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Orphanet: Noonan syndrome
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class="row g-0"> <div class="col-12"> <div class="result-detail"> <div class="d-flex justify-content-between mb-4 mx-4"> <h2>Noonan syndrome</h2> <div class="btn text-white bg-orpa-blue" role="button" id="suggest-modal-btn" data-orphacode="648"> <span id="spinner" class="spinner-border-sm" role="status" aria-hidden="true"></span> <i class="fas fa-pen me-1"></i>Suggest an update </div> </div> <div class="alert d-none mx-4"> <span class="success d-none"> Your message has been sent </span> <span class="error d-none"> Your message has not been sent. Please contact an administrator. </span> </div> <div class="modal fade" id="suggest-modal" tabindex="-1" aria-labelledby="#suggest-modal" aria-hidden="true"> <div class="modal-dialog modal-xl"> <div class="modal-content rounded-0"> <div class="modal-header rounded-0 py-0 justify-content-between text-white px-2 bg-orpa-blue"> Comment Form <div type="button" class="p-1" data-bs-dismiss="modal" aria-label="Close">X</div> </div> <div class="modal-body" data-orphacode="648"> </div> </div> </div> </div> <div class="mx-4 mb-4 p-4 service-color-box"> <strong class="d-block mb-3 service-color">Disease definition</strong> <p> A rare, highly variable, multisystemic disorder mainly characterized by short stature, distinctive facial features, congenital heart defects, cardiomyopathy and an increased risk to develop tumors in childhood. </p> </div> <div class="mx-4 mb-4 p-4 bg-gray"> <p class="fs-5 d-block mb-2 fw-bold">ORPHA:648</p> <p> <a href=" /en/disease/classification/list/name/Noonan-syndrome?orphaCode=648">Classification level: Disorder</a> </p> <div class="row"> <div class="col-6"> <p> <strong>Source: PubMed ID</strong> <a target="_blank" href="//pubmed.ncbi.nlm.nih.gov/17222357">17222357</a> <a target="_blank" href="//pubmed.ncbi.nlm.nih.gov/20301303">20301303</a> <a target="_blank" href="//pubmed.ncbi.nlm.nih.gov/30335302">30335302</a> </p> </div> <div class="col-3"> <p class=""> <strong>Prevalence: </strong> <span>1-5 / 10 000</span> </p> <p><strong>Inheritance: </strong><span>Autosomal dominant, Autosomal recessive</span></p> <p><strong>Age of onset: </strong><span>Antenatal, Childhood, Infancy, Neonatal</span></p> </div> <div class="col-3"> <p> <strong>ICD-10: </strong> Q87.1 </p> <p><strong>ICD-11: </strong> <a target="_blank" href="https://icd.who.int/browse11/l-m/en#/http://id.who.int/icd/entity/1044395354">LD2F.15</a> </p> <p><strong>OMIM: </strong> <a target="_blank" href="//omim.org/entry/618624">618624</a> <a target="_blank" href="//omim.org/entry/619745">619745</a> <a target="_blank" href="//omim.org/entry/618499">618499</a> <a target="_blank" href="//omim.org/entry/619087">619087</a> <a target="_blank" href="//omim.org/entry/163950">163950</a> <a target="_blank" href="//omim.org/entry/605275">605275</a> <a target="_blank" href="//omim.org/entry/609942">609942</a> <a target="_blank" href="//omim.org/entry/610733">610733</a> <a target="_blank" href="//omim.org/entry/611553">611553</a> <a target="_blank" href="//omim.org/entry/613224">613224</a> <a target="_blank" href="//omim.org/entry/613706">613706</a> <a target="_blank" href="//omim.org/entry/615355">615355</a> <a target="_blank" href="//omim.org/entry/616559">616559</a> <a target="_blank" href="//omim.org/entry/616564">616564</a> </p> <p><strong>UMLS: </strong> C0028326 </p> <p><strong>MeSH: </strong> D009634 </p> <p><strong>GARD: </strong> <a target="_blank" href="//rarediseases.info.nih.gov/diseases/10955/index">10955</a> </p> <p><strong>MedDRA: </strong> <span> 10029748 </span> </p> </div> </div> </div> <div class="h2 ms-4 mb-4">Summary</div> <div class="mx-4 summary"> <div class="fs-5 orpha-blue">Epidemiology</div> <p class="mx-4">The birth prevalence of Noonan syndrome (NS) is estimated between 1:1000 to 1:2500.