Adult Summary Report Secondary Findings in Adult Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening A Current Version Rule-Out Dashboard Release History Status (Adult): Passed (Consensus scoring is Complete) Curation Status (Adult): Released Status (Pediatric): Passed (Consensus scoring is Complete) P

Condition: Noonan syndrome
Mode(s) of Inheritance: Autosomal Dominant
Actionability Assertion
Gene Disease Pairs(s)
Final Assertion
BRAF0013379 (noonan syndrome 7; ns7)
Assertion Pending
KRAS0012371 (noonan syndrome 3; ns3)
Assertion Pending
NRAS0013186 (noonan syndrome 6; ns6)
Assertion Pending
PTPN110008104 (noonan syndrome 1; ns1)
Assertion Pending
RAF10012690 (noonan syndrome 5; ns5)
Assertion Pending
RIT10014143 (noonan syndrome 8; ns8)
Assertion Pending
SOS10012547 (noonan syndrome 4; ns4)
Assertion Pending
SOS20014691 (noonan syndrome 9; ns9)
Assertion Pending
Actionability Rationale
This report was generated prior to the implementation of the process for making actionability assertions. An actionability assertion will be made, but may take time due to the substantial backlog of topics that need assertions.
Final Consensus Scoresa
Outcome / Intervention Pair
Nature of the
Cardiac manifestations / Cardiac surveillance

Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
Noonan syndrome (NS) is reported to occur in 1:1000 and 1:2500 live births.
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Clinical Features
(Signs / symptoms)
NS is characterized by facial dysmorphism, short stature, congenital heart defects, and developmental delay. Cardiac issues include pulmonary valve stenosis (PVS; the most common), hypertrophic cardiomyopathy (HCM), atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. There is a spectrum of other clinical outcomes associated with NS. Coagulation defects may manifest as severe surgical hemorrhage, clinically mild bruising, or laboratory abnormalities with no clinical consequences. Lymphatic abnormalities may be localized or widespread; dorsal limb lymphedema is the most common. Ocular abnormalities include strabismus, refractive errors, amblyopia, and nystagmus. Hearing loss can be present. Renal abnormalities are generally mild; dilation of the renal pelvis as the most common. Mild intellectual disability and language impairments can be present. Male pubertal development and subsequent fertility may be delayed or inadequate; puberty may be delayed in females, but normal fertility is the rule. Physical findings include broad or webbed neck, chest deformity, cryptorchidism, and bone and joint anomalies. Skin differences include follicular keratosis over extensor surfaces and face, café-au-lait spots, and lentigines. Giant-cell granulomas can occur. There is an increased risk of myeloproliferative disorder (MPD), juvenile myelomonocytic leukemia (JMML), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and solid tumors, such as rhabdomyosarcoma and neuroblastoma. Hepatosplenomegaly is frequent; the cause is likely related to subclinical myelodysplasia.
1 2 3 4 5 6 7 8 9 10 11 12
Natural History
(Important subgroups & survival / recovery)
HCM usually presents early in life: the median age at diagnosis is five months and more than 50% of individuals with NS and HCM are diagnosed by age six months. HCM is variable in severity and natural history. The condition resolves in some, but rapidly progresses and may be fatal in others. The severity of NS is the same in males and females.
There are no phenotypic features exclusive to a specific genotype; however, there are significant differences in the risk of various NS manifestations based on the causative gene. PTPN11 is associated with a predisposition to JMML, which runs a more benign course in NS compared to the general population. Patients with PTPN11 variants are more likely to have PVS, but less likely to have atrial septal defects and HCM. PTPN11 has also been associated more with short stature, pectus deformity, easy bruising, characteristic facial appearance, and cryptorchidism compared to other causes of NS. SOS1 is associated with more frequent ectodermal abnormalities and PVS and a greater likelihood of normal development and stature compared to other causes of NS and more cardiac septal defects than PTPN11. RAF1 and RIT1 are associated with increased rates of HCM. RIT1 is associated with a high prevalence of perinatal abnormalities, cardiovascular disease, and lymphatic abnormalities but lower prevalence of short stature and intellectual disability. KRAS is associated with greater likelihood and severity of intellectual disability and developmental delays. BRAF is associated with florid ectodermal manifestations.
