Noonan syndrome

7 Interesting Facts of Noonan syndrome

  • Noonan syndrome is a congenital syndrome characterized by variable phenotype that may include:
    • Dysmorphic facial features
      • Most prominent in infants and become less dramatic with age; distinctive features may include down-slanting palpebral fissures; ptosis; hypertelorism; and low-set, posteriorly rotated ears
    • Sternal deformity and webbed neck
    • Congenital heart disease (eg, pulmonary valve stenosis, hypertrophic cardiomyopathy)
    • Cryptorchidism, lymphatic abnormalities, and bleeding disorders
    • Postnatal short stature and pubertal delay
  • Prenatal diagnosis may be suspected mainly based on abnormalities seen on prenatal ultrasonography; targeted prenatal molecular testing may confirm diagnosis
  • Postnatal diagnosis is largely clinical; genetic testing may play a role in certain patients
  • Baseline screening for associated congenital anomalies at the time of diagnosis includes echocardiography and ECG with cardiology consultation, CBC with differential, prothrombin time/partial thromboplastin time, renal ultrasonography, hearing and ophthalmologic assessments, and multidisciplinary developmental evaluation
  • Treatment mainly involves promoting growth, managing associated congenital anomalies, and monitoring for acquired diseases that frequently are associated with Noonan syndrome
    • Cardiovascular disease (eg, pulmonic stenosis, hypertrophic cardiomyopathy) is managed in standard fashion according to established guidelines for general population
    • Feeding difficulties, gastrointestinal reflux, and failure to thrive in infancy may require multidisciplinary care (eg, nutrition specialist, gastroenterologist, feeding team)
    • Treatment of bleeding diathesis is driven by presence specific factor deficiency and/or platelet abnormality
    • Short stature may be managed with hGH treatment in consultation with endocrinologist
    • Pubertal delay is managed with sex hormone induction in consultation with endocrinologist
    • Developmental delay often requires multidisciplinary care (eg, occupational and physical therapy, speech therapy, early intervention program)
  • Lifelong monitoring for cardiac manifestations (eg, development of hypertrophic cardiomyopathy, pulmonary valve dysfunction) requires consultation with cardiologist
  • Prognosis is good for most patients; among patients who develop cardiomyopathy, up to 25% die in the first year from heart failure 


  • Abnormalities in coagulation cascade and platelet count are not uncommon and may result in excessive bleeding with invasive surgical procedures
    • Screen for and define precise hemostatic abnormality before elective surgery so that abnormalities can be appropriately managed 

Noonan syndrome is a congenital syndrome characterized by a variable phenotype that may include: 

Distinctive facial dysmorphology, sternal deformity, and webbed neck

Congenital heart disease (eg, pulmonary valve stenosis, hypertrophic cardiomyopathy)


Lymphatic abnormalities and bleeding disorders

Postnatal short stature and pubertal delay

Developmental delay and mild learning disabilities

Clinical Presentation


  • Timing of diagnosis varies. Some patients are diagnosed in infancy, but in others the condition does not become evident until childhood or adolescence
    • Common presentations include a variety of manifestations, either alone or in combination
      • Dysmorphic facial or other characteristic features (eg, webbed neck, sternal deformity)
      • Congenital heart disease or hypertrophic cardiomyopathy
      • Failure to thrive with feeding difficulties in infants
      • Lymphedema, excess nuchal folds, or cryptorchidism in newborns
      • Easy bruising or excessive bleeding with surgical procedures
      • Slowed linear growth or short stature in children
  • Findings from prenatal screenings may suggest Noonan syndrome
    • Nonspecific abnormalities that may be found on ultrasonography include:
      • Increased nuchal translucency and polyhydramnios
      • Congenital cardiac defects, cystic hygroma, pleural effusion, edema, or renal abnormalities
    • Results of targeted genetic testing of fetal samples may confirm specific pathogenic variants known to cause Noonan syndrome
    • Karyotype is within reference range 
  • Family history
    • Parent may have Noonan syndrome, whether diagnosed or not
    • If family history history is negative, carefully assess parents; this may uncover subtle findings consistent with Noonan syndrome that were not previously recognized

Physical examination

  • Findings are variable
  • Neonates: birth weight, length, and head circumference are usually within reference range because intrauterine growth generally is typical 
  • Dysmorphic features characteristically evolve considerably with age 
    • Neonates
      • Facial dysmorphology
        • Large head compared with face 
        • High forehead with narrow temples 
        • Wide-set eyes (ie, ocular hypertelorism) 
        • Downward slant of palpebral fissures 
        • Epicanthal folds 
        • Short, broad nose with depressed root and full tip 
        • Deeply grooved philtrum 
        • Full lips with high, wide peaks to the vermilion border of upper lip 
        • Small chin (micrognathia) 
        • Oval, low-set, posteriorly rotated ears with thick helixes 
        • Low posterior hairline 
      • General dysmorphology
        • Short neck 
        • Excess nuchal skin 
        • Swelling of the dorsal aspect of hands and feet 
    • Infants
      • Large head 
      • Wispy hair
      • Tall and prominent forehead 
      • Thickly hooded, prominent eyes and ptosis
      • Hypertelorism 
      • Wide-based, depressed nose with bulbous, upturned tip
      • Cupid bow appearance of upper lip 
    • Children and adolescents
      • Facial dysmorphology
        • Inverted triangle–shaped head (ie, wide forehead tapering to pointed chin)
        • Thick, curly or woolly hair is common; thin, sparse hair has also been reported 
        • Face often lacks expression (ie, myopic facies) 
        • Coarse facial features 
      • General dysmorphology
        • Broad, webbed neck and prominent trapezius musculature 
        • Pectus sternal deformity with prominent superior sternum (pectus carinatum) and depressed inferior sternum (pectus excavatum) 
        • Widely spaced nipples
        • Cubitus valgus deformity of upper extremity (ie, increased carrying angle at elbow joint)
    • Adults
      • Facial dysmorphology
        • Inverted triangle–shaped head
        • High anterior hairline
        • Prominent nasolabial folds
      • General dysmorphology
        • Transparent, wrinkled skin 
    • Features that persist in most age groups include:
      • Arched and diamond-shaped eyebrows 
      • Vivid blue or blue-green irises 
      • Ptosis, hypertelorism, epicanthal folds, and downward slant of palpebral fissures 
      • High-arched palate 
      • Low-set, posteriorly rotated ears with thick helixes 
      • Low posterior hairline 

