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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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Noonan Syndrome

Includes: BRAF-Related Noonan Syndrome, KRAS-Related Noonan Syndrome, MAP2K1- Related Noonan Syndrome, NRAS-Related Noonan Syndrome, PTPN11-Related Noonan Syndrome, RAF1-Related Noonan Syndrome, SOS1-Related Noonan Syndrome

, MD and , MD.

Author Information
, MD
Department of Genetics
Children's Hospital of Eastern Ontario
Ottawa, Ontario, Canada
, MD
Cardiovascular Genetics
Children’s Hospital Boston
Boston, Massachusetts

Initial Posting: ; Last Update: August 4, 2011.

Summary

Disease characteristics. Noonan syndrome (NS) is characterized by short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, characteristic facies, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one third of affected individuals have mild intellectual disability.

Diagnosis/testing. NS is diagnosed on clinical grounds by observation of key features. Affected individuals have normal chromosome studies. Molecular genetic testing identifies a mutation in PTPN11 in 50% of affected individuals, SOS1 in approximately 13%, RAF1 in 3% to 17%, and KRAS in fewer than 5%. Other genes in which mutations have been reported to cause Noonan syndrome in fewer than 1% of cases include NRAS, BRAF, and MAP2K1.

Management. Treatment of manifestations: Cardiovascular anomalies in NS are usually treated as in the general population. Developmental disabilities are addressed by early intervention programs and individualized education strategies. Treatment for serious bleeding is guided by knowledge of the specific factor deficiency or platelet aggregation anomaly. Growth hormone (GH) treatment increases growth velocity.

Surveillance: Monitoring of anomalies found in any system, especially cardiovascular abnormalities.

Genetic counseling. NS is inherited in an autosomal dominant manner. Although many individuals with NS have a de novo mutation, an affected parent is recognized in 30%-75% of families. The risk to sibs of a proband depends on the genetic status of the parents. If a parent is affected, the risk is 50%. When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low (<1%). Each child of an individual with Noonan syndrome has a 50% chance of inheriting the mutation. Prenatal testing is possible if the disease-causing allele has been identified in an affected family member.

Diagnosis

Clinical Diagnosis

Diagnosis of Noonan syndrome (NS) is made clinically by observation of key features. Those cardinal features of NS are well delineated:

  • Short stature
  • Congenital heart defect
  • Developmental delay of variable degree
  • Broad or webbed neck
  • Unusual chest shape with superior pectus carinatum, inferior pectus excavatum
  • Apparently low-set nipples
  • Cryptorchidism in males
  • Characteristic facies. The facial appearance of NS shows considerable change with age, being most striking in the newborn period and middle childhood, and most subtle in the adult. Key features found irrespective of age include low-set, posteriorly rotated ears with fleshy helices; vivid blue or blue-green irises; and eyes that are often wide-spaced, with epicanthal folds and thick or droopy eyelids.
  • Other:
    • Coagulation defects. Coagulation screens such as prothrombin time, activated partial thromboplastin time, platelet count, and bleeding time may show abnormalities. Specific testing should identify the particular coagulation defect, such as von Willebrand disease, thrombocytopenia, varied coagulation factor defects (factors V, VIII, XI, XII, protein C), and platelet dysfunction.
    • Lymphatic dysplasias

Diagnostic criteria developed by van der Burgt in 1997 were published in van der Burgt [2007]. While they have not been used extensively in North America, they are of particular value in the research domain, and are embedded in new management guidelines developed by Dyscerne in the United Kingdom [Noonan Syndrome Guideline Development Group 2010; click Image guidelines.jpg for full text (pdf)]. This clinical management guideline also provides details of recommended baseline investigations and age-specific management. Similar recommendations are provided in Romano et al [2010]. Click Image guidelines.jpg for full text (pdf).

Molecular Genetic Testing

Genes. The genes (PTPN11, SOS1, RAF1, KRAS, NRAS, BRAF, and MAP2K1) in which mutations are known to cause Noonan syndrome are included in Table 1 and Table A.

Evidence for possible additional locus heterogeneity. It is presumed that additional loci causal for the NS phenotype may be identified. Evidence against linkage of the NS phenotype to 12q (the PTPN11 locus) in some families was suggested in the original report [Jamieson et al 1994]. It is unclear whether any of the families in this report may have had a mutation in any of the other genes in which mutation can cause Noonan syndrome.

Testing by gene

Testing by multigene panel. Multigene panels can be used for the simultaneous analysis of some or all of the genes in the RasMAPK pathway associated with Noonan syndrome. These panels vary by methods used and genes included; thus, the ability of a panel to detect a causative mutation or mutations in any given individual with the Noonan syndrome phenotype also varies.

Table 1. Summary of Molecular Genetic Testing Used in Noonan Syndrome (NS)

Gene SymbolProportion of NS Attributed to Mutations in This GeneTest Method Mutations Detected
PTPN1150%Sequence analysis / mutation scanning 1, 2, 3Sequence variants 4
Deletion / duplication analysis 5Partial-and whole-gene deletion 6
SOS110%-13% 7Sequence analysis / mutation scanning 1, 2, 8Sequence variants 4
Deletion / duplication analysis 5Partial-and whole-gene deletion 6
RAF13%-17%Sequence analysis 2, 9Sequence variants 4
Deletion / duplication analysis 5Partial- and whole-gene deletion 6
KRAS<5%Sequence analysis Sequence variants 4
Deletion / duplication analysis 5Partial- and whole-gene deletion 6
NRAS4 individuals to dateSequence analysisSequence variants 4
BRAF<2% 10Sequence analysis / mutation scanning 1, 2Sequence variants 4
Deletion / duplication analysis 5Partial- and whole-gene deletion 6
MAP2K1<2% 11Sequence analysis 2Sequence variants 4
Deletion / duplication analysis 5Partial- and whole-gene deletion 6

1. Sequence analysis and mutation scanning of the entire gene can have similar detection frequencies; however, detection rates for mutation scanning may vary considerably between laboratories based on specific protocol used.