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2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
At diagnosis, individuals with NS should undergo:
• Cardiac evaluation by a cardiologist, including electrocardiogram and echocardiogram
• Kidney ultrasound
• Coagulation screening with CBC with differential and prothrombin time/activated partial thromboplastin time; repeat after 6-12 months of age if initial screen performed in infancy
• Detailed eye examination
• Hearing test
• Evaluate failure to thrive, growth, and feeding problems
• Developmental, neuropsychological, and behavioral assessment. (Tier 2)
2 3
At diagnosis of NS, individuals with NS should also undergo:
• Complete physical and neurologic examination
• Clinical and radiographic assessment of spine and rib cage. (Tier 4)
Treatment of complications of NS is generally standard and does not differ from treatment from the general population, including cardiovascular anomalies, developmental delay, cryptorchidism, hearing problems, lymphedema, thyroid abnormalities, and epilepsy. (Tier 2)
Preoperative evaluation with CBC with differential count, prothrombin time/activated partial thromboplastin time, specific factor activity (factor XI, factor XII, factor IX, factor VIII, von Willebrand factor), and platelet function (bleeding time or platelet aggregation) for bleeding risk should be performed, with hematology consultation as needed for management of bleeding risk. (Tier 2)
2 3
Potential pregnancy difficulties, for example those arising from coagulation defects during childbirth, should be considered and planned for as appropriate. (Tier 2)
A low threshold for investigation of neurological symptoms is recommended (e.g. consider Arnold-Chiari malformation and hydrocephalus if patient presents with headache or other neurological symptoms). (Tier 2)
Recommended surveillance in adulthood includes:
• Cardiovascular: Individuals without heart disease should have cardiac reevaluation every 5 years. Adults should not discontinue periodic cardiac evaluations even if their evaluations in childhood or adolescence were normal; unexpected cardiac findings can occur at any point.
• Thyroid: Screen for thyroid abnormalities every 3-5 years
• Fertility: Care providers should be made aware of the increased risk of infertility in males
• Vision: Patients should be referred to an ophthalmologist for assessment
• Dental: Routine follow-up is essential. (Tier 2)
2 3
To assess for MPD/JMML in patients with NS with certain variants in PTPN11 and KRAS, a physical exam (with assessment of the spleen) and CBC with differential should be performed every 3-6 months from ages 0-5 years. There are no data indicating that this strategy leads to a survival advantage, but the sometimes more aggressive course of MPD and JMML may justify this recommendation in selected patients. (Tier 2)
Circumstances to Avoid
Aspirin and aspirin-containing medications should be avoided due to a tendency for bleeding. (Tier 2)
Due to risk of skin problems, skin dryness, which can be worsened by long hot baths, perfumed soaps and dry atmospheres, should be avoided. (Tier 2)
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
Prevalence of Genetic Mutations
The prevalence of pathogenic variants associated with NS was not available. However, molecular genetic testing identifies a pathogenic variant in PTPN11 in 40-50% of affected individuals; SOS1 in 10-13%; RAF1 and RIT1 each in 5%; KRAS in <5%; and NRAS, BRAF, and SOS2 in <1%. (Tier 3)
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Variant testing will provide a diagnosis of NS in 70% of cases; in 30% the responsible gene remains unknown. (Tier 4)
(Include any high risk racial or ethnic subgroups)
More than 80% of patients with NS have an abnormality of the cardiovascular system. HCM is present in about 20-30% and approximately 50% have an unusual electrocardiographic pattern characterized by left-axis deviation, an abnormal R/S ratio over the left precordial leads, and an abnormal Q wave. The prevalence of these outcomes may vary by gene:
• PTPN11: HCM in 6%, pulmonic stenosis in 71%, and septal defects in 12%
• SOS1: HCM in 12%, pulmonic stenosis in 62%, septal defects in 25%
• RAF1: HCM in 80-95%
• RIT1: HCM in 45-75%. (Tier 3)
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However, significant bias in the frequency of congenital heart disease may exist because many clinicians have in the past required the presence of cardiac anomalies for diagnosis of NS. (Tier 4)
Renal abnormalities are present in 10-11% of individuals with NS. (Tier 3)
Approximately 50% to 70% of individuals with NS have short stature. (Tier 3)
2 4 8
Cryptorchidism is noted in 60-80% of males with NS. (Tier 4)
1 2
Disordered bleeding has been reported for 30% to 65% of individuals with NS. A variety of small studies have shown that while 50%-89% of those with NS have either a history of bleeding and/or abnormal hemostatic lab results, only 10%-42% have both. (Tier 3)
1 2 5
In a study of 151 subjects with NS, 76% had feeding difficulties, 94% had ocular problems, 50% had hypermobility of joints/hypotonia, 13% had recurrent seizures, 3% had hearing loss, and 3% had peripheral neuropathy. (Tier 3)
Oral findings in patients with NS include a high arched palate (55-100%), dental malocclusion (50–67%), articulation difficulties (72%), and micrognathia (33%–43%). (Tier 3)
Lymphatic manifestations are seen in 20% of individuals with NS. (Tier 3)
2 5
Hypothyroidism is described in 5% of individuals with NS, although antimicrosomal thyroid antibodies are more frequently found (38%). (Tier 4)
One study found that of 641 patients with a confirmed germline PTPN11 variant, 16 (2.5%) developed an MPD and 20 (3.1%) developed JMML. (Tier 3)
Relative Risk
(Include any high risk racial or ethnic subgroups)
One study of 571 molecularly confirmed cases of NS reported four cases of JMML, two of brain tumor, one ALL, and one neuroblastoma, and calculated a childhood cancer standardized incidence ratio of 7.9 (95% CI: 3.2-16.2) compared to population-based incidence rates, indicating that individuals with NS are at an almost eightfold greater risk of developing a childhood cancer than those in the general population. (Tier 3)
1 6
NS has variable expressivity. (Tier 4)
Some adults with NS are only ascertained after the birth of their more seriously affected child. (Tier 3)
