pages=658–665 |doi=10.1038/jid.2013.370 |pmc=3945730 |pmid=24008425}}</ref> In some cases of PXE, mutations in ''ABCC6'' cannot be found, and other genes such as ''ENPP1'' may be implicated.<ref>{{Cite journal |display-authors=6 |vauthors=Jin L, Jiang Q, Wu Z, Shao C, Zhou Y, Yang L, Uitto J, Wang G |date=May 2015 |title=Genetic heterogeneity of pseudoxanthoma elasticum: the Chinese signature profile of ABCC6 and ENPP1 mutations |department=primary |journal=The Journal of Investigative Dermatology |volume=135 |issue=5 |pages=1294–1302 |doi=10.1038/jid.2015.10 |pmc=4402129 |pmid=25615550}}</ref>

==Pathophysiology==
In PXE, there is mineralization (accumulation of [[calcium in biology|calcium]] and other minerals) and fragmentation of the [[elastin]]-containing fibers in [[connective tissue]], but primarily in the midlaminar layer of the dermis, Bruch's membrane and the midsized [[artery|arteries]].<ref>{{Cite journal |vauthors=Gheduzzi D, Sammarco R, Quaglino D, Bercovitch L, Terry S, Taylor W, Ronchetti IP |year=2003 |title=Extracutaneous ultrastructural alterations in pseudoxanthoma elasticum |department=primary |journal=Ultrastructural Pathology |volume=27 |issue=6 |pages=375–84 |doi=10.1080/716100800 |pmid=14660276}}</ref> Recent studies have confirmed that PXE is a metabolic disease, and that its features arise because metabolites of vitamin K cannot reach peripheral tissues.<ref>{{Cite journal |vauthors=Li Q, Jiang Q, Pfendner E, Váradi A, Uitto J |date=January 2009 |title=Pseudoxanthoma elasticum: clinical phenotypes, molecular genetics and putative pathomechanisms |department=review |journal=Experimental Dermatology |volume=18 |issue=1 |pages=1–11 |doi=10.1111/j.1600-0625.2008.00795.x |pmc=3349969 |pmid=19054062}}</ref> Low levels of PPi cause mineralization in peripheral tissues.<ref name=":3" />

==Diagnosis==
[[File:Histopathology of pseudoxanthoma elasticum.jpg|thumb|Histopathology of pseudoxanthoma elasticum: Fragmentation and calcification of middermal elastic fibers on Alizarin Red staining.<ref name="HosenLamoen2012"/>]]
The diagnostic criteria for PXE are the typical skin biopsy appearance and the presence of [[angioid streaks]] in the retina. Criteria were established by consensus of clinicians and researchers at the 2010 biennial research meeting of the PXE Research Consortium.<ref>{{Cite journal |vauthors=Uitto J, Bercovitch L, Terry SF, Terry PF |date=July 2011 |title=Pseudoxanthoma elasticum: progress in diagnostics and research towards treatment : Summary of the 2010 PXE International Research Meeting |department=review |journal=American Journal of Medical Genetics. Part A |volume=155A |issue=7 |pages=1517–26 |doi=10.1002/ajmg.a.34067 |pmc=3121926 |pmid=21671388}}</ref> and confirmed at the 2014 meeting<ref>{{Cite journal |vauthors=Uitto J, Jiang Q, Váradi A, Bercovitch LG, Terry SF |date=June 2014 |title=Visual Acuity in Pseudoxanthoma Elasticum |department=review |journal=Expert Opinion on Orphan Drugs |volume=2 |issue=6 |pages=567–577 |doi=10.1517/21678707.2014.908702 |pmc=4219573 |pmid=25383264}}</ref> These consensus criteria state that definitive PXE is characterized by two pathogenic mutations in the ''ABCC6'' or ocular findings – angioid streaks > 1 DD or peau d'orange in an individual <20 years of age together with skin findings:
* Characteristic pseudoxanthomatous papules and plaques on the neck or flexural creases.{{cn|date=September 2021}}
* Diagnostic histopathological changes in lesional skin: Calcified elastic fibers in the mid and lower dermis, confirmed by positive calcium stain{{cn|date=September 2021}}