</p> <div class="fs-5 orpha-blue">Clinical description</div> <p class="mx-4">NS typically presents in the neonatal period with feeding difficulties and failure to thrive. Characteristic facial features are often more obvious in infancy : high broad forehead, hypertelorism, palpebral ptosis and downward slanting palpebral fissures, low-set, thick, posteriorly rotated ears, deep philtrum, micrognathia, curly hair and a short neck with sometimes a pterygium colli. With age, the face becomes triangular, with marked skinfolds. The most common congenital heart defect is pulmonary valve stenosis (50-60%) with pulmonic valve dysplasia and various types of cardiac malformations (atrial septal defects, ventricular septal defects ect.). Hypertrophic cardiomyopathy of antenatal onset is common (20%) and may be stable or rapidly progressive. Dilation of coronary arteries and moya-moya disease may develop with aging. Growth delay affects 50%, uncommonly associated with growth hormone deficiency. Weight gain is difficult and many patients remain lean throughout life. Major orthopedic manifestations include sternal deformity, talipes equinovarus, and progressive scoliosis (onset at adolescence). Skin is often dry and sometimes hyperkeratotic on hands and feet. Hair is curly and may be thick or sparse. Peripheral lymphedema may be present and may be progressive and extensive in some. Ocular anomalies (strabismus, refractive errors), and dental crowding are common. Hearing loss is present in 10%. Delayed speech and learning difficulties affect 30-40%. Intellectual disability (often mild) is present in 10-20%. Dyspraxia (clumsiness), attention deficit disorder, agitation, mood disorders and emotional disturbances are not rare, as well as difficulties in identifying and expressing emotions, which can lead to more difficult social interactions. Motor development and puberty are delayed and short stature is present in 50%. Unilateral or bilateral cryptorchidism is present in two-thirds of boys, and hypofertility may affect males, but not females. Thyroid dysfunction may occur. Coagulation defects are frequent but rarely clinically significant. In childhood, there is an increased risk of tumors and leukemias (noteworthy juvenile myelomonocytic leukemia), with a cumulative cancer risk of about 4% by age 20. The risk of common adult cancer does not appear increased.</p> <div class="fs-5 orpha-blue">Etiology</div> <p class="mx-4">NS is caused by mutations in <i>PTPN11</i> (12q24.13) seen in 50% of cases, <i>SOS1</i> (2p22.1) in 15%, <i>RAF1</i> (3p25.2), <i>RIT1</i> (1q22) and <i>LZTR1</i>(22q11.21), and less commonly in other genes associated with the RAS/MAPK signaling pathway. The clinical spectrum of NS may differ slightly between causative genes, and some forms have been described as ''Noonan like'' (NS-like disorder with juvenile myelomonocytic leukemia and NS-like disorder with loose anagen hair).</p> <div class="fs-5 orpha-blue">Diagnostic methods</div> <p class="mx-4">The diagnosis relies on clinical manifestations but may be difficult because of the highly variable presentation. Molecular genetic testing of the causative genes helps diagnosis and genetic counseling. Mild cases may remain undiagnosed and only brought to clinical attention in adulthood after the birth of a more severely affected child.