Question 1 of 10

    Noonan Syndrome

    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.

    Noonan Syndrome arises due to the following process: congenital.

    Presentation

    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].

    Entire body system
    Atrial Septal Defect
    • Many children with atrial septal defects have no symptoms.[rarediseases.org]
    • These may include pulmonary stenosis and atrial septal defect .[nicklauschildrens.org]
    • They may have: Narrowing of the valve that moves blood from the heart to the lungs Swelling and weakening of the heart muscle Atrial septal defects Blood Excessive bruising Nosebleeds Prolonged bleeding after an injury or surgery Blood cancer ( leukemia[webmd.com]
    Multiple Congenital Anomalies
    • congenital anomalies and intellectual disability.[invitae.com]
    • Diagnostic methods Noonan syndrome is a heterogeneous but clinically recognisable, multiple congenital anomaly syndrome.[ojrd.biomedcentral.com]
    Pediatric Disorder
    • NS is one of the RASopathies, which are a class of pediatric disorders associated with genes that are members of the mitogen-activated protein kinase (Ras/ MAPK ) pathway.[invitae.com]
    Pulmonary Valve Stenosis
    • Hypertrophic cardiomyopathy is common in those with critical congenital pulmonary valve stenosis.[dermnetnz.org]
    • Disease Pulmonary valve stenosis Pulmonary valve stenosis is a heart valve disorder that involves the pulmonary valve.[scripps.org]
    • STENOSIS ), and some degree of MENTAL RETARDATION .[hon.ch]
    • The most common include: pulmonary valve stenosis – the pulmonary valve allows blood with reduced oxygen content (deoxygenated) to leave the heart and go to the lungs.[betterhealth.vic.gov.au]
    • STENOSIS), and some degree of INTELLECTUAL DISABILITY.[profiles.umassmed.edu]
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  • Face, Head & Neck
    Hypertelorism
    • These individuals had small stature, hypertelorism, mild mental retardation and often ptosis and skeletal abnormalities, as well as undescended testes in the males.[whonamedit.com]
    • 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]
    • The facial features may include: low-set or rotated ears, and Hypertelorism (widely spaced eyes).[vibrationdata.com]
    • The distinctive facial features consist of a broad forehead, hypertelorism, downslanting palpebral fissures, a high-arched palate, and low-set, posteriorly rotated ears.[flybase.org]
    • S hort stature U nusual facies (Ocular hypertelorism, low set ears) N eck is webbed B leeding disorders U nusual chest shape (sunken- chest appearance) R AS MAPK mutation N ose is flat S tenosis (Pulmonic stenosis) Noon an syndrome![medicowesome.com]
    Short Neck
    • 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]
    • Patients with Noonan syndrome also have a characteristic appearance: short neck, cervical skin fold, low set ears, hypertelorism.[asperbio.com]
    • Other clinical manifestations of Noonan syndrome include: Webbed neck Short neck/low posterior hair line Pectus excavatum (sunken sternum) or pectus carinatum (protruding sternum) Scoliosis – abnormal lateral curvature of the spine Lymphoedema Bleeding[dermnetnz.org]
    • Head, Face, and Mouth Widely spaced eyes Deep groove between the nose and mouth Low-set ears that arch backward Short neck Extra skin on the neck (“webbing”) Small lower jaw High arch in the roof of the mouth Crooked teeth Bones and Chest Short height[webmd.com]
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  • neurologic
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  • Skin
    Pterygium Colli
    • The neck is usually webbed (pterygium colli) and the ears low-set.[disorders.eyes.arizona.edu]
    • 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]
    • Funke O, Pterygium colli.[heartviews.org]
    • During later childhood, the face may appear relatively coarse and begin to appear more triangular in shape; in addition, the neck lengthens, causing the webbing of the neck (pterygium colli) to appear more pronounced and/or the large, triangular muscles[rarediseases.org]
    • This swelling subsequently regresses and results in excess nuchal skin and pterygium colli after birth.[ojrd.biomedcentral.com]
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  • urogenital
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  • Eyes
    Epicanthal Folds
    • Clinical Characteristics Ocular Features: Noonan syndrome has prominent anomalies of the periocular structures including downward-slanting lid fissures, hypertelorism, epicanthal folds, high upper eyelid crease, and some limitation of ocular mobility[disorders.eyes.arizona.edu]
    • […] height/final height quicker Excess skin on the back of the neck Low hairline at the nape of the neck High hairline at the front of the head Large head Triangular face shape Broad forehead Short neck, webbed neck Hypertelorism (widely set eyes) (95%) Epicanthal[en.wikipedia.org]
    • The characteristic facial features include hypertelorism, epicanthal folds, down-slanting palpebral fissures, expressive triangular-shaped eyebrows, and ptosis.[touchendocrinology.com]
    • Facial features, which tend to change with age, may include hypertelorism, downward-slanting eyes, epicanthal folds, and low-set and posteriorly rotated ears.[mayomedicallaboratories.com]
    • There may be ptosis, epicanthic folds and low-set ears.[patient.info]
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  • Workup

