Noonan syndrome

Actionability Pediatric Summary Report

Secondary Findings in Pediatric Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Genes: BRAF (HGNC:1097) KRAS (HGNC:6407) NRAS (HGNC:7989) PTPN11 (HGNC:9644) RAF1 (HGNC:9829) RIT1 (HGNC:10023) SOS1 (HGNC:11187) SOS2 (HGNC:11188)
• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 07/01/2019
• Curation Status: Released (1.0.3)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
BRAF	Noonan syndrome 7 (0013379)	613706	Assertion Pending
KRAS	Noonan syndrome 3 (0012371)	609942	Assertion Pending
NRAS	Noonan syndrome 6 (0013186)	613224	Assertion Pending
PTPN11	Noonan syndrome 1 (0008104)	163950	Assertion Pending
RAF1	Noonan syndrome 5 (0012690)	611553	Assertion Pending
RIT1	Noonan syndrome 8 (0014143)	615355	Assertion Pending
SOS1	Noonan syndrome 4 (0012547)	610733	Assertion Pending
SOS2	Noonan syndrome 9 (0014691)	616559	Assertion Pending

Actionability Assertion Rationale

• This topic was initially scored prior to development of the process for making actionability assertions. The Pediatric AWG decided to defer making an assertion until after the topic could be reviewed through the update process.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Cardiac manifestations / Cardiac surveillance	2	3C	0D	3	8CD

Severity of Outcome

Prevalence of the Genetic Condition

Noonan syndrome (NS) is reported to occur in 1:1000 and 1:2500 live births.

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.

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.

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

Unknown

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

Unknown

Variant testing will provide a diagnosis of NS in 70% of cases; in 30% the responsible gene remains unknown.

Tier 4

Penetrance (Includes any high-risk racial or ethnic subgroups)

>= 40 %

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

Unknown

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

5-39 %

Renal abnormalities are present in 10-11% of individuals with NS.

Tier 3

>= 40 %

About 50% of school-aged children with NS meet diagnostic criteria for a developmental coordination disorder. Up to one fourth of affected individuals have learning disabilities and 10-40% require special education.

Tier 3

>= 40 %

Approximately 50% to 70% of individuals with NS have short stature.

Tier 3

>= 40 %

Cryptorchidism is noted in 60-80% of males with NS.

Tier 4

>= 40 %

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

>= 40 %

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

>= 40 %

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

5-39 %

Lymphatic manifestations are seen in 20% of individuals with NS.

Tier 3

5-39 %

Hypothyroidism is described in 5% of individuals with NS, although antimicrosomal thyroid antibodies are more frequently found (38%).

Tier 4

1-4 %

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 (Includes any high-risk racial or ethnic subgroups)

>3

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

Expressivity

NS has variable expressivity.

Tier 4

Some adults with NS are only ascertained after the birth of their more seriously affected child.

Tier 3

Intervention Effectiveness

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

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

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

Short stature due to NS is an FDA-approved indication for growth hormone (GH) treatment. The rationale for GH treatment of individuals with NS includes: significant short stature compared with normal peers; possible impairment of the GH-insulin-like-growth-factor type I (GH-IGF-I) axis in NS; and documented response to GH treatment in studies.

Tier 3

No high-quality controlled trails on the use of GH to impact adult height in NS are available. Data from 2 uncontrolled prospective studies that assessed adult height after GH use indicated a standard deviation score of 1.4 ± 0.8, corresponding to 9.5 ± 5.4 cm. Data from 2 uncontrolled prospective studies that assessed near-adult height after GH use indicated a standard deviation score of 1.3 ± 0.9, corresponding to 8.6 ± 5.9 cm. However, the lack of control groups in these studies represents a bias and impacts the interpretation of the effectiveness of GH in NS.

