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Noonan Syndrome

, MD and , MD.

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Initial Posting: ; Last Update: February 25, 2016.

Summary

Clinical characteristics.

Noonan syndrome (NS) is characterized by characteristic facies, 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, 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 fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.

Diagnosis/testing.

NS is diagnosed on clinical grounds by observation of key features. Affected individuals have normal chromosome studies. Molecular genetic testing identifies a pathogenic variant in PTPN11 in 50% of affected individuals, SOS1 in approximately 13%, RAF1 and RIT1 each in 5%, and KRAS in fewer than 5%. Other genes in which pathogenic variants have been reported to cause Noonan syndrome in fewer than 1% of cases include NRAS, BRAF, and MAP2K1. Several additional genes associated with a Noonan-syndrome-like phenotype in fewer than ten individuals have been identified.

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 pathogenic variant, 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 pathogenic variant. Prenatal testing is possible if the NS-related pathogenic variant has been identified in an affected family member.

Diagnosis

Suggestive Findings

Noonan syndrome (NS) should be suspected in individuals with the following key features:

  • Characteristic facies. The facial appearance of NS shows considerable change with age, being most striking in young 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, downslanted, and with epicanthal folds and fullness or droopiness of the upper eyelids (ptosis).
  • Short stature
  • Congenital heart defect, most commonly pulmonary valve stenosis, atrial septal defect, and/or hypertrophic cardiomyopathy
  • Developmental delay of variable degree
  • Broad or webbed neck
  • Unusual chest shape with superior pectus carinatum, inferior pectus excavatum
  • Widely set nipples
  • Cryptorchidism in males
  • Other:
    • Coagulation defects. Coagulation screens (e.g., 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 of the lungs, intestines, and/or lower extremities

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 management guidelines developed by Dyscerne in the United Kingdom [Noonan Syndrome Guideline Development Group 2010]. This clinical management guideline also provides details of recommended baseline investigations and age-specific management. Similar recommendations are provided in Romano et al [2010] (full text) and Roberts et al [2013].

Establishing the Diagnosis

The diagnosis of NS is established in a proband with identification of a heterozygous pathogenic variant in one of the genes listed in Table 1.

Molecular testing approaches can include use of a multi-gene panel, serial single-gene testing, and more comprehensive genomic testing.

  • A multi-gene panel that includes the genes listed in Table1 and other genes of interest (see Differential Diagnosis) is the test of choice for an individual suspected of having Noonan syndrome. Because of significant phenotypic overlap with cardiofaciocutaneous syndrome and Costello syndrome, most available panels include the genes for these diagnoses, too. Note: The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time.
  • Serial single-gene testing can be considered if panel testing is not feasible. Approximately 50% of individuals with NS have a pathogenic missense variant in PTPN11; therefore, single-gene testing starting with PTPN11 would be the next best first test. Appropriate serial single-gene testing if PTPN11 testing is non-diagnostic can be determined by the individual’s phenotype (e.g., RIT1 if there is hypertrophic cardiomyopathy, SHOC2 if there is a loose anagen hair phenotype); however, continued sequential single-gene testing is not recommended as it is more costly than panel testing.

    Since Noonan syndrome occurs through a gain-of-function mechanism and large intragenic deletions or duplications have not been reported, testing for intragenic deletions or duplications is unlikely to result in a diagnosis; however, rare cases have been reported for some genes (see Table 1).
  • More comprehensive genomic testing (if available) including whole-exome sequencing (WES) or whole-genome sequencing (WGS) may be considered if use of a multi-gene panel and/or serial single-gene testing fails to confirm a diagnosis in an individual with features of NS. For issues to consider in interpretation of genomic test results, click here.

Table 1.

