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| {{Infobox_Disease | | | __NOTOC__ |
| Name = Noonan syndrome |
| | {{Noonan syndrome}} |
| Image = Noonan.jpg|
| | {{Patient}} |
| Caption = A 12-year-old girl with Noonan syndrome. Note the typical webbed neck and the severe scoliosis.|
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| DiseasesDB = 29094 |
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| ICD10 = {{ICD10|Q|87|1|q|80}} |
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| ICD9 = {{ICD9|759.89}} |
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| ICDO = |
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| OMIM = 163950 |
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| MedlinePlus = 001656 |
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| eMedicineSubj = |
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| eMedicineTopic = |
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| MeshID = D009634 |
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| }} | |
| {{SI}} | |
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| {{CMG}} | | {{CMG}} {{AE}} [[User:Sergekorjian|Serge Korjian]], [[User:YazanDaaboul|Yazan Daaboul]] |
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| ==Overview== | | ==[[Noonan syndrome overview|Overview]]== |
| '''Noonan Syndrome''' (NS) is a relatively common [[congenital]] genetic condition which affects both males and females. It used to be referred to as the male version of [[Turner's syndrome]]<ref>{{cite journal |author=Curcić-Stojković O, Nikolić L, Obradović D, Krstić A, Radić A |title=[Noonan's syndrome. (Male Turner's syndrome, Turner-like syndrome)] |journal=Med Pregl |volume=31 |issue=7-8 |pages=299–303 |year=1978 |pmid=692497}}</ref>; however, the genetic causes of Noonan syndrome and Turner syndrome are distinct. The principal features include congenital heart malformation, short stature, learning problems, indentation of the chest, impaired blood clotting, and a characteristic configuration of facial features. The [[syndrome]] is named after Dr Jacqueline Noonan.
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| It is believed that between approximately 1 in 1,000 and 1 in 2,500 children worldwide are born with NS. It is one of the most common genetic syndromes associated with congenital heart disease, similar in frequency to [[Down syndrome]]. However, the range and severity of features can vary greatly in patients with NS. Therefore, the syndrome is not always identified at an early age.
| | ==[[Noonan syndrome historical perspective|Historical Perspective]]== |
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| ==History== | | ==[[Noonan syndrome pathophysiology|Pathophysiology]]== |
| Jacqueline Noonan was practicing as a pediatric cardiologist at the University of Iowa when she noticed that children with a rare type of heart defect, [[pulmonary stenosis|valvular pulmonary stenosis]], often had a characteristic physical appearance with [[short stature]], [[webbed neck]], [[wide spaced eyes]], and [[low-set ears]]. Both boys and girls were affected. Even though these characteristics were sometimes seen running in families, [[karyotype|chromosomes]] appeared grossly normal. She studied 833 patients at the congenital heart disease clinic, looking for other congenital abnormalities, and in 1962 presented a paper: "Associated non-cardiac malformations in children with congenital heart disease". This described 9 children who in addition to congenital heart disease had characteristic faces, chest deformities and short stature. Both males and females were found to be similarly affected, and the chromosomes were apparently normal.
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| Dr John Opitz, a former student of Dr Noonan, first began to call the condition "Noonan Syndrome" when he saw children who looked like those whom Dr Noonan had described. Dr Noonan later produced a paper entitled "Hypertelorism with Turner Phenotype", and in 1971 at the Symposium of Cardiovascular defects, the name 'Noonan Syndrome' became officially recognized.
| | ==[[Noonan syndrome causes|Causes]]== |
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| ==Pathophysiology== | | ==[[Noonan syndrome differential diagnosis|Differentiating Noonan syndrome from other Diseases]]== |
| [[Image:Autodominant.jpg|thumb|left| NS may be inherited in an [[autosomal dominant]] pattern with variable expression.]] | |
| Recurrence in siblings and apparent transmission from parent to child has long suggested a genetic defect with [[autosomal dominant]] inheritance and variable expression. A person with NS has up to a 50% chance of transmitting it to a child. The fact that an affected parent is not always identified for children with NS suggests several possibilities:
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| # a parent could carry the gene without being affected (incomplete [[penetrance]])
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| # manifestations are variably expressed and could be so subtle as to go unrecognized (variable [[expressivity]])
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| # a high proportion of cases represent new, sporadic [[mutation]]s or
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| # Noonan syndrome is [[heterogeneous]], comprising more than one similar condition of differing cause, some not inherited.