Associated congenital anomalies

  • Cardiac anomalies
    • Occur in 50% to 80% of patients with Noonan syndrome and may include: 
      • Pulmonary valve stenosis (20%-50%) 
        • Often occurs with dysplastic pulmonary valve 
        • May be isolated or may occur with other cardiac defects 
      • Hypertrophic cardiomyopathy (20%-30%) 
        • May be congenital or develop in childhood 
        • May be mild or severe
      • Atrial septal defect (6%-10%) 
      • Less common anomalies include ventricular septal defect, peripheral pulmonary stenosis, atrioventricular canal, aortic stenosis, mitral valve abnormalities, aortic coarctation, tetralogy of Fallot, and coronary artery anomalies 
  • Gastrointestinal abnormalities
    • Feeding difficulties (eg, poor suck, prolonged feeding time) and recurrent vomiting and reflux 
      • Very common in neonates and infants
      • May result in failure to thrive
        • Self-limited, although poor weight gain may persist up to 18 months 
    • Intestinal malrotation, immature gut motility, and delayed gastrointestinal motor development are reported
  • Renal and genitourinary anomalies
    • Renal anomalies (10%-11%) 
      • Usually minor and include solitary kidney, renal pelvis dilation, and duplicated collecting system 
      • Structural anomalies may increase risk for development of urinary tract infection 
    • Cryptorchidism (80% of boys) (Related: Undescended testis)
      • May be unilateral or bilateral 
      • May require surgical orchiopexy if testes fail to descend by age 1 year 
  • Musculoskeletal deformities
    • Sternal deformity
      • Characteristically with pectus carinatum superiorly and pectus excavatum inferiorly 
    • Cubitus valgus (increased carrying angle) and talipes equinovarus (club foot) 
    • Scoliosis 
  • Dermatologic signs 
    • Thick, curly hair or thin, sparse hair
    • Dystrophic nails
    • Extra prominence on finger and toe pads
    • Hyperelastic skin
    • Multiple moles and pigmented nevi 
    • Multiple lentigines
    • Keratosis pilaris
  • Central nervous system malformations
    • Arnold-Chiari malformation (extension of cerebellar tonsils into spinal canal)
    • Cerebrovascular anomalies (eg, arteriovenous malformations, aneurysms, hypoplasia of the posterior vessels, moyamoya) (Related: Moyamoya)
  • Lymphatic abnormalities
    • Lymphedema involving dorsal foot and hand 
    • Cystic hygroma (ie, congenital lymphatic collection, usually in the neck or axilla)
    • Chylothorax
    • Pulmonary lymphangiectasis
    • Chylous ascites
    • Genital edema
    • Hydrops fetalis (rare) 
  • Hematologic anomalies
    • Increased bleeding tendency
      • Potential hematologic abnormalities include thrombocytopenia, platelet dysfunction, and coagulation factor deficiencies 
      • Manifestations are usually mild; severe, excessive, spontaneous bleeding is uncommon 
        • Most common include easy bruising, epistaxis, and menorrhagia 
      • May result in significant bleeding with surgical procedures 
    • Myeloproliferative disorder
      • May develop in infants, often during first few months of life 
      • Characterized by hepatosplenomegaly, leukocytosis with monocytosis, and thrombocytopenia 
  • Endocrinologic
    • Short stature (50%-70%) 
      • Postnatal growth failure is usually observable from about the first year of life 
      • During childhood, mean height usually follows along third percentile on standard growth chart 
      • During adolescence, delayed puberty and attenuated pubertal growth spurt often result in a sharp, progressive decline in growth 
      • Some catch-up growth is achieved owing to delayed bone maturity; patients may continue slow growth until around age 20 years 
    • Delayed puberty
      • May occur in both boys and girls
  • Developmental and behavioral
    • Developmental delay
      • Early motor milestones are delayed, often owing to hypotonia and joint hyperextensibility 
      • Poor coordination and clumsiness
    • Learning difficulties
    • Behavioral manifestations
      • Risk for attention-deficit/hyperactivity disorder symptoms is increased 
      • Stubbornness and irritability have been reported but association is not well established 