Molecular Genetic Testing Used in Noonan Syndrome (NS)

Gene 1Proportion of NS Attributed to Pathogenic Variants in This GeneProportion of Pathogenic Variants 2 Detected by Test Method
Sequence analysis 3Gene-targeted deletion/duplication analysis 4
PTPN1150% 5Nearly 100%Rare duplication 6, diagnosis of NS questioned 7
SOS110%-13% 8100%Unknown 9
RAF15% 10Nearly 100%One reported case with a duplication 11, diagnosis of NS questioned 7
One reported case of a deletion 12
RIT15% 10100%Unknown 9
KRAS<5% 13100%Unknown 9
NRAS8 individuals and 4 families 14100%Unknown 9
BRAF<2% 15100%Unknown 9
MAP2K1<2% 16100%Unknown 9
Others 17NA
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

5.
6.
7.
8.

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

9.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

10.
11.
12.
13.
14.
15.
16.
17.

Recent reports have implicated several additional genes associated with a Noonan syndrome-like phenotype in fewer than ten individuals each including RRAS (2 probands) [Flex et al 2014], RASA2 (3 probands) [Chen et al 2014b], A2ML1 (3 probands) [Vissers et al 2015], SOS2 (8 probands) [Cordeddu et al 2015, Yamamoto et al 2015] and LZTR1 (4 probands) [Yamamoto et al 2015].

Clinical Characteristics

Clinical Description

Prenatal features. Advanced paternal age has been observed in cohorts with simplex NS [Tartaglia et al 2004a]. Common perinatal findings include: polyhydramnios; lymphatic dysplasia including increased nuchal translucency and cystic hygroma; relative macrocephaly; and cardiac and renal anomalies [Myers et al 2014]. In chromosomally normal fetuses with increased nuchal translucency, it is estimated that 5%-15% have PTPN11-associated NS [Bakker et al 2014].

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 IGF-I- 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 pathogenic variant [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%.

  • 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 individuals with NS. It usually presents early in life: the median age at diagnosis is five months and more than 50% of individuals with NS and hypertrophic cardiomyopathy are diagnosed by age six months [Hickey et al 2011, Wilkinson et al 2012].
  • 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].
  • An electrocardiographic abnormality is documented in approximately 90% of individuals with NS and may be present without concomitant structural defects. Extreme right axis deviation with superior counterclockwise frontal QRS loop, superior or left axis deviation, or left anterior hemiblock or an RSR’ pattern in lead V1 are common findings [Sharland et al 1992].

Psychomotor development. Early developmental milestones may be delayed, likely in part as a result of the combination of joint hyperextensibility and hypotonia. The average age for sitting unsupported is around ten months and for walking is 21 months [Sharland et al 1992]. About 50% of school-aged children meet diagnostic criteria for a developmental coordination disorder [Lee et al 2005a] and impaired manual dexterity is significantly correlated with verbal and nonverbal intellectual functioning [Pierpont et al 2009].

Most school-age children perform well in a normal educational setting, but 25% have learning disabilities [Lee et al 2005a] and 10%-15% require special education [van der Burgt et al 1999]. Intellectual abilities are, in general, mildly lowered in children with NS. IQ scores below 70 are seen in 6%-23% across studies [van der Burgt et al 1999, Pierpont et al 2015]. Studies conflict with regard to strength in verbal versus nonverbal performance and no clear pattern has emerged [Lee et al 2005a, Pierpont et al 2009]. 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. The average age at first words is around 15 months and simple two-word phrases emerge on average from age 31 to 32 months [Pierpont et al 2010a].

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 2010b]. 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.

There is emerging evidence that attention and executive functioning are one of the most common neuropsychological challenges for children with NS [Pierpont et al 2015]. Studies that rely on screening measures rather than comprehensive diagnostic assessments suggest that children with NS are at heightened risk for autism spectrum disorders; however, further research is needed [Pierpont 2015].

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 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]. In one study of adults with NS, 49% reported that they had been diagnosed and treated for depression and/or anxiety [Smpokou et al 2012].

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 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 vermilion 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 palpebral fissures, hypertelorism, and full or ptotic upper eyelids. 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 with subsequent studies suggesting a lower rate of coagulopathy [Derbent et al 2010]. The coagulopathy may manifest as severe surgical hemorrhage, clinically mild bruising, or laboratory abnormalities with no clinical consequences. 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 [reviewed in Briggs & Dickerman 2012].

