Noonan syndrome is an autosomal dominant genetic condition characterized by distinctive facial features, short stature, cardiac defects, coagulopathy, skeletal abnormalities, and normal to mild cognitive impairment. In most affected individuals, it is a result of mutations in one or more of the following genes: PTPN11, SOS1, KRAS, BRAF, NRAS, RAF1, MEK1.
Individuals with Noonan syndrome have abnormal facial features, congenital heart disease, short stature, and chest deformity . 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 . 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 . 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 .
Entire Body System
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]
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]
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]
These may include pulmonary stenosis and atrial septal defect. [nlm.nih.gov]
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]
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.  Skin findings These include the following: Lymphedema (See the images below) Lymphedema of the feet in an infant is shown. [emedicine.medscape.com]
Older individuals can also develop lymphedema, usually in the ankles and lower legs. [medicinenet.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]
Inheritance LEOPARD syndrome is an autosomal dominant multiple congenital anomaly syndrome, with high penetrance and markedly variable expression. [atlasgeneticsoncology.org]
Jaw & Teeth
We describe an infant prenatally diagnosed with hydrops fetalis ultimately found to have Noonan syndrome (NS). [ncbi.nlm.nih.gov]
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]
[…] 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]
fetalis, nonimmune, and/or atrial septal defect, Capillary malformation-arteriovenous malformation 1 51 HRAS Costello syndrome, Congenital myopathy with excess of muscle spindles AD 43 31 KAT6B Ohdo syndrome, SBBYS variant, Genitopatellar syndrome AD [blueprintgenetics.com]
Taybi H (1990) Radiology of syndromes, metabolic disorders and skeletal dysplasias. 3rd edn. Year Book, Chicago, pp 337–338 Google Scholar 14. [doi.org]
Skeletal dysplasia was proven to be secondary to a disorder of RAS-mitogen activated protein kinase (MAPK) pathway which is essential for regulation of cell differentiation and growth including bone homeostasis. [bone-abstracts.org]
The other features include skeletal dysplasia, bone fractures, severe pain, and limited mobility. Hyperthyroidism has been reported. [accessanesthesiology.mhmedical.com]
dysplasia MVRCS association Nail-patella syndrome Nance-Horan syndrome Neu-Laxova syndrome Neurocutaneous syndrome Nodular embryo Noonan syndrome Noonan's syndrome Oculo-cerebro-cutaneous syndrome Oculodentodigital syndrome Oculodento-osseous dysplasia [icd9data.com]
Low-Set Posteriorly Rotated Ears
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]
posteriorly rotated ears with a thickened helix, and a broad forehead), congenital heart defects and unusual pectus deformity. [orpha.net]
E, Patient 279914 aged 6.8 years showing a convergent squint, ptosis, low‐set posteriorly rotated ears and wide neck. [onlinelibrary.wiley.com]
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]
J Indian Soc Pedod Prev Dent 2007;25:144-7 Ullrich (1930) and Turner (1938) described females with a syndrome of short stature, sexual infantilism and a pattern of characteristic minor anomalies like pterygium colli. [jisppd.com]
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]
epicanthal folds, ptosis, ocular hypertelorism), and micrognathia. Individuals with Noonan syndrome often may have either pectus excavatum or pectus carinatum. Scoliosis may also be present. [symptoma.com]
External features were hypertelorism (74%), downward sloping palpebral apertures (38%), epicanthic folds (39%) and ptosis (48%). [nature.com]
(A) Frontal views showing a triangular face with pointed chin; tall forehead; bilateral ptosis, predominantly on the right; sparse eyebrows; epicanthic folds and protruding ears. [frontiersin.org]
Newborns have broad and high forehead, wide-spaced and downward slanting palpebral fissures, ptosis, epicanthal folds, depressed nasal root with upturned nasal tip, high arched palate, micrognathia, low posterior hairline and the short and/or webbed neck [news-medical.net]
Face, Head & Neck
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]
The facial features may include: low-set or rotated ears, and Hypertelorism (widely spaced eyes). Another characteristic is "Pectus excavatum," which is a concave shape in the chest. [vibrationdata.com]
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]
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]
Mild Cognitive Impairment
Noonan syndrome is an autosomal dominant genetic condition characterized by distinctive facial features, short stature, cardiac defects, coagulopathy, skeletal abnormalities, and normal to mild cognitive impairment. [symptoma.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) . Noonan syndrome should be considered in individuals with pulmonary valve stenosis, eye abnormalities (e.g., epicanthal folds, ptosis, ocular hypertelorism), and micrognathia . 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 . 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 . The most common cardiac conditions are pulmonary valve stenosis and hypertrophic cardiomyopathy. Tests that can be used to evaluate the heart include echocardiogram , 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).
Genetic testing permits definitive diagnosis of Noonan syndrome . 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  . 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]
However GH treatment for NS is still controversial. [doi.org]
Growth may be stimulated by treatment with growth hormone. After satisfactory growth, testosterone treatment may help boys whose testes are underdeveloped. Testosterone stimulates the development of a more masculine appearance. [merckmanuals.com]
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]
However further studies are needed to determine overall long-term prognosis. 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]
The finding is poorly understood with notable variability in course and prognosis, but is significantly associated with mortality in infancy. [news-medical.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]
Etiology In approximately 50% of cases, the disease is caused by missense mutations in the PTPN11 gene (12q24.1), resulting in a gain of function of the non-receptor protein tyrosine phosphatase SHP-2 protein. [orpha.net]
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]
Noonan syndrome occurs across all ethnic groups equally. Pathophysiology The mutation of the RAS/MAPK pathway involved Noonan syndrome classifies NS as RASopathy. [statpearls.com]
In NS, the underlying pathophysiological mechanism involves dysregulation of the RAS-MAPK signaling, almost always due to a gain-of-function variant in one of the associated genes. [eyewiki.aao.org]
Early surgical revascularization should be pursued in order to prevent symptom progression. [ncbi.nlm.nih.gov]
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]
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