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Noonan syndrome

Noonan syndrome
Classification & external resources
ICD-10 Q87.1
ICD-9 759.89
OMIM 163950
DiseasesDB 29094
MedlinePlus 001656
eMedicine ped/1616 
MeSH D009634

Noonan Syndrome (NS) is a relatively common congenital genetic condition which affects both males and females. It used to be referred to as the male version of Turner's syndrome[1]; however, the genetic causes of Noonan syndrome and Turner syndrome are distinct. The principal features include congenital heart malformation, short stature, learning problems, indentation of the chest, impaired blood clotting, and a characteristic configuration of facial features. The syndrome is named after Dr Jacqueline Noonan.

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.



  Recurrence in siblings and apparent transmission from parent to child has long suggested a genetic defect with autosomal dominant inheritance and variable expression. A person with NS has up to a 50% chance of transmitting it to a child. The fact that an affected parent is not always identified for children with NS suggests several possibilities:

  1. a parent could carry the gene without being affected (incomplete penetrance)
  2. manifestations are variably expressed and could be so subtle as to go unrecognized (variable expressivity)
  3. a high proportion of cases represent new, sporadic mutations or
  4. Noonan syndrome is heterogeneous, comprising more than one similar condition of differing cause, some not inherited.

In most of the families with multiple affected members, NS maps to chromosome 12q24.1. In 2001, it was reported that approximately half of a group of patients with Noonan syndrome carried a mutation of the PTPN11 gene at that location, which encodes protein tyrosine phosphatase SHP-2.[2] The SHP2 protein is a component of several intracellular signal transduction pathways involved in embryonic development that modulate cell division, differentiation, and migration, including that mediated by the epidermal growth factor receptor. The latter pathway is important in the formation of the cardiac semilunar valves. It has recently been shown that activating mutations in SOS1 also give rise to NS.[3] Shp2 and SOS1 both have roles as positive regulators of the Ras/MAP kinase pathway suggesting that dysregulation of this pathway may play a major role in the genesis of this syndrome.[4] Additional mutations in KRAS [5] and RAF1[6] genes have been reported to cause Noonan syndrome in a smaller percentage of individuals with the syndrome.

Manifestations by organ system

The most prevalent (common) signs are highlighted in bold with frequency listed in parentheses.

HEART(2/3 of patients have a heart defect)

Pulmonary Valvular Stenosis(50%)
Septal defects: atrial(10%) or ventricular(less common)
Heart murmur


Failure to thrive as an infant
Decreased appetite
Digestive problems
Frequent or forceful vomiting
Swallowing difficulties


Cryptorchidism (undescended testicles)(almost all males)


Posterior cervical Hygroma (webbed neck)
Lymphedema (build-up of body fluid due to poor functioning of the lymphatic system)


Poor coordination
Motor delay
Mental retardation —(1/3 of patients have mild MR)
Learning disabilities
Speech and language delays


Some patients with Noonan Syndrome suffer from severe joint pain or muscle pain often with no identifiable cause


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
Combined Coagulation deficiencies


Arnold Chiari Malformation (Type 1) has been noted in some patients with Noonan Syndrome

By physical appearance


Short stature
Cervical (neck) spine fusion
Prominence of breast bone (pectus carinatum)
Depression of breast bone (pectus excavatum)
Joint contractures or tightness
Joint hyperextensibility or looseness
Growth retardation
Winging of the scapula
Hypotonia (low muscle tone)


Excess skin on the back of the neck
Low hairline at the nape of the neck
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


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)


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)


Lymphedema (swelling of the extremities)
Keloids (scar hypertrophy)
Hyperkeratosis - overdevelopment of outer skin layer
Pigmented nevi (birthmark)


Despite identification of four 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 patient can be tested for mutations in the PTPN11, SOS1, or KRAS genes, however 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 such a 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.


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 later produced a paper entitled "Hypertelorism with Turner Phenotype", and in 1971 at the Symposium of Cardiovascular defects, the name 'Noonan Syndrome' became officially recognized.

See also

  • 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[7]
  • 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.
  • PTPN11— a gene mutated in Noonan Syndrome and LEOPARD Syndrome
  • SOS1— a gene mutated in Noonan Syndrome
  • KRAS— A gene mutated in Noonan Syndrome and Cardiofaciocutaneous syndrome.
  • Dermatoglyphics


  1. ^ Curcić-Stojković O, Nikolić L, Obradović D, Krstić A, Radić A (1978). "[Noonan's syndrome. (Male Turner's syndrome, Turner-like syndrome)]". Med Pregl 31 (7-8): 299-303. PMID 692497.
  2. ^ Tartaglia M, et al. Nature Genetics 2001;29:465-468
  3. ^ Roberts AE, et al. Nature Genetics Published online: 3 December 2006
  4. ^ Bentires-Alj M, et al. Nat Med. 2006; 12:283-285
  5. ^ Shubbert, S. et al. (2006) Germline KRAS mutations cause Noonan syndrome. Nature Genetics, 29, 465-468.
  6. ^ Razzaque, M. A. et al. Nature Genetics Published online: 1 July 2007
  7. ^ CDC. (2004). Fetal Alcohol Syndrome: Guidelines for Referral and Diagnosis. Can be downloaded at

short stature (Aarskog-Scott syndrome, Cockayne syndrome, Cornelia de Lange Syndrome, Dubowitz syndrome, Noonan syndrome, Robinow syndrome, Silver-Russell dwarfism, Seckel syndrome, Smith-Lemli-Opitz syndrome)

limbs (Holt-Oram syndrome, Klippel-Trenaunay-Weber syndrome, Nail-patella syndrome, Rubinstein-Taybi syndrome, Sirenomelia, VACTERL association)

overgrowth (Beckwith-Wiedemann syndrome, Sotos syndrome, Weaver syndrome)

Marfan syndrome - Alport syndrome - Bardet-Biedl syndrome - Zellweger syndrome
Otherspleen: Asplenia - Splenomegaly

endocrine glands: Persistent thyroglossal duct - Thyroglossal cyst

Situs inversus - Conjoined twins

Cowden syndrome - Hamartoma
  This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Noonan_syndrome". A list of authors is available in Wikipedia.
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