===Differential diagnosis===
[[File:PXE-like papillary dermal elastolysis.jpg|thumb|The differential diagnosis ''PXE-like papillary dermal elastolysis'': Small flesh-colored papules in the neck region.<ref name="HosenLamoen2012">{{Cite journal |last=Hosen |first=Mohammad J. |last2=Lamoen |first2=Anouck |last3=De Paepe |first3=Anne |last4=Vanakker |first4=Olivier M. |year=2012 |title=Histopathology of Pseudoxanthoma Elasticum and Related Disorders: Histological Hallmarks and Diagnostic Clues |journal=Scientifica |volume=2012 |pages=1–15 |doi=10.6064/2012/598262 |issn=2090-908X |pmc=3820553 |pmid=24278718 |doi-access=free}}<br>-[https://creativecommons.org/licenses/by/3.0/ Creative Commons Attribution 3.0 Unported] license</ref>]]
[[File:Histopathology of PXE-like papillary dermal elastolysis.jpg|thumb|Histopathology of PXE-like papillary dermal elastolysis: Loss of elastic fibers in the papillary dermis and abnormal pattern in the reticular dermis (arrow)<ref name="HosenLamoen2012"/>]]
{|class="wikitable"
|+Pseudoxanthoma elasticum versus histopathological differential diagnoses<br>on light microscopy (LM) and [[electron microscopy]] (EM)<ref name="HosenLamoen2012"/>
|-
| Pseudoxanthoma elasticum || LM: Mid-dermal calcification and fragmentation of elastic fibers<br>EM: Mineralization in elastic fiber core
|-
| PXE-like disease with [[coagulation deficiency]] || LM: Middermal calcification and fragmentation of elastic fibers<br>EM: Mineralization in elastic fiber periphery
|-
| [[Hemoglobinopathies]] || LM: Middermal calcification and fragmentation of elastic fibers<br>EM: Mineralization in elastic fiber core
|-
| PXE-like papillary dermal elastolysis || LM: Selective elastic tissue elimination in the papillary dermis and presence of melanophages
|-
| [[White fibrous papulosis]] of the neck || LM: Dermal fibrosis in papillary and mid-reticular dermis
|-
| [[Late-onset focal dermal elastosis]] || EM: Decrease of elastic fibers; fragmentation of remaining fibers<br>LM: Accumulation of elastic fibers in mid- and reticular dermis without fragmentation or calcification
|-
| [[Perforating calcific elastosis]] || LM: Middermal calcification and degeneration of elastic fibers with transepidermal elimination
|-
| [[Buschke–Ollendorff syndrome]] || LM: Increased amount of hypertrophic elastic fibers in dermis<br>EM: Altered translucent elastic fibers
|-
| [[Elastosis perforans serpiginosa]] || LM: Transepidermal or perifollicular perforating canals
|-
| [[Papular elastorrhexis]] || LM: Thickening of collagen bundles next to loss and fragmentation of elastic fibers
|-
| [[Upper dermal elastolysis]] || LM: Complete loss of elastic fibers in the upper dermis
|-
| [[Middermal elastolysis]] || LM: Complete absence of elastic fibers in the middermis
|-
| [[Linear focal elastosis]] || LM: Massive basophilic fibers; clumping of elastic fibers in papillary dermis
|-
| [[Elastoderma]] || LM: Increased, intertwining thin elastic fibers in papillary and upper reticular dermis
|-
| [[Calcinosis cutis]] || LM: Deposits of calcium in the dermis
|}

==Treatment==
There is no confirmed treatment that directly interferes with the disease process.<ref name="Marconi_2015" /><ref name="Germain_2017" />

Cosmetic surgery to remove excessive skin has been used to improve aesthetic appearance in PXE patients<ref name="Marconi_2015" /> but because of the non-life-threatening nature of these symptoms, should be used with caution.<ref name="Germain_2017" />

One of the most critical symptom of PXE is [[choroidal neovascularization]] which can lead to deterioration of central vision. [[Photodynamic therapy]] has been used as a treatment, but this has been replaced with [[endothelial growth factor]] (VEGF) inhibitors (such as [[bevacizumab]], [[ranibizumab]], and [[aflibercept]])<ref name="Germain_2017" /> with efficacy similar to their use in treatment of [[macular degeneration|age-related macular degeneration]].<ref name="Finger" />

To limit cardiovascular symptoms, reduction of cardiovascular risk factors through lifestyle changes is recommended.<ref name="Germain_2017" /> Generally clinicians recommend avoidance of non-steroidal anti-inflammatory drugs (NSAIDS) that increase bleeding risk, such as [[aspirin]], and [[ibuprofen]] to prevent eye and gastrointestinal bleeding.<ref name="Germain_2017" />