  • Genetic variants that encode for various products involved in the RAS-MAPK (mitogen-activated protein kinase) signal transduction pathway are responsible for disease
    • RAS-MAPK signal transduction pathway is vital for cell differentiation, growth, and senescence 
    • Expression may vary markedly among people with the same pathogenic variant for syndrome 
    • Known pathogenic variants may involve the following genes; some general genotype-phenotype correlations are noted:
      • PTPN11 (OMIM #163950) 
        • Gain-of-function mutations are responsible for about 50% of cases 
        • Short stature is more prevalent in patients with PTPN11 mutation; pulmonic stenosis is common 
        • Hypertrophic cardiomyopathy is relatively less prevalent in patients with PTPN11 mutation 
        • Germline pathogenic variants at certain specific codons—61, 71, 72, and 76—are significantly associated with leukemogenesis and identify a group of patients at increased risk for juvenile myelomonocytic leukemia 
      • SOS1 (OMIM #610733) 
        • Missense mutations at locus 2p22.1 are present in from 10% to 28% of patients 
        • Pulmonic stenosis is more frequent in SOS1 mutation–positive patients than in those without SOS1 or PTPN11 mutations; ectodermal manifestations are common 
        • Developmental delay and short stature is much less prevalent in patients with SOS1 mutation than in the general Noonan population 
      • RAF1 (OMIM #611553) 
        • Mutations in RAF1 cause Noonan syndrome in 5% to 15% of people 
        • Hypertrophic cardiomyopathy is much more frequent in RAF1 mutation–positive patients (80%-95%) than in general Noonan syndrome population; multiple nevi, lentigines, and café au lait spots are common 
      • RIT1 (OMIM #615355) 
        • Heterozygous mutations at locus 1q22 are responsible for up to 5% of cases 
        • Cardiovascular manifestations, especially hypertrophic cardiomyopathy, and lymphatic problems occur more frequently in RIT1 mutation–positive patients than in general Noonan syndrome population 
      • KRAS (OMIM #609942) 
        • Heterozygous mutations at locus 12p12.1 are responsible for less than 2% to 5% of cases 
        • Severe phenotypic effects are typical; majority have cardiac involvement, and profound intellectual disability may occur 
        • Unusual association of Noonan syndrome with craniosynostosis is noted in families with KRAS mutation–positive patients 
      • Rarely, pathogenic variants responsible for disease occur in other known loci (eg, NRAS, SHOC2, CBL, BRAF, MAP2K1)
Pathologic variantCardiovascularGrowthDevelopmentalSkin and hairOther
PTPN11↑ ↑ Pulmonic stenosis↑ Short statureLittle to none↑ Bleeding diathesis
↓ Hypertrophic cardiomyopathy↓ Insulinlike growth factor 1 concentrations↑ Juvenile myelomonocytic leukemia
↓ Atrial septal defect
SOS1↑ Pulmonic stenosis↓ Short stature↓ Intellectual disability↑ Cutaneous findings (eg, keratosis pilaris) similar to cardiofaciocutaneous syndrome↑ Macrocephaly
↓ Atrial septal defect↓ Language delays
RAF1↑ ↑ Hypertrophic cardiomyopathy↑ Nevi
 ↑ Lentigines
↑ Café au lait spots
RIT1↑ Cardiovascular manifestations↓ Short stature↓ Intellectual disability↓ Cutaneous findings↑ Lymphatic manifestations
KRAS↑ Severe cognitive delay↑ Cutaneous findings similar to cardiofaciocutaneous syndrome

Caption: Findings noted are more prevalent in Noonan patients with specific pathologic variant compared to Noonan patients without specific pathologic variant.

Citation: Data from Aarskog-Scott syndrome; AAS. Online Mendelian Inheritance in Man. OMIM website. Johns Hopkins University. Updated April 24, 2013. Accessed January 8, 2020, #305400; Cardiofaciocutaneous syndrome 1; CFC1. Online Mendelian Inheritance in Man. OMIM website. Johns Hopkins University. Updated June 13, 2019. Accessed January 8, 2020, OMIM #115150; Costello syndrome; CSTLO. Online Mendelian Inheritance in Man. OMIM website. Johns Hopkins University. Updated January 5, 2016. Accessed January 8, 2020, OMIM #218040; Leopard syndrome 1; LPRD1. Online Mendelian Inheritance in Man. OMIM website. Johns Hopkins University. Updated August 9, 2019. Accessed January 8, 2020, OMIM #151100; Neurofibromatosis, type 1; NF1. Online Mendelian Inheritance in Man. OMIM website. Johns Hopkins University. Updated October 31, 2017. Accessed January 8, 2020, OMIM #162200; Noonan syndrome 1; NS1. Online Mendelian Inheritance in Man. OMIM website. Johns Hopkins University. Updated October 15, 2019. Accessed January 8, 2020, OMIM #163950; Noonan syndrome 3; NS3. Online Mendelian Inheritance in Man. OMIM website. Johns Hopkins University. Updated May 18, 2011. Accessed January 8, 2019, OMIM #609942; Noonan syndrome 4; NS4. Online Mendelian Inheritance in Man. OMIM website. Johns Hopkins University. Updated December 4, 2014. Accessed January 8, 2020, OMIM #610733; Noonan syndrome 5; NS5. Online Mendelian Inheritance in Man. OMIM website. Johns Hopkins University. Updated October 20, 2016. Accessed January 8, 2020, OMIM #611553; Noonan syndrome 8; NS8. Online Mendelian Inheritance in Man. OMIM website. Johns Hopkins University. Updated November 22, 2019. Accessed January 8, 2020, OMIM #615355; Phenotypic series – PS163950. Online Mendelian Inheritance in Man. OMIM website. Johns Hopkins University. Accessed January 8, 2020, PS163950; Roberts AE et al: Noonan syndrome. Lancet. 381(9863):333-42, 2013; and Romano AA et al: Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. 126(4):746-59, 2010.

Risk factors and/or associations

  • Estimated incidence for severe phenotype is 1 per 1000 to 2500 live births 
  • Many pathogenic variants are a result of sporadic (de novo) mutation 
    • Affected parent may be identified in up to 75% of families 
  • Familial inheritance is autosomal dominant 
    • Risk of sibling also having Noonan syndrome is dependent on genetic status of parents
      • 50% chance when 1 parent is affected 
      • Less than 1% chance if neither parent is affected 
    • If a parent has Noonan syndrome, risk of children having the syndrome is 50% 
Other risk factors/associations
  • Advanced paternal age may be a risk factor in patients without known genetic association of Noonan syndrome 