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. There are case reports of keratoconus and axenfeld anomaly [Lee & Sakhalkar 2014, Guerin et al 2015].

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 Noonan syndrome with multiple lentigines discussion in Genetically Related Disorders).

Other

  • Arnold-Chiari I malformation. Eleven cases of Arnold-Chiari malformation have been reported in the medical literature, although the true incidence in NS is not known [Keh et al 2013, Mitsuhara et al 2014, Zarate et al 2014, Ejarque et al 2015].
  • Hepatosplenomegaly is frequent; the cause is likely related to subclinical myelodysplasia.
  • Juvenile myelomonocytic leukemia (JMML). Individuals with Noonan syndrome and a germline pathogenic variant in PTPN11 have a predisposition to this unusual childhood leukemia. In general, JMML in Noonan syndrome runs a more benign course.
  • Other malignancies. One study of individuals with Noonan syndrome caused by a pathogenic variant in PTPN11 supports a threefold increased risk of malignancy [Jongmans et al 2011].
  • Overall risk of malignancy. Kratz et al reported on a cohort of 632 individuals with molecularly confirmed NS (inclusive of Noonan syndrome with multiple lentigines) and found four cases of JMML, two of brain tumor, two of ALL, and one neuroblastoma, and calculated a childhood cancer standardized incidence ratio of 8.1 [Kratz et al 2015]. Individuals with NS are at an eightfold greater risk of developing a childhood cancer than are those without NS.
  • 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 pathogenic variants 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 pathogenic variants 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 pathogenic variant 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 recognized in persons with cardiofaciocutaneous syndrome caused by mutation of 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 pathogenic variants 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 pathogenic variants 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 presence or absence of a pathogenic variant in PTPN11 does not affect the likelihood of developmental delay, although individuals with the p.Asn308Asp pathogenic variant are said to be more likely to receive normal education [Jongmans et al 2004].

Germline pathogenic variants 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 pathogenic variant [Binder et al 2005] leads to reduced efficacy of short-term growth hormone (GH) treatment in individuals with a PTPN11 pathogenic variant [Binder et al 2005, Ferreira et al 2005, Limal et al 2006]. However, careful review of height data reveals that individuals with a PTPN11 pathogenic variant 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 p.Asp61del 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 pathogenic variant 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 pathogenic variant 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 pathogenic variants 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 pathogenic variants generally have average or higher-level skills.

RAF1. Studies emphasize a striking correlation with hypertrophic cardiomyopathy, with 95% of affected individuals with a RAF1 pathogenic variant 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 pathogenic variants 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 pathogenic missense KRAS variant.

NRAS. Few individuals with an NRAS pathogenic variant have been reported. The clinical features appear to be typical with no particular or distinctive phenotype observed [Cirstea et al 2010].

BRAF, MAP2K1. The rare individuals with a pathogenic variant in BRAF or MAP2K1 also appear to have features of classic Noonan syndrome, albeit with florid ectodermal manifestations [Nava et al 2007, Nyström et al 2008, Sarkozy et al 2009].

RIT1. Compared to the prevalence of hypertrophic cardiomyopathy overall in NS (20%), there is an overrepresentation of HCM in individuals with a pathogenic variant in (70%-75%) [Aoki et al 2013, Yaoita et al 2016]. Analysis of affected individuals also suggests a high prevalence of perinatal abnormalities, high birth weight, relative macrocephaly, curly hair, hyperpigmentation, and wrinkled palms and soles but lower prevalence of short stature, pectus deformity, or intellectual disability [Bertola et al 2014, Yaoita et al 2016].

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.

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 (OMIM) 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 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%), MAP2K1 and MAP2K2 (~25%), and KRAS (<2%-3%). Rarely, individuals have a pathogenic variant in a gene usually associated with Noonan syndrome [Narumi et al 2008, Nyström 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 pathogenic variant has been identified [Tartaglia et al 2003a; Tröger et al 2003]. Germline pathogenic variants occurring most commonly in exon 2 of the HRAS proto-oncogene have been shown to cause Costello syndrome [Aoki et al 2005].