    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.

    Treatment

    Prognosis

    Complications

    Cardiomyopathy
    • For example, there is an increase in hypertrophic cardiomyopathy in patients with a mutation of KRAS and an increased risk of juvenile myelomonocytic leukemia for a mutation of PTPN11.[en.wikipedia.org]
    • Biventricular hypertropic obstructive cardiomyopathy in Noonan syndrome.[radiopaedia.org]
    • Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood.[rasopathiesnet.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 cardiomyopathy[uniprot.org]
    • Pulmonic stenosis and hypertrophic cardiomyopathy are the most common forms of cardiac disease, but a variety of other lesions are also observed.[flybase.org]
    Congenital Heart Disease
    • She studied 833 patients at the congenital heart disease clinic, looking for other congenital abnormalities, and in 1963 presented a paper: "Associated non-cardiac malformations in children with congenital heart disease".[en.wikipedia.org]
    • It has been also confirmed that mutations in the PTPN11 gene have a very high incidence of congenital heart disease of at least 80%.[news-medical.net]
    • Noonan syndrome is characterised by: Distinctive facial appearance Short stature Chest deformity Congenital heart disease.[dermnetnz.org]
    • Many with Noonan syndrome will have congenital heart disease, and February is Congenital Heart Awareness Month.[friendshipcircle.org]
    • Characteristics may include: congenital heart disease, short stature, distinctive facial features, dental problems, bruising, bleeding, and learning difficulties.[vibrationdata.com]
    Cryptorchidism
    • Most males with this disorder have undescended testicles (cryptorchidism).[hon.ch]
    • Males: cryptorchidism (70-80%), infertility.[pedclerk.bsd.uchicago.edu]
    • Other features All of the following: intellectual disability, cryptorchidism, and lymphatic vessel dysplasia One of the following: intellectual disability, cryptorchidism, or lymphatic vessel dysplasia Until recently, diagnosis was made solely on the[aafp.org]
    • 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]
    • Additional relatively frequent features include multiple skeletal defects (chest and spine deformities), webbed neck, mental retardation, cryptorchidism, and bleeding diathesis (summary by Tartaglia et al., 2002 pubmed:11992261 ).[flybase.org]
    Growth Retardation
    • Additionally, at age 2 years, growth retardation was more severe and frequent in patients with PTPN11 mutations than in those with mutations in SOS1 or NSML- PTPN11 .[emedicine.medscape.com]
    • Despite these recent finding, the underlying mechanisms of growth retardation and GH therapy in NS remain to be further explored in order to improve treatment for short stature.[hoajonline.com]
    • retardation Winging of the scapula Extra fold of skin at the inner corner of the eye Vision defects such as: Strabismus Bulging eyes Inward or outward turning of the eye Nystagmus - jerking movement of the eye Chronic ear infections Dental defects Poor[dovemed.com]
    • Postnatal growth retardation resulting in short stature occurs in fewer than 50% of affected persons.[rasopathiesnet.org]
    • Short stature and failure to thrive Growth retardation is an important feature of Noonan syndrome and approximately 50- 70% of patients have short stature.[flipper.diff.org]
    Mental Retardation
    • Additional relatively frequent features include multiple skeletal defects (chest and spine deformities), webbed neck, mental retardation, cryptorchidism, and bleeding diathesis (summary by Tartaglia et al., 2002 pubmed:11992261 ).[flybase.org]
    • Iris coloboma, ptosis, hypertelorism, and mental retardation: Baraitser-Winter syndrome or Noonan syndrome?.[invitae.com]
    • A child may be affected by Noonan syndrome in various ways: unusual facial characteristics, short stature, heart defects, other physical problems, and sometimes mental retardation; these symptoms also vary from patient to patient.[eurordis.org]
    • These include: Craniofacial telecanthus , hypertelorism low-set ears , rotated ears /- thickened helix epicanthus facial asymmetry mental retardation microgenia low neck hairline Cervico-thoracic pterigium colli : webbed neck winged scapulae pectus excavatum[radiopaedia.org]
    Skeletal Dysplasia
    • 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]
    Thrombocytopenia
    • Thrombocytopenia and abnormal platelet function with abnormalities of coagulation factors are found in about 50% of cases resulting in easy bruising and prolonged bleeding.[disorders.eyes.arizona.edu]
    • Due to coagulation factor deficiencies, platelet dysfunction, and/or thrombocytopenia, affected individuals may have a history of abnormal and easy bruising and bleeding.[rarediseases.org]
    • Bleeding disorders Easy bruising Amegakaryocytic thrombocytopenia (low platelet count) Blood clotting disorders Von Willebrand disease Prolonged activated partial thromboplastin time Partial deficiency of Factor VIII:C Partial deficiency of Factor XI:[en.wikipedia.org]
    • Polyarthritis, papillary rash on lower limbs, Coombs positive hemolytic anemia, lymphopenia, thrombocytopenia.[omicsonline.org]
    • Thrombocytopenia in SOS1 mutation.[pedclerk.bsd.uchicago.edu]
    Turner Syndrome
    • Syndrome Female Pseudo-Turner Syndrome Female Pseudo Turner Syndrome Pseudo-Turner Syndrome, Female Syndrome, Female Pseudo-Turner Turner Syndrome, Male Turner Syndrome, Male Syndrome, Male Turner Turner's Syndrome, Male Male Turner's Syndrome Syndrome[profiles.umassmed.edu]
    • Webbing of the neck with Turner's syndrome in the male.[heartviews.org]
    • It is referred to as the male version of Turner's syndrome; however, the genetic causes of Noonan syndrome and Turner syndrome are distinct and both males and females are affected.[en.wikipedia.org]
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  • Etiology