Diagnostic Procedures

Primary diagnostic tools

  • Prenatal diagnosis
    • Diagnosis may be suspected based on a constellation of findings noted on screening prenatal studies: 
      • Nonspecific ultrasonographic abnormalities (eg, increased nuchal translucency, cystic hygroma, polyhydramnios, multiple effusions, cardiac anomaly) and fetal karyotype within reference range
    • Results of targeted prenatal genetic testing may confirm diagnosis with samples obtained through chorionic villus sampling or amniocentesis
    • Detailed fetal ultrasonography and fetal echocardiography are indicated to assess for additional abnormalities (eg, cardiac, renal, hydrops fetalis) when diagnosis is suspected or confirmed 
  • Postnatal diagnosis
    • Largely based on clinical features 
      • Consider diagnosis in any patient who either presents personally with 2 or more of the following key features or has a first-degree relative with Noonan syndrome or any of the following key features: 
        • Characteristic facial features
        • Congenital heart defect (eg, pulmonic stenosis, atrial septal defect) and/or hypertrophic cardiomyopathy
        • Characteristic chest deformity (eg, superior pectus carinatum, inferior pectus excavatum)
        • Undescended testes
        • Short stature
        • Delayed puberty (either sex) and/or male infertility
        • Developmental delay and/or learning disability
      • Diagnostic scoring system may assist in diagnosis 
    • Results of genetic testing can aid in diagnosis, which is particularly useful:
      • To establish diagnosis in mildly affected patients 
      • To differentiate from other syndromes with similar presentation 
      • To enable specific treatment, monitoring, and prognostic guidance given known genotype-phenotype correlations 
      • To allow for preimplantation, prenatal, and postnatal genetic testing with defined familial pathogenic variant 
  • Obtain baseline screening for associated congenital anomalies at the time of diagnosis, including: 
    • Complete physical and neurologic examination
    • Growth parameter plotting
    • Cardiac evaluation (eg, echocardiography, ECG)
    • Auditory and ophthalmologic assessments
    • Coagulation studies (ie, CBC with differential, prothrombin time/partial thromboplastin time)
    • Renal ultrasonography and urinalysis, if needed
    • Clinical and radiographic spine and rib cage assessments
    • Multidisciplinary developmental evaluation
    • Consult with clinical geneticist or genetic counselor (or both)


  • Genetic testing
    • Results can confirm diagnosis in 70% or more cases; negative test results do not exclude diagnosis 
    • Genetic confirmation may influence genetic counseling, management, and prognosis 
    • Consult with a clinical geneticist to help choose appropriate test or genetic testing protocol 
      • Online resources are available to help identify appropriate laboratory studies and testing panels 
    • Testing methods
      • Multigene panel
        • First choice test for patients thought to have Noonan syndrome 
        • Chip-based sequencing is faster and cheaper than sequencing each individual gene of interest 
        • Must choose which multigene panel to use 
        • Often includes testing for other genes of interest that are responsible for other syndromes with phenotypic overlap (eg, cardiofaciocutaneous syndrome, Costello syndrome) 
        • Specific genes included in panel and sensitivity of testing for each gene vary by individual testing panel and laboratory study 
      • Serial single gene testing
        • Consider if multigene testing panel is not available 
        • Strategy often involves 
          • About half of patients with Noonan syndrome have pathogenic missense variant in PTPN11; therefore, start with PTPN11 pathogenic variants
          • If PTPN11 pathogenic variant is not identified, focus subsequent testing on identifying other specific genes most likely to be involved based on patient phenotype (eg, RAF1 if hypertrophic cardiomyopathy is present)
      • Comprehensive genomic testing
        • Consider exome sequencing (protein-coding genes) or genome sequencing if multigene panel or serial gene testing fails to confirm diagnosis 


  • Prenatal ultrasonography
    • Findings may include: 
      • Cystic hygroma or increased nuchal translucency
      • Cardiac abnormalities
        • Rarely diagnosed on routine prenatal screening
      • Multiple effusions (eg, hydrothorax, ascites); hydrops is rare 
      • Polyhydramnios

Functional testing

  • ECG
    • Majority of patients exhibit an ECG abnormality characteristic of Noonan syndrome that is independent of any cardiac defect or structural abnormality of the chest wall 
      • ECG findings are abnormal in up to 90% of patients 
    • ECG findings may include: 
      • Almost 60% of patients exhibit an unusual pattern consisting of: 
        • Left axis deviation 
        • Abnormal R/S ratio over left precordium (ie, R/S ratio lower than lower limits of reference range and R voltage in V₅ through V₆ less than 50% of mean) 
        • Giant Q waves (Q voltage greater than upper limits of reference range) and wider than typical QRS complexes 
      • Left anterior hemiblock 
      • RSR’ pattern in V₁ 
      • Extreme right axis deviation with superior counterclockwise frontal QRS loop 
    • Other findings may suggest hypertrophic cardiomyopathy or reflect changes consistent with significant underlying congenital heart lesion

Other diagnostic tools

  • Clinical diagnostic criteria for Noonan syndrome include either of the following: 
    • Typical facial dysmorphology (major characteristic 1A) and 1 of the following:
      • 1 additional major characteristic from categories 2A through 6A
      • 2 additional minor characteristics from categories 2B through 6B
    • Suggestive facial dysmorphology (major characteristic 1B) and 1 of the following:
      • 2 additional major characteristics from categories 2A through 6A
      • 3 additional minor characteristics from categories 2B through 6B
FeatureA = Major characteristicsB = Minor characteristics
1 = Facial featuresTypical facial dysmorphologySuggestive facial dysmorphology
2 = Cardiac manifestationsPulmonary valve stenosis, hypertrophic cardiomyopathy, and/or ECG results typical of Noonan syndromeOther defect
3 = HeightLess than third percentileLess than tenth percentile
4 = Chest wall anomaliesPectus carinatum/excavatumBroad thorax
5 = Family historyFirst-degree relative with definite Noonan syndromeFirst degree relative with suggestive Noonan syndrome
6 = Other featuresAll of the following: intellectual disability, cryptorchidism, and lymphatic vessel dysplasia1 of the following: intellectual disability, cryptorchidism, or lymphatic vessel dysplasia

Caption: Clinical diagnosis of Noonan syndrome may be established by either of the following: typical face plus 1 major (A) or 2 minor (B) clinical characteristics, or suggestive face plus 2 major (A) or 3 minor (B) clinical characteristics. Definitive Noonan syndrome is defined as 1 major (A) plus 1 other major (A) or 2 minor (B) characteristics, or 1 minor (B) characteristic plus 2 major (A) characteristics or 3 minor (B) characteristics.