Tier 1

Surveillance

Recommended surveillance in childhood includes:

• Cardiovascular: Individuals without heart disease should have cardiac reevaluation annually until the age of 3, then every 5 years

• Growth: Children should be weighed and measured regularly (three times yearly for first 3 years of life and yearly thereafter) by the primary care provider; data should be plotted on appropriate growth charts

• Development: Developmental screening annually and specifically at primary and secondary school entry

• Vision: Eye evaluations at least every 2 years

• Hearing: Annual hearing test throughout early childhood

• Orthopedics: Annual exam of chest and back to monitor for scoliosis

• Dental: Careful oral exam at each visit

• Coagulation: Screening should be carried out at least once during childhood

• Cryptorchidism: Check for cryptorchidism

• Puberty: The likelihood of delayed puberty should be anticipated

• Thyroid: Screen for thyroid abnormalities every 3-5 years in older children.

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

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

Nature of 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.

Context: Adult Pediatric

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.

Context: Adult Pediatric

Tier 3

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.

Context: Adult Pediatric

Tier 4

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			BRAF			613706	0013379	0018997
KRAS			609942	0012371	0018997
NRAS			613224	0013186	0018997
PTPN11			163950	0008104	0018997
RAF1			611553	0012690	0018997
RIT1			615355	0014143	0018997
SOS1			610733	0012547	0018997
SOS2			616559	0014691	0018997

References List

Allanson JE. (2007) Noonan syndrome. American journal of medical genetics. Part C, Seminars in medical genetics. 145C(3):274-9.

DYSCERNE - Noonan Syndrome Guideline Development Group. Management of Noonan Syndrome: A Clinical Guideline. Publisher: University of Manchester (2010) URL: https://rasopathiesnet.org/wp-content/uploads/2014/01/265_Noonan_Guidelines.pdf

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) 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). European heart journal. 35(39):2733-79.

Giacomozzi C, Deodati A, Shaikh MG, Ahmed SF, Cianfarani S. (2015) The impact of growth hormone therapy on adult height in noonan syndrome: a systematic review. Hormone research in paediatrics. 83(3):167-76.

JE Allanson, AE Roberts. Noonan Syndrome. (2001) [Updated Aug 08 2019]. In: MP Adam, HH Ardinger, RA Pagon, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1124/

NOONAN SYNDROME 1; NS1. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 163950, (2019) World Wide Web URL: http://omim.org/

NOONAN SYNDROME 3; NS3. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 609942, (2011) World Wide Web URL: http://omim.org/

NOONAN SYNDROME 4; NS4. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 610733, (2014) World Wide Web URL: http://omim.org/

NOONAN SYNDROME 6; NS6. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 613224, (2017) World Wide Web URL: http://omim.org/

NOONAN SYNDROME 7; NS7. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 613706, (2011) World Wide Web URL: http://omim.org/

NOONAN SYNDROME 8; NS8. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 615355, (2017) World Wide Web URL: http://omim.org/

NOONAN SYNDROME 9; NS9. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 616559, (2016) World Wide Web URL: http://omim.org/

Noonan syndrome. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=648

PROTEIN-TYROSINE PHOSPHATASE, NONRECEPTOR-TYPE, 11; PTPN11. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 176876, (2019) World Wide Web URL: http://omim.org/

Romano AA, Allanson JE, Dahlgren J, Gelb BD, Hall B, Pierpont ME, Roberts AE, Robinson W, Takemoto CM, Noonan JA. (2010) Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. 126(4):746-59.

V-RAF MURINE SARCOMA VIRAL ONCOGENE HOMOLOG B1; BRAF. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 164757, (2019) World Wide Web URL: http://omim.org/

Villani A, Greer MC, Kalish JM, Nakagawara A, Nathanson KL, Pajtler KW, Pfister SM, Walsh MF, Wasserman JD, Zelley K, Kratz CP. (2017) Recommendations for Cancer Surveillance in Individuals with RASopathies and Other Rare Genetic Conditions with Increased Cancer Risk. Clinical cancer research : an official journal of the American Association for Cancer Research. 23(12):e83-e90.