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{{Short description|Human |
{{Short description|Human genetic disorder}} |
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{{Infobox medical condition (new) |
{{Infobox medical condition (new) |
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| synonyms = Partial gigantism-nevi-hemihypertrophy-macrocephaly syndrome, Wiedemann syndrome |
| synonyms = Partial gigantism-nevi-hemihypertrophy-macrocephaly syndrome, Wiedemann syndrome |
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| image = NIH_Proteus_Patient.jpg |
| image = NIH_Proteus_Patient.jpg |
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| caption = Alex Green, a 7-year-old boy with Proteus syndrome, confirmed to have the AKT1 p.E17K somatic variant. Alex died at the age of 9. |
| caption = Alex Green, a 7-year-old boy with Proteus syndrome, confirmed to have the [[AKT1]] p.E17K [[Somatic (biology)|somatic]] variant. Alex died at the age of 9. |
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| ⚫ | '''Proteus syndrome''' is a rare disorder with a genetic background<ref name="Andrews">{{cite book |last1=James |first1=William |last2=Berger |first2=Timothy |last3=Elston |first3=Dirk |year=2005 |title=Andrews' Diseases of the Skin: Clinical Dermatology |edition=10th |publisher=Saunders |isbn=978-0-7216-2921-6 |page=554}}</ref> that can cause tissue overgrowth involving all three [[Germ layer|embryonic lineages]]. Patients with Proteus syndrome tend to have an increased risk of embryonic tumor development.<ref name="Fitz2">Freedberg, et al. (2003). ''Fitzpatrick's Dermatology in General Medicine''. (6th ed.). McGraw-Hill. {{ISBN|0-07-138076-0}}.</ref> The clinical and [[Radiography|radiographic]] symptoms of Proteus syndrome are highly variable, as are its orthopedic manifestations.<ref name=elsobky2015/><ref>{{cite journal |vauthors=Jamis-Dow CA, Turner J, Biesecker LG, Choyke PL | title = Radiologic manifestations of Proteus syndrome | journal = Radiographics | volume = 24 | issue = 4 | pages = 1051–68 | year = 2004 | pmid = 15256628 | doi = 10.1148/rg.244035726 | doi-access = free }}</ref> |
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| ⚫ | '''Proteus syndrome''' is a rare disorder with a genetic background<ref name="Andrews">{{cite book |last1=James |first1=William |last2=Berger |first2=Timothy |last3=Elston |first3=Dirk |year=2005 |title=Andrews' Diseases of the Skin: Clinical Dermatology |edition=10th |publisher=Saunders |isbn=978-0-7216-2921-6 |page=554}}</ref> that can cause tissue overgrowth involving all three [[Germ layer|embryonic lineages]]. |
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Only a few more than 200 cases have been confirmed worldwide, with estimates that about 120 people are currently alive with the condition.<ref name="BBC">[http://news.bbc.co.uk/2/hi/uk_news/england/lancashire/6621331.stm Woman's 11-stone legs may be lost] at [[BBC]]</ref> As attenuated forms of the disease may exist, there could be many people with Proteus syndrome who remain undiagnosed. Those most readily diagnosed are also the most severely disfigured. |
Only a few more than 200 cases have been confirmed worldwide, with estimates that about 120 people are currently alive with the condition.<ref name="BBC">[http://news.bbc.co.uk/2/hi/uk_news/england/lancashire/6621331.stm Woman's 11-stone legs may be lost] at [[BBC]]</ref> As attenuated forms of the disease may exist, there could be many people with Proteus syndrome who remain undiagnosed. Those most readily diagnosed are also the most severely disfigured. |
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== Signs and symptoms == |
== Signs and symptoms == |
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[[File:A woman with scales on her upper body and grossly enlarged l Wellcome V0007397.jpg|thumb|[[Portugal|Portuguese]] illustration of a foreign woman with deformities indicative of Proteus syndrome, 1695]] |
