Author: Luisa Guarrasi
Date: 08/03/2015




Noonan syndrome is a relatively common genetic multisystem disease that causes multiple congenital abnormalities, people affected have abnormal development of multiple parts of the body. This heterogeneous developmental disorder is caused by mutations in genes involved in the Ras/MAPK signaling pathway, a major mediator of early and late developmental processes.

Noonan syndrome is characterized by distinctive facial features, short stature, webbed neck, skeletal malformations (in particular thoracic and sternal deformities), congenital heart defects, increased bleeding tendency and many other clinical manifestations such as varying degrees of developmental delay, cryptorchidism, renal anomalies, vision problems, hearing loss, and lymphatic malformations. It is a condition that affects many areas of the body but the clinical features may be variously expressed.

It used to be called Turner-like syndrome because certain clinical characteristics resemble those seen in Turner syndrome, however patients can be easily differentiated because Noonan syndrome affects both males and females and patients have a normal karyotype.

This syndrome may be inherited in an autosomal dominant manner but most cases are due to de novo mutations and occur in people with no family history of the disorder.

Mutations that cause Noonan syndrome alter genes encoding proteins with important roles in the RAS-MAPK signaling pathway, leading to pathway dysregulation. Noonan Syndrome in fact belongs to a group of genetic syndromes called RASopathies because they are caused by mutations in genes that encode components or regulators of the Ras/mitogen-activated protein kinase (MAPK) pathway. These disorders include: Noonan Syndrome, Costello Syndrome, LEOPARD Syndrome (Noonan Syndrome with multiple lentigines), Cardio-facio-cutaneous Syndrome (CFC), Capillary malformation-arteriovenous Malformation Syndrome (CM-AVM), LegiusSyndrome and Neurofibromatosis type 1 (NF1).

The Ras-MAPK pathway plays a crucial role in regulating cell cycle and cellular growth, differentiation, migration and apoptosis, all of which are critical to normal development therefore a dysregulation of this pathway has profound effects on both embryonic and postnatal development.


Noonan syndrome is characterized by marked variable expressivity, which makes it difficult to identify mildly affected individuals. The overall incidence is believed to be between 1/1000 and 1/2500 live births. There is no predilection by race or sex.


The phenotypical expression of NS is extremely variable with some affected subjects showing only minor features of the syndrome. NS is caused by aberrant RAS-MAPK signaling transduction and it is genetically heterogeneous. This explains, in part, the marked clinical variability documented.

The main phenotypical features of Noonan syndrome include short stature, facial anomalies, congenital heart defects. Other clinical manifestations include : delayed puberty, cryptorchidism, pectus carinatum, pectus excavatum, scoliosis, varying degrees of intellectual disabilities (cognitive/learning disabilities) only in about 25% of cases, lymphatic abnormalities, coagulopathy.

● Short stature and failure to thrive

Growth retardation is an important feature of Noonan syndrome and approximately 50- 70% of patients have short stature. At birth, they are usually of normal length and weight, but growth is stunted over time. Abnormal levels of growth hormone may contribute to the slow growth. A delayed pubertal growth spurt has been documented in both sexes, bone maturity is also usually delayed.

By adulthood about 1/3 of people with NS have normal height, but short stature remains more common. The mean final adult height is 63 to 66 inches (160 to 168 cm) in males and 59 to 61 inches (150 to 155 cm) in females.

● Facial anomalies

People with Noonan syndrome have typical facial dysmorphology. The main distinctive facial features are:

-epicanthal folds
-downslanted palpebral fissures
-broad, high forehead
-Low-set , posteriorly rotated ears with a thick helix
-dysmorphic ears
-flat nasal bridge
-high arched palate
-bad alignment of teeth
-short neck/webbed neck
-low hairline at the nape of the neck

Nevertheless, the phenotypical expression is highly variable and these facial features may change with age. Facial anomalies can often be difficult to recognize in the newborn. In fact, the mean age at diagnosis from the literature is nine years, and the delay in recognizing the distinctive characteristics probably reflects the evolving phenotype. In particular, ocular and nasal bridge anomalies become less evident with increasing age.

Figure 1 - Newborn with NS

Figure 2 - Infant with NS

Figure 3 - Child/adolescent with NS

Figure 4 - Adult with NS

● Congenital heart defects

The prevalence of congenital heart defects in Noonan syndrome varies from 50 to 80% in the reported series from the literature. Noonan syndrome is one of the most common genetic diseases associated with congenital cardiac defects, being second for frequency only to Down syndrome.

The most common forms of congenital heart disease associated with this disorder include:

- Pulmonary valve stenosis: often associated with a thickened and dysplastic valve. It is usually difficult to obtain a satisfactory result using the transcatheter balloon dilatation of such dysplastic valves, so surgical intervention is more likely to be needed.

- Hypertrophic cardiomyopathy: involves predominantly the ventricular septum as asymmetric septal hypertrophy, but may also affect the ventricular free walls. Left ventricular outflow tract obstruction may occasionally be produced.

Others cardiac defects reported in Noonan syndrome are: atrial or ventricular septal defects, atrioventicular septal defect, coarctation of the aorta , left atrioventricular valve anomalies, patent ducts arteriosus and tetralogy of Fallot.

● Skeletal malformations

Thoracic deformities typically observed in Noonan syndrome are pectus excavatum and pectus carinatum. Some affected people may also have scoliosis and some may have upper limb abnormalities, especially bilateral cubitus valgus.