Citation: Data from Bhambhani V et al: Noonan syndrome. Am Fam Physician. 89(1):37-43, 2014; Jorge AA et al: Noonan syndrome and related disorders: a review of clinical features and mutations in genes of the RAS/MAPK pathway. Horm Res. 71(4):185-93, 2009; and van der Burgt I: Noonan syndrome. Orphanet J Rare Dis. 2:4, 2007.

Differential Diagnosis

Most common

Treatment Goals

  • Promote growth with goal of attaining height within reference range for age, puberty at a typical age, and eventual adult height within reference range
    • hGH treatment to promote linear growth
    • Estrogen or testosterone treatment to induce puberty if delayed
  • Manage congenital abnormalities associated with disease
  • Monitor for commonly associated disease manifestations

Recommendations for specialist referral

  • Refer patients with suspected Noonan syndrome to geneticist or developmental pediatrician for further diagnostic, management, and genetic counseling recommendations 
  • Refer patients with short stature and pubertal delay to an endocrinologist for further diagnostic and treatment recommendations 

Treatment Options

Monitor and manage acquired disease frequently associated with syndrome

  • Cardiac disease
    • Manage pulmonic valve stenosis, hypertrophic cardiomyopathy, and other cardiovascular anomalies according to established guidelines for general population 
    • Pulmonary valve stenosis is often treated with balloon valvuloplasty but carries a high reintervention rate (Related: Pulmonic stenosis)
      • Some require pulmonary valvectomy or pulmonary homograph repair 
    • Hypertrophic cardiomyopathy may require long-term β-blocker therapy or surgical myomectomy to reduce outflow obstruction 
    • About one-third of adult patients require long-term management with medications, defibrillator, or pacemaker for heart failure or arrhythmia 
  • Failure to thrive, feeding difficulties, and gastrointestinal reflux in infancy
    • May require consultation with gastroenterologist and/or feeding team for further diagnostic and treatment recommendations 
      • May require placement of temporary feeding tube
    • Consult nutrition specialist to optimize nutritional status 
    • Gastrointestinal reflux may require antireflux medications 
  • Bleeding diathesis
    • Treatment is driven by specific factor deficiency or platelet aggregation defect in consultation with hematologist 
    • Avoid aspirin and aspirin-containing medications owing to potential for exacerbating a bleeding diathesis 
  • Endocrine disease
    • Short stature may require hGH treatment in consultation with endocrinologist 
      • hGH is approved to treat slowed linear growth, when present, but its use is controversial 
        • Improves short-term speed of height growth; however, effect on adult height is not definitely known 
        • Some authorities have raised concerns about use in patients with hypertrophic cardiomyopathy, but there is minimal evidence for adverse effect 
    • Delayed puberty may need to be induced with sex hormone treatment (ie, estrogen for girls, testosterone for boys) in consultation with endocrinologist
      • Induction of puberty is indicated for lack of secondary sex characteristics in girls at 13 years of age and boys at 14 years of age 
  • Developmental disabilities
    • Are managed in consultation with multidisciplinary recommendations for early intervention programs and individualized education strategies 
      • Except for SOS1 cases, referral in infancy may be appropriate
    • Speech, occupational, and/or physical therapy and other specialized care may be indicated based on multidisciplinary recommendations 

Drug therapy

  • Recombinant hGH 
    • No standard dose is established 
    • Somatropin (Recombinant rhGH) Solution for injection; Children: Up to 0.066 mg/kg/day subcutaneously is recommended. Prior to initiating somatropin, ensure that the patient has short stature. Not all children with Noonan syndrome have short stature.

Nondrug and supportive care

  • Genetic counseling
    • Recommended for affected patients in adolescence or young adulthood for preconception planning 
    • May need familial evaluation to determine future offspring’s risk for Noonan syndrome by identifying subtle findings in a previously unidentified affected parent
  • Provide patients and families with resources regarding education and support 
    • Support organizations include: 
      • Noonan Syndrome Foundation 
      • NORD Noonan Syndrome 
      • Magic Foundation 


