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'{{Infobox medical condition (new) | name = Costello syndrome | image = Autosomal dominant - en.svg | caption = Costello syndrome is inherited in an autosomal dominant manner. | synonyms = Faciocutaneoskeletal syndrome | complications = | onset = | duration = | types = | causes = | risks = | diagnosis = | differential = | prevention = | treatment = | medication = | prognosis = | frequency = | deaths = }} '''Costello syndrome''', also called '''faciocutaneoskeletal syndrome''' or '''FCS syndrome''', is a rare [[genetic disorder]] that affects many parts of the body. It is characterized by delayed development and [[intellectual disabilities]], distinctive facial features, unusually flexible joints, and loose folds of extra skin, especially on the hands and feet.<ref name="Andrews">James, William; Berger, Timothy; Elston, Dirk (2005). ''Andrews' Diseases of the Skin: Clinical Dermatology''. (10th ed.). Saunders. {{ISBN|0-7216-2921-0}}.</ref>{{rp|571}} [[Heart]] abnormalities are common, including a very fast heartbeat ([[tachycardia]]), structural [[Congenital heart defect|heart defects]], and overgrowth of the [[Myocardium|heart muscle]] ([[hypertrophic cardiomyopathy]]). Infants with Costello syndrome may be large at birth, but grow more slowly than other children and have difficulty feeding. Later in life, people with this condition have relatively [[short stature]] and many have reduced levels of [[growth hormone]]s. It is a [[RASopathy]].{{citation needed|date=March 2017}} Beginning in early childhood, people with specific mutations on the Costello syndrome gene variant have an increased risk of developing certain cancerous and noncancerous tumors. Small growths called [[papilloma]]s are the most common noncancerous tumors seen with this condition. They usually develop around the nose and mouth. The most frequent cancerous tumor associated with Costello syndrome is a [[soft tissue]] tumor called a [[rhabdomyosarcoma]]. Other cancers also have been reported in children and adolescents with this disorder, including a tumor that arises in developing [[Neuron|nerve cells]] ([[neuroblastoma]]) and a form of [[bladder cancer]] ([[transitional cell carcinoma]]). Costello syndrome was discovered by Jack Costello, a New Zealand paediatrician, in 1977.<ref>{{cite web |url=http://costellokids.com/cs_description/about.htm |title=Cs description |access-date=2010-12-29 |url-status=dead |archive-url=https://web.archive.org/web/20101121041249/http://costellokids.com/cs_description/about.htm |archive-date=2010-11-21 }}</ref><ref name="NZ_Herald_3530432">{{cite news |url=http://www.nzherald.co.nz/nz/news/article.cfm?c_id=1&objectid=3530432 |title=Discovery offers key to children's disease |date=24 October 2003 |work=[[The New Zealand Herald]] |access-date=26 September 2011 }}</ref> He is credited with first reporting the syndrome in the Australian Paediatric Journal, Volume 13, No.2 in 1977.<ref name="pmid907573">{{cite journal |author=Costello JM |title=A new syndrome: mental subnormality and nasal papillomata |journal=Aust Paediatr J |volume=13 |issue=2 |pages=114–8 |date=June 1977 |pmid=907573 |doi= 10.1111/j.1440-1754.1977.tb01135.x|s2cid=24745057 }}</ref> ==Signs and symptoms== This condition is characterized by delayed development and intellectual disability, loose folds of skin (which are especially noticeable on the hands and feet), unusually flexible joints, and distinctive facial features including a large mouth with full lips. ==Genetics== Costello syndrome is caused by any of at least five different mutations in the ''[[HRAS]]'' gene on [[Chromosome 11 (human)|chromosome 11]]. This [[gene]] provides instructions for making a [[protein]], H-Ras, that helps control [[cell growth]] and [[cell division|division]]. Mutations that cause Costello syndrome lead to the production of an H-Ras protein that is permanently active. Instead of triggering cell growth in response to particular signals from outside the cell, the overactive protein directs cells to grow and divide constantly. This unchecked cell division may predispose those affected to the development of [[benign tumor|benign]] and [[Cancer|malignant]] tumors. It remains unclear how mutations in ''HRAS'' cause other features of Costello syndrome, but many of the signs and symptoms may result from cell overgrowth and abnormal cell division.