Formerly, dietary restriction of calcium was tried with no benefit, and in fact accelerated mineralization in mice.<ref>{{Cite journal |vauthors=Jiang Q, Uitto J |date=September 2012 |title=Restricting dietary magnesium accelerates ectopic connective tissue mineralization in a mouse model of pseudoxanthoma elasticum (Abcc6(-/-) ) |department=primary |journal=Experimental Dermatology |volume=21 |issue=9 |pages=694–9 |doi=10.1111/j.1600-0625.2012.01553.x |pmc=3422765 |pmid=22897576}}</ref> There are a number of potential treatments that are currently being tested or have just undergone testing including magnesium,<ref>{{Cite journal |display-authors=6 |vauthors=Rose S, On SJ, Fuchs W, Chen C, Phelps R, Kornreich D, Haddican M, Singer G, Wong V, Baum D, Vekaria A, Gagliotti M, Huang R, Suárez-Fariñas M, Terry SF, Lebwohl M |date=July 2019 |title=Magnesium supplementation in the treatment of pseudoxanthoma elasticum: A randomized trial |department=primary |journal=Journal of the American Academy of Dermatology |volume=81 |issue=1 |pages=263–265 |doi=10.1016/j.jaad.2019.02.055 |pmid=30826287 |doi-access=free}}</ref> etidronate,<ref>{{Cite journal |display-authors=6 |vauthors=Kranenburg G, de Jong PA, Bartstra JW, Lagerweij SJ, Lam MG, Ossewaarde-van Norel J, Risseeuw S, van Leeuwen R, Imhof SM, Verhaar HJ, de Vries JJ, Slart RH, Luurtsema G, den Harder AM, Visseren FL, Mali WP, Spiering W |date=March 2018 |title=Etidronate for Prevention of Ectopic Mineralization in Patients With Pseudoxanthoma Elasticum |department=primary |journal=Journal of the American College of Cardiology |volume=71 |issue=10 |pages=1117–1126 |doi=10.1016/j.jacc.2017.12.062 |pmid=29519353 |doi-access=free}}</ref> PPi,<ref>{{Cite journal |display-authors=6 |vauthors=Dedinszki D, Szeri F, Kozák E, Pomozi V, Tőkési N, Mezei TR, Merczel K, Letavernier E, Tang E, Le Saux O, Arányi T, van de Wetering K, Váradi A |date=November 2017 |title=Oral administration of pyrophosphate inhibits connective tissue calcification |department=primary |journal=EMBO Molecular Medicine |volume=9 |issue=11 |pages=1463–1470 |doi=10.15252/emmm.201707532 |pmc=5666306 |pmid=28701330}}</ref> and tissue-nonspecific alkaline phosphatase inhibitors.<ref>{{Cite journal |display-authors=6 |vauthors=Li Q, Huang J, Pinkerton AB, Millan JL, van Zelst BD, Levine MA, Sundberg JP, Uitto J |date=February 2019 |title=-/- Mouse Model of PXE but Not in the Enpp1 Mutant Mouse Models of GACI |department=primary |journal=The Journal of Investigative Dermatology |volume=139 |issue=2 |pages=360–368 |doi=10.1016/j.jid.2018.07.030 |pmc=6342656 |pmid=30130617}}</ref>

Given that ABCC6 [[heterozygous]] mutations result in few symptoms of PXE, this disease is a candidate for [[gene therapy]].  Some initial proof-of-principle experiments have been done in mice that have relieved some of symptoms of PXE, but as with all gene therapy treatments, there are many hurdles that must be overcome including insuring that the treatment will be long-lasting and reducing the risk of insertional [[mutagenesis]] and severe immune reactions.<ref name="Germain_2017" />

==Epidemiology==
The reported prevalence of pseudoxanthoma elasticum is about 1:25,000. Females are twice as likely to be affected as males. The disease occurs in all ethnicities, but [[Afrikaner]]s are more likely to have PXE as a result of a [[founder effect]] (i.e., higher prevalence in the small group of people from whom Afrikaners descend).<ref>{{Cite journal |display-authors=6 |vauthors=Le Saux O, Beck K, Sachsinger C, Treiber C, Göring HH, Curry K, Johnson EW, Bercovitch L, Marais AS, Terry SF, Viljoen DL, Boyd CD |date=October 2002 |title=Evidence for a founder effect for pseudoxanthoma elasticum in the Afrikaner population of South Africa |department=primary |journal=Human Genetics |volume=111 |issue=4–5 |pages=331–8 |doi=10.1007/s00439-002-0808-1 |pmid=12384774 |s2cid=11117332}}</ref>

==History==
The first description of PXE that distinguished it from other [[xanthoma]] conditions was by Dr Ferdinand-Jean Darrier in 1896.<ref>{{Cite journal |vauthors=Darrier FJ |year=1896 |title=Pseudoxanthoma elasticum |journal=Monatschr Prakt Dermatol |language=German |volume=23 |pages=609–17}}</ref> The eponym "Grönblad-Strandberg syndrome" is used in older literature, after two physicians who made further discoveries in the disease manifestations.<ref>{{WhoNamedIt|synd|1059}}</ref>

