|Classification and external resources|
A 12-year-old female with Noonan syndrome. Typical webbed neck. Double structural curve with rib deformity.
Noonan syndrome (NS) is a relatively common autosomal dominant congenital disorder that affects both males and females equally:550. It used to be referred to as the male version of Turner's syndrome (and is still sometimes described in this way); however, the genetic causes of Noonan syndrome and Turner syndrome are distinct. The principal features include congenital heart defect (typically pulmonary valve stenosis) also ASD, hypertrophic cardiomyopathy, short stature, learning problems, pectus excavatum, impaired blood clotting, and a characteristic configuration of facial features including a webbed neck and a flat nose bridge. The syndrome is named after Dr. Jacqueline Noonan. It is a RASopathy, as the syndrome is in the family of RAS-MAPK pathway disorders.
It is believed that between approximately 1 in 1,000 and 1 in 2,500 children worldwide are born with NS. It is one of the most common genetic syndromes associated with congenital heart disease, similar in frequency to Down syndrome. However, the range and severity of features can vary greatly in patients with NS. Therefore, the syndrome is not always identified at an early age.
- 1 Characteristics
- 1.1 By organ system
- 1.2 By physical appearance
- 2 Causes
- 3 Diagnosis
- 4 History
- 5 See also
- 6 References
- 7 External links
Often called a "hidden" condition, the person affected may have no obvious casual signs to the onlooker, but the problems may be many and complex. The most prevalent (common) signs are highlighted in bold with frequency listed in parentheses.
By organ system
Up to ~85% of people have one of the heart defects:
- Pulmonary Valvular Stenosis —(between 50-60%)
- Septal defects: atrial —(between 10-25%) or ventricular —(between 5-20%)
- Heart murmur
- Hypertrophic Cardiomyopathy - HCM (between 12-35%)
- Failure to thrive as an infant
- Decreased appetite
- Digestive problems
- Frequent or forceful vomiting
- Swallowing difficulties
- Intestinal malrotation
- Cryptorchidism (undescended testicles) —
- Posterior cervical hygroma (webbed neck)
- Lymphedema (build-up of body fluid due to poor functioning of the lymphatic system)
- intellectual disability usually mild; Jaqueline Noonan has stated that she met a pharmacist in his 60's who diagnosed himself.
- Motor development delay
- Learning disabilities
- Speech-language pathology
- Autism, pervasive developmental disorder can occur
- frequent illnesses, pain, headaches and fatigue that can affect school attendence is possible.
- Neuropsychological testing recommended to find strengths and challenges to tailor support needed for school, career.
- 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:C
- Partial deficiency of Factor XII:C
- Platelet dysfunction
- Combined coagulation defects
- Many people affected by Noonan Syndrome suffer from joint pain or muscle pain, particularly in adulthood, which varies in severity. The cause is unknown.
- Arnold-Chiari Malformation (Type 1), which can lead to hydrocephalus has been noted in some patients
By physical appearance
Stature and posture
- Short stature
- Cervical (neck) spine fusion
- Prominence of breast bone (pectus carinatum)
- Depression of breast bone (pectus excavatum)
- Joint contractures or tightness
- Joint hypermobility or looseness
- Growth retardation
- Winging of the scapula
- Hypotonia (low muscle tone) and Hypermobility Syndrome
- Lordosis (increased hollow in the back) due to poor stomach muscle tone
- 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, posterior cervical
- Curly hair
- Widely set eyes (hypertelorism) —(95%)
- Drooping of the eyelids (ptosis (eyelid))
- Epicanthal folds (extra fold of skin at the inner corner of the eye)
- Proptosis (bulging eyes)
- Refractive visual errors
- Inward or outward turning of the eyes (strabismus)
- Nystagmus - jerking movement of the eyes
- Small, upturned nose
Ears and hearing
- Low set ears —(over 90%)
- Backward rotated ears —(over 90%)
- Thick helix of ear (outer rim) —(over 90%)
- Incomplete folding of ears
- Chronic Otitis media (ear infections)
Mouth and speech
- Deeply grooved philtrum (top lip line) —(over 90%)
- Micrognathia (undersized lower jaw)
- High Arched palate
- Dental problems
- Articulation Difficulties
- Poor tongue control
- Bluntly ended fingers
- Extra padding on fingers and toes
- Edema of the back of hands and tops of feet
- Cubitus valgus (elbow deformity: with abnormal turning-in)
- Lymphedema -lymph swelling of the extremities
- Keloid formation, excessive scar formation
- Hyperkeratosis - overdevelopment of outer skin layer
- Pigmented nevi darkly pigmented skin spots
- Connective Tissue Disease
Recurrence in siblings and apparent transmission from parent to child has long suggested a genetic defect with autosomal dominant inheritance and variable expression. Mutations in the Ras/mitogen activated protein kinase signaling pathways are known to be responsible for ~70% of NS cases.