2. Some laboratories offer sequencing of select exons. Note: The exons sequenced may vary by laboratory. Some laboratories offer a tiered approach to testing: if mutation is not identified in the selected exons, the remaining exons are sequenced.

3. Some laboratories offer sequence analysis of exons 1-4, 7-9, and 11-14 before analysis of the entire coding region.

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

5. Testing that detects deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, real-time PCR, multiplex ligation-dependent probe amplification (MLPA), or array GH may be used.

6. No deletions or duplications involving PTPN11, KRAS, SOS1, RAF1, BRAF, or MAP2K1 as causative of Noonan syndrome have been reported. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)

7. Approximately 16%-20% of individuals with a clinical diagnosis of Noonan syndrome who do not have an identified PTPN11 mutation are found to have an SOS1 mutation [Roberts et al 2007, Tartaglia et al 2007].

8. Some laboratories offer sequence analysis of exons 7, 11, and 17 before analysis of the entire coding region.

9. Some laboratories offer sequence analysis of exons 7, 14, and 17 before analysis of the entire coding region.

10. Sarkozy et al [2009]

11. Nava et al [2007]

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Females and males are equally likely to have Noonan syndrome (NS).

Growth. Birth weight is usually normal, although edema may cause a transient increase. Infants with NS frequently have feeding difficulties. This period of failure to thrive is self-limited, although poor weight gain may persist for up to 18 months.

Length at birth is usually normal. Postnatal growth failure is often obvious from the first year of life [Otten & Noordam 2009]. Mean height then follows the third centile from ages two to four years until puberty, when below-average growth velocity and an attenuated adolescent growth spurt tend to occur. As bone maturity is usually delayed, prolonged growth into the 20s is possible.

Final adult height approaches the lower limit of normal: 161-167 cm in males and 150-155 cm in females. Growth curves have been developed from these cross-sectional retrospective data. One study suggests that 30% of affected individuals have height within the normal adult range, while more than 50% of females and nearly 40% of males have an adult height below the third centile [Noonan et al 2003].

Decreased IGF1 and IGF-binding protein 3, together with low responses to provocation, suggest impaired growth hormone release, or disturbance of the growth hormone/insulin-like growth factor I axis, in many affected persons. Mild growth hormone resistance related to a post-receptor signaling defect, which may be partially compensated for by elevated growth hormone secretion, is reported in individuals with NS and a PTPN11 mutation [Binder et al 2005]. See Management for discussion of growth hormone (GH) treatment.

Cardiovascular. 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. The frequency of congenital heart disease is estimated at between 50% and 80%. An electrocardiographic abnormality is documented in approximately 90% of individuals with NS and may be present without concomitant structural defects.

  • Pulmonary valve stenosis, often with dysplasia, is the most common anomaly in NS, found in 20%-50% of affected individuals; it may be isolated or associated with other cardiovascular defects.
  • Hypertrophic cardiomyopathy is found in 20% to 30% of affected individuals. It may present at birth, in infancy, or in childhood.
  • Other structural defects frequently observed include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Coarctation of the aorta is more common than previously thought [Noonan 2005b].

Psychomotor development. Early developmental milestones may be delayed, likely in part as a result of the combination of joint hyperextensibility and hypotonia.

Most school-age children perform well in a normal educational setting, but 25% have learning disabilities [Lee et al 2005a] and 10% to 15% require special education [van der Burgt et al 1999]. Mild intellectual disability is observed in up to one third of affected individuals. Verbal performance is frequently lower than nonverbal performance. There may be a specific cognitive disability, either in verbal or praxic reasoning, requiring a special academic strategy and school placement.

Articulation deficiency is common (72%) but usually responds well to speech therapy. Language delay may be related to hearing loss, perceptual motor disabilities, or articulation deficiencies.

A study of the language phenotype of children and adults with NS showed that language impairments in general are more common in NS than in the general population and, when present, are associated with a higher risk for reading and spelling difficulties [Pierpont et al 2010]. Language is significantly correlated with nonverbal cognition, hearing ability, articulation, motor dexterity, and phonologic memory. No specific aspect of language was selectively affected in those with NS.

Psychological health. Few details of psychological health in Noonan syndrome are reported. No particular syndrome of behavioral disability or psychopathology is observed, and self-esteem is comparable to age-related peers [Lee et al 2005a]. Noonan [2005a] has documented problems in a cohort of 51 adults: depression was found in 23%, and occasional substance abuse and bipolar disease was reported. Similar findings were not reported in a large UK cohort followed over many years [Shaw et al 2007].

Detailed psychological assessment of a small group of 11 affected individuals identified anxiety, panic attacks, social introversion, impoverished self-awareness, and marked difficulties in identifying and expressing feelings and emotions (alexithymia) [Verhoeven et al 2008]. This same research team suggests that in adulthood mild problems in attention, organizational skills, psychosocial immaturity, and alexithymia may be found, and thus assessment of social cognition and personality may be appropriate [Wingbermuehle et al 2009].

Genitourinary. Renal abnormalities, generally mild, are present in 11% of individuals with NS. Dilatation of the renal pelvis is most common. Duplex collecting systems, minor rotational anomalies, distal ureteric stenosis, renal hypoplasia, unilateral renal agenesis, unilateral renal ectopia, and bilateral cysts with scarring are reported less commonly.

