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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.


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].

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 (NS) is the most common non-chromosomal syndrome seen in children and is characterized by short stature, dysmorphic facial features, chest deformity, a wide range of congenital heart defects and developmental delay of variable degree.[ncbi.nlm.nih.gov]
  • Analyzes chromosomes in newborns and infants for changes that can explain certain birth defects or developmental delays. Multiple testing options providing information on the genetic health of your baby during the first and second trimesters.[integratedgenetics.com]
  • It is our hope that this information can be added in the futur Noonan syndrome (NS) includes findings of short stature, heart defects, distinctive facial features, and developmental delays.[gemssforschools.org]
  • Friez, Developmental Delay: Gene Testing, Molecular Pathology in Clinical Practice, 10.1007/978-3-319-19674-9_7, (101-119), (2016). Christina Lissewski, Sarina G.[doi.org]
Pulmonary Valve Stenosis
  • The most common cardiac conditions are pulmonary valve stenosis and hypertrophic cardiomyopathy.[symptoma.com]
  • Definition: A multifaceted disorder characterized by short stature, webbed neck, ptosis, skeletal malformations, hypertelorism, hormonal imbalance, CRYPTORCHIDISM, multiple cardiac abnormalities (most commonly including PULMONARY VALVE STENOSIS ), and[hon.ch]
  • KW - Noonan syndrome KW - Poor growth KW - Pulmonary valve stenosis UR - UR - M3 - Articolo VL - 12 SP - 120 EP - 123 JO - Area Pediatrica T2 - Area Pediatrica JF - Area Pediatrica SN - 1591-0075 IS - 3 ER -[moh-it.pure.elsevier.com]
  • STENOSIS), and some degree of INTELLECTUAL DISABILITY.[profiles.umassmed.edu]
  • Congenital heart disease is common in most cases of Noonan syndrome, with the most common defect being pulmonary valve stenosis. Cutaneous symptoms of Noonan syndrome are varied and literature on the topic is limited.[dermnetnz.org]
Atrial Septal Defect
  • 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]
  • ., 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[symptoma.com]
Failure to Thrive in Infancy
  • […] to thrive in infancy Faltering weight in infancy Weight faltering in infancy [ more ] 0001531 High, narrow palate Narrow, high-arched roof of mouth Narrow, highly arched roof of mouth [ more ] 0002705 Hypertrophic cardiomyopathy Enlarged and thickened[rarediseases.info.nih.gov]
  • Failure to thrive from infancy to puberty (75%) Decreased appetite Digestive problems Frequent or forceful vomiting Swallowing difficulties Intestinal malrotation Need for a feeding tube Low gut motility Gastroparesis (delayed gastric emptying) Cryptorchidism[en.wikipedia.org]
  • Behavioral characteristics include failure to thrive in infancy (40%), motor developmental delay (20%), learning disability (15%), language delay (20%), mild hearing loss (12%), and mild mental retardation (up to 35%).[indianpediatrics.net]
  • […] to thrive in infancy, sometimes requiring tube feeding thin hair that becomes wooly and curly with age abnormal pigmentation males with uni- or bilateral cryptorchidism (up to 80%) renal anomalies (dilation of renal pelvis) hearing impairments cleft[invitae.com]
  • […] to thrive in infancy as a result of severe postnatal feeding difficulties; short stature; developmental delay or intellectual disability; coarse facial features (full lips, large mouth, full nasal tip); curly or sparse, fine hair; loose, soft skin with[rasopathiesnet.org]
Multiple Congenital Anomalies
  • congenital anomalies and intellectual disability.[invitae.com]
  • Diagnostic methods Noonan syndrome is a heterogeneous but clinically recognisable, multiple congenital anomaly syndrome. Scoring systems can help the diagnostic process [ 2 ].[ojrd.biomedcentral.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]
  • Clinical description The main facial features of NS are hypertelorism with down-slanting palpebral fissures, ptosis and low-set posteriorly rotated ears with a thickened helix.[orpha.net]
  • , posteriorly rotated ears 0000368 Micrognathia Little lower jaw Small jaw Small lower jaw [ more ] 0000347 Midface retrusion Decreased size of midface Midface deficiency Underdevelopment of midface [ more ] 0011800 Muscle weakness Muscular weakness 0001324[rarediseases.info.nih.gov]
  • set posteriorly rotated ears with thick helix (90%) Vivid blue or blue-green eyes (lighter than expected for background) thickened or ptotic eyelids hypertelorism Neonate and Infancy [ edit ] (age features are most striking) tall forehead hypertelorism[en.wikibooks.org]
Pterygium Colli
  • 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]
  • The neck is usually webbed (pterygium colli) and the ears low-set. The sternum may be deformed.[disorders.eyes.arizona.edu]
  • This swelling subsequently regresses and results in excess nuchal skin and pterygium colli after birth.[ojrd.biomedcentral.com]
Epicanthal Folds
  • ., 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]
  • 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]
  • There may be ptosis, epicanthic folds and low-set ears. Facial features are easiest to recognise in the infant or young child. There is a relatively large head with a high forehead, low posterior hairline and a short uptilted nose.[patient.info]
  • 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 folds (extra fold[en.wikipedia.org]
Skeletal Dysplasia
  • 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]
  • 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]
Hypertelorism
  • 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]
  • 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]
  • 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]
  • 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]
  • 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]
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]
  • Short neck. Low hairline across the neck. Vision problems: crossed eyes, squinting. Children often need glasses. Heart defect – this is usually discovered during pregnancy. May need medication and/or surgery. Low birth weight.[growingup.net]
  • Patients with Noonan syndrome also have a characteristic appearance: short neck, cervical skin fold, low set ears, hypertelorism.[asperbio.com]
  • Facial features include widely spaced eyes, light colored eyes, low set ears, a short neck, and a small lower jaw. Heart problems may include pulmonary valve stenosis.[en.wikipedia.org]
  • neck with extra skin folds at the back Some children with Noonan syndrome may experience intellectual disability or behavioural problems, such as clumsiness or irritability.[healthdirect.gov.au]
Delayed Milestone
  • 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]
Cryptorchidism
  • […] facial features that evolve with age; a broad, webbed neck; increased bleeding tendency; and a high incidence of congenital heart disease, failure to thrive, short stature, feeding difficulties, sternal deformity, renal malformation, pubertal delay, cryptorchidism[ncbi.nlm.nih.gov]
  • Webbed neck, chest deformity, cryptorchidism, mental retardation and bleeding diatheses also are frequently associated with this disease. This syndrome is relatively common, with an estimated incidence of 1 in 1,000-2,500 live births.[ncbi.nlm.nih.gov]
  • 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]
  • 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]
  • 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]