{{citation needed|date=March 2017}} ''HRAS'' is a [[proto-oncogene]] in which somatic mutations in healthy people can contribute to cancer. Whereas children with Costello syndrome typically have a mutation in ''HRAS'' in every cell of their bodies, an otherwise healthy person with a tumor caused in part by ''HRAS'' mutation will only have mutant ''HRAS'' within the tumor. The test for the mutation in cancer tumors can also be used to test children for Costello syndrome.{{citation needed|date=September 2021}} Costello syndrome is inherited in an [[autosomal dominant]] manner, which means one copy of the altered gene is sufficient to cause the disorder. Almost all cases have resulted from new mutations, and occur in people with no history of the disorder in their family. This condition is rare; as of 20 April 2007, 200 to 300 cases have been reported worldwide.{{citation needed|date=September 2021}} ==Diagnosis== Costello Syndrome can be difficult for doctors to immediately clinically diagnose, as there are similar conditions that resemble this syndrome. A physician will start by assessing the child's height, the size of the head, and birth weight.{{citation needed|date=September 2021}} Full genome and Exome next generation DNA testing is the primary diagnostic tool for Costello Syndrome.{{citation needed|date=September 2021}} ==Treatments== At the 2005 [[American Society of Human Genetics]] meeting, [[Francis Collins (geneticist)|Francis Collins]] gave a presentation about a treatment he devised for children affected by [[Progeria]]. He discussed how [[farnesyltransferase inhibitor]]s (FTIs) affects H-Ras. After his presentation, members of the Costello Syndrome Family Network discussed the possibility of FTIs helping children with Costello syndrome. Mark Kieran, who presented at the 1st International Costello Syndrome Research Symposium in 2007, agreed that FTIs might help children with Costello syndrome. He discussed with Costello advocates what he had learned in establishing and running the Progeria [[clinical trial]] with an FTI, to help them consider next steps.{{Citation needed|date=October 2009}} Another medication that affects H-Ras is [[Lovastatin]], which is planned as a treatment for [[neurofibromatosis type I]]. When this was reported in mainstream news, the Costello Syndrome Professional Advisory Board was asked about its use in Costello Syndrome. Research into the effects of Lovastatin was linked with [[Alcino J. Silva|Alcino Silva]], who presented his findings at the 2007 symposium. Silva also believed that the medication he was studying could help children with Costello syndrome with cognition.{{Citation needed|date=October 2009}} A third medication that might help children with Costello syndrome is a MEK inhibitor that helps inhibit the pathway closer to the cell nucleus.{{Citation needed|date=October 2009}} ==Research== Spanish researchers reported the development of a Costello mouse, with the G12V mutation, in early 2008.<ref>{{Cite journal| last1 = Schuhmacher | first1 = A.| last2 = Guerra | first2 = C.| last3 = Sauzeau | first3 = V.| last4 = Cañamero | first4 = M.| last5 = Bustelo | first5 = X.| last6 = Barbacid | first6 = M.| title = A mouse model for Costello syndrome reveals an Ang II-mediated hypertensive condition| journal = The Journal of Clinical Investigation| volume = 118| issue = 6| pages = 2169–2179| year = 2008| pmid = 18483625| pmc = 2381749| doi = 10.1172/JCI34385| url = https://digital.csic.es/bitstream/10261/59310/1/A%20mouse%20model.pdf}}</ref> Although the G12V mutation is rare among children with Costello syndrome, and the G12V mouse does not appear to develop tumors as expected, information about the mouse model's heart may be transferable to humans. Italian and Japanese researchers published their development of a Costello zebrafish in late 2008, also with the G12V mutation.