Male pubertal development and subsequent fertility may be normal, delayed, or inadequate. Deficient spermatogenesis may be related to cryptorchidism, which is noted in 60% to 80% of males; however, a recent study of male gonadal function identified Sertoli cell dysfunction in males with cryptorchidism and those with normal testicular descent, suggesting an intrinsic defect leading to hypergonadotrophic hypogonadism [Marcus et al 2008].

Puberty may be delayed in females, with a mean age at menarche of 14.6±1.17 years. Normal fertility is the rule.

Facial features. Differences in facial appearance, albeit subtle at certain ages, are a key clinical feature.

  • In the neonate, tall forehead, hypertelorism with downslanting palpebral fissures, low-set, posteriorly rotated ears with a thickened helix, a deeply grooved philtrum with high, wide peaks to the vermillion border of the upper lip, and a short neck with excess nuchal skin and low posterior hairline are found.
  • In infancy, eyes are prominent, with horizontal fissures, hypertelorism, and thickened or ptotic lids. The nose has a depressed root, wide base, and bulbous tip.
  • In childhood, facial appearance is often lacking in affect or expression, as in an individual with a myopathy.
  • By adolescence, facial shape is an inverted triangle, wide at the forehead and tapering to a pointed chin. Eyes are less prominent and features are sharper. The neck lengthens, accentuating skin webbing or prominence of the trapezius muscle.
  • In the older adult, nasolabial folds are prominent, and the skin appears transparent and wrinkled.

Bleeding diathesis. Most persons with NS have a history of abnormal bleeding or bruising. Early studies reported that about one third of all individuals with NS have one or more coagulation defects. More recently a lower rate of coagulopathy has been suggested [Derbent et al 2010]. That coagulopathy may manifest as severe surgical hemorrhage, clinically mild bruising, or laboratory abnormalities with no clinical consequences.

Lymphatic. Varied lymphatic abnormalities are described in individuals with NS. They may be localized or widespread, prenatal, and/or postnatal. Dorsal limb (top of the foot and back of the hand) lymphedema is most common. Less common findings include: intestinal, pulmonary, or testicular lymphangiectasia; chylous effusions of the pleural space and/or peritoneum; and localized lymphedema of the scrotum or vulva.

Prenatal features suggestive of Noonan syndrome, likely of a lymphatic nature, include: transient or persistent cystic hygroma, polyhydramnios, and (rarely) hydrops fetalis [Gandhi et al 2004, Yoshida et al 2004b, Joó et al 2005].

Ocular. Ocular abnormalities including strabismus, refractive errors, amblyopia, and nystagmus occur in up to 95% of affected individuals. Anterior segment and fundus changes are less common.

Dermatologic. Skin differences, particularly follicular keratosis over extensor surfaces and face, are relatively common and may occasionally be as severe as those found in cardiofaciocutaneous syndrome (see Differential Diagnosis).

Café-au-lait spots and lentigines are described in NS more frequently than in the general population (see LEOPARD syndrome discussion in Genetically Related Disorders).

Other

  • Arnold-Chiari I malformation has been reported several times [Holder-Espinasse & Winter 2003], and the author is aware of at least three other individuals with this anomaly [Author, personal observation].
  • Hepatosplenomegaly is frequent; the cause is likely related to subclinical myelodysplasia.
  • Juvenile myelomonocytic leukemia (JMML) is often caused by somatic mutations in PTPN11 (see Genetically Related Disorders) [Tartaglia et al 2003b, Tartaglia et al 2004b, Hasle 2009]. Additionally, individuals with Noonan syndrome and a germline mutation in PTPN11 have a predisposition to this unusual childhood leukemia. In general, JMML in Noonan syndrome runs a more benign course, a finding that may be related to the higher gain-of-function effect of somatic mutations leading to leukemogenesis [Tartaglia et al 2006].
  • Other malignancies. One recent study of individuals with Noonan syndrome caused by a mutation in PTPN11 supports a threefold increased risk of malignancy [Jongmans et al 2011].
  • Myeloproliferative disorders, either transient or more fulminant, can also occur in infants with Noonan syndrome [Kratz et al 2005].
  • Noonan-like/multiple giant-cell lesion syndrome. The giant-cell granulomas and bone and joint anomalies in Noonan-like/multiple giant-cell lesion syndrome are recognized to be part of the Noonan syndrome spectrum. They can resemble cherubism, an autosomal dominant disorder caused by mutations in SH3BP2 (see Cherubism), lesions observed in neurofibromatosis (see Neurofibromatosis Type 1), or lesions observed in the Ramon syndrome with juvenile rheumatoid arthritis (polyarticular pigmented villonodular synovitis).

    Noonan-like/multiple giant-cell lesion syndrome is caused by mutations in PTPN11 [Jafarov et al 2005, Wolvius et al 2006] and SOS1 [Beneteau et al 2009, Neumann et al 2009]. One family with Noonan-like/multiple giant-cell lesion syndrome has a PTPN11 mutation reported in Noonan syndrome without giant cell lesions [Tartaglia et al 2002]; thus, additional genetic factors may be necessary for the giant cell proliferation to occur.
  • These multiple giant cell lesions are also recently recognized in persons with cardiofaciocutaneous syndrome caused by BRAF and MEK1 [Neumann et al 2009]. Thus dysregulation of the Ras-MAPK pathway represents the common and basic molecular event predisposing to giant-cell lesion formation, arguing against the existence of Noonan-like/multiple giant-cell lesion syndrome as a separate entity.

Genotype-Phenotype Correlations

PTPN11. Analysis of a large cohort of individuals with Noonan syndrome (NS) [Tartaglia et al 2001, Tartaglia et al 2002] has suggested that PTPN11 mutations are more likely to be found when pulmonary stenosis is present, whereas hypertrophic cardiomyopathy is less prevalent among individuals with NS caused by PTPN11 abnormalities.

