Individuals with Noonan syndrome have abnormal facial features, congenital heart disease, short stature, and chest deformity [1]. Skeletal, genitourinary, neurologic, lymphatic, and eye findings may also be present. Abnormal facial features include a deep groove in the area between the mouth and nose (philtrum), widely spaced eyes that are strikingly blue or blue-green in color, low-set ears, and short, and webbed neck [2]. Coagulation disorders are present in half of people with Noonan syndrome; affected individuals may report excessive bruising, nosebleeds, or excessive bleeding upon an injury or surgery. Less often, women with Noonan syndrome will present with menorrhagia (excessive bleeding) during menstruation [3]. Cryptorchidism (undescended testes) and infertility in males have been associated with Noonan syndrome. Affected individuals may have cognitive impairment. Cognitive impairment may include low to average intelligence, slower processing speed, deficits in language skills, impaired memory and attention deficits [4].

• Pulmonary Valve Stenosis

  The most common cardiac conditions are pulmonary valve stenosis and hypertrophic cardiomyopathy. [symptoma.com]

  Pulmonary valve stenosis and hypertrophic cardiomyopathy are the most prevalent cardiovascular abnormalities. We report on a 14-year-old girl with NS due to SOS1 mutation with pulmonary stenosis and idiopathic coronary ectasia. [ncbi.nlm.nih.gov]

  Echocardiographic findings showed a dysplasic pulmonary valve in 4 (24%) of our cases of pulmonary valve stenosis. [scielo.br]

• Developmental Delay

  This degree of developmental delay was atypical for an individual with Noonan syndrome, raising concerns for a chromosomal abnormality. Array-CGH showed an interstitial duplication of 10 Mb including the PTPN11 gene. [ncbi.nlm.nih.gov]

  Noonan syndrome is a disorder that involves unusual facial characteristics, short stature, heart defects present at birth, bleeding problems, developmental delays, and malformations of the bones of the rib cage. [genome.gov]

  In general, these conditions share the findings of short stature, congenital heart defects, and developmental delays. [unmc.edu]

• Atrial Septal Defect

  We report a child with Noonan syndrome status post pulmonary stenosis and atrial septal defect repair, who developed bilateral coronary artery aneurysms. [ncbi.nlm.nih.gov]

  The principal features include congenital heart defect (typically pulmonary valve stenosis; also atrial septal defect and hypertrophic cardiomyopathy), short stature, learning problems, pectus excavatum, impaired blood clotting, and a characteristic configuration [dbpedia.org]

  Noonan syndrome in patients with such mutations is more often associated with pulmonary stenosis or atrial septal defect, bleeding diathesis and juvenile myelomonocytic leukemia. [news-medical.net]

  septal defect, ventricular septal defect, and patent ductus arteriosus.3,4 The incidence is estimated to be from 1 in 1000 to 1 in 2500.5,6 The diagnosis is made clinically, but there can be a spectrum of expression of the phenotype from mild to severe [jamanetwork.com]

• Lymphedema

  Noonan syndrome (NS) is characterized by short stature and elevated risk of lymphedema. The mechanism underlying lymphedema may be mediated by vascular endothelial growth factors (VEGFs). [ncbi.nlm.nih.gov]

  Talipes equinovarus, radioulnar synostosis, cervical spine fusion, and joint contractures are less common findings. [13] Skin findings These include the following: Lymphedema (See the images below) Lymphedema of the feet in an infant is shown. [emedicine.medscape.com]

  Aside from face and heart abnormalities, there may be associated bleeding abnormalities, scoliosis, infertility in males, lymphedema, and intellectual disability. [rxlist.com]

• Multiple Congenital Anomalies

  Noonan syndrome (NS) is a multiple congenital anomaly syndrome caused by germline mutations in genes coding for components of the Ras-mitogen-activated protein kinase (RAS-MAPK) pathway. [ncbi.nlm.nih.gov]

  congenital anomalies and intellectual disability. [invitae.com]

  GonzalezI From the Genetics Clinic Unit of the Children's InstituteI and the Department of HematologyII, Hospital das Clínicas, Faculty of Medicine, University of São Paulo ABSTRACT OBJECTIVE: Noonan syndrome is a multiple congenital anomaly syndrome, [scielo.br]

• Jaw Mass

  This is a case of a 20-year-old woman who presented with a left jaw mass which was resected and found to be a giant cell granuloma of the mandible. [ncbi.nlm.nih.gov]

• Heart Murmur

  murmur in the first few hours of life. [revespcardiol.org]

  Echocardiography was performed due to heart murmur and patent ductus arteriosus and mild coarctation of aorta were found; during short follow-up the ductus closed spontaneously and the coarctation remained unchanged. [doi.org]