A person with NS has up to a 50% chance of transmitting it to their offspring. The fact that an affected parent is not always identified for children with NS suggests several possibilities:
- manifestations could be so subtle as to go unrecognized (variable expressivity)
- NS is heterogeneous, comprising more than one similar condition of differing causes, some not inherited, or
- a high proportion of cases represent new, sporadic mutations.
|Type||Online Mendelian Inheritance in Man database||Gene||Description|
|NS1||163950||PTPN11||In most families with multiple affected members, NS maps to chromosome 12 q24.1. Approximately half of a group of patients with NS carried a mutation of the PTPN11 gene at that location, which encodes protein tyrosine phosphatase SHP-2. This protein is a component of several intracellular signal transduction pathways involved in embryonic development that modulate cell division, differentiation, and migration, including one mediated by the epidermal growth factor receptor, which is important in the formation of the half-moon shaped heart valves.
Duplication of chromosome region 12q24 encompassing gene PTPN11 can also result in an apparent NS.
|NS2||605275||unknown (autosomal recessive)|
|NS3||609942||KRAS||Mutations in KRAS genes can cause NS in a smaller percentage of individuals, as reported 2006.|
|NS4||610733||SOS1||Activating mutations in SOS1 can give rise to NS, as reported 2006. SHP-2 and SOS1 positively regulate the Ras/MAP kinase pathway, suggesting that its dysregulation plays a role in NS development.|
|NS5||611553||RAF1||Mutations in RAF1genes can cause NS in a smaller percentage of individuals, as reported in 2007.|
Despite identification of six causative genes, the diagnosis of Noonan syndrome is still based on clinical features. In other words, it is made when a physician feels that a patient has enough of the features to warrant the label indicating association.
The following genes are known to cause NS with the percentage of cases in brackets. PTPN11 (50%) RAF1 (3-17%) SOS1 (10%), KRAS (1%), NRAS (unknown) or BRAF (unknown).
An absence of a mutation will not exclude the diagnosis as there are more as yet undiscovered genes that cause NS. The principal values of making a genetic diagnosis are that it guides additional medical and developmental evaluations, it excludes other possible explanations for the features, and it allows more accurate recurrence risk estimates. With more genotype-phenotype correlation studies being performed, a positive genetic diagnosis, will help the clinician to be aware of possible anomalies specific to that certain gene mutation. For example, there is an increase in hypotrophic cardiomyopathy in patients with a mutation on the KRAS gene, and an increased risk of Juvenile myelomonocytic leukemia for a mutation of the PTPN11 gene. In the future, further studies may lead to a targeted management of Noonan Syndrome symptoms, depending on what genetic mutation a patient has.
Jacqueline Noonan was practicing as a pediatric cardiologist at the University of Iowa when she noticed that children with a rare type of heart defect, valvular pulmonary stenosis, often had a characteristic physical appearance with short stature, webbed neck, wide spaced eyes, and low-set ears. Both boys and girls were affected. Even though these characteristics were sometimes seen running in families, chromosomes appeared grossly normal. She studied 833 patients at the congenital heart disease clinic, looking for other congenital abnormalities, and in 1962 presented a paper: "Associated non-cardiac malformations in children with congenital heart disease". This described 9 children who in addition to congenital heart disease had characteristic faces, chest deformities and short stature. Both males and females were found to be similarly affected, and the chromosomes were apparently normal.