Noonan syndrome-like disorder with loose anagen hair (OMIM). Germline pathogenic variants 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 pathogenic missense SHOC2 variant, 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 pathogenic variant in about 5% of individuals with Noonan syndrome. Most have the classic loose anagen hair [Cordeddu et al 2009].

Noonan syndrome-like disorder with or without JMML (OMIM). Germline pathogenic variants in CBL cause a variable phenotype characterized by a relatively high frequency of neurologic features, predisposition to juvenile myelomonocytic leukemia, and low prevalence of cardiac defects, reduced growth, and cryptorchidism [Martinelli et al 2010, Niemeyer et al 2010, Martinelli et al 2015].

Due to the significant phenotypic overlap with classic NS, most RASopathy diagnostic gene panels include testing for the common SHOC2 variant and CBL gene sequencing.

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

Neurofibromatosis 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 NS and NF1 [Colley et al 1996, Bertola et al 2005]. However, most often it appears to be a NS-like facial appearance in an individual with a pathogenic variant in NF1, sometimes in the presence of a variant NF1 phenotype [Stevenson et al 2006, Nyström et al 2009].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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 to include CBC with differential, PT/PTT (repeat after 12 months if younger than 12 months at the time of first screening [Romano et al 2010, Roberts et al 2013]
  • 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
  • Consultation with a clinical geneticist and/or genetic counselor

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] (full text); a separate set has been published by an American consortium working with the Noonan Syndrome Support Group [Romano et al 2010] (full text) and in the Lancet [Roberts et al 2013].

Treatment of cardiovascular anomalies is generally the same as in the general population. Pulmonary valve stenosis treated with percutaneous balloon pulmonary valvuloplasty has a higher re-intervention rate versus pulmonary valve stenosis without NS [Prendiville et al 2014]. There is substantial early mortality associated with hypertrophic cardiomyopathy; infants presenting before age six months in congestive heart failure have the worst prognosis (2-year survival of 30%) [Hickey et al 2011, Wilkinson et al 2012].

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:
    • Significant short stature compared with normal peers;
    • Possible impairment of the GH-insulin-like-growth-factor type I (GH-IGF-I) axis; and
    • Documented response to GH treatment in studies.
  • 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 stature due to Noonan syndrome is an FDA-approved indication for growth hormone treatment.

Short- and long-term studies have demonstrated a consistent and significant increase in height velocity in children with Noonan syndrome who have been treated [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].

Subsequent studies have shown that children with prepubertal NS growth hormone deficiency have been shown to increase their growth rate with growth hormone therapy at a rate equivalent to girls with Turner syndrome but at a lower rate than that seen in idiopathic growth hormone deficiency [Lee et al 2015, Zavras et al 2015].

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 eye examination if a refraction error or strabismus is found, urinalysis if there are structural abnormalities of the collecting system. Despite the apparent increased incidence of hematologic and solid tumor malignancies, no surveillance strategies have been evaluated or recommended.

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 (NS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • 30%-75% of individuals diagnosed with NS have an affected parent.
  • A proband with NS may have the disorder as the result of a de novo pathogenic variant in an NS-related gene.
    • In simplex cases (i.e., those with no known family history), paternal origin of the de novo pathogenic variant 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 pathogenic variant in the proband is known.

Sibs of a proband. The risk to the sibs of a proband depends on the genetic status of the proband’s parents:

  • If a parent is affected or has the pathogenic variant identified in the proband, the risk to the sibs is 50%.
  • When the parents are clinically unaffected and the NS-related pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to the sibs of a proband appears to be low (<1%) but greater than that of the general population because of the possibility of germline mosaicism (germline mosaicism for the PTPN11 c.922A>G pathogenic variant is reviewed by Yoon et al [2013]; click here for text).