Additional cohort analyses have linked PTPN11 mutations to short stature, pectus deformity, easy bruising, characteristic facial appearance [Yoshida et al 2004a, Zenker et al 2004], and cryptorchidism [Jongmans et al 2004]. In contradistinction, the study of Allanson et al [2010] failed to establish any facial phenotype-genotype correlation.

The likelihood of developmental delay does not differ in mutation-positive and -negative groups, although individuals with the p.Asn308Asp mutation are said to be more likely to receive normal education [Jongmans et al 2004].

Mutations at codons 61, 71, 72, and 76 are significantly associated with leukemogenesis and identify a subgroup of individuals with NS at risk for JMML [Niihori et al 2005].

The post-receptor signaling defect causing mild growth hormone resistance in individuals with NS and a PTPN11 mutation [Binder et al 2005] leads to reduced efficacy of short-term growth hormone (GH) treatment in mutation-positive individuals [Binder et al 2005, Ferreira et al 2005, Limal et al 2006]. However, careful review of height data reveals that individuals with a PTPN11 mutation presented with more severe short stature and, therefore, reached a lower final height despite a similar height gain [Noordam et al 2008].

An in-frame three-nucleotide PTPN11 deletion (p.Gly60del) in a female infant with severe features of Noonan syndrome, including hydrops fetalis and juvenile myelomonocytic leukemia [Yoshida et al 2004a], has been reported. The D61del three nucleotide PTPN11 deletion has also been reported in a child with typical rather than severe NS [Lee et al 2005b]

SOS1. Tartaglia et al [2007] concluded that the phenotype in 22 individuals with NS who had an SOS1 mutation fell within the spectrum of NS, but emphasized the more frequent occurrence of ectodermal abnormalities and a greater likelihood of normal development and stature in these individuals compared to others with NS. In a companion paper, Roberts et al [2007] reported that 14 individuals with NS who had a SOS1 mutation did not differ in development and stature from other individuals with NS. Cardiac septal defects were found more frequently than in individuals with NS and mutations in PTPN11. The study did not make specific mention of ectodermal findings.

Pierpont et al [2009] have studied intellectual abilities in Noonan syndrome and report that individuals with SOS1 mutations generally have average or higher-level skills.

RAF1. The studies reported to date emphasize a striking correlation with hypertrophic cardiomyopathy, with 95% of affected individuals with a RAF1 mutation showing this feature, in comparison with the overall prevalence in NS of 18%. This suggests that pathologic cardiomyocyte hypertrophy occurs because of increased Ras signaling. Multiple nevi, lentigines, and/or café au lait spots were reported in one third of people with RAF1-associated NS.

KRAS. The phenotype associated with mutations in KRAS tends to be atypical, with greater likelihood and severity of intellectual disability [Zenker et al 2007] in these individuals than in others with NS. Kratz et al [2009] reported the somewhat unusual feature of craniosynostosis in two unrelated probands with NS and a missense KRAS mutation.

NRAS. To date few individuals with an NRAS mutation have been reported. The clinical features appear to be typical with no particular or distinctive phenotype observed [Cirstea et al 2010]. The rare individuals with a mutation in BRAF or MEK1 also appear to have features of classic Noonan syndrome, albeit with florid ectodermal manifestations [Nava et al 2007, Nystrom et al 2008, Sarkozy et al 2009].

Penetrance

Penetrance of NS is difficult to determine because of ascertainment bias and variable expressivity with frequent subtlety of features. Many affected adults are diagnosed only after the birth of a more obviously affected infant.

Anticipation

Anticipation has not been described in NS.

Nomenclature

An early term for NS, "male Turner syndrome," incorrectly implied that the condition would not be found in females.

In 1949, O Ullrich reported affected individuals and noted a similarity between their features and those in a strain of mice bred by Bonnevie (webbed neck and lymphedema). The term Bonnevie-Ullrich syndrome became popular, particularly in Europe.

Prevalence

NS is common and reported to occur in between 1:1000 and 1:2500 persons. Mild expression is likely to be overlooked.

Differential Diagnosis

Turner syndrome, found only in females, is differentiated from Noonan syndrome (NS) by demonstration of a sex chromosome abnormality on cytogenetic studies in individuals with Turner syndrome. The phenotype of Turner syndrome is actually quite different from that of NS, when one considers face, heart, development, and kidneys. In Turner syndrome, renal anomalies are more common, developmental delay is much less frequently found, and left-sided heart defects are the rule.

Like NS, Watson syndrome is characterized by short stature, pulmonary valve stenosis, variable intellectual development, and skin pigment changes (e.g., café au lait patches). The Watson syndrome phenotype also overlaps with that of neurofibromatosis type 1; the two are now known to be allelic [Allanson et al 1991].

Cardiofaciocutaneous (CFC) syndrome and NS have the greatest overlap in features. CFC syndrome has similar cardiac and lymphatic findings [Noonan 2001, Armour & Allanson 2008]. In CFC syndrome, intellectual disability is usually more severe, with a higher likelihood of structural central nervous system anomalies; skin pathology is more florid; gastrointestinal problems are more severe and long lasting; and bleeding diathesis is rare. Facial appearance tends to be coarser, dolichocephaly and absent eyebrows are more frequently seen, and blue eyes are less commonly seen. To date, the four genes in which mutation is known to cause CFC syndrome are BRAF (~75%-80%), MAP2K1 and MAP2K2 (~10%-15%), and KRAS (<5%). Rarely, individuals have a mutation in a gene usually associated with Noonan syndrome [Narumi et al 2008, Nystrom et al 2008].