  Many patients with this condition may not experience any symptoms at all, the only sign being a heart murmur on auscultation. [aboutkidshealth.ca]

  For example, in mild asymptomatic cases of pulmonary stenosis, the condition may initially be suspected through the detection of an abnormal heart murmur during such stethoscopic evaluation. [rarediseases.org]

• Hydrops Fetalis

  Prenatal findings of polyhydramnios, hydrops fetalis and cystic hygroma in combination with an increased nuchal translucency have been found most frequently in NS [ 8 - 10 ]. [raredisorders.imedpub.com]

  We describe an infant prenatally diagnosed with hydrops fetalis ultimately found to have Noonan syndrome (NS). [ncbi.nlm.nih.gov]

  Antenatal presentation of an increased nuchal translucency, hydrothoraces or hydrops fetalis are common in these disorders and represent abnormalities in lymphatic development. [nature.com]

  […] resonance imaging of the brain) Ocular Dysmorphic findings, vision problems Detailed eye examination in infancy and/or at diagnosis — Eye reevaluation as indicated if abnormal or every two years thereafter Pregnancy Congenital heart defects, effusion, hydrops [aafp.org]

• Blepharoptosis

  Eyelid abnormalities such as ocular hypertelorism and blepharoptosis are the most commonly observed eye complications. We report a case of Noonan syndrome associated with mature cataract that required operation. [ncbi.nlm.nih.gov]

  Lopez et al. reported a case of unilateral eyelid angiofibroma with complete blepharoptosis as the presenting sign of TSC [78]. [hindawi.com]

• Low-Set Posteriorly Rotated Ears

  Patient 7 (male) presented with dysmorphic facies typical of CFC with low-set posteriorly rotated ears, and hypertelorism. [nature.com]

  The distinctive facial features consist of a broad forehead, hypertelorism, downslanting palpebral fissures, a high-arched palate, and low-set, posteriorly rotated ears. Cardiac involvement is present in up to 90% of patients. [flybase.org]

  Definition A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic [uniprot.org]

  A, Patient 303983 aged 7.5 and 14 years showing hypertelorism and low‐set posteriorly rotated ears. B, Patient 287232 aged 5 years showing low‐set ears, pointed chin and pectus excavatum. [onlinelibrary.wiley.com]

• Pterygium Colli

  colli), thoracic abnormalities, congenital heart defects and short stature, associated with a very frequent ocurrence of juvenile myelomonocytic leukemia. [orpha.net]

  Background: Noonan syndrome is often described as a “Male Turner syndrome” presenting with pterygium colli, short stature, pectus excavatum, webbed neck, down-slanting palpebral fissures and eyelid ptosis, and congenital heart disease (most commonly, [mhaus.org]

  Symptoms are variable and range from facial dysmorphia (broad forehead, hypertelorism, low ears and outward-sloping eyelid axis), proportionate short stature, pterygium colli, breast deformations, cryptorchidism, intellectual disability, a slight tendency [medical-genetics.de]

• Widely Spaced Nipples

  […] intermamillary distance Wide-spaced nipples Widely spaced nipples Widely-spaced nipples [ more ] 0006610 30%-79% of people have these symptoms Abnormal bleeding Bleeding tendency 0001892 Abnormal dermatoglyphics Abnormal fingerprints 0007477 Abnormal [rarediseases.info.nih.gov]

  Clinical phenotype (facial dysmorphism, soft hair, short neck, broad chest, widely spaced nipples, mild pectus carinatum, deep palmar creases, unilateral cryptorchidism), and moderate pulmonary valve stenosis with mild psychomotor delay were indicative [ncbi.nlm.nih.gov]

  spaced eyes Depressed nasal bridge Down -slanting palpebral fissures Low set ears, posteriorly rotated High arched palate Misalignment of the teeth Micrognathia Short neck with webbing Low hairline on the neck Widely spaced nipples Pectus excavatum or [pedclerk.bsd.uchicago.edu]

  The chest is broad with widely spaced nipples and a specific chest shape which consists of pectus carinatum superiorly and pectus excavatum inferiorly. The hands show brachydactyly and persistence of fetal fingertip pads. [patient.info]

  Thorax: Sternal deformities including pectus carinatum involving the superior sternum and pectus excavatum involving the inferior sternum.[5] Widely spaced nipples.[2] Cardiovascular: Classic finding is pulmonic stenosis often associated with dysplasia [eyewiki.aao.org]

• Hypertelorism

  Craniofacial anomalies in affected patients include hypertelorism and severe open bite associated with masticatory dysfunction. We treated a Noonan syndrome patient with a skeletal open bite. [ncbi.nlm.nih.gov]