Offspring of a proband. Each child of an individual with NS has a 50% chance of inheriting the NS-related pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected, his or her family members may be 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 or at risk.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with NS has an NS-related pathogenic variant or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations such as alternate paternity or maternity (e.g., with assisted reproduction) and 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, allelic variants, 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 NS-related pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of the gene of interest or custom prenatal testing.
  • 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, Schlüter 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 NS will be made in approximately 5%-15% 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, Bakker et al 2014] 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 NS 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 NS-related pathogenic variant 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.

  • My46 Trait Profile
  • 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: ContactUs@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
609591RIC-LIKE PROTEIN WITHOUT CAAX MOTIF 1; RIT1
609942NOONAN SYNDROME 3; NS3
610733NOONAN SYNDROME 4; NS4
611553NOONAN SYNDROME 5; NS5
613224NOONAN SYNDROME 6; NS6
613706NOONAN SYNDROME 7; NS7
615355NOONAN SYNDROME 8; NS8

BRAF

Gene structure. 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. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. Four variants have been associated with NS (exon 6 p.Thr241Met and p.Thr241Arg, exon 13 p.Trp531Cys, and exon 15 p.Leu597Val); all showed slight increase in MEK phosphorylation in vitro [Sarkozy et al 2009]. Two exon 6 variants (c.721A>C;p.Thr241Pro and c.735A>G;p.Leu245Phe) have been reported in Noonan syndrome with multiple lentigines [Koudova et al 2009, Sarkozy et al 2009]. These variants are novel, never having been identified as somatic pathogenic variants in cancer. Two pathogenic variants were de novo and one was familial.

Table 2.

BRAF Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequence
c.722C>Tp.Thr241MetNM_004333​.4
c.722C>Gp.Thr241Arg
c.1593G>Cp.Trp531Cys
c.1789C>Gp.Leu597Val

Note on variant classification: Variants listed in the table have been provided by the authors. 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. The protein product of BRAF is B-RAF, a serine/threonine protein kinase that is one of the many direct downstream effectors of R-RAF. 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) [Sithanandam et al 1990, Solit et al 2006].

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. NS-associated variants are primarily observed in exons 6, 13, and 15 (versus CFC-associated BRAF variants: exons 6, 12, 15, and 16) [Sarkozy et al 2009]. The NS-related variants are different from the CFC-related variants, although why some variants are associated with a NS phenotype and some a CFC phenotype is not understood.

KRAS

Gene structure. 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. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. The association between abnormal K-RAS and Noonan syndrome is the first evidence of a role in embryonic development. These gain-of-function pathogenic variants confer biochemical and cellular phenotypes similar to Noonan syndrome-associated SHP-2 pathogenic variants [Kratz et al 2007].

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 [Kratz et al 2007]. Strong gain-of-function KRAS pathogenic variants may be incompatible with life.

MAP2K1

Gene structure. MEK exists as a multi-gene family. MAP2K1 spans approximately 104 kb. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. Pathogenic missense variants in MAP2K1 cause Noonan syndrome in fewer than 2% of clinically diagnosed individuals.

Normal gene product. MAP2K1 encodes a threonine/tyrosine kinase with the ability to activate ERK1 and ERK2. The normal protein encoded by MAP2K1 is dual-specificity mitogen-activated protein kinase kinase 1 (MEK1). Although the MEK1 and related MEK2 (encoded by MAP2K2) proteins have approximately 85% amino acid identity, they do not serve redundant purposes as determined in mouse development.

Abnormal gene product. Three individuals with NS had a novel pathogenic variant in exon 2 of MAP2K1. These pathogenic variants were found in exons already identified as mutational hot spots in cardiofaciocutaneous syndrome [Nava et al 2007].