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| In most of the families with multiple affected members, NS maps to [[Chromosome 12 (human)|chromosome 12]]q24.1. In 2001, it was reported that approximately half of a group of patients with Noonan syndrome carried a mutation of the ''PTPN11'' gene at that location, which encodes protein tyrosine phosphatase SHP-2.<ref>{{cite journal |author=Tartaglia M, Mehler EL, Goldberg R, ''et al'' |title=Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome |journal=Nat. Genet. |volume=29 |issue=4 |pages=465–8 |year=2001 |pmid=11704759 |doi=10.1038/ng772}}</ref> The SHP2 protein is a component of several intracellular [[signal transduction]] pathways involved in embryonic development that modulate cell division, differentiation, and migration, including that mediated by the [[epidermal growth factor]] [[receptor (biochemistry)|receptor]]. The latter pathway is important in the formation of the cardiac semilunar [[heart valve|valve]]s. It has recently been shown that activating mutations in [[SOS1]] also give rise to NS.<ref>{{cite journal |author=Roberts AE, Araki T, Swanson KD, ''et al'' |title=Germline gain-of-function mutations in SOS1 cause Noonan syndrome |journal=Nat. Genet. |volume=39 |issue=1 |pages=70–4 |year=2007 |pmid=17143285 |doi=10.1038/ng1926}}</ref> Shp2 and SOS1 both have roles as positive regulators of the [[Ras]]/[[MAP kinase]] pathway suggesting that dysregulation of this pathway may play a major role in the genesis of this syndrome.<ref>{{cite journal |author=Bentires-Alj M, Kontaridis MI, Neel BG |title=Stops along the RAS pathway in human genetic disease |journal=Nat. Med. |volume=12 |issue=3 |pages=283–5 |year=2006 |pmid=16520774 |doi=10.1038/nm0306-283}}</ref> Additional mutations in KRAS <ref>{{cite journal |author=Schubbert S, Zenker M, Rowe SL, ''et al'' |title=Germline KRAS mutations cause Noonan syndrome |journal=Nat. Genet. |volume=38 |issue=3 |pages=331–6 |year=2006 |pmid=16474405 |doi=10.1038/ng1748}}</ref> and ''RAF1''<ref>{{cite journal |author=Razzaque MA, Nishizawa T, Komoike Y, ''et al'' |title=Germline gain-of-function mutations in ''RAF1'' cause Noonan syndrome |journal=Nat. Genet. |volume=39 |issue=8 |pages=1013–7 |year=2007 |pmid=17603482 |doi=10.1038/ng2078}}</ref> genes have been reported to cause Noonan syndrome in a smaller percentage of individuals with the syndrome. Chromosomal abnormalities, such as a duplication of chromosome region 12q24 encompassing gene ''PTPN11'' can result in an apparent Noonan syndrome<ref>[http://www.ncbi.nlm.nih.gov/pubmed/18348260 Shchelochkov OA et al], Am J Med Genet A, 2008 Apr 15;146A(8):1042-8</ref>.
| | ==[[Noonan syndrome epidemiology and demographics|Epidemiology and Demographics]]== |
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| ==Manifestations by organ system== | | ==[[Noonan syndrome natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
| The most prevalent (common) signs are highlighted in '''bold''' with frequency listed in parentheses.