</p> <div class="fs-5 orpha-blue">Differential diagnosis</div> <p class="mx-4">Differential diagnoses include Cardio-Facio-Cutaneous syndrome, Costello syndrome, Neurofibromatosis type 1, Noonan syndrome with multiple lentigines (all RASopathies), Baraitser-Winter, Aarskog and Escobar syndromes.</p> <div class="fs-5 orpha-blue">Antenatal diagnosis</div> <p class="mx-4">Prenatal diagnosis is possible on chorionic villi or amniotic fluid. Prenatal signs of NS are nonspecific: increased nuchal translucency, cystic hygroma and/or ascites (that may lead to fetal demise), polyhydramnios, cardiomyopathy and congenital heart defect.</p> <div class="fs-5 orpha-blue">Genetic counseling</div> <p class="mx-4">Inheritance of NS is autosomal dominant, except <i>LZTR1</i> which can be either dominant or recessive. Genetic counseling should be offered to affected families.</p> <div class="fs-5 orpha-blue">Management and treatment</div> <p class="mx-4">Treatment requires a multidisciplinary approach. Cardiovascular anomalies are treated with standard approaches. Treatment of growth retardation with growth hormone is still controversial. Developmental disabilities should be addressed early.</p> <div class="fs-5 orpha-blue">Prognosis</div> <p class="mx-4">The prognosis is variable since the presentation ranges from mild/unrecognized manifestations in adulthood to severe disorder with life-threatening heart disease or malignancy in infancy. Severe cardiomyopathy may lead to early demise.</p> <span class="expert-list fst-italic fw-lighter"> Last update: <span class="fw-bold">April 2020</span> </span> <span class="expert-list fst-italic fw-lighter"> - Expert reviewer(s): <span class="fw-bold">Pr Alain VERLOES | <a class="fw-normal" href="/en/expert-centres/network/485586">ITHACA</a>*</span> </span> <p class="mt-3"> * <a target="" href="/en/expert_centres/european-reference-network">European Reference Network</a> </p> </div> <div class="mx-4 mb-3 mt-4 fw-bold"> <i class="fas fa-book orpha-blue fs-4"></i> A summary on this disease is available in <span> <a href="/fr/disease/detail/648">Français</a> (2020) <img src="/build/images/ERN.png" alt="Logo ERN"> </span> <span> <a href="/es/disease/detail/648">Español</a> (2020) </span> <span> <a href="/de/disease/detail/648">Deutsch</a> (2020) <img src="/build/images/ERN.png" alt="Logo ERN"> </span> <span> <a href="/it/disease/detail/648">Italiano</a> (2020) <img src="/build/images/ERN.png" alt="Logo ERN"> </span> <span> <a href="/pt/disease/detail/648">Português</a> (2008) </span> <span> <a href="/nl/disease/detail/648">Nederlands</a> (2020) <img src="/build/images/ERN.png" alt="Logo ERN"> </span> <span> <a href="/pl/disease/detail/648">Polski</a> (2025) </span> <span> <a href="https://www.orpha.net/data/patho/GR/-Noonan-GrgrAbs206.pdf">Ελληνικά</a> (2008.pdf) </span> <span> <a href="https://www.orpha.net/data/patho/SK/Noonan-syndrome.pdf">Slovenčina</a> (2008.pdf) </span> <span> <a href="http://www.orpha.net/data/patho/Pro/ru/Noonan_syndrome_KZ_kz_PRO_ORPHA648.pdf">Русский</a> (2020.pdf) </span> <span> <a href="http://www.orpha.net/data/patho/Pro/other/Noonan_syndrome_JP_ja_PRO_ORPHA648.pdf">日本語</a> (2020.pdf) </span> </div> <div class="m-4 bg-gray p-4"> <div class="h4" id="detailed-info"><i class="fas fa-file"></i> Detailed information</div> <div class="row mt-2 small"> <div class="col-md-6 col-12"> <h5 class="fw-bold