Costello syndrome shares features with both NS and CFC [Hennekam 2003, Gripp et al 2006, Kerr et al 2006]. Many individuals with Costello syndrome have been studied molecularly; no PTPN11 mutation has been identified [Tartaglia et al 2003a; Tröger et al 2003]. Germline mutations occurring most commonly in exon 2 of the HRAS proto-oncogene have been shown to cause Costello syndrome [Aoki et al 2005].

Noonan-like syndrome with loose anagen hair. Germline mutations in SHOC2 usually lead to a phenotype of Noonan-like features; a small proportion of those affected have the classic Noonan syndrome phenotype [Kerr, personal experience]. The recurrent missense SHOC2 mutation, 4A>G, has been found in a subgroup with features of NS but also growth hormone deficiency; distinctive hyperactive behavior that improves with age in most; hair anomalies including easily pluckable, sparse, thin slow-growing hair (loose anagen hair); darkly pigmented skin with eczema or ichthyosis; hypernasal voice; and an over-representation of mitral valve dysplasia and septal defects in comparison with classic NS [Cordeddu et al 2009]. Sequence analysis of all exons detects a mutation in about 5% of individuals with Noonan syndrome. Most have the classic loose anagen hair [Cordeddu et al 2009].

Other. NS should be distinguished from other syndromes/conditions with developmental delay, short stature, congenital heart defects, and distinctive facies, especially the following:

Neurofibromatosis type 1 (NF1) shares some features with NS, including short stature, learning difficulties and café au lait patches. Infrequently, affected individuals also have a NS-like facial appearance. This could be caused by chance concurrence of Noonan syndrome and NF1 [Colley et al 1996, Bertola et al 2005]. However, most often it appears to be a Noonan-like face in an individual with mutation-proven NF1, sometimes in the presence of a variant NF1 phenotype [Stevenson et al 2006, Nystrom et al 2009].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Noonan syndrome (NS), the following evaluations are recommended:

  • Complete physical and neurologic examination
  • Plotting of growth parameters on NS growth charts
  • Cardiac evaluation with echocardiography and electrocardiography
  • Ophthalmologic evaluation
  • Hearing evaluation
  • Coagulation screen
  • Renal ultrasound examination; urinalysis if the urinary tract is anomalous
  • Clinical and radiographic assessment of spine and rib cage
  • Brain and cervical spine MRI if neurologic symptoms are present
  • Multidisciplinary developmental evaluation
  • Genetics consultation

Treatment of Manifestations

Treatment of the complications of Noonan syndrome is generally standard and does not differ from treatment in the general population.

Management guidelines have been developed by Dyscerne, a European consortium [Noonan Syndrome Guideline Development Group 2010; click Image guidelines.jpg for full text (pdf)]; a separate set has been published by an American consortium working with the Noonan Syndrome Support Group [Romano et al 2010; click Image guidelines.jpg for full text (pdf)].

Treatment of cardiovascular anomalies is generally the same as in the general population.

Developmental disabilities should be addressed by early intervention programs and individualized education strategies.

The bleeding diathesis in Noonan syndrome can have a variety of causes. Specific treatment for serious bleeding may be guided by knowledge of a factor deficiency or platelet aggregation anomaly. Factor VIIa has been successfully used to control bleeding caused by hemophilia, von Willebrand disease, thrombocytopenia, and thrombasthenia. It has also been used in an infant with Noonan syndrome whose platelet count and prothrombin and partial thromboplastin times were normal, to control severe postoperative blood loss resulting from gastritis [Tofil et al 2005].

Studies of growth hormone (GH) treatment have been published from the UK, Japan [Ogawa et al 2004], the Netherlands [Noordam 2007, Noordam et al 2008], Sweden [Osio et al 2005], and the United States [Romano et al 2009]. The rationale for GH treatment of individuals with Noonan syndrome includes (1) significant short stature compared with normal peers; (2) possible impairment of the GH-insulin-like-growth-factor type I (GH-IGF-I) axis; and (3) documented response to GH treatment in recent studies. In the US, but not in Europe, short stature associated with Noonan syndrome may be an indication for treatment independent of the status of the GH-IGF-I axis. In Europe, GH treatment is the standard of care for children with abnormalities of the GH-IGF-I axis and could be used when GH physiology is normal. No standard dose has been established; no correlation between dosage used and final height is apparent.

Short- and long-term studies have demonstrated a consistent and significant increase in height velocity in children with Noonan syndrome who have been treated. GH therapy appears to be effective in increasing short-term growth in children with Noonan syndrome and is well tolerated. Data on final height are encouraging. Substantial height gain during prepubertal years and puberty contributes to final height within the general population range in the majority of those treated, especially males [Osio et al 2005, Noordam et al 2008, Romano et al 2009]. The increase in height SD varies from 0.6 to 1.8 SD and may depend on age at start of treatment, duration of study, age at onset of puberty, and/or GH sensitivity [Osio et al 2005, Noordam et al 2008, Dahlgren 2009].

Surveillance

If anomalies are found in any system (see Evaluations Following Initial Diagnosis), periodic follow-up should be planned and life-long monitoring may be necessary; for example, periodic echocardiography if cardiovascular abnormalities are present, periodic eye examination if a refraction error or strabismus is found, urinalysis if there are structural abnormalities of the collecting system.

Agents/Circumstances to Avoid

Aspirin therapy should be avoided because it may exacerbate a bleeding diathesis.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Noonan syndrome is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Many affected individuals have de novo mutations; however, an affected parent is recognized in 30%-75% of families. In simplex cases (i.e., those with no known family history), paternal origin of the mutation has been found universally to date [Tartaglia et al 2004a]. In this cohort, advanced paternal age was observed along with a significant sex-ratio bias favoring transmission to males, a finding that is thus far unexplained.
  • It is appropriate to evaluate both parents, including a thorough physical examination with particular attention to the features of NS; echo- and electrocardiography; coagulation screening; and review of photographs of the face at all ages, searching for characteristic features of NS. Molecular genetic testing of parents is possible if the disease-causing mutation in the proband is known.