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

  • The medicines will usually be tested against another treatment called a control. This will either be a dummy treatment (a placebo) or a standard treatment already in use.[nhs.uk]
  • 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]
  • There is no specific treatment. Your provider will suggest treatment to relieve or manage symptoms. Growth hormone has been used successfully to treat short height in some people with Noonan syndrome.[nlm.nih.gov]
  • Comprehensive Treatments in One Location: Some children with Noonan syndrome benefit from treatment with growth hormone to help with their growth.[nyp.org]
  • Age-based Noonan syndrome-specific growth charts and treatment guidelines are available.[ncbi.nlm.nih.gov]

Prognosis

  • Prognosis With special care and counselling, the majority of children with NS will grow up and function normally in the adult world. Signs and symptoms lessen with age and most adults with NS do not require special medical care.[orpha.net]
  • Prognosis The outcome is assessed on the extent and severity of the problems in the individual patient. Most individuals with NS are able to lead normal lives.[patient.info]
  • Prognosis in terms of life expectancy generally depends on the severity of the heart defect. The Noonan Syndrome Foundation Email: info@teamnoonan.org Article including guidelines on the management of individuals with Noonan syndrome: Alicia A.[cincinnatichildrens.org]
  • Long-term prognosis tends to depend on the presence and severity of heart defects.[medicalnewstoday.com]

Etiology

  • 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]
  • 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.[doi.org]
  • (Etiology) Noonan Syndrome is caused by mutation in one of the following genes: PTPN11 gene SOS1 gene RAF1 gene KRAS gene NRAS gene BRAF gene The mutation can be inherited from a parent who carries the defective gene; the gene is inherited in an autosomal[dovemed.com]
  • Lupski Genetics in Medicine (2019) Pathogenic gene screening in 91 Chinese patients with short stature of unknown etiology with a targeted next-generation sequencing panel Lulu Yang, Chenhui Zhang, Wei Wang, Junqi Wang, Yuan Xiao, Wenli Lu, Xiaoyu Ma,[doi.org]

Epidemiology

  • Summary Epidemiology The incidence of NS is estimated to be between 1:1000 and 1:2500 live births.[orpha.net]
  • Epidemiology It is inherited in an autosomal dominant manner.[patient.info]
  • Idiopathic short stature: definition, epidemiology, and diagnostic evaluation. Growth Horm IGF Res. 2008 Apr;18(2):89–110. Callaway SR, Lesher JL. Keratosis pilaris atrophicans: case series and review. PediatrDermatol. 2004 Feb;21(1):14–7.[pedclerk.bsd.uchicago.edu]
  • EPIDEMIOLOGY Noonan syndrome is characterized by marked variable expressivity, which makes it difficult to identify mildly affected individuals. The overall incidence is believed to be between 1/1000 and 1/2500 live births.[flipper.diff.org]
Sex distribution
Age distribution

Pathophysiology

  • The final chapter covers the critical area of treatment including prospects emerging from an improved understanding of the pathophysiology of these disorders.[karger.com]
  • (eds) Growth disorders—pathophysiology and treatment. Chapman & Hall Medical, London, pp 623–639 Google Scholar 20. Ranke MB, Heidemann P, Knupfer C et al. (1988) Noonan syndrome: growth and clinical manifestations in 144 cases.[link.springer.com]
  • Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test Noonan syndrome (NS) is an autosomal dominant disorder of variable expressivity characterized by short stature, congenital heart[mayomedicallaboratories.com]

Prevention

  • Hospital for Sick Children Health A-Z Search a complete list of child health articles expand_more View All Drug A-Z Search a list of articles about medications expand_more View All Learning Hubs Browse a complete list of content groups Healthy Living & Prevention[aboutkidshealth.ca]
  • 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 Couples with a family history of Noonan syndrome may want to consider genetic counseling before having children. Images References Ali O, Donohoue PA. Noonan syndrome. In: Kliegman RM, Stanton BF, St. Geme JW, Schor NF, eds.[ufhealth.org]

References

Article

  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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Last updated: 2018-06-22 09:54