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Proteus syndrome causes an overgrowth of skin, bones, muscles, fatty tissues, and blood and [[lymphatic vessel]]s. Proteus syndrome is a progressive condition wherein children are usually born without any obvious deformities. Tumors of skin and bone growths appear as they age typically in early childhood. The musculoskeletal manifestations are cardinal for the diagnosis of Proteus syndrome.<ref name=elsobky2015/> The severity and locations of these various asymmetrical growths vary greatly but typically the skull, one or more limbs, and soles of the feet will be affected. There is a risk of premature death in affected individuals due to [[deep vein thrombosis]] and [[pulmonary embolism]] caused by the vessel malformations that are associated with this disorder. Because of carrying excess weight and enlarged limbs, [[arthritis]] and muscle pain may also be symptoms. Further risks may occur due to the mass of extra tissue.{{citation needed|date=November 2020}} |
Proteus syndrome causes an overgrowth of skin, bones, muscles, fatty tissues, and blood and [[lymphatic vessel]]s. Proteus syndrome is a progressive condition wherein children are usually born without any obvious deformities. Tumors of skin and bone growths appear as they age typically in early childhood. The musculoskeletal manifestations are cardinal for the diagnosis of Proteus syndrome.<ref name=elsobky2015/> The severity and locations of these various asymmetrical growths vary greatly but typically the skull, one or more limbs, and soles of the feet will be affected. There is a risk of premature death in affected individuals due to [[deep vein thrombosis]] and [[pulmonary embolism]] caused by the vessel malformations that are associated with this disorder. Because of carrying excess weight and enlarged limbs, [[arthritis]] and muscle pain may also be symptoms. Further risks may occur due to the mass of extra tissue.{{citation needed|date=November 2020}} |
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The disorder itself does not uniformly cause learning impairments: the distribution of intelligence deficits among those with Proteus syndrome appears higher than that of the general population, although this is difficult to determine with statistical significance.<ref>{{cite journal |vauthors=Turner JT, Cohen MM, Biesecker LG | title = Reassessment of the Proteus syndrome literature: application of diagnostic criteria to published cases | journal = American Journal of Medical Genetics | volume = 130A | issue = 2 | pages = 111–122 | date = Oct 1, 2004 | pmid = 15372514 | doi = 10.1002/ajmg.a.30327 | s2cid = 41588085 | url = https://zenodo.org/record/1229111 }}<!--| access-date = July 31, 2011 --></ref> In addition, the presence of visible deformity |
The disorder itself does not uniformly cause learning impairments: the distribution of intelligence deficits among those with Proteus syndrome appears higher than that of the general population, although this is difficult to determine with statistical significance.<ref>{{cite journal |vauthors=Turner JT, Cohen MM, Biesecker LG | title = Reassessment of the Proteus syndrome literature: application of diagnostic criteria to published cases | journal = American Journal of Medical Genetics | volume = 130A | issue = 2 | pages = 111–122 | date = Oct 1, 2004 | pmid = 15372514 | doi = 10.1002/ajmg.a.30327 | s2cid = 41588085 | url = https://zenodo.org/record/1229111 }}<!--| access-date = July 31, 2011 --></ref> In addition, the presence of visible deformity have a negative effect on the social experiences of the affected individual, causing emotional difficulties, [[social rejection]] and stigma.{{citation needed|date=November 2020}} |
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Affected individuals are at increased risk for developing certain tumors including unilateral [[ovarian cystadenoma]]s, [[testicular tumor]]s, [[meningioma]]s, and monomorphic [[adenoma]]s of the [[parotid gland]].{{Citation needed|date=March 2009}} |
Affected individuals are at increased risk for developing certain tumors including unilateral [[ovarian cystadenoma]]s, [[testicular tumor]]s, [[meningioma]]s, and monomorphic [[adenoma]]s of the [[parotid gland]].{{Citation needed|date=March 2009}} |
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== Genetics == |
== Genetics == |