<ref>{{Cite journal| last1 = Santoriello | first1 = C.| last2 = Deflorian | first2 = G.| last3 = Pezzimenti | first3 = F.| last4 = Kawakami | first4 = K.| last5 = Lanfrancone | first5 = L.| last6 = D'adda Di Fagagna | first6 = F.| last7 = Mione | first7 = M.| title = Expression of H-RASV12 in a zebrafish model of Costello syndrome causes cellular senescence in adult proliferating cells| journal = Disease Models & Mechanisms| volume = 2| issue = 1–2| pages = 56–67| year = 2009| pmid = 19132118| pmc = 2615164| doi = 10.1242/dmm.001016}}</ref> The advent of animal models may accelerate identification of treatment options. ==Historical== That [[Mutation|genetic mutation]]s in ''HRAS'' cause Costello syndrome was first reported in 2005.<ref>{{Cite journal| last1 = Aoki | first1 = Y.| last2 = Niihori | first2 = T.| last3 = Kawame | first3 = H.| last4 = Kurosawa | first4 = K.| last5 = Ohashi | first5 = H.| last6 = Tanaka | first6 = Y.| last7 = Filocamo | first7 = M.| last8 = Kato | first8 = K.| last9 = Suzuki | first9 = Y.| last10 = Kure | first10 = S.| last11 = Matsubara | first11 = Y.| title = Germline mutations in HRAS proto-oncogene cause Costello syndrome| journal = Nature Genetics| volume = 37| issue = 10| pages = 1038–1040| year = 2005| pmid = 16170316| doi = 10.1038/ng1641| s2cid = 22119631}}</ref> These mutations, along with mutations that cause [[cardiofaciocutaneous syndrome]], found soon after, surprised geneticists and changed how genetic syndromes can be grouped.{{Citation needed|date=October 2009}} Before this, geneticists looked for new mutations in genes with mutations that caused syndromes similar to the unknown syndrome.{{Citation needed|date=October 2009}} For example, researchers looked at and around the most common [[Noonan syndrome]] mutation, [[PTPN11]], but did not find anything related to Costello syndrome or cardiofaciocutaneous syndrome.{{Citation needed|date=October 2009}} The first mutation that is now identified as one of the Costello syndrome [[allele]]s was found unexpectedly when Japanese researchers used the DNA of children with Costello syndrome as a control, looking for another Noonan gene <!-- Does the ref at the end of the following paragraph resolve all these CN tags? --> Geneticists realized that the syndromes they were grouping together clinically according to their signs and symptoms were related in a way they had never realized: the mutations that cause Costello syndrome, Noonan syndrome and cardiofaciocutaneous syndromes are linked by their cellular function, not by being on or close to a gene with a known mutation. The cellular function that links them is a common [[signal transduction|signalling pathway]] that brings information from outside the cell to the nucleus. This pathway is called the [[Ras/MapK pathway|Ras-MAP-kinase signal transduction pathway]] (Ras-MAPK Pathway).<ref>Lisa Schoyer, 2007 Costello syndrome medical symposium.</ref> ==References== {{Reflist}} ''Some text in this article was originally taken from http://ghr.nlm.nih.gov/condition=costellosyndrome, a [[public domain]] source'' == External links == {{Medical resources | DiseasesDB = 32846 | ICD10 = | ICD9 = | ICDO = | OMIM = 218040 | MedlinePlus = | eMedicineSubj = | eMedicineTopic = | MeshID = | Orphanet = 2143 }} * [https://web.archive.org/web/20070312102958/http://www.genetests.org/query?dz=costello GeneReviews: Costello Syndrome] * [https://web.archive.org/web/20091214090609/http://www.postpals.co.uk/pals/Daisy+N GeneReviews: Daisy's battle with Costello Syndrome] {{Deficiencies of intracellular signaling peptides and proteins}} [[Category:Genodermatoses]] [[Category:RASopathies]] [[Category:Autosomal dominant disorders]] [[Category:Syndromes affecting the heart]] [[Category:Syndromes with craniofacial abnormalities]] [[Category:Rare syndromes]]'