  Noonan: Hypertelorism with Turner phenotype. A new syndrome with associated congenital heart disease. American Journal of Diseases of Children, Chicago, 1968, 116: 373-380. J. M. Opitz, P. D. [whonamedit.com]

  It is characterized by short stature, webbed neck, hypertelorism, low-set ears, deafness, and thrombocytopenia or abnormal platelet function. [fpnotebook.com]

  Neonate and Infancy [ edit ] (age features are most striking) tall forehead hypertelorism with downslant palpebral fissures (95%) prominent eyes Nose has depressed root, wide base, bulbous tip Deeply grooved philtrum High wide peaks to vermillion border [en.wikibooks.org]

• Short Neck

  Noonan syndrome is an autosomal, dominantly inherited disease; it is physically characterized by short stature, short neck, webbed neck, abnormal auricles, high arched palate, and cardiovascular malformation. [ncbi.nlm.nih.gov]

  Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. [uniprot.org]

  neck with or without pterygium colli), thoracic abnormalities, congenital heart defects and short stature, associated with a very frequent ocurrence of juvenile myelomonocytic leukemia. [orpha.net]

• Delayed Milestone

  Some children with Noonan syndrome can have delayed milestones or learning difficulties. However, when recognized early, they respond well to additional support. [aboutkidshealth.ca]

  milestones Mean age sitting 10 mth, walking 21 mth, two-word sentence 31 mth 10-15 % require special ed IQ usually within normal range, but mild MR seen in 1/3 Verbal lower than nonverbal performance Usually good peer, social interactions and self-esteem [en.wikibooks.org]

  Delayed milestones (predicted by feeding difficulty). Average age to walk is 21 months. [pedclerk.bsd.uchicago.edu]

  History revealed that the child had delayed milestones and had undergone cardiac surgery and a surgery in her anal region three years back. [jisppd.com]

• Cryptorchidism

  Noonan syndrome (NS) is a genetic condition presenting with typical facies, cardiac defects, short stature, variable developmental deficit, cryptorchidism, skeletal, and other abnormalities. [ncbi.nlm.nih.gov]

  However, in our study, no difference in Sertoli cell markers was shown between cryptorchid and non-cryptorchid NS patients. [eje.bioscientifica.com]

  Cryptorchidism may be present in males. Males have an increased risk of infertility even if without a previous diagnosis of cryptorchidism. Most females are not at risk for infertility. [statpearls.com]

  Introduction Noonan syndrome is a relatively common autosomal dominant syndrome characterized by dysmorphic facial features, cardiac abnormalities, short stature, chest wall abnormalities, and cryptorchidism. [pedclerk.bsd.uchicago.edu]

  Boys frequently present with cryptorchidism and manifest delayed puberty. Caused by activating mutations in multiple genes in the Ras/mitogen-activated protein kinase (MAPK) signal transduction pathway. The most commonly implicated gene is PTPN11. [bestpractice.bmj.com]

Workup for Noonan syndrome consists of a patient and family history, physical findings, confirmation of specific abnormalities associated with Noonan syndrome through radiological, laboratory, and genetic tests. A definitive diagnosis of individuals with the Noonan syndrome is achieved by genetic testing. Family history should be elicited for any immediate family members that have mild facial abnormalities and cardiac defects.

Physical findings commonly associated with Noonan syndrome include short stature, congenital heart defects (e.g., pulmonary valve stenosis, cardiac hypertrophy, atrial septal defect), broadened neck or webbed neck, either a protruding chest or pectus excavatum, low-set nipples, undescended testicles, abnormal facial characteristics (e.g., bright blue or green colored iris, wide-spaced eyes, low-set fleshy ears) [1]. Noonan syndrome should be considered in individuals with pulmonary valve stenosis, eye abnormalities (e.g., epicanthal folds, ptosis, ocular hypertelorism), and micrognathia [5]. Individuals with Noonan syndrome often may have either pectus excavatum or pectus carinatum. Scoliosis may also be present.

Occasionally the disorder will be diagnosed prenatally when there is an abnormal maternal serum triple screen, non-invasive prenatal testing, or prenatal ultrasound [6]. Ultrasound abnormalities associated with Noonan syndrome consist of polyhydramnios, cystic hygroma, anatomical cardiac abnormalities, and fetal musculoskeletal anomalies.

Most people with Noonan syndrome have congenital heart disease [7]. The most common cardiac conditions are pulmonary valve stenosis and hypertrophic cardiomyopathy. Tests that can be used to evaluate the heart include echocardiogram [8], cardiac catheterization (to examine the rate of cardiac blood flow and measure the pressure within the heart), and an electrocardiography to screen for electrical abnormalities or arrhythmias (e.g., left anterior hemiblock, left axis deviation).