NRAS

Gene structure. NRAS comprises seven exons. There are two main NRAS transcripts of 4.3 kb and 2 kb. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. The four pathogenic variants reported in association with NS are p.Ile24Asn, p.Pro34Leu, p.Thr50Ile, and p.Gly60Glu [Cirstea et al 2010, Runtuwene et al 2011, Denayer et al 2012]. The p.Thr50Ile 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 mutated protein resulted in enhanced downstream phosphorylation in the presence of serum. Protein modeling suggests that p.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 p.Gly60Glu variant resulted in enhanced downstream phosphorylation in the presence of serum and that mutated protein accumulated constitutively in the active GTP-bound form [Cirstea et al 2010]. Protein variant p.Ile24Asn is classified as pathogenic because of its occurrence in a highly conserved residue and de novo origin. It was shown to be a mildly activating pathogenic variant resulting in enhanced downstream signalling and causing developmental defects, including cell migration defects during gastrulation in zebrafish embryos [Runtuwene et al 2011]. Pro34 is located in the switch I region of RAS, and another pathogenic variant in this residue (p.Pro34Arg) has been shown to accumulate in the GTP-bound conformation and to strongly activate the MAPK pathway [Schubbert et al 2006].

Table 3.

NRAS Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.71T>Ap.Ile24AsnNM_002524​.4
c.101C>Tp.Pro34Leu
c.149C>Tp.Thr50Ile
c.179G>Ap.Gly60Glu

Note on variant classification: Variants listed in the table have been provided by the authors. 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. 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 more than 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 p.Thr50Ile or p.Gly60Glu in cellular models resulted in enhanced phosphorylation of MEK and ERK in the presence of serum or after epidermal growth factor (EGF) stimulation [Cirstea et al 2010]. Similar to germline KRAS pathogenic variants causing Noonan syndrome and cardiofaciocutaneous syndrome, germline NRAS alterations do not affect residues commonly altered in human cancers and appear to be less activating in dysregulating intracellular signaling in vitro compared with cancer-associated somatic pathogenic variants (see Cancer and Benign Tumors.

PTPN11

Gene structure. The gene comprises 15 exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. Tartaglia et al [2001] identified a pathogenic variant in PTPN11 as causative of Noonan syndrome. Pathogenic missense variants in PTPN11 were identified in 50% of affected individuals examined; 95% of these pathogenic variants 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 pathogenic variants alter sensitivity to activation from binding partners. One in-frame deletion, p.Gly60del, has been described [Yoshida et al 2004a]. PTPN11 duplications and deletions, although rare, have most often been associated with a “Noonan-like” phenotype [Shchelochkov et al 2008, Graham et al 2009, Luo et al 2012, Chen et al 2014a]. Given the known gain-of-function mechanism of disease (hyperactivation of the pathway), it is debatable how gene deletion or duplication could truly cause Noonan syndrome [Lissewski et al 2015].

See Table 4.

Table 4.

Selected PTPN11 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.922A>Gp.Asn308AspNM_002834​.3
NP_002825​.3
c.179_181delGTGp.Gly60del
c.181_183delGATp.Asp61del

Note on variant classification: Variants listed in the table have been provided by the authors. 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].

RAF1

Gene structure. RAF1 comprises 17 exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. The consensus 14-3-3 recognition site includes amino acid residues p.Arg256, p.Ser257, p.Ser259, and p.Pro261 in exon 7. Many of the pathogenic variants 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 [Pandit et al 2007]. Other pathogenic variants reside in the RAF activation segment in CR3 and show reduced or absent kinase activity. However, they still result in constitutive ERK activation.

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 p.Ser259 residue in CR2 is particularly important [Pandit et al 2007]. 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 p.Ser259 and p.Ser261. Dephosphorylation of p.Ser259 facilitates binding of RAF1 to RAS-GTP and propagation of the signal through the RAS-MAPK cascade via RAF1 MEK kinase activity [Pandit et al 2007]. 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 pathogenic variants increase and prolong RAS activation and downstream signaling through enhanced RAS-GEF activity and reduced 14-3-3 binding and autoinhibition.

RIT1

Gene structure. RIT belongs to the RAS subfamily of small GTPases. It is located at 1q22 and consists of six exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. Pathogenic missense variants are estimated to cause aproximately 5% of NS. The majority of pathogenic variants reported in NS cluster within the switch II region that corresponds to RAS [Aoki et al 2016].