  • Lifelong monitoring for commonly acquired diseases and other conditions associated with Noonan syndrome include:
    • Hearing
      • Annual hearing tests throughout early childhood 
      • Refer to ear, nose, and throat specialist for recurrent otitis media or serous otitis 
    • Ocular
      • Recommend detailed screening ophthalmology examination at least every 2 years for patients without known ocular abnormality 
    • Dental (malocclusion)
      • Refer to dentist between ages 1 and 2 years, with annual dental evaluations thereafter 
      • Primary care physician should perform oral examination at each visit 
    • Cardiovascular
      • Children and adults without known heart disease require cardiac reevaluation every 5 years with consulting cardiologist 
      • Patients with known heart disease require regular individualized follow-up as directed by consulting cardiologist 
      • European guidelines recommend annual screening echocardiogram to assess for signs of hypertrophic cardiomyopathy until age 3 years, at ages 5 and 10 years, and during adolescence 
    • Feeding difficulties and failure to thrive (in infancy)
      • Monitor weight gain for failure to thrive, feeding difficulties (eg, poor suck, prolonged feeding time), and recalcitrant gastrointestinal reflux
      • Refer patients with poor weight gain, failure to thrive, difficulty feeding, or recurrent reflux to pediatric gastroenterologist and/or feeding team for further diagnostic and treatment recommendations 
    • Renal and genitourinary
      • Repeat renal ultrasonography and other monitoring may be necessary in consultation with nephrologist, depending on initial findings 
      • Patients with underlying structural abnormalities may be at increased risk for urinary tract infection; maintain low threshold for obtaining urinalysis and urine culture if urinary tract infection symptoms develop
      • Monitor clinical examination findings in infants with undescended testes; refer to urologist by age 1 year for possible orchiopexy if testes remain undescended 
    • Skeletal
      • Monitor annually for deformities with clinical back examination for scoliosis and chest examination for pectus deformity of sternum 
        • hGH treatment may worsen scoliosis 
      • Order radiographic evaluation of spine if scoliosis is significant on examination 
      • Refer to orthopedic surgeon if functionally restrictive chest deformity is suspected
    • Dermatologic
      • Perform cutaneous examination at each primary care physician visit
      • Refer to dermatologist as clinically indicated for concerning moles and nevi, or difficult-to-manage keratosis pilaris 
    • Central nervous system
      • Monitor clinically for manifestations of craniosynostosis (eg, abnormal cranial shape), cerebrovascular anomalies, and Arnold-Chiari malformation (eg, signs of increased intracranial pressure or hydrocephalus, headaches, increasing head circumference, seizures) 
      • Maintain low threshold for investigation of clinical manifestations with appropriate ancillary studies (eg, EEG, MRI of the brain)
    • Lymphatic
      • Monitor clinically for manifestations of lymphedema secondary to lymphatic vessel dysplasia, hypoplasia, or aplasia 
      • Refer to lymphedema clinic when clinically indicated 
    • Hematologic and oncologic
      • Bleeding tendencies secondary to factor deficiency or qualitative or quantitative platelet defects
        • CBC and coagulation studies
          • Repeat CBC and coagulation studies 6 to 12 months after initial screening if first screening is performed in infancy 
          • European guidelines recommend at least 1 screening examination during mid- to late childhood (ages 5-11 years) 
        • Monitor for clinical symptoms of bleeding
          • If excessive, unusual, or persistent bleeding occurs, then obtain coagulation studies (eg, CBC, prothrombin time/partial thromboplastin time) 
          • Refer these patients for further evaluation (eg, specific factor assays, platelet function studies) and treatment recommendations 
        • Preoperative monitoring
          • Obtain screening CBC and coagulation studies (ie, prothrombin time/partial thromboplastin time) 
          • Refer patients with screening test results outside reference range to a hematologist for second-tier testing (eg, factor levels, platelet aggregation studies) 
        • Monitor for splenomegaly
          • Obtain screening CBC with differential for patients with splenomegaly 
        • Monitor for hepatosplenomegaly
          • Obtain screening CBC with differential and liver function test results for patients with hepatosplenomegaly 
        • Malignancy
          • Aside from screening CBC and obtaining liver function test results in presence of hepatosplenomegaly, no specific surveillance strategy is available
    • Endocrine
      • Growth delay and short stature
        • Monitor linear growth on Noonan syndrome age–based growth chart 
        • Monitor closely at each patient visit, a minimum of 3 times a year until age 3 years, then annually thereafter 
        • Refer patients with growth delay (eg, growth deceleration, height less than −2 standard deviations) to endocrinologist with experience managing patients requiring hGH treatment 
      • Delayed puberty
        • Monitor clinically for pubertal development
        • Refer patients with pubertal delay to endocrinologist for further diagnostic and treatment recommendations 
      • Fertility issues in men
        • Fertility clinic evaluation may be required for men with inability to conceive 
    • Developmental, cognitive, behavioral, and neuropsychiatric
      • Developmental delay and learning deficiencies
        • Perform development screening assessment beginning in the second half of the first year of life and annually until age 18 years 
        • May require multidisciplinary evaluation if screening assessment is abnormal to assess need for early developmental intervention and individualized educational plan
      • Speech deficits
        • Recommend formal speech evaluation if indicated clinically to assess for deficits and need for individualized treatment plan
      • Behavioral and neuropsychiatric deficits
        • Obtain baseline neuropsychologic assessment at primary school entry with follow-up based on results of initial testing 
  • Monitoring during hGH therapy
    • Limited data do not show significantly increased risk of worsening cardiomyopathy or negative effects on the heart; however, theoretical concerns exist regarding worsening cardiac status and increasing ventricular wall thickness during treatment 
      • Monitor cardiac function with periodic clinical examination and echocardiography 
    • Increased risk of hematologic malignancy is an additional theoretical (as yet undetermined) concern during treatment
      • No specific monitoring recommendations are available
    • Additional monitoring parameters are directed by consulting endocrinologist
  • Preoperative monitoring
    • Evaluate for coagulation abnormalities before initiating any surgical procedures 
    • Preoperative evaluation for malignant hyperthermia risk may be indicated for certain subgroups (eg, hypertrophic cardiomyopathy with creatine phosphokinase levels within reference range to elevated) 
    • Manage patients with hemodynamically significant cardiac disease in accordance with usual principles for patients with cardiovascular risk factors 