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[[File:Proteus Syndrome - NHGRI - NHI.jpg|thumb|Proteus syndrome is an [[overgrowth disorder]] caused by a rare [[Mosaic (genetics)|genetic mosaicism]]. A genetic mutation during embryonic development gives rise to overgrowth in a subset of the individual's cells]] |
[[File:Proteus Syndrome - NHGRI - NHI.jpg|thumb|Proteus syndrome is an [[overgrowth disorder]] caused by a rare [[Mosaic (genetics)|genetic mosaicism]]. A genetic mutation during embryonic development gives rise to overgrowth in a subset of the individual's cells.]] |
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In 2011 researchers determined the cause of Proteus syndrome. In 26 of 29 patients who met strict clinical criteria for the disorder, Lindhurst ''et al.'' identified an activating mutation in [[AKT1]] [[kinase]] in a mosaic state |
In 2011 researchers determined the cause of Proteus syndrome. In 26 of 29 patients who met strict clinical criteria for the disorder, Lindhurst ''et al.'' identified an activating mutation in [[AKT1]] [[kinase]] in a mosaic state.<ref name=Lindhurst2012>{{cite journal |vauthors=Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K, Turner J, Cannons JL, Bick D, Blakemore L, Blumhorst C, Brockmann K, Calder P, Cherman N, Deardorff MA, Everman DB, Golas G, Greenstein RM, Kato BM, Keppler-Noreuil KM, Kuznetsov SA, Miyamoto RT, Newman K, Ng D, O'Brien K, Rothenberg S, Schwartzentruber DJ, Singhal V, Tirabosco R, Upton J, Wientroub S, Zackai EH, Hoag K, Whitewood-Neal T, Robey PG, Schwartzberg PL, Darling TN, Tosi LL, Mullikin JC, Biesecker LG | title = A mosaic activating mutation in AKT1 associated with the Proteus syndrome. | journal = N Engl J Med | volume = 365 | issue = 7 | pages = 611–9 | date = Aug 18, 2011 | pmid = 21793738 | pmc = 3170413 | doi = 10.1056/NEJMoa1104017 }}</ref> |
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Previous research had suggested the condition linked to [[PTEN (gene)|PTEN]] on [[chromosome 10]],<ref>{{cite journal |vauthors=Smith JM, Kirk EP, Theodosopoulos G, Marshall GM, Walker J, Rogers M, Field M, Brereton JJ, Marsh DJ | title = Germline mutation of the tumour suppressor PTEN in Proteus syndrome | journal = J. Med. Genet. | volume = 39 | issue = 12 | pages = 937–40 | year = 2002 | pmid = 12471211 | pmc = 1757209 | doi = 10.1136/jmg.39.12.937 }}</ref> while other research pointed to [[chromosome 16]].<ref>{{cite journal |vauthors=Cardoso MT, de Carvalho TB, Casulari LA, Ferrari I | title = Proteus syndrome and somatic mosaicism of the chromosome 16 | journal = Panminerva Medica | volume = 45 | issue = 4 | pages = 267–71 | year = 2003 | pmid = 15206168 | url = http://cat.inist.fr/?aModele=afficheN&cpsidt=15505734 }}</ref> Prior to the findings regarding AKT1 in 2011, other researchers expressed doubt regarding the involvement of PTEN or [[GPC3]], which codes for [[glypican 3]] and may play a role in regulating cell division and growth regulation.<ref name="pmid15372512">{{cite journal |vauthors=Thiffault I, Schwartz CE, Der Kaloustian V, Foulkes WD | title = Mutation analysis of the tumor suppressor PTEN and the glypican 3 (GPC3) gene in patients diagnosed with Proteus syndrome | journal = Am. J. Med. Genet. A | volume = 130A | issue = 2 | pages = 123–7 | date = October 2004 | pmid = 15372512 | doi = 10.1002/ajmg.a.30335 | s2cid = 32014732 }}</ref><ref name="entrez_2719">{{cite web | title = Entrez Gene: GPC3 glypican 3| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2719}}</ref> |
Previous research had suggested the condition linked to ''[[PTEN (gene)|PTEN]]'' on [[chromosome 10]],<ref>{{cite journal |vauthors=Smith JM, Kirk EP, Theodosopoulos G, Marshall GM, Walker J, Rogers M, Field M, Brereton JJ, Marsh DJ | title = Germline mutation of the tumour suppressor PTEN in Proteus syndrome | journal = J. Med. Genet. | volume = 39 | issue = 12 | pages = 937–40 | year = 2002 | pmid = 12471211 | pmc = 1757209 | doi = 10.1136/jmg.39.12.937 }}</ref> while other research pointed to [[chromosome 16]].<ref>{{cite journal |vauthors=Cardoso MT, de Carvalho TB, Casulari LA, Ferrari I | title = Proteus syndrome and somatic mosaicism of the chromosome 16 | journal = Panminerva Medica | volume = 45 | issue = 4 | pages = 267–71 | year = 2003 | pmid = 15206168 | url = http://cat.inist.fr/?aModele=afficheN&cpsidt=15505734 }}</ref> Prior to the findings regarding ''AKT1'' in 2011, other researchers expressed doubt regarding the involvement of ''PTEN'' or ''[[GPC3]]'', which codes for [[glypican 3]] and may play a role in regulating cell division and growth regulation.