Sibs of a proband

Offspring of a proband. Each child of an individual with NS has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation and/or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

High-risk pregnancy

  • Molecular genetic testing. If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

    Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
  • Ultrasound examination. For pregnancies at 50% risk, high-resolution ultrasound examination is also possible. Prenatal features are nonspecific but may include polyhydramnios, hydronephrosis, pleural effusion, edema, cardiac defects, distended jugular lymphatic sacs, cystic hygroma, and increased nuchal translucency [Nisbet et al 1999, Schluter et al 2005, Houweling et al 2010]. Cystic hygroma may be accompanied by scalp edema, polyhydramnios, pleural and pericardial effusions, ascites, and/or frank hydrops fetalis. The presence of these findings should suggest the diagnosis of NS. In addition, a search for a cardiac defect should be made, although Menashe et al [2002] has pointed out how infrequently such a defect will be detected prenatally. Among fetuses with normal chromosomes, the diagnosis of Noonan syndrome will be made in approximately 1%-3% of cases with nuchal edema detected in the first trimester [Reynders et al 1997, Adekunle et al 1999, Nisbet et al 1999, Hiippala et al 2001] and 10% of second-trimester fetuses with a cystic hygroma [Lee et al 2009]. Treatment of these complications is the same as that in the general population.

Low-risk pregnancy. Although the ultrasonographic findings described suggest the diagnosis of Noonan syndrome in high-risk pregnancies, they are nonspecific and may be associated with cardiovascular defects or other chromosomal and non-chromosomal syndromes.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • Noonan Syndrome Foundation
    Email: info@teamnoonan.org
  • RASopathiesNet
    244 Taos Road
    Atlandena CA 91001
    Phone: 626-676-7694
    Email: lisa@rasopathies.org
  • Human Growth Foundation (HGF)
    997 Glen Cove Avenue
    Suite 5
    Glen Head NY 11545
    Phone: 800-451-6434 (toll-free)
    Fax: 516-671-4055
    Email: hgf1@hgfound.org
  • MAGIC Foundation
    6645 West North Avenue
    Oak Park IL 60302
    Phone: 800-362-4423 (Toll-free Parent Help Line); 708-383-0808
    Fax: 708-383-0899
    Email: info@magicfoundation.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table B. OMIM Entries for Noonan Syndrome (View All in OMIM)

163950NOONAN SYNDROME 1; NS1
164757V-RAF MURINE SARCOMA VIRAL ONCOGENE HOMOLOG B1; BRAF
164760V-RAF-1 MURINE LEUKEMIA VIRAL ONCOGENE HOMOLOG 1; RAF1
164790NEUROBLASTOMA RAS VIRAL ONCOGENE HOMOLOG; NRAS
176872MITOGEN-ACTIVATED PROTEIN KINASE KINASE 1; MAP2K1
176876PROTEIN-TYROSINE PHOSPHATASE, NONRECEPTOR-TYPE, 11; PTPN11
182530SON OF SEVENLESS, DROSOPHILA, HOMOLOG 1; SOS1
190070V-KI-RAS2 KIRSTEN RAT SARCOMA VIRAL ONCOGENE HOMOLOG; KRAS
609942NOONAN SYNDROME 3; NS3
610733NOONAN SYNDROME 4; NS4
611553NOONAN SYNDROME 5; NS5
613224NOONAN SYNDROME 6; NS6
613706NOONAN SYNDROME 7; NS7

PTPN11

Normal allelic variants. Tartaglia et al [2001] identified mutation of PTPN11 as causative of Noonan syndrome. The gene comprises 15 exons.

Pathologic allelic variants. Missense mutations in PTPN11 were identified in 50% of affected individuals examined. Ninety-five percent of these mutations alter residues at or close to the SH2-PTP interacting surfaces, which are involved in switching between active and inactive conformations of the protein and cause catalytic activation and gain of function. Five percent of the mutations alter sensitivity to activation from binding partners. One in-frame deletion, p.Gly60del, has been described [Yoshida et al 2004a]. See Table 2.

Table 2. Selected PTPN11 Pathologic Allelic Variants

DNA Nucleotide Change Protein Amino Acid ChangeReference Sequences
c.922A>Gp.Asn308AspNM_002834​.3
NP_002825​.3
c.179_181delGTG p.Gly60del

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. PTPN11 encodes tyrosine-protein phosphatase non-receptor type 11 (SHP-2), a widely expressed extracellular protein that has two tandemly arranged SRC-2 homology 2 (SH2) domains at the N terminus (N-SH2 and C-SH2), a single catalytic protein tyrosine phosphatase (PTP) domain, and a carboxy tail with two TP sites and a proline-rich stretch. The SH2-PTP interaction maintains the protein in an inactive state. The protein is a key molecule in the cellular response to growth factors, hormones, cytokines, and cell adhesion molecules. It is required in several intracellular signal transduction pathways that control diverse developmental processes (including cardiac semilunar valvulogenesis and blood cell progenitor commitment and differentiation) and has a role in modulating cellular proliferation, differentiation, migration, and apoptosis [Tartaglia et al 2002, Fragale et al 2004].

Abnormal gene product. Activation of tyrosine-protein phosphatase non-receptor type II stimulates epidermal growth factor-mediated RAS/ERK/MAPK activation, increasing cell proliferation [Tartaglia et al 2002, Fragale et al 2004].