  • Acquired disease
    • Ocular findings occur in up to 95% of patients and may include: 
      • Nystagmus
      • Refractive error
      • Strabismus
      • Amblyopia
      • Anterior segment problems (eg, prominent corneal nerves, cataract, anterior stromal dystrophy)
      • Fundal changes (eg, optic head drusen, optic disk hypoplasia, coloboma)
    • Auditory deficits
      • Sensorineural hearing loss is relatively common 
    • Dental/oral findings 
      • Malocclusion
      • Articulation difficulty
    • Cardiac anomalies
      • Pulmonary stenosis 
        • Often associated with dysplastic valve 
        • Most require periodic monitoring only 
        • About one-third of patients require surgery or procedure for valve dysfunction 
        • Pulmonary valve insufficiency and right ventricular dysfunction may develop after valve repair 
      • Hypertrophic cardiomyopathy 
        • Develops in 20% to 30% of patients overall 
        • May develop anywhere from prenatal period to late childhood
          • Mean age at diagnosis is 5 months, and more than 50% of patients are diagnosed by age 6 months 
        • May be mild or severe; natural history is variable and unpredictable
          • May resolve in some patients or become rapidly progressive in others 
          • Up to 25% of patients with Noonan syndrome and hypertrophic cardiomyopathy die from heart failure associated with cardiomyopathy within the first year of development 
        • Dilated cardiomyopathy may evolve from hypertrophic cardiomyopathy; restrictive cardiomyopathy also occurs 
        • Left-sided obstructive lesions may develop in adulthood 
      • Other less common complications in adult patients may include:
        • Mild aortic insufficiency 
        • Substantial right ventricular outflow tract obstruction caused by subpulmonary or pulmonary valve stenosis
        • Aortic root dilation
        • Aortic dissection
        • Giant aneurysm of the sinuses of Valsalva
        • Constrictive pericarditis
        • Idiopathic pulmonary hypertension
      • Arrhythmias are relatively uncommon 
    • Gastrointestinal disorders
      • Feeding difficulties (eg, poor suck, prolonged feeding time) 
        • Common in infancy
        • May lead to failure to thrive and may require temporary nasogastric feedings 
        • Feeding difficulties often resolve by age 15 months 
      • Gastrointestinal reflux and recurrent vomiting
        • Common in infancy 
        • May compound feeding difficulties and lead to failure to thrive
        • Reflux and recurrent vomiting often resolve early in second year of life 
    • Genitourinary complications
      • Cryptorchidism 
        • Extremely common in male infants; may require orchiopexy if testes have not descended by age 1 year
      • Renal abnormalities are usually minor and include solitary kidney, renal pelvis dilation, and duplicated collecting system 
        • Structural anomalies may increase risk for development of urinary tract infection
    • Musculoskeletal anomalies
      • Sternal deformities
        • Characteristic deformity consists of pectus carinatum superiorly and pectus excavatum inferiorly 
      • Hypotonia, joint laxity, and hyperextensibility are common 
      • Poor coordination and clumsiness
      • Cubitus valgus (increased carrying angle at elbow) and talipes equinovarus (club foot) 
      • Genu valgum (medial angulation of the knee) 
      • Scoliosis
        • Develops in 15% to 30% of children, and about two-thirds require surgical correction 
      • Pigmented villonodular synovitis
        • Proliferative synovial lesion involving joints, tendons, and bursae 
        • Often polyarticular in distribution 
      • Giant cell granulomatous lesions
        • Multiple giant cell granulomatous tumors may develop in bones, joints, and soft tissue
        • Characteristic jaw involvement presents with progressive, often bilateral, mandibular swelling, which resembles cherubism and with lesions seen in neurofibromatosis type 1 and craniofaciocutaneous syndrome 
        • Primarily occurs in patients with pathogenic variants involving PTPN11 and SOS1 
    • Dermatologic characteristics 
      • Thick, curly hair or thin, sparse hair
      • Keratosis pilaris involving extensor surfaces and face is relatively common 
      • Dystrophic nails
      • Extra prominence on pads of fingers and toes
      • Hyperelastic skin
      • Multiple lentigines and café au lait spots
      • Moles and nevi
    • Lymphatic signs
      • Peripheral lymphedema occurs in up to 20% of patients 
        • May occur in infants; typically resolves in the first few years of life 
        • May develop later in adolescence or adulthood 
      • Less common lymphatic abnormalities include: 
        • Chylous effusions of the pleural space and peritoneum
        • Anomalous thoracic cage lymphatic vessels, aplasia, or absence of thoracic duct
        • Pulmonary, testicular, or intestinal lymphangiectasia
        • Hypoplastic leg lymphatic vessels, hypoplastic inguinal and iliac lymphatic vessels
        • Localized lymphedema of scrotum or vulva
    • Hematologic and oncologic disorders
      • Bleeding diathesis
        • Most patients develop easy bruising or bleeding 
          • An identifiable coagulation defect is identified in up to one-third of patients and may include 1 or more of the following: 
            • Clotting factor deficiencies
              • Factor XI
                • Most common deficiency encountered in patients with Noonan syndrome 
                • About 25% of patients have partial factor XI deficiency 
              • Factor XII and VIII
                • Represent the next most common factor deficiencies encountered 
            • Platelet abnormalities
              • Thrombocytopenia
                • Often secondary to decreased megakaryocyte numbers and/or splenomegaly 
              • Qualitative platelet dysfunction 
            • Screen for and define precise hemostatic abnormality before elective surgery so that abnormalities can be appropriately managed 
      • Malignancy and other hematologic complications
        • Transient monocytosis is reported 
        • Overall risk of developing childhood malignancy is up to 8-fold higher than that of the general population 
          • Patients with PTPN11 mutation–positive disease may be at increased risk for unusual childhood leukemia (ie, juvenile myelomonocytic leukemia)
          • Myeloproliferative disorder may occur in infants and is often a benign variant 
            • Less commonly, infants develop fulminant disease progressing to aggressive leukemia 
          • Acute lymphoblastic leukemia, acute myeloid leukemia, and juvenile monomyelocytic leukemia develop more frequently than in general population 
          • Patients may be at increased risk for certain types of solid tumors (eg, neuroblastoma, rhabdomyosarcoma) 
        • Unknown whether or not hGH treatment further elevates increased baseline risk for neoplasia 
      • Hepatosplenomegaly
        • Common and may be related to subclinical myelodysplasia 
    • Autoimmune disorders
      • Although development of thyroid antibodies is common, incidence of clinical hypothyroidism is similar to general population 
      • Systemic lupus erythematosus and celiac disease are uncommonly reported
    • Endocrine disorders
      • Short stature
        • Postnatal growth failure is usually observable from about the first year of life 
        • Children usually track along the third percentile on standard growth chart 
        • Delayed onset of puberty and attenuated pubertal growth spurt often contribute to a sharp and progressive decline in growth during adolescence 
        • Bone age is usually delayed (mean delay about 2 years); therefore, some catch-up growth often occurs, sometimes into the 20s 
        • Growth hormone secretory dynamics vary among patients 
          • Spontaneous growth hormone secretion may be normal or subnormal 
          • Growth hormone resistance may occur 
        • Mean final adult height is 161 to 167 cm in men and 150 to 155 cm in women 
      • Delayed puberty in boys and girls
        • Up to 35% of boys enter puberty after age 13.5 years 
        • Up to 44% of girls enter puberty after age 13 years; mean age of menarche is almost 15 years 
        • Puberty may progress at a rapid pace (under 2 years) 
        • By comparison, typical pubertal development occurs between ages 8 and 13.4 years in girls and ages 9 and 14 years in boys 
      • Male infertility
        • Sertoli cell dysfunction and cryptorchidism may play a role in impaired gonadal function and defective spermatogenesis 
        • Fertility does not appear to be affected in women 
    • Developmental, behavioral, and social interaction
      • Developmental delay and learning difficulty
        • About 25% of people with Noonan syndrome have learning disabilities 
          • About 10% to 15% of people with Noonan syndrome require special education 
        • Delayed developmental milestones
          • Early motor milestones delay
            • Average age for sitting unsupported is around 10 months 
            • Average age for walking is about 21 months 
          • Language delay
            • Average first words occur around age 15 months 
            • Average simple 2-word phrases occur around age 31 to 32 months 
            • May be secondary to hearing loss, perceptual motor disabilities, and articulation difficulties 
        • About 50% of school-aged children are diagnosed with developmental coordination disorder 
      • Behavioral manifestations
        • May include stubbornness, irritability, body image problems, poor self-esteem, and social inadequacy 
      • Other subtle deficits may include:
        • Social cognition impairments and alexithymia (difficulty identifying and expressing emotions) 
        • Language impairments and communication difficulties 
        • Delayed visual recognition memory 
    • Speech disorders
      • Articulation difficulties are common and respond well to speech therapy 
    • Neuropsychiatric disease
      • Attention and executive function tasks are challenging for many patients 
        • Prevalence of attention-deficit/hyperactivity disorder is increased 
      • Limited information is available about the prevalence of psychiatric disease 
      • Seizures
        • Recurrent seizures may develop in a minority of affected patients 