<ref name="pmid15372512">{{cite journal |vauthors=Thiffault I, Schwartz CE, Der Kaloustian V, Foulkes WD | title = Mutation analysis of the tumor suppressor PTEN and the glypican 3 (GPC3) gene in patients diagnosed with Proteus syndrome | journal = Am. J. Med. Genet. A | volume = 130A | issue = 2 | pages = 123–7 | date = October 2004 | pmid = 15372512 | doi = 10.1002/ajmg.a.30335 | s2cid = 32014732 }}</ref><ref name="entrez_2719">{{cite web | title = Entrez Gene: GPC3 glypican 3| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2719}}</ref> |
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==Diagnosis== |
==Diagnosis== |
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===Differential diagnosis=== |
===Differential diagnosis=== |
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* [[Macrodystrophia lipomatosa]]<ref name=Abdulhady2018>{{cite journal|last1=Abdulhady|first1=H|last2=El-Sobky|first2=TA|last3=Elsayed|first3=NS|last4=Sakr|first4=HM|title=Clinical and imaging features of pedal macrodystrophia lipomatosa in two children with differential diagnosis review.|journal= Journal of Musculoskeletal Surgery and Research|volume=2|issue=3|pages=130|date=11 June 2018|doi= 10.4103/jmsr.jmsr_8_18|s2cid=80970016}}</ref> |
* [[Macrodystrophia lipomatosa]]<ref name=Abdulhady2018>{{cite journal|last1=Abdulhady|first1=H|last2=El-Sobky|first2=TA|last3=Elsayed|first3=NS|last4=Sakr|first4=HM|title=Clinical and imaging features of pedal macrodystrophia lipomatosa in two children with differential diagnosis review.|journal= Journal of Musculoskeletal Surgery and Research|volume=2|issue=3|pages=130|date=11 June 2018|doi= 10.4103/jmsr.jmsr_8_18|s2cid=80970016|doi-access=free}}</ref> |
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* Fibrolipomatous hamartoma |
* Fibrolipomatous hamartoma |
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* [[Neurofibromatosis]] type 1<ref name= Genereviews1>{{Cite book| url=https://www.ncbi.nlm.nih.gov/books/NBK1109/| title=Neurofibromatosis 1.|last1= Friedman|first1=JM|date=11 January 2018| website=GeneReviews|access-date=30 April 2018| publisher=University of Washington, Seattle}}</ref> |
* [[Neurofibromatosis]] type 1<ref name= Genereviews1>{{Cite book| url=https://www.ncbi.nlm.nih.gov/books/NBK1109/| title=Neurofibromatosis 1.|last1= Friedman|first1=JM|date=11 January 2018| website=GeneReviews|access-date=30 April 2018| publisher=University of Washington, Seattle| pmid=20301288}}</ref> |
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* [[Klippel–Trénaunay syndrome]]<ref name=Sung2015>{{cite journal|last1=Sung|first1= HM|last2=Chung|first2= HY|last3=Lee|first3= SJ|last4=et|first4= al|title= Clinical experience of the Klippel-Trenaunay syndrome.|journal= Arch Plast Surg|volume= 42|issue= 5|pages= 552–8|date=2015|doi= 10.5999/aps.2015.42.5.552|pmid=26430625|pmc= 4579165}}</ref> |
* [[Klippel–Trénaunay syndrome]]<ref name=Sung2015>{{cite journal|last1=Sung|first1= HM|last2=Chung|first2= HY|last3=Lee|first3= SJ|last4=et|first4= al|title= Clinical experience of the Klippel-Trenaunay syndrome.|journal= Arch Plast Surg|volume= 42|issue= 5|pages= 552–8|date=2015|doi= 10.5999/aps.2015.42.5.552|pmid=26430625|pmc= 4579165}}</ref> |
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* [[Parkes Weber syndrome]] |
* [[Parkes Weber syndrome]] |
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== Treatment == |
== Treatment == |
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A team of doctors in Australia have trial |
A team of doctors in Australia have trial-tested the drug [[rapamycin]] in the treatment of a patient said to have Proteus syndrome and have found it to be an effective remedy.<ref>{{cite journal |vauthors=Marsh DJ, Trahair TN, Martin JL, Chee WY, Walker J, Kirk EP, Baxter RC, Marshall GM | s2cid = 2870300 | title = Rapamycin treatment for a child with germline PTEN mutation | journal = Nature Clinical Practice Oncology | volume = 5 | issue = 6 | pages = 357–361 | date = April 22, 2008 | pmid = 18431376 | doi = 10.1038/ncponc1112 }}</ref> However, the diagnosis of Proteus syndrome in this patient has been questioned by others.<ref>{{cite journal |vauthors=Cohen MM, Turner JT, Biesecker LG | title = Proteus Syndrome: Misdiagnosis with PTEN Mutations | journal = American Journal of Medical Genetics | volume = 122A | issue = 4 | pages = 323–324 | date = November 1, 2003 | pmid = 14518070 | doi = 10.1002/ajmg.a.20474| s2cid = 26811086 }}</ref> |