KRAS

Normal allelic variants. The gene comprises four exons spanning 45 kb. Alternative splicing produces two isoforms (4a and 4b) that differ at the C terminus. In 98% of transcripts, exon 4a is spliced out; and only exon 4b is available for translation into protein. The effector or switch domains are part of exons 1 and 2, while binding to guanine nucleotide exchange factors occurs in exon 3.

Pathologic allelic variants. Somatic KRAS and NRAS mutations have been found in myeloid malignancies and other cancers. The association between abnormal Kras and Noonan syndrome is the first evidence of a role in embryonic development. These gain-of-function mutations confer biochemical and cellular phenotypes similar to Noonan syndrome-associated SHP-2 mutations.

Normal gene product. Ras proteins regulate cell fates by cycling between active guanosine triphosphate (GTP)-bound and inactive guanosine diphosphate (GDP)-bound conformations. They are key regulators of the RAS-RAF-MEK-ERK pathway, which is important for proliferation, growth, and death of cells.

Abnormal gene product. The abnormal K-Ras protein induces hypersensitivity of primary hematopoietic progenitor cells to growth factors and deregulates signal transduction in a cell lineage-specific manner. Strong gain-of-function KRAS mutations may be incompatible with life.

SOS1

Normal allelic variants. SOS1 comprises 23 exons and encodes a 150-kd multidomain protein.

Pathologic allelic variants. Noonan syndrome-associated SOS1 missense mutations are hypermorphic; that is, they increase signaling through the RasMAPK pathway. The vast majority are located in highly conserved sites. They cluster at codons encoding residues implicated in the maintenance of SOS1 in its autoinhibited form. One such cluster is found in the codons encoding the PH domain and may disrupt the autoinhibited conformation by destabilizing the conformation of the DH domain. Another cluster resides in codons encoding the helical linker between the DH and REM domains. A third cluster affects codons of residues that mediate the interaction between the DH and REM domains.

Normal gene product. SOS1 (son of sevenless homolog 1) protein comprises a RAS-GEF (guanine nucleotide exchange factor) domain, a conserved histone-like fold, Dbl homology (DH) and plekstrin homology (PH) domains, a helical linker, a RAS exchange motif (REM), and a proline-rich region. The Dbl homology domain may act as a guanine nucleotide exchange factor (GEF) for the RAC family small G proteins (RAC-GEF). SOS1 has two RAS binding sites: an effector site in the Cdc25 domain and an allosteric site formed by the REM and Cdc25 domains. RAS binding to the allosteric site enhances RAS-GEF activity. The DH-PH module controls RAS binding at this site and likely acts as an intramolecular inhibitor of RAS-GEF activity. The entire N terminus functions as an integrated unit to inhibit the REM-Cdc25 domain.

SOS1 is a RAS-specific guanine nucleotide exchange factor (GEF). The protein is autoinhibited owing to complex regulatory intra- and intermolecular interactions. After receptor tyrosine kinase (RTK) stimulation, SOS1 is recruited to the plasma membrane, where it acquires a catalytically active conformation. It then, in turn, catalyzes activation of the RAS-MAPK pathway by conversion of RAS-GDP to RAS-GTP.

Abnormal gene product. Noonan syndrome-associated SOS1 mutations abrogate autoinhibition, increasing and prolonging RAS activation and downstream signaling through enhanced RAS-GEF activity. Somatic SOS1 mutations have not been found in cancer.

RAF1

Normal allelic variants. RAF1 comprises 17 exons.

Pathologic allelic variants. The consensus 14-3-3 recognition site includes amino acid residues Arg256, Ser257, Ser259, and Pro261 in exon 7. Many of the mutations identified in Noonan syndrome cluster in this CR2 domain, interfere with 14-3-3 binding, and cause greater kinase activity than wild-type protein, both basally and after EGF stimulation. Other mutations reside in the RAF activation segment in CR3 and show reduced or absent kinase activity. However, they still result in constitutive ERK activation. Somatic RAF1 mutations have only rarely been found in cancer. Most of these cancer-causing mutations do not cluster in the CR2 and CR3 hot spots.

Normal gene product. RAF1 is ubiquitously expressed and encodes a protein of 648 amino acids with three domains. It has three conserved regions (CR). CR1 (exons 2-5) encode a RAS-binding domain (RBD) and a cysteine-rich domain (CRD). CR2 lies in exon 7, while CR3, which spans exons 10-17, encodes an activation segment. The gene is highly regulated with numerous serine and threonine residues that can be phosphorylated, resulting in activation or inactivation. The Ser259 residue in CR2 is particularly important. In the inactive state, the N terminus of RAF1 interacts with and inactivates the kinase domain at the C terminus. This conformation is stabilized by 14-3-3 protein dimers that bind to phosphorylated Ser259 and Ser261. Dephosphorylation of Ser259 facilitates binding of RAF1 to RAS-GTP and propagation of the signal through the RAS-MAPK cascade via RAF1 MEK kinase activity. CR1 and CR2 both have negative regulatory function, removal of which results in oncogenic activity. The kinase domain, CR3, also associates with 14-3-3.

Abnormal gene product. Noonan syndrome-associated RAF1 mutations increase and prolong RAS activation and downstream signaling through enhanced RAS-GEF activity and reduced 14-3-3 binding and autoinhibition.

NRAS

Normal allelic variants. NRAS comprises seven exons. There are two main NRAS transcripts of 4.3 kb and 2 kb.