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| '''HEART''' —''(2/3 of patients have a heart defect)''
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| :'''Pulmonary Valvular Stenosis''' —''(50%)''
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| :Septal defects: [[atrial septal defect|atrial]] —''(10%)'' or [[ventricular septal defect|ventricular]] —''(less common)''
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| :[[Heart murmur]]
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| :[[Cardiomyopathy]]
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| '''GASTROINTESTINAL SYSTEM'''
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| :[[Failure to thrive]] as an infant
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| :[[Decreased appetite]]
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| :Digestive problems
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| :Frequent or forceful [[vomiting]]
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| :[[Swallowing difficulties]]
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| '''GENITO-URINARY SYSTEM'''
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| :'''[[Cryptorchidism]] (undescended testicles)''' — ''(almost all males)''
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| '''LYMPHATIC SYSTEM'''
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| :Posterior cervical [[Hygroma]] (webbed neck)
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| :[[Lymphedema]] (build-up of body fluid due to poor functioning of the lymphatic system)
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| '''DEVELOPMENTAL'''
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| :[[Clumsiness]]
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| :[[Poor coordination]]
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| :Motor delay
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| :'''[[Mental retardation]]''' ''—(1/3 of patients have mild MR)''
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| :[[Learning disabilities]]
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| :Speech and language delays
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| '''MUSCULOSKELETAL'''
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| :Some patients with Noonan Syndrome suffer from severe [[joint pain]] or [[muscle pain]] often with no identifiable cause
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| '''HEMATOLOGIC'''
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| :Easy bruising
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| :[[Thrombocytopenia|Amegakaryocytic Thrombocytopenia]] (low platelet count)
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| :[[Blood Clotting]] Disorders
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| :[[Von Willebrand disease]]
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| :Prolonged activated [[partial thromboplastin time]]
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| :Partial deficiency of [[Factor VIII]]:C
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| :Partial deficiency of [[Factor XI]]:C
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| :Partial deficiency of [[Factor XII]]:C
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| :Combined Coagulation deficiencies
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| '''NEUROLOGICAL'''
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| Arnold Chiari Malformation (Type 1) has been noted in some patients with Noonan Syndrome
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| ===By physical appearance=== | |
| '''STATURE/POSTURE'''
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| :[[Short stature]]
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| :Cervical (neck) spine fusion
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| :[[Scoliosis]]
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| :Prominence of breast bone ([[pectus carinatum]])
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| :Depression of breast bone ([[pectus excavatum]])
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| :Joint contractures or tightness
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| :Joint hyperextensibility or looseness
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| :[[Growth retardation]]
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| :Winging of the [[scapula]]
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| :[[Hypotonia]] (low muscle tone)
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| '''HEAD'''
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| :'''Excess skin on the back of the neck'''
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| :'''Low hairline at the nape of the neck'''
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| :[[Large head]]
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| :Triangular face shape
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| :Broad forehead
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| :Short neck, webbed neck, posterior cervical
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| :[[Curly hair]]
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| '''EYES'''
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| :'''Widely set eyes ([[hypertelorism]])''' —''(95%)''
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| :Drooping of the eyelids ([[ptosis (eyelid)]])
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| :'''[[Epicanthal fold]]s''' (extra fold of skin at the inner corner of the eye)
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| :[[Proptosis]] (bulging eyes)
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| :Refractive visual errors
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| :Inward or outward turning of the eyes ([[strabismus]])
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| :[[Nystagmus]] - jerking movement of the eyes
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| '''NOSE'''
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| :Small, upturned nose
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| '''EARS/HEARING'''
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| :'''Low set ears''' —''(over 90%)''
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| :'''Backward rotated ears''' —''(over 90%)''
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| :'''Thick helix of ear''' (outer rim) —''(over 90%)''
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| :Incomplete folding of ears
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| :Chronic [[Otitis media]] (ear infections)
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| '''MOUTH/SPEECH'''
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| :'''Deeply grooved philtrum''' (top lip line) —''(over 90%)''
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| :[[Micrognathia]] (undersized lower jaw)
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| :High Arched palate
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| :Dental problems
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| :Articulation Difficulties
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| :Poor tongue control
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| '''LIMBS/EXTREMITIES'''
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| :Bluntly ended fingers
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| :Extra padding on fingers and toes
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| :[[Edema]] of the back of hands and tops of feet
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| :[[Cubitus valgus]] (elbow deformity: with abnormal turning-in)
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| '''SKIN'''
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| :Lymphedema (swelling of the extremities)
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| :[[Keloids]] (scar [[Organ hypertrophy|hypertrophy]])
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| :[[Hyperkeratosis]] - overdevelopment of outer skin layer
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| :[[nevus|Pigmented nevi]] (birthmark)
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| ==Diagnosis== | | ==Diagnosis== |
| Despite identification of four causative genes, the diagnosis of Noonan syndrome is still based on clinical features. In other words, it is made when a physician feels that a patient has enough of the features to warrant the label indicating association. The patient can be tested for mutations in the PTPN11, SOS1, or KRAS genes, however absence of a mutation will not exclude the diagnosis as there are more as yet undiscovered genes that cause NS. The principal values of making such a diagnosis are that it guides additional medical and developmental evaluations, it excludes other possible explanations for the features, and it allows more accurate recurrence risk estimates.