mt-4">General public</h5> <div class="mt-3"> <strong class="mb-2"> <i class="fas fa-angle-right fs-6 orpha-blue"></i> Article for general public </strong> <div class="mt-1"> <a target="_blank" href="http://www.orpha.net/data/patho/Pub/fr/Noonan-FRfrPub206v01.pdf">Français (2006.pdf)</a> <span class="fst-italic small"> - Orphanet</span> <br /> </div> <div class="mt-1"> <a target="_blank" href="http://www.orpha.net/data/patho/Pub/Ext/de/SyndromeDieMitAngeborenenHerzfehlernEinhergehen_DE_de_PUB_ORPHA156532.pdf">Deutsch (2015.pdf)</a> <span class="fst-italic small"> - BVHK</span> <br /> </div> <div class="mt-1"> <a target="_blank" href="https://www.noonancantabria.es/sindrome-noonan/#guias">Español (2015)</a> <span class="fst-italic small"> - Asoc Sínd Noonan Cantabria</span> <br /> </div> <div class="mt-1"> <a target="_blank" href="https://www.socialstyrelsen.se/kunskapsstod-och-regler/omraden/sallsynta-halsotillstand/om-kunskapsdatabasen/sok-bland-sallsynta-halsotillstand/noonans-syndrom/">Svenska (2013)</a> <span class="fst-italic small"> - Socialstyrelsen</span> <br /> </div> </div> <h5 class="fw-bold mt-4">Guidelines</h5> <div class="mt-3"> <strong class="mb-2"> <i class="fas fa-angle-right fs-6 orpha-blue"></i> Emergency guidelines </strong> <div class="mt-1"> <a target="_blank" href="http://www.orpha.net/data/patho/Emg/Int/fr/CardiomyopathieHypertrophique_FR_fr_EMG_ORPHA217569.pdf">Français (2018.pdf)</a> <span class="fst-italic small"> - Orphanet Urgences</span> <br /> </div> </div> <div class="mt-3"> <strong class="mb-2"> <i class="fas fa-angle-right fs-6 orpha-blue"></i> Anesthesia guidelines </strong> <div class="mt-1"> <a target="_blank" href="https://www.orphananesthesia.eu/en/rare-diseases/published-guidelines/noonan-syndrome.html">English (2015)</a> <span class="fst-italic small"> - Orphananesthesia</span> <br /> </div> <div class="mt-1"> <a target="_blank" href="https://www.orphananesthesia.eu/en/rare-diseases/published-guidelines/noonan-syndrome.html">Čeština (2015)</a> <span class="fst-italic small"> - Orphananesthesia</span> <br /> </div> <div class="mt-1"> <a target="_blank" href="https://www.orphananesthesia.eu/en/rare-diseases/published-guidelines/noonan-syndrome.html">Italiano (2015)</a> <span class="fst-italic small"> - Orphananesthesia</span> <br /> </div> </div> <div class="mt-3"> <strong class="mb-2"> <i class="fas fa-angle-right fs-6 orpha-blue"></i> Clinical practice guidelines </strong> <div class="mt-1"> <a target="_blank" href="http://www.has-sante.fr/jcms/c_2679254/fr/rasopathies-syndromes-de-noonan-cardio-facio-cutane-et-apparentes">Français (2021)</a> <span class="fst-italic small"> - PNDS</span> <br /> </div> <div class="mt-1"> <a target="_blank" href="https://register.awmf.org/de/leitlinien/detail/007-108">Deutsch (2023)</a> <span class="fst-italic small"> - AWMF</span> <br /> </div> <div class="mt-1"> <a target="_blank" href="http://www.orpha.net/data/patho/Pro/en/NoonanGuidelines2011.pdf">English (2011.pdf)</a> <span class="fst-italic small"> - Dyscerne</span> <br /> </div> <div class="mt-1"> <a target="_blank" href="http://www.orpha.net/data/patho/Pro/other/noonan_syndroom_klinische_richtlijn.pdf">Nederlands (2010.pdf)</a> <span class="fst-italic small"> - Dyscerne</span> <br /> </div> </div> </div> <div class="col-md-6 col-12"> <h5 class="fw-bold mt-4">Disease review articles</h5> <div class="mt-3"> <strong class="mb-2"> <i class="fas fa-angle-right fs-6 orpha-blue"></i> Review article </strong> <div class="mt-1"> <a target="_blank" href="http://www.ojrd.com/content/2/1/4">English (2007)</a> <span class="fst-italic small"> - Orphanet J Rare Dis</span> <br /> </div> </div> <div class="mt-3"> <strong class="mb-2"> <i class="fas fa-angle-right fs-6 orpha-blue"></i> Clinical genetics review </strong> <div class="mt-1"> <a target="_blank" href="http://www.ncbi.nlm.nih.gov/books/n/gene/noonan/">English (2022)</a> <span class="fst-italic small"> - GeneReviews</span> <br /> </div> </div> <h5 class="fw-bold mt-4">Genetic testing</h5> <div class="mt-3"> <strong class="mb-2"> <i class="fas fa-angle-right fs-6 orpha-blue"></i> Guidance for genetic testing </strong> <div class="mt-1"> <a target="_blank" href="https://anpgm.fr/media/documents/ANPGM_030-v2-Cardiomyopathies.pdf">Français (2016.pdf)</a> <span class="fst-italic small"> - ANPGM</span> <br /> </div> <div class="mt-1"> <a target="_blank" href="https://leitlinien.dgk.org/files/2015_Positionspapier_DGK_DGPK_Gendiagnostik.pdf">Deutsch (2015.pdf)</a> <span class="fst-italic small"> - Kardiologe</span> <br /> </div> </div> </div> </div> <p class="small mt-4"> <img src="/build/images/ERN.png" alt="Logo ERN">: produced/endorsed by ERN(s) <img src="/build/images/FSMR.png" alt="Logo FSMR">: produced/endorsed by FSMR(s) </p> </div> <div class="m-4 service-color-box p-4"> <div class="h4 mb-4"><i class="fas fa-file"></i> Additional information</div> <div class="row"> <div class="col-4"> <p class="fw-bold">Further information on this disease</p> <ul class="list-unstyled"> <li class="my-1"> <i class="fas fa-angle-right orpha-blue"></i> <a href="/en/disease/classification/list/name/Noonan-syndrome?orphaCode=648"> Classification(s) (14)</a> </li> <li class="my-1"> <i class="fas fa-angle-right orpha-blue"></i> <a href="/en/disease/gene/list/648?mode=name"> Gene(s) (15)</a> </li> <li class="my-1"> <i class="fas fa-angle-right orpha-blue"></i> <a href="/en/disease/disability/detail/648"> Disability</a> </li> <li class="my-1"> <i class="fas fa-angle-right orpha-blue"></i> <a href="/en/disease/sign/648"> Clinical Signs and Symptoms</a> </li> <li class="my-1"> <i class="fas fa-angle-right orpha-blue"></i> <a target="_blank" href="https://pubmed.ncbi.nlm.nih.gov/?term=Noonan+Syndrome%5BTW%5D+OR+Noonan+Syndrome%5BTIAB%5D+OR+%22noonan+syndrome%22%5BMeSH+Terms%5D"> Publications in PubMed</a> </li> </ul> </div> <div class="col-4"> <p class="fw-bold">Patient-centred resources for this disease</p> <ul class="list-unstyled"> <li class="my-1"> <i class="fas fa-angle-right orpha-blue"></i> <a href="/en/expert-centres/centres/648?name=Noonan%20syndrome&consulting=medical&age=all&official=0"> Expert centre(s) (611) </a> </li> <li class="my-1"> <i class="fas fa-angle-right orpha-blue"></i> <a href="/en/expert-centres/networks?orphaCode=648&diseaseName=Noonan%20syndrome"> Networks of expert centre (32) </a> </li> <li class="my-1"> <i class="fas fa-angle-right orpha-blue"></i> <a href="/en/diagnostic-tests/diagnostics?orphaCode=648&diseaseName=Noonan%20syndrome"> Diagnostic tests (227) </a> </li> <li class="my-1"> <i class="fas fa-angle-right orpha-blue"></i> <a href="/en/patient-organisations?orphaCode=648&diseaseName=Noonan%20syndrome"> Patient organisation(s) (161) </a> </li> <li class="my-1"> <i class="fas fa-angle-right orpha-blue"></i> <a href="/en/patient-organisations/federations-alliances?orphaCode=648&diseaseName=Noonan%20syndrome"> Federation/alliance(s) (44) </a> </li> <li class="my-1"> <i class="fas fa-angle-right orpha-blue"></i> <a href="/en/drug?orphaCode=648&diseaseName=Noonan%20syndrome&status=all&mode=pat"> Orphan