Bleeding disorders have been associated with Noonan syndrome. Coagulation studies are used to screen for coagulation factor deficiencies and platelet dysfunction.

Genetic testing permits definitive diagnosis of Noonan syndrome [9]. Affected individuals will have normal chromosome studies. Mutations in the PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, or MEK1 genes are identified in two-thirds of people with Noonan syndrome [10] [7]. The clinician should keep in mind that not all patients with Noonan syndrome have a detectable alteration in one of these genes and therefore a failure to identify a mutation in one of the aforementioned genes does not exclude the diagnosis of Noonan syndrome.

This case illustrates that diuretics treatment can be the first-line treatment of PLE regardless of the causative physiology, and can be effective in refractory PLE with Noonan syndrome. [ncbi.nlm.nih.gov]

It has not been investigated whether they would benefit from a substitutive treatment and whether this treatment would influence the effect of GH treatment on final height. [frontiersin.org]

The new therapeutic option brings infants promising Noonan syndrome treatment. [healtheuropa.eu]

[…] this treatment for other types of heart disease. [santemontreal.qc.ca]

Juvenile myelomonocytic leukemia (JMML) is a rare childhood neoplasm with poor prognosis except in the setting of Noonan syndrome, where prognosis is generally favorable. [ncbi.nlm.nih.gov]

Am J Med Genet A 2008; 146A: 620-628 Am J Cardiol 2007; 100:736-41 Noonan-LEOPARD Syndromes Genotype – Prognosis Correlations “PREDICTIVE MEDICINE” Gene-prognosis correlation 18. [slideshare.net]

However further studies are needed to determine overall long-term prognosis.[1] In terms of ocular prognosis, it appears that the severity of visual findings varies with an individual’s genetic variant. [eyewiki.aao.org]

Prognosis 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. [orpha.net]

Noonan syndrome (NS) is an etiologically heterogeneous disorder caused by mutations in the RAS-MAPK signaling pathway. [ncbi.nlm.nih.gov]

Noonan syndrome is phenotypically and etiologically heterogeneous. Detecting specific mutations in a patient ensures the correct diagnosis and appropriate care. Reproduction options can also be considered when familial mutations are found. [cadth.ca]

Moreover, using phoshoproteomics we show hypo- and hypertyrosyl phosphorylation of Fer kinase and PZR (Protein zero related), respectively and study their roles as (potential) interacting proteins in the etiology of both NS and LS. [universiteitleiden.nl]

In that report I spoke in terms of a "new syndrome" in order to stress that this condition could affect not only males but also females, and that it was also clinically and etiologically different from the true Turner 6 syndrome. [archpedi.jamanetwork.com]

It is unknown whether the development or progression of tumors is augmented by GH therapy, however there is concern based on epidemiological, animal and in vitro studies. [ncbi.nlm.nih.gov]

Summary Epidemiology The incidence of NS is estimated to be between 1:1000 and 1:2500 live births. [orpha.net]

While the underlying pathophysiologic mechanism of PIG is unclear, we suggest that the mitogen-activated protein kinase signal transduction pathway members (PTPN11, KRAS, SOS1, RAF1, SHOC2, NRAS) involved in cellular growth factor signaling, which are [ncbi.nlm.nih.gov]

The final chapter covers the critical area of treatment including prospects emerging from an improved understanding of the pathophysiology of these disorders. [bol.com]

Over the last decade, knowledge on clinical and genetic features and pathophysiologic backgrounds of Noonan syndrome has increased. [mdpi.com]

Although treatment algorithms are similar between LS patients with ventricular hypertrophy and patients with familial HCM, without an evidence-based diagnosis, despite their analogous character it is clear that the pathophysiology and dynamics of HCM [revespcardiol.org]

For example, severe heart defects may need to be repaired with surgery, and growth hormone medication may be used to help prevent restricted growth. [nhs.uk]

Prevention and outlook As many cases of Noonan syndrome occur randomly, there is currently no known way to prevent the condition developing. [medicalnewstoday.com]

Currently, there are no specific methods or guidelines to prevent Noonan Syndrome, since it is a genetic condition Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy [dovemed.com]

Prevention Because some cases of Noonan syndrome occur spontaneously, there's no known way to prevent it. However, if you have a family history of this syndrome, talk to your doctor about the benefits of genetic counseling before you have children. [mayoclinic.org]

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3. Rohrer T. Noonan syndrome: introduction and basic clinical features. Horm Res. 2009;72 Suppl 2:3-7.
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