4. What is the Nature of the Intervention?
Nature of Intervention
NS is a multisystem disorder that requires various tests, screening, assessments, referrals, and multidisciplinary interventions at different stages of life. Cardiac surveillance is lifelong. Potential treatment includes GH, which has been used without significant adverse events. Among combined 889 patients from 6 articles that reported adult-height outcomes in patients with NS on GH there were only 5 reported cardiac events (2 mild progressions of PVS, 1 HCM, 1 increased biventricular hypertrophy, and 1 cardiac decompensation). No effects on other comorbidities associated with NS have been noted.
2 3 4
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
There are several disorders with significant phenotypic overlap with NS, such as Turner syndrome. Many adults with NS are only ascertained after the birth of their more seriously affected child. (Tier 3)
2 5
For many years before the understanding of their underlying genetic causes, cardiofaciocutaneous syndrome and Costello syndrome were often confused for NS. Mild expression is likely to be overlooked; many with milder forms escape early detected and are identified later in life. Because of differences in prognosis, recurrence concerns, and treatment, accurate diagnosis is essential. (Tier 4)
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Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

Gene Disease Associations
Disease Associations
Primary MONDO Identifier
Additional MONDO Identifiers
OMIM Identifier
Reference List
1. JE Allanson, AE Roberts. Noonan Syndrome. 2001 Nov 15 [Updated 2019 Aug 08]. In: MP Adam, HH Ardinger, RA Pagon, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from:
2. Romano AA, Allanson JE, Dahlgren J, Gelb BD, Hall B, Pierpont ME, Roberts AE, Robinson W, Takemoto CM, Noonan JA. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. (2010) 126(4):746-59.
3. DYSCERNE - Noonan Syndrome Guideline Development Group. Management of Noonan Syndrome: A Clinical Guideline. Publisher: University of Manchester. (2010) Website:
4. Giacomozzi C, Deodati A, Shaikh MG, Ahmed SF, Cianfarani S. The impact of growth hormone therapy on adult height in noonan syndrome: a systematic review. Horm Res Paediatr. (2015) 83(3):167-76.
5. Allanson JE. Noonan syndrome. Am J Med Genet C Semin Med Genet. (2007) 145C(3):274-9.
6. Villani A, Greer MC, Kalish JM, Nakagawara A, Nathanson KL, Pajtler KW, Pfister SM, Walsh MF, Wasserman JD, Zelley K, Kratz CP. Recommendations for Cancer Surveillance in Individuals with RASopathies and Other Rare Genetic Conditions with Increased Cancer Risk. Clin Cancer Res. (2017) 23(12):e83-e90.
7. Noonan syndrome. Orphanet encyclopedia,
8. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. NOONAN SYNDROME 1; NS1. MIM: 163950: 2019 Mar 29. World Wide Web URL:
9. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. NOONAN SYNDROME 3; NS3. MIM: 609942: 2011 May 18. World Wide Web URL:
10. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. NOONAN SYNDROME 7; NS7. MIM: 613706: 2011 Mar 03. World Wide Web URL:
11. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. NOONAN SYNDROME 8; NS8. MIM: 615355: 2017 Mar 03. World Wide Web URL:
12. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. NOONAN SYNDROME 9; NS9. MIM: 616559: 2016 Oct 25. World Wide Web URL:
13. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. NOONAN SYNDROME 4; NS4. MIM: 610733: 2014 Dec 01. World Wide Web URL:
14. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. PROTEIN-TYROSINE PHOSPHATASE, NONRECEPTOR-TYPE, 11; PTPN11. MIM: 176876: 2019 Sep 06. World Wide Web URL:
15. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. V-RAF MURINE SARCOMA VIRAL ONCOGENE HOMOLOG B1; BRAF. MIM: 164757: 2019 Jun 13. World Wide Web URL:
16. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. NOONAN SYNDROME 6; NS6. MIM: 613224: 2017 Sep 26. World Wide Web URL:
17. Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, Hagege AA, Lafont A, Limongelli G, Mahrholdt H, McKenna WJ, Mogensen J, Nihoyannopoulos P, Nistri S, Pieper PG, Pieske B, Rapezzi C, Rutten FH, Tillmanns C, Watkins H. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J. (2014) 35(39):2733-79.
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