Pathologic allelic variants. The two pathologic variants reported in association with NS are Thr50Ile and Gly60Glu, both in exon 3. The Thr50-to-Ile substitution is located within a conserved residue located in the beta-2-beta-3 loop connecting the two switch regions. In vitro functional expression studies showed that the mutant protein resulted in enhanced downstream phosphorylation in the presence of serum. Protein modeling suggests that Thr50 interacts with the polar heads of membrane phospholipids and is an integral part of a region that controls RAS membrane orientation. In vitro functional expression studies showed that the Gly60Glu mutant protein resulted in enhanced downstream phosphorylation in the presence of serum and that mutant protein accumulated constitutively in the active GTP-bound form.

Normal gene product. RAS proteins act as molecular switches through cycling between inactive GDP-bound and active GTP-bound states. In its active form, Ras can interact productively with over 20 effectors including Raf, phosphatidylinositol-3-kinase, and Ral-GDP dissociation simulator (GDS). This activates the Raf-MEK-MAPK cascade which promotes cell proliferation, differentiation, or survival.

Abnormal gene product. Expression of the NS-associated NRAS substitutions Thr50Ile or Gly60Glu in model cells resulted in enhanced phosphorylation of MEK and ERK in the presence of serum or after epidermal growth factor (EGF) stimulation. Similar to germline KRAS mutations causing Noonan syndrome and cardiofaciocutaneous syndrome, germline NRAS alterations do not affect residues commonly mutated in human cancers and appear to be less activating in dysregulating intracellular signaling in vitro compared with cancer-associated somatic mutations.

BRAF

Normal allelic variants. BRAF encodes B-Raf, a member of the Raf family, which also includes C-Raf and A-Raf encoded by the X-linked gene ARAF. BRAF spans approximately 190 kb and comprises 18 exons.

Pathologic allelic variants. The spectrum of BRAF mutations in individuals with Noonan syndrome is restricted to only two variants in three cases. These variants are novel, never having been identified in cancer. Two mutations were de novo and one was familial.

Normal gene product. The protein product of BRAF is B-Raf, a serine/threonine protein kinase that is one of the many direct downstream effectors of Ras. The Raf/MEK/ERK module of kinases is critically involved in cell proliferation, differentiation, motility, apoptosis, and senescence. B-Raf has only two known downstream effectors, mitogen-activated protein kinase 1 and 2 (also known as MEK1 and MEK2).

The three conserved regions (CR) in B-Raf:

  • CR1 (conserved region 1), containing the Ras binding domain and the cysteine-rich domain, both of which are required for recruitment of B-Raf to the cell membrane
  • CR2, the smallest of the conserved regions
  • CR3, the kinase domain containing the glycine-rich loop (exon 11) and the activation segment (exon 15) of the catalytic domain

Exons 3-6 encode a RAS-binding domain (RBD) and a cysteine-rich domain (CRD), while the kinase domain is encoded by exons 11-17.

BRAF is ubiquitously expressed and encodes a protein of 766 amino acids. It is activated following GTP-bound RAS binding, and phosphorylates and activates the dual specificity mitogen-activated protein kinase kinases (MEK1 and MEK2).

Abnormal gene product. A 722C>T transition, exon 6, Thr241Met has been reported in association with NS; a closely related mutant protein, Thr241Pro, has been reported in one individual with LEOPARD syndrome. In vitro studies showed a slight increase in MEK phosphorylation. A 1789 C>T transversion, exon 15, Leu597Val, has been reported in a single case of NS.

MAP2K1

Normal allelic variants. MEK, like Raf, exists as a multigene family. MAP2K1 spans approximately 104 kb.

Pathologic allelic variants. Missense mutations in MAP2K1 cause Noonan syndrome in fewer than 2% of clinically diagnosed individuals. Somatic mutations have been reported in ovarian cancer [Estep et al 2007] and lung cancer [Marks et al 2008].

Normal gene product. MAP2K1 encodes threonine/tyrosine kinases with the ability to activate ERK1 and ERK2. The normal protein encoded by MAPK21 is dual specificity mitogen-activated protein kinase kinase 1 (MEK1). The MEK1 and MEK2 proteins have approximately 85% amino acid identity. MEK1 and MEK2 proteins do not serve redundant purposes as determined in mouse development.

Abnormal gene product. Three individuals with NS had a novel mutation in exon 2 of MAP2K1. These mutations were found in exons already identified as mutational hot spots in cardiofaciocutaneous syndrome.

References

Published Guidelines/Consensus Statements

  1. Noonan Syndrome Guideline Development Group. Management of Noonan syndrome – a clinical guideline (pdf). University of Manchester: DYSCERNE. Available online. 2010. Accessed 7-25-11.
  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 (pdf). Available online. 2010. Accessed 7-25-11. [PubMed: 20876176]

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Suggested Reading

  1. Tartaglia M, Gelb BD. Noonan syndrome. Atlas of Genetics and Cytogenetics Oncology and Haematology. Available online. 2005. Accessed 8-1-11.

Chapter Notes

Revision History

  • 4 August 2011 (me) Comprehensive update posted live
  • 7 October 2008 (me) Comprehensive update posted live
  • 6 September 2007 (cd) Revision: mutations in RAF1 associated with Noonan syndrome
  • 22 December 2006 (cd) Revision: SOS1 mutations responsible for some cases of Noonan syndrome; clinical testing available
  • 22 May 2006 (cd) Revision: prenatal testing for Noonan syndrome caused by KRAS mutations clinically available
  • 16 May 2006 (cd) Revision: KRAS testing clinically available
  • 1 May 2006 (ja) Revision: mutations in KRAS cause Noonan syndrome
  • 9 March 2006 (me) Comprehensive update posted to live Web site
  • 17 December 2003 (me) Comprehensive update posted to live Web site
  • 15 November 2001 (me) Review posted to live Web site
  • 2 August 2001 (ja) Original submission
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