PXE has the distinction of being the only disease for which a layperson is the discover of the mutated gene. The ''ABCC6'' gene mutation was discovered simultaneously by four research teams, all of which published at the same time. The principal investigators were (in order of the date of publication): Jouni Uitto,<ref name=":0" /> Arthur Bergen,<ref name=":1" /> Charles Boyd,<ref name="LeSaux" /> and Klaus Lindpainter.<ref name=":2" /> The gene was patented by Charles D. Boyd, Katalin Csiszar, Olivier LeSaux, Zsolt Urban, Sharon Terry, and assigned to PXE International by these co-inventors.  Between the filing and 2013, when the Supreme Court of the United States declared that genes may not be patented.<ref>{{Cite news |last=Liptak |first=Adam |name-list-style=vanc |date=2013-06-13 |title=Justices, 9-0, Bar Patenting Human Genes |url=https://www.nytimes.com/2013/06/14/us/supreme-court-rules-human-genes-may-not-be-patented.html |access-date=2019-08-24 |work=The New York Times |language=en-US |issn=0362-4331}}</ref> PXE International freely licensed the gene to any lab for clinical testing and research. PXE International continues to hold and maintain other patents (diagnosis and treatment patents).<ref>{{Cite web |last=Katalin Csiszar |last2=Olivier LeSaux |last3=Zsolt Urban |last4=Sharon Terry |last5=Charles D. Boyd |title=Methods and Composition for Diagnosing and Treating Pseudoxanthoma Elasticum and Related Conditions |url=https://assignment.uspto.gov/patent/index.html#/patent/search/resultAbstract?id=7364904&type=patNum |access-date=2019-08-24 |website=assignment.uspto.gov |publisher=United States Patent and Trademark Office}}</ref><ref>{{Cite web |last=Charles D. Boyd |last2=Katalin Csiszar |last3=Olivier LeSaux |last4=Zsolt Urban |last5=Sharon Terry |title=Methods for Diagnosing Pseudoxanthoma Elasticum |url=https://assignment.uspto.gov/patent/index.html#/patent/search/resultAbstract?id=6780587&type=patNum |access-date=2019-08-24 |website=assignment.uspto.gov |publisher=United States Patent and Trademark Office}}</ref>

PXE International, a support organization, was founded in 1995, by Patrick and [[Sharon F. Terry|Sharon Terry]],<ref>{{Cite journal |vauthors=Terry SF |year=2003 |title=Learning genetics |journal=Health Affairs |volume=22 |issue=5 |pages=166–71 |doi=10.1377/hlthaff.22.5.166 |pmid=14515892}}</ref><ref>{{Cite journal |vauthors=Terry SF |date=March 2016 |title=Life as a numerator: Putting the person in personal genomics |journal=Applied & Translational Genomics |volume=8 |pages=40–1 |doi=10.1016/j.atg.2016.01.007 |pmc=4796705 |pmid=27047760}}</ref><ref>{{Citation |last=Terry |first=Sharon |title=Science didn't understand my kids' rare disease until I decided to study it |date=15 June 2017 |url=https://www.ted.com/talks/sharon_terry_science_didn_t_understand_my_kids_rare_disease_until_i_decided_to_study_it |access-date=2019-08-24 |language=en |name-list-style=vanc}}</ref><ref>{{Cite web |title=Sharon Terry: When Siblings Get A Rare Diagnosis, Can Their Parents Find the Cure? TED Radio Hour. |url=https://www.npr.org/2017/09/29/554102828/sharon-terry-when-siblings-get-a-rare-diagnosis-can-their-parents-find-the-cure |access-date=2019-08-24 |website=NPR.org |language=en}}</ref> following the diagnosis of their two children. It has a registry of 4,600 affected individuals.

== Images ==
<gallery>
Image:Pseudoxanthoma_elasticum_1.JPG|Pseudoxanthoma elasticum of the posterior lateral neck.
Image:Pseudoxanthoma_elasticum_2.JPG|Pseudoxanthoma elasticum of the left axillary fold.
</gallery>

== See also ==
* [[List of cutaneous conditions]]

== References ==
{{Reflist}}

== External links ==
* [https://www.pxe.org PXE international]

{{Medical resources
|  DiseasesDB     = 10876
|  ICD10          = {{ICD10|Q|82|8|q|80}}<br />([[ILDS]] Q82.81)
|  ICD9           = {{ICD9|757.39}}
|  OMIM           = 264800
|  MedlinePlus    = <!--no page-->
|  eMedicineSubj  = derm
|  eMedicineTopic = 359
|  eMedicine_mult = {{eMedicine2|oph|475}}
|  MeshID         = D011561
}}
* {{GeneTests|pxe}}
* {{NLM|pseudoxanthomaelasticum}}

{{Congenital malformations and deformations of integument}}
{{ABC transporter disorders}}

[[Category:Autosomal recessive disorders]]
[[Category:Abnormalities of dermal fibrous and elastic tissue]]