    Epidemiology

    Sex distribution
    Age distribution

    Pathophysiology

    Prevention

    Summary

    Patient Information

    Self-assessment

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    References

    1. Romano AA, Allanson JE, Dahlgren J, et al. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. 2010;126:746-59.
    2. Roberts AE, Allanson JE, Tartaglia M, Gelb BD. Noonan syndrome. Lancet. 2013;381:333-42.
    3. Rohrer T. Noonan syndrome: introduction and basic clinical features. Horm Res. 2009;72 Suppl 2:3-7.
    4. Roelofs RL, Janssen N, Wingbermühle E, Kessels RP, Egger JI. Intellectual development in Noonan syndrome: a longitudinal study. Brain Behav. 2016;6:e00479.
    5. Wilkinson JD, Lowe AM, Salbert BA, et al. Outcomes in children with Noonan syndrome and hypertrophic cardiomyopathy: A study from the Pediatric Cardiomyopathy Registry. Am Heart J. 2012;164:442-8.
    6. Baldassarre G, Mussa A, Dotta A, et al. Prenatal features of Noonan syndrome: prevalence and prognostic value. Prenat Diagn. 2011;31:949-54.
    7. Sznajer Y, Keren B, Baumann C, Pereira S, Alberti C, Elion J, Cavé H, Verloes A. The spectrum of cardiac anomalies in Noonan syndrome as a result of mutations in the PTPN11 gene. Pediatrics. 2007;119:e1325-31.
    8. Prendiville TW, Gauvreau K, Tworog-Dube E, Patkin L, Kucherlapati RS, Roberts AE, Lacro RV. Cardiovascular disease in Noonan syndrome. Arch Dis Child. 2014;99:629-34.
    9. Allanson JE, Roberts AE. Noonan Syndrome. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from http://www.ncbi.nlm.nih.gov/books/NBK1124/
    10. Kouz K, Lissewski C, Spranger S, et al. Genotype and phenotype in patients with Noonan syndrome and a RIT1 mutation. Genet Med. 2016;18:1226-34.

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