Noonan Syndrome


Noonan syndrome is a relatively common autosomal dominant syndrome characterized by dysmorphic facial features, cardiac abnormalities, short stature, chest wall abnormalities, and cryptorchidism.

Although autosomal dominant inheritance has been described, 60% of cases are due to de novo mutations. It is the second most common syndromic cause of congenital heart disease after Down’s syndrome affecting 1/1000-2500 live births. Noonan syndrome is caused by a missense mutation in the PTPN11 gene on chr 12q24.1 in 50% of cases. Other mutations include SOS1 (10-15%), RAF1 (5-10%), KRAS (3%), NRAS, and BRAF. As many as 20% of cases are idiopathic. 

NS is typically inherited in an autosomal dominant pattern with variable expression.


Intrauterine findings

  • Lymphatic dysfunction
    • Polyhydramnios
    • Nuchal translucency
    • Prefrontal edema
    • Hydrothorax
    • Lymphedema of the hands and feet at birth
  • Normal karyotype


Physical exam findings

A 3 month old infant with Noonan syndrome.  Note the eyebrow slant and left-side eyelid dropping.

Same infant, with low-set, posteriorly rotated, and an abnormally formed ear.

  • Short stature (50 – 70%)
    • Normal birth weight and height
    • Decreased height velocity in the first year of life
    • Thought to be caused by low levels of growth hormone
  • Deeply grooved philtrum
  • Hypertelorism: Widely spaced eyes
  • Depressed nasal bridge
  • Down-slanting palpebral fissures
  • Low set ears, posteriorly rotated
  • High arched palate
  • Misalignment of the teeth
  • Micrognathia
  • Short neck with webbing
  • Low hairline on the neck
  • Widely spaced nipples
  • Pectus excavatum or pectus carinatum (up to 90% have both, usually pectus carinatum superiorly and pectus excavatum inferiorly)
  • Scoliosis
  • As patients age, facial shape becomes increasingly triangular


Systems affected

  • Cardiovascular
    • Pulmonary valve stenosis (60%).  ECG variations such as intraventricular conduction delay (50%).  ASD (25%).  Pulmonary artery stenosis (15%)  Hypertrophic cardiomyopathy (up to 70% in RAF1 mutation)  Less commonly: PDA, tetralogy of Fallot, VSD, coarctation of the aorta
  • Heme
    • Coagulopathy in 60% of patients. Caused by deficiency in Factor VIII, XI, XII or aPTT.  Easy bruising, particularly in PTPN11 mutation.  Thrombocytopenia in SOS1 mutation.  Epistaxis, prolonged bleeding following injury & menorrhagia
  • Skeletal
    • Cubitus valgus, Scoliosis, Talipesequinovarus, Pectuscarinatum superiorly, pectusexcavatum inferiorly
  • Lymphatics
    • Lymphedema, Intestinal/pulmonary lymphangiectasia
  • Genitourinary
    • Delayed puberty; start at 13-14 with lower growth spurt.  Males: cryptorchidism (70-80%), infertility. Females: normal puberty and fertility with menarche at 14.5yrs
  • Development
    • Usually normal development but some have mild intellectual delay, particularly seen in KRAS mutation.  Feeding difficulty, recurrent vomiting, poor sucking, prolonged feeding.  Can lead to failure to thrive.  Usually resolves by 1-2years old
    • Speech impairment, possibly due to hearing impairment caused by recurrent otitis media.
    • Delayed milestones (predicted by feeding difficulty).  Average age to walk is 21 months.  Speaking 2-word sentences at 31 months
  • Cutaneous abnormalities
    • Keratosis pilaris atrophicansfaciei, Hyperelastic skin, Dystrophic nails
  • Other
    • Predisposition to myeloproliferative disorders, seen most often in PTPN11 mutations.  High spontaneous remission rate.
    • Occular abnormalities, strabismus seen in 50-60% & refractive errors seen in 70%
    • Neurological abnormalities such as behavioral problems including irritability and poor self-esteem.  Seizures in 10%, Migraines in 45%
    • Recurrent otitis media, particularly seen in the first year of life can lead to hearing loss if not properly treated


Differential diagnosis

  • Turner’s syndrome: presents with similar dysmorphic facies, short stature and widely-spaced nipples but differs in that patients have an abnormal karyotype (45XO),  only females are affected, patients have left-sided heart abnormalities, and renal pathology and developmental delay are more common
  • Costello syndrome: Caused by a mutation in the HRAS protooncogene, Costello syndrome also presents with cardiac abnormalities, ECG anomalies, decreased growth velocity in the post-natal period caused by low growth hormone levels, feeding difficulties, misalignment of the teeth, and issues with vision. Unlike Noonan syndrome, Costello syndrome is associated with Chiari I malformation, macrosomia, and significantly higher risk of papillomas, rhabdomyosarcomas, and neuroblastomas
  • Cardio-facio-cutaneous syndrome: Like Noonan syndrome, patients have hypertelorism, down-slanting palpebral fissures, micrognathia, low-set ears, pulmonic valve stenosis, and keratosis pilaris. Unlike Noonan syndrome, however, cardio-facio-cutaneous syndrome is extremely rare, with an estimated 200-300 patients affected worldwide. Noonan syndrome is less likely to have intellectual disability and more likely to have lymphedema and cryptorchidism.
  • LEOPARD syndrome: Also referred to as Noonan Syndrome with Multiple Lentigines (NSML). Patients classically have lentiginosis, ECG abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, growth delays/arrest, and sensorineural deafness. The condition is extremely rare with only ~100 reported cases in the literature. Noonan syndrome more commonly is associated with webbed neck, cryptorchidism, coagulopathy, and abnormalities of the lymphatics leading to lymphedema and less commonly associated with lentiginosisthan LEOPARD syndrome.


Diagnosis (prenatal vs postnatal)


Table 1: Noonan Syndrome, major and minor diagnostic criteria. 
Hormone Research in Paediatrics Online

Clinical dx

  • If typical facies
    • 1 major or 2 minor signs
  • If suggestive facies
    • 2 major or 3 minor signs

Molecular genetic testing via FISH

  • Look for PTPN11 or MAPK pathway mutations in patients with characteristic facies
  • Confirms the diagnosis in 70% of patients



  • Slow growth rate: Monitor rate of growth three times per year for the first three years then annually after that
  • Short stature: Noonan syndrome is an indication for the administration of growth hormone. Patients should be referred to an endocrinologist for management of growth hormone dosing.
  • Cardiovascular: patient should be assessed by a pediatric cardiologist at the time of diagnosis; patients without abnormalities on first assessment should be seen every five years for follow up
  • Hematologic: Patients should have coagulation studies drawn at the time of diagnosis. Follow up should be performed by a specialist
  • Vision/auditory issues: hearing and vision exams should be performed at the time of diagnosis in infancy and followed every year thereafter
  • Neurological issues: Headaches or seizures should prompt a thorough neurological evaluation including head MRI
  • Skeletal abnormalities: Annual screening of the back and chest should be performed with radiographic follow up in the event of any abnormalities.
  • Cryptorchidism: Males with undescended testes by one years of age should be referred to a pediatric urologist for orchiopexy
  • Special educational support for those with intellectual disability


Family Resources

Having a child with Noonan Syndrome can present a challenge for families, so adequate support resources is key.  CLICK ON THE LINK BELOW for more information.

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