  • Adult height
    • Final adult height
      • Approaches lower end of reference range for most patients 
      • Below the third percentile in up to about 40% of males and 50% of females 
    • Patients treated with hGH
      • Final effects depend on age at start of treatment, duration of treatment, age at onset of puberty, and individual sensitivity to growth hormone 
      • Increase in height varies from 0.6 to 1.8 standard deviation 
  • Intelligence
    • Within reference range for most people with Noonan syndrome 
    • About 20% have some degree of intellectual impairment (IQ under 70) 
    • Impaired social and communication skills are noted in some 
  • Hypertrophic cardiomyopathy
    • May resolve in some patients or become rapidly progressive in others 
    • Early mortality is high
      • Among patients who develop cardiomyopathy, up to 25% die in the first year from heart failure 
      • Infants in congestive heart failure presenting before age 6 months have the worst prognosis 
    • Rate of sudden death is less than that experienced by people with inherited hypertrophic cardiomyopathy 
  • Myeloproliferative disorders
    • Most infants who develop myeloproliferative disorders have a favorable prognosis, improving by age 1 year without specific treatment 
  • Long-term mortality data are scarce 


At-risk populations

  • Parents of a proband
    • 30% to 75% of patients diagnosed have an affected parent 
  • Siblings of a proband
    • Risk depends on genetic status of parents
      • Risk is low (less than 1%) but higher than in general population when parents are unaffected 
      • Risk is 50% when a parent is affected or pathologic variant is identified in a parent 
  • Children of a proband
    • Each child has a 50% risk of inheritance 

Screening tests

  • Evaluation of parents, siblings (when parent is affected), and children of proband includes: 
    • Careful physical examination to evaluate for specific features of Noonan syndrome
      • Review photographs of affected faces at all ages
    • Echocardiography and ECG
    • Coagulation screening
    • Genetic testing of parents if pathologic variant is known in proband

Screening for associated congenital anomalies

  • Hearing loss
    • Refer to audiologist for age-appropriate evaluation in infancy or at time of initial diagnosis 
  • Ocular abnormalities
    • Refer to ophthalmologist for detailed eye examination at time of diagnosis 
  • Cardiac anomalies
    • Refer to cardiologist for cardiac evaluation, echocardiogram, and ECG 
    • Patients without congenital heart defect on initial evaluation require cardiac reevaluation every 5 years 
  • Feeding difficulties in infancy
    • Observe feeding to assess quality of suck and swallow coordination; determine need for lactation consultant and early feeding team intervention
    • Additional testing (eg, swallow study, reflux studies) may be indicated based on findings and specific clinical presentation 
  • Renal anomalies
    • Obtain renal ultrasonography
    • Repeat imaging may be indicated depending on findings at time of diagnosis on initial screening examination 
  • Scoliosis
    • Clinically assess spine and obtain imaging, if necessary 
  • Hematologic anomalies and disorders of hemostasis
    • CBC with differential and coagulation studies (prothrombin time/partial thromboplastin time) at time of diagnosis; consider measuring bleeding time 
      • Repeat 6 to 12 months after initial screening if it was done in infancy 
      • Other guidelines recommend baseline laboratory screening test results to be obtained in children at 5 years of age or younger if major procedures are required 
    • Refer patients with baseline coagulation study results outside reference range to hematologist for second-tier studies (ie, specific factor assays and platelet function studies) 
  • Growth
    • Plot on Noonan syndrome age-based growth chart and monitor growth at each primary care visit 
  • Developmental delay and learning deficiencies
    • Obtain formal multidisciplinary developmental assessment in second half of first year of life or at time of diagnosis 
    • Obtain baseline neuropsychological assessment at the time of primary school entry 


  • Preimplantation genetic diagnosis may be available to families with known pathogenic gene variant 


Roberts AE et al: Noonan syndrome. Lancet. 381(9863):333-42, 2013 Reference


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