Normal gene product. The RIT1 protein has a 50% sequence commonality with RAS but lacks the carboxyl-terminal CAAX motif found in several other RAS-like proteins [Lee et al 1996]. The encoded protein is involved in regulating p38 MAPK-dependent signaling cascades related to cellular stress. This protein also cooperates with nerve growth factor to promote neuronal development and regeneration [Wes et al 1996].

Abnormal gene product. Gain-of-function variants result in increased MEK-ERK signaling [Aoki et al 2013].

SOS1

Gene structure. SOS1 comprises 23 exons and encodes a 150-kd multidomain protein. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. Noonan syndrome-associated SOS1 pathogenic missense variants are hypermorphic; that is, they increase signaling through the RAS-MAPK pathway [Roberts et al 2007]. 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 [Soisson et al 1998]. 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 pathogenic variants abrogate autoinhibition, increasing and prolonging RAS activation and downstream signaling through enhanced RAS-GEF activity [Roberts et al 2007, Tartaglia et al 2007].

Cancer and Benign Tumors

Sporadic tumors (including leukemia and solid tumors) occurring as single tumors in the absence of any other findings of Noonan syndrome may harbor somatic nucleotide variants in PTPN11, KRAS, NRAS, BRAF, or MAP2K1 that are not present in the germline; thus, predisposition to these tumors is not heritable. See Catalogue of somatic mutations in cancer.

  • Leukemia and solid tumors. Juvenile myelomonocytic leukemia (JMML) accounts for one third of myelodysplastic syndrome (MDS) and about 2% of leukemia. Pathogenic variants in NRAS, KRAS, and NF1 have been shown to deregulate the RAS-MAPK pathway leading to JMML in about 40% of affected individuals. Somatic pathogenic variants in exons 3 and 13 of PTPN11 have been demonstrated in 34% individuals with JMML in one cohort [Tartaglia et al 2003b, Tartaglia et al 2004b, Hasle 2009].

    Pathogenic variants in exon 3 were also found in 19% of children with MDS with an excess of blast cells, which often evolves into acute myeloid leukemia (AML) and is associated with poor prognosis. Nonsyndromic AML, especially the monocyte subtype FAB-MD, has been shown to be caused by PTPN11 pathogenic variants. All of these pathogenic variants cause gain of function in tyrosine-protein phosphatase non-receptor type II (SHP-2), likely leading to an early initiating lesion in JMML oncogenesis with increased cell proliferation attributable, in part, to prolonged activation of the RAS-MAPK pathway.

    The spectrum of leukemogenesis associated with PTPN11 pathogenic variants has been extended to include childhood acute lymphoblastic leukemia (ALL). Pathogenic variants were observed in 8% of individuals with B-cell precursor ALL, but not among children with T-lineage ALL [Tartaglia et al 2004b]. Additionally, Bentires-Alj et al [2004] have described SHP-2-activating PTPN11 pathogenic variants in solid tumors including breast, lung, and gastric neoplasms and neuroblastoma.
  • Somatic RAF1 nucleotide variants have only rarely been found in cancer; most of these cancer-causing variants do not cluster in the regions that are germline mutational hot spots in Noonan syndorme.
  • NRAS variants are commonly observed in somatic cancer; they occur in different regions than germline NRAS variants that cause Noonan syndrome.
  • MAP2K1 somatic variants have been reported in ovarian cancer [Estep et al 2007] and lung cancer [Marks et al 2008].
  • Somatic SOS1 pathogenic variants have not been found in cancer.
  • Recent studies have identified somatic RIT1 pathogenic variants in lung adenocarcinoma, and myeloproliferative or mixed myelodysplastic/myeloproliferative neoplasms [Berger et al 2014, Cancer Genome Atlas Research Network 2014].

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 7-1-16.
  2. Roberts AE, Allanson JE, Tartaglia M, Gelb BD. Noonan syndrome. Available online. Accessed 7-1-16.
  3. 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 7-1-16. [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 7-1-16.

Chapter Notes

Revision History

  • 25 February 2016 (ha) Comprehensive update posted live
  • 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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