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The Proteus syndrome research team in the [[National Human Genome Research Institute]] at the [[United States National Institutes of Health]] have initiated a [[Phases of clinical research|Phase 0]] dose finding trial with the AKT1 inhibitor ARQ 092, which is being developed by the |
The Proteus syndrome research team in the [[National Human Genome Research Institute]] at the [[United States National Institutes of Health]] have initiated a [[Phases of clinical research|Phase 0]] dose finding trial with the AKT1 inhibitor ARQ 092, which is being developed by the Arqule Corporation. In earlier tests on tissue and cell samples obtained from patients, ARQ 092 reduced [[phosphorylation]] of AKT and downstream targets of AKT in as little as two hours.<ref>{{Cite journal|last1=Lindhurst|first1=Marjorie J.|last2=Yourick|first2=Miranda R.|last3=Yu|first3=Yi|last4=Savage|first4=Ronald E.|last5=Ferrari|first5=Dora|last6=Biesecker|first6=Leslie G.|date=2015-12-11|title=Repression of AKT signaling by ARQ 092 in cells and tissues from patients with Proteus syndrome|journal=Scientific Reports|language=en|volume=5|pages=17162|doi=10.1038/srep17162|issn=2045-2322|pmc=4675973|pmid=26657992|bibcode=2015NatSR...517162L}}</ref> The Phase 0 trial opened in November 2015.<ref>{{cite journal |title= Dose Finding Trial of ARQ 092 in Children and Adults With Proteus Syndrome |website= [[ClinicalTrials.gov]] |id= NCT02594215 |url= https://clinicaltrials.gov/ct2/show/NCT02594215 |publisher= [[National Human Genome Research Institute]] (NHGRI) |date= Oct 31, 2015 }}</ref> This trial is based on [[in vitro]] data showing inhibition of AKT1 in [[Cell lineage|cell lines]] from patients with Proteus syndrome.<ref>{{cite journal |title= Repression of AKT signaling by ARQ 092 in cells and tissues from patients with Proteus syndrome |first1= Marjorie J. |last1= Lindhurst |first2= Miranda R. |last2= Yourick |first3= Yi |last3= Yu |first4= Ronald E. |last4= Savage |first5= Dora |last5= Ferrari |first6= Leslie G. |last6= Biesecker |journal= Scientific Reports |volume= 5 |id= 17162 |doi= 10.1038/srep17162 |date= 2015 |pmid=26657992 |pmc=4675973 |page=17162|bibcode= 2015NatSR...517162L }}</ref> |
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== Notable cases == |
== Notable cases == |
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In a 1986 article in the ''British Medical Journal'', [[Michael Cohen (doctor)|Michael Cohen]] and J.A.R. Tibbles |
In a 1986 article in the ''[[The BMJ|British Medical Journal]]'', [[Michael Cohen (doctor)|Michael Cohen]] and J.A.R. Tibbles proposed the idea that [[Joseph Merrick]] (an Englishman known as the "Elephant Man") had Proteus syndrome. However, the exact condition that Joseph Merrick had is still not known with certainty.<ref>{{cite journal |vauthors=Tibbles JA, Cohen MM | title = The Proteus syndrome: the Elephant Man diagnosed | journal = Br Med J (Clin Res Ed) | volume = 293 | issue = 6548 | pages = 683–5 | year = 1986 | pmid = 3092979 | pmc = 1341524 | doi = 10.1136/bmj.293.6548.683 }}</ref><ref>[http://www.unboundmedicine.com/medline/ebm/record/11399837/full_citation/The_improbable_%22Elephant_Man%22_ – Spiring P (2001). "The Improbable Elephant Man". ''Biologist'' (London) 48(3) 104.], [https://archive.today/20130114030554/http://www.telegraph.co.uk/scienceandtechnology/science/sciencenews/4764093/Two-wrongs-dont-make-a-right---until-someone-joins-them-up.html Article] in [[The Sunday Telegraph]], [http://news.bbc.co.uk/2/hi/health/3084483.stm – BBC News, [http://www.eurekalert.org/pub_releases/2003-07/dhc-ada071803.php – ''Eurekalert!''], [https://www.telegraph.co.uk/news/uknews/1436744/Science-uncovers-handsome-side-of-the-Elephant-Man.html Article] in [[The Daily Telegraph]]</ref> |