designation(s) and orphan drug(s) (5) </a> </li> </ul> </div> <div class="col-4"> <p class="fw-bold">Research activities on this disease</p> <ul class="list-unstyled"> <li class="my-1"> <i class="fas fa-angle-right orpha-blue"></i> <a href="/en/research-trials/research-projects?orphaCode=648&diseaseName=Noonan%20syndrome"> Research project(s) (92) </a> </li> <li class="my-1"> <i class="fas fa-angle-right orpha-blue"></i> <a href="/en/research-trials/clinical-trials?orphaCode=648&diseaseName=Noonan%20syndrome"> Clinical trial(s) (3) </a> </li> <li class="my-1"> <i class="fas fa-angle-right orpha-blue"></i> <a href="/en/research-trials/biobanks?orphaCode=648&diseaseName=Noonan%20syndrome"> Biobank(s) (14) </a> </li> <li class="my-1"> <i class="fas fa-angle-right orpha-blue"></i> <a href="/en/research-trials/registries?orphaCode=648&diseaseName=Noonan%20syndrome"> Registry(ies) (37) </a> </li> <li class="my-1"> <i class="fas fa-angle-right orpha-blue"></i> <a href="/en/institutions/expert-networks?orphaCode=648&diseaseName=Noonan%20syndrome"> Network of experts (7) </a> </li> </ul> <p class="fw-bold">Newborn screening</p> <ul class="list-unstyled"> <li class="my-1"> <i class="fas fa-angle-right orpha-blue"></i> <a target="_blank" href="https://nbs.orphanet.app/?lang=en">Newborn screening library</a> </li> </ul> </div> </div> </div> <div class="mx-4"> <small>The documents contained in this website are presented for information purposes only. The material is in no way intended to replace professional medical care by a qualified specialist and should not be used as a basis for diagnosis or treatment.</small> </div> </div> </div> </div> </div> </main> </div> </article> </article> </main> <script src="/build/runtime.f3575a88.js" defer></script><script src="/build/755.5a8586e9.js" defer></script><script src="/build/673.f47275b8.js" defer></script><script src="/build/467.7cd7293e.js" defer></script><script src="/build/app.3c0fe482.js" defer></script> <script type="application/json" data-placeholders> {"gene":"Gene name or symbol","name":"Disease name","orpha":"ORPHAcode","mim":"OMIM disease","mimg":"OMIM gene","omim":"OMIM disease","icd10":"ICD-10","icd11":"ICD-11"} </script> <script type="application/ld+json"> { "@context": "http://schema.org/", "@type": "MedicalCondition", "@id": "https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=648", "identifier": "648", "name": { "@type": "PronounceableText", "inLanguage": "EN", 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"description": "A rare, highly variable, multisystemic disorder mainly characterized by short stature, distinctive facial features, congenital heart defects, cardiomyopathy and an increased risk to develop tumors in childhood." } </script> </body> <footer> <section class="partners bg-white my-3 d-print-none"> <h3 class="fs-5 text-center orpha-blue fw-bold">With the support of</h3> <div class="row col-lg-10 mx-auto my-4"> <ul class="list-unstyled d-inline-flex col-12 col-lg-6 flex-wrap justify-content-evenly align-items-center border-blue"> <li class="d-inline"> <a title="Site Internet de l'Inserm" href="//www.inserm.fr/" target="_blank"> <img src="/build/images/partners/logo-inserm.png" height="20px" alt="Site Internet de l'Inserm"> </a> </li> <li class="d-inline"> <a title="Link to the French Ministry of Health" href="//www.sante.gouv.fr/" target="_blank"> <img src="/build/images/partners/logo-sante_jeunesse_sports.png" alt="Link to the French Ministry of Health"> </a> </li> <li 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