Dr. John Opitz, a former student of Dr. Noonan, first began to call the condition "Noonan Syndrome" when he saw children who looked like those whom Dr. Noonan had described. Dr. Noonan produced a paper entitled "Hypertelorism with Turner Phenotype" in 1968, and in 1971 at the Symposium of Cardiovascular defects, the name 'Noonan Syndrome' became officially recognized.
- Turner syndrome — a different disorder which is often confused with Noonan syndrome because of several physical features that they have in common.
- Fetal alcohol syndrome — another disorder that is sometimes confused with Noonan syndrome because of some common facial features and mental retardation
- Rasopathies, particulalrly :
- Costello Syndrome
- Legius syndrome
- Leopard syndrome— A related disorder caused by mutations in PTPN11 that are catalytically inactivating.
- Cardiofaciocutaneous syndrome — A related disorder which also affects genes encoding elements of the Ras/MAP kinase pathway.
- James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0.
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- "Noonan syndrome" at Dorland's Medical Dictionary
- Charity Nebbe (27 February 2014). "Noonan Syndrome with guest Dr Jaqueline Noonan". Iowa Public Radio, Talk of Iowa. Retrieved 27 February 2014.
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- Schubbert S, Zenker M, Rowe SL, et al (2006). "Germline KRAS mutations cause Noonan syndrome". Nat. Genet. 38 (3): 331–6. doi:10.1038/ng1748. PMID 16474405.
- Roberts AE, Araki T, Swanson KD, et al (2007). "Germline gain-of-function mutations in SOS1 cause Noonan syndrome". Nat. Genet. 39 (1): 70–4. doi:10.1038/ng1926. PMID 17143285.
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- Razzaque MA, Nishizawa T, Komoike Y, et al (2007). "Germline gain-of-function mutations in RAF1 cause Noonan syndrome". Nat. Genet. 39 (8): 1013–7. doi:10.1038/ng2078. PMID 17603482.
- De Luca, A.; Bottillo, I.; Sarkozy, A.; Carta, C.; Neri, C.; Bellacchio, E.; Schirinzi, A.; Conti, E.; Zampino, G.; Battaglia, A.; Majore, S.; Rinaldi, M. M.; Carella, M.; Marino, B.; Pizzuti, A.; Digilio, M. C.; Tartaglia, M.; Dallapiccola, B. (2005). "NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome". American Journal of Human Genetics 77 (6): 1092–1101. doi:10.1086/498454. PMC 1285166. PMID 16380919.
- Noonan, JA (1968). "Hypertelorism with Turner phenotype. A new syndrome with associated congenital heart disease". Hypertelorism with Turner phenotype. A new syndrome with associated congenital heart disease. Noonan JA. Am J Dis Child. Oct; 116 (4): 373–80. PMID 4386970.
- CDC. (2004). Fetal Alcohol Syndrome: Guidelines for Referral and Diagnosis. Can be downloaded at http://www.cdc.gov/fas/faspub.htm.
|Wikimedia Commons has media related to Noonan syndrome.|
- Noonan Syndrome Foundation USA, 501c3 Charitable Organization
- Noonan Syndrome Foundation Brochure
- 2014 Noonan Syndrome Conference Details
- Noonan Syndrome Registration Form
- Noonan Syndrome Foundation Online Support Group Facebook
- Management of Noonan Syndrome - Clinical Guideline DOI:10.1542/peds.2009-3207
- GeneReviews: Noonan syndrome
- Medline Plus - Noonan Syndrome
- Noonan syndrome on the Open Directory Project
- Noonan Syndrome Is a RASopathy - The RASopathies Foundation
- The Noonan Syndrome Association UK charity for families and individuals affected by Noonan Syndrome