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[[Mandy Sellars]] has been diagnosed by some doctors as having this condition.<ref name=BBC /> Her legs and feet have grown at a disproportionate rate since birth. However, in 2013, Sellars' case was profiled on British television in a special called Shrinking My 17 Stone Legs, in which it was determined that Sellars' condition was not, in fact, Proteus syndrome, but rather the often-misdiagnosed [[PIK3CA-related overgrowth spectrum]], a syndrome caused by a [[P110α|PIK3CA]] gene mutation.{{citation needed|date=November 2020}} |
[[Mandy Sellars]] has been diagnosed by some doctors as having this condition.<ref name=BBC /> Her legs and feet have grown at a disproportionate rate since birth. However, in 2013, Sellars's case was profiled on British television in a special called ''Shrinking My 17 Stone Legs'', in which it was determined that Sellars's condition was not, in fact, Proteus syndrome, but rather the often-misdiagnosed [[PIK3CA-related overgrowth spectrum]], a syndrome caused by a [[P110α|PIK3CA]] gene mutation.{{citation needed|date=November 2020}} |
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== See also == |
== See also == |
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Latest revision as of 04:20, 23 November 2024
| Proteus syndrome | |
|---|---|
| Other names | Partial gigantism-nevi-hemihypertrophy-macrocephaly syndrome, Wiedemann syndrome |
 | |
| Alex Green, a 7-year-old boy with Proteus syndrome, confirmed to have the AKT1 p.E17K somatic variant. Alex died at the age of 9. | |
| Specialty | Medical genetics  |
Proteus syndrome is a rare disorder with a genetic background[1] that can cause tissue overgrowth involving all three embryonic lineages. Patients with Proteus syndrome tend to have an increased risk of embryonic tumor development.[2] The clinical and radiographic symptoms of Proteus syndrome are highly variable, as are its orthopedic manifestations.[3][4]
Only a few more than 200 cases have been confirmed worldwide, with estimates that about 120 people are currently alive with the condition.[5] As attenuated forms of the disease may exist, there could be many people with Proteus syndrome who remain undiagnosed. Those most readily diagnosed are also the most severely disfigured.
The syndrome is named after the Greek sea-god Proteus, who could change his shape. The condition appears to have been first described in the American medical literature by Samia Temtamy and John Rogers in 1976.[6][7] American pathologist Michael Cohen described it in 1979.[8]
Signs and symptoms
[edit]
Proteus syndrome causes an overgrowth of skin, bones, muscles, fatty tissues, and blood and lymphatic vessels. Proteus syndrome is a progressive condition wherein children are usually born without any obvious deformities. Tumors of skin and bone growths appear as they age typically in early childhood. The musculoskeletal manifestations are cardinal for the diagnosis of Proteus syndrome.[3] The severity and locations of these various asymmetrical growths vary greatly but typically the skull, one or more limbs, and soles of the feet will be affected. There is a risk of premature death in affected individuals due to deep vein thrombosis and pulmonary embolism caused by the vessel malformations that are associated with this disorder. Because of carrying excess weight and enlarged limbs, arthritis and muscle pain may also be symptoms. Further risks may occur due to the mass of extra tissue.[citation needed]
The disorder itself does not uniformly cause learning impairments: the distribution of intelligence deficits among those with Proteus syndrome appears higher than that of the general population, although this is difficult to determine with statistical significance.[9] In addition, the presence of visible deformity have a negative effect on the social experiences of the affected individual, causing emotional difficulties, social rejection and stigma.[citation needed]
Affected individuals are at increased risk for developing certain tumors including unilateral ovarian cystadenomas, testicular tumors, meningiomas, and monomorphic adenomas of the parotid gland.[citation needed]