| | [[Noonan syndrome history and symptoms| History and Symptoms]] | [[Noonan syndrome physical examination | Physical Examination]] | [[Noonan syndrome laboratory findings|Laboratory Findings]] | [[Noonan syndrome imaging findings|Imaging Findings]] | [[Noonan syndrome ECG findings|ECG Findings]] | [[Noonan syndrome other diagnostic studies|Other Diagnostic Studies]] |
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| ==See also== | | ==Treatment== |
| *[[Turner syndrome]] — a different disorder which is often confused with Noonan syndrome because of several physical features that they have in common.
| | [[Noonan syndrome management and follow-up|Management & Follow-up]] | [[Noonan syndrome genetic counseling|Genetic Counseling]] |
| *[[Fetal alcohol syndrome]] — another disorder that is sometimes confused with Noonan syndrome because of some common facial features and mental retardation<ref>CDC. (2004). ''Fetal Alcohol Syndrome: Guidelines for Referral and Diagnosis''. Can be downloaded at http://www.cdc.gov/fas/faspub.htm.</ref>
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| *[[Leopard syndrome]]— A related disorder caused by mutations in PTPN11 that are catalytically inactivating.
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| *[[Cardiofaciocutaneous syndrome]] — A related disorder which also affects genes encoding elements of the Ras/MAP kinase pathway.
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| *[[PTPN11]]— a gene mutated in Noonan Syndrome and LEOPARD Syndrome
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| *[[SOS1]]— a gene mutated in Noonan Syndrome
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| *[[KRAS]]— A gene mutated in Noonan Syndrome and Cardiofaciocutaneous syndrome.
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| *[[Dermatoglyphics]]
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| ==References== | | ==Case Studies== |
| {{Reflist|2}}
| | [[Noonan syndrome case study one|Case#1]] |
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| ==External links==
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| *[http://www.noonansyndrome.org/home.htm The Noonan Syndrome Support Group Inc]
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| *[http://www.genetests.org/profiles/noonan GeneReviews: Noonan syndrome]
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| {{Phakomatoses and other congenital malformations not elsewhere classified}}
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| {{SIB}}
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| | [[Category:Up-To-Date]] |
| | [[Category:Cardiology]] |
| | [[Category:Congenital heart disease]] |
| | [[Category:Disease]] |
| [[Category:Genetic disorders]] | | [[Category:Genetic disorders]] |
| [[Category:Syndromes]] | | [[Category:Syndromes]] |
| [[Category: Cardiology]]
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| [[Category: Disease state]]
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| [[category: Congenital heart disease]]
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| [[de:Noonan-Syndrom]]
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| [[fr:Syndrome de Noonan]]
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| [[it:Sindrome di Noonan-LEOPARD]]
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| [[nl:Syndroom van Noonan]]
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| [[pl:Zespół Noonan]]
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| [[tr:Noonan sendromu]]
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