Hemimegalencephaly is often found to be associated.[10]
Orthopaedic features
[edit]The musculoskeletal manifestations of Proteus syndrome are frequent and recognizable. Patients tend to demonstrate a unique pattern of skeletal abnormalities. The orthopaedic features are usually bilateral, asymmetrical, progressive and involving all four limbs and spine. Affected patients usually have localized periarticular limb distortions, limb length discrepancy, and spine deformity. Patients with Proteus syndrome can have regular bone configuration and contours despite the bone enlargement.[3] Patients can also exhibit deformation of the skull in the form of dolichocephaly or elongated skull and facial abnormalities. Because of the rarity of the syndrome and the variability of signs, the orthopaedic management should be individualized.[3]
Genetics
[edit]
In 2011 researchers determined the cause of Proteus syndrome. In 26 of 29 patients who met strict clinical criteria for the disorder, Lindhurst et al. identified an activating mutation in AKT1 kinase in a mosaic state.[11]
Previous research had suggested the condition linked to PTEN on chromosome 10,[12] while other research pointed to chromosome 16.[13] Prior to the findings regarding AKT1 in 2011, other researchers expressed doubt regarding the involvement of PTEN or GPC3, which codes for glypican 3 and may play a role in regulating cell division and growth regulation.[14][15]
Diagnosis
[edit]Differential diagnosis
[edit]- Macrodystrophia lipomatosa[16]
- Fibrolipomatous hamartoma
- Neurofibromatosis type 1[17]
- Klippel–Trénaunay syndrome[18]
- Parkes Weber syndrome
- Sotos syndrome
- Hemangiomas[19]
Classification
[edit]Many sources classify Proteus syndrome to be a type of nevus syndrome. The lesions appear to be distributed in a mosaic manner.[20] It has been confirmed that the disorder is an example of genetic mosaicism.[11]
Treatment
[edit]A team of doctors in Australia have trial-tested the drug rapamycin in the treatment of a patient said to have Proteus syndrome and have found it to be an effective remedy.[21] However, the diagnosis of Proteus syndrome in this patient has been questioned by others.[22]
The Proteus syndrome research team in the National Human Genome Research Institute at the United States National Institutes of Health have initiated a Phase 0 dose finding trial with the AKT1 inhibitor ARQ 092, which is being developed by the Arqule Corporation. In earlier tests on tissue and cell samples obtained from patients, ARQ 092 reduced phosphorylation of AKT and downstream targets of AKT in as little as two hours.[23] The Phase 0 trial opened in November 2015.[24] This trial is based on in vitro data showing inhibition of AKT1 in cell lines from patients with Proteus syndrome.[25]
Notable cases
[edit]In a 1986 article in the British Medical Journal, Michael Cohen and J.A.R. Tibbles proposed the idea that Joseph Merrick (an Englishman known as the "Elephant Man") had Proteus syndrome. However, the exact condition that Joseph Merrick had is still not known with certainty.[26][27]
Mandy Sellars has been diagnosed by some doctors as having this condition.[5] Her legs and feet have grown at a disproportionate rate since birth. However, in 2013, Sellars's case was profiled on British television in a special called Shrinking My 17 Stone Legs, in which it was determined that Sellars's condition was not, in fact, Proteus syndrome, but rather the often-misdiagnosed PIK3CA-related overgrowth spectrum, a syndrome caused by a PIK3CA gene mutation.[citation needed]
See also
[edit]- Epidermal nevus syndrome
- Mosaic (genetics)
- Overgrowth syndrome
- List of radiographic findings associated with cutaneous conditions
References
[edit]- ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology (10th ed.). Saunders. p. 554. ISBN 978-0-7216-2921-6.
- ^ Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine. (6th ed.). McGraw-Hill. ISBN 0-07-138076-0.
- ^ a b c d El-Sobky, Tamer Ahmed; Elsayed, Solaf M.; El Mikkawy, Dalia M.E. (2015). "Orthopaedic manifestations of Proteus syndrome in a child with literature update". Bone Reports. 3: 104–108. doi:10.1016/j.bonr.2015.09.004. PMC 5365241. PMID 28377973.
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