● Genital anomalies / Delayed puberty / Fertility issues

Up to three quarters of males with Noonan syndrome may have undescended testes. Cryptorchidism adversely affects male fertility. Men with Noonan syndrome are however likely to be fertile if they have normally descended testes. Pubertal development can be delayed in both sexes, and fertility does not appear to be affected in females.

● Developmental anomalies (cognitive/learning disabilities)

Most children diagnosed with Noonan syndrome have normal mental capacities and attend regular schools but some have special educational needs and some have mild intellectual disability. Although most individuals have normal intelligence there is an increased risk of speech delay and learning difficulties, which could be related to hearing loss or recurrent otitis media that frequently occurs in this syndrome. Tests for hearing are recommended in children with Noonan syndrome, as are tests for vision, because of the association of strabismus and refractive errors with this syndrome.

Some studies, investigating patterns of cognitive functioning in school-aged children, showed that Noonan syndrome is not associated with substantial deficits at the level of intellectual capacities. However, the correlation between phenotypic and cognitive expression reveals that a severe Noonan syndrome phenotype (i.e. more severe cardiac defects, more evident facial and skeletal anomalies ) is associated with a specific pattern of deficits and capacities in cognitive functioning.

● Bleeding disorders

Increased bleeding tendency is frequently reported in patients with Noonan syndrome and it is due to coagulation factor deficiency, quantitative or qualitative platelet defects. Some people may have easy bruising after minor trauma, nosebleeds or prolonged bleeding following injury or surgery. Women with a bleeding disorder typically have menorrhagia or excessive bleeding during childbirth.

Various coagulation factor deficiencies have been detected. The most common abnormality is a partial factor XI deficiency, but VIII and XII factor anomalies have also been described. Combined coagulation factor deficiencies may also occur. The involvement of several factors and the possible presence of combined abnormalities imply that anomalies in regulatory factors of the coagulation system may be the cause.

● Other clinical manifestations

Noonan syndrome can cause a variety of other signs and symptoms.

Some affected individuals have eye problems (anterior segment problems: prominent corneal nerves, cataract, anterior stromal dystrophy, nystagmus, refractive errors, strabismus) or hearing problems (hearing loss, recurrent otitis media).

This syndrome can also cause lymphatic abnormalities, the most common problem is lymphedema: infants with Noonan syndrome may be born with puffy hands and feet caused by a lymphedema, which can go away on its own. Older individuals can also develop lymphedema, usually in the ankles and lower legs.

Affected infants may also have feeding difficulties (poor sucking function, prolonged feeding time, recurrent vomiting and reflux), which typically get better by age 1 or 2.

Renal malformations (renal pelvis dilation, solitary kidney, duplex collecting system) occur in a fairly small number of patients.

Various skin conditions may be observed (dystrophic nails, extra prominence on pads of fingers and toes, follicular keratosis, hyperelastic skin, thick curly hair or thin sparse hair).

Noonan syndrome -
Clinical manifestations of Noonan syndrome -


Noonan syndrome is a genetic disorder that occurs in familial or sporadic form. Familial recurrence is consistent with an autosomal dominant mode of inheritance but sporadic cases , due to de novo mutations, are more common accounting for 60% of cases. A predominance of maternal transmission is noted in familial cases, this has been thought to be due to infertility in affected males, which may be related to cryptorchidism.

Noonan syndrome is caused by mutations in genes involved in RAS-MAPK signaling pathway, an important mediator of developmental processes. Mutations in genes encoding proteins with a crucial role in RAS-MAPK signal transduction are responsible of a group of syndromes called RASopathies and Noonan syndrome is the most common of this group.

RAS-MAPK pathway transduces signals that instruct the cell to grow and divide, to differentiate, to migrate and to survive, therefore this pathway regulates several important cell processes. This regulation tightly controls the growth of cells and tissues and is especially important for proper development. Therefore mutations in genes encoding proteins involved in RAS-MAPK pathway cause dysregulation of this pathway with deleterious effects on both embryonic and later stages of development. In RASopathies there is a hyperactivation of RAS-MAPK pathway, leading to important developmental defects.

Known causative genes account for 70–80% of clinically diagnosed NS patients, but the genetic basis for the remaining 20–30% of cases is unknown.

Many genes are related with Noonan syndrome, in particular PTPN11, SOS1, RAF1, KRAS (most cases of NS result from mutations in one of these four genes). Mutations in NRAS, HRAS, BRAF, SHOC2, MAP2K1, MAP2K2 and CBL have also been associated with NS in a smaller percentage of cases. A recent study discovered the importance of a new gene, RIT1, in Noonan syndrome. All of these genes encode proteins that regulate the activation of RAS-MAPK pathway.

Defects in these genes cause the overactivation of proteins involved in growth and development, proteins that are important in signaling pathways needed for the proper formation of several types of tissue during development. It follows that mutations in one of these genes cause proteins to be continuously active and this constant activation disrupts the regulation of systems that control cell proliferation, migration, differentiation and apoptosis, leading to the characteristic features of Noonan syndrome. An increased RAS-MAPK pathway activation, as result of defective proteins due to gene mutations, has a causative role in NS pathogenesis.

The RASopathies - Annu Rev Genomics Hum Genet. 2013; 14:355-69. doi: 10.1146/annurev-genom-091212-153523. Epub 2013 Jul 15

The RASopathies as an example of RAS/MAPK pathway disturbances - clinical presentation and molecular pathogenesis of selected syndromes.

● NS –caused by mutations in the PTPN11 gene (“protein tyrosine phosphatase, non-receptor type11”)(PTPN11)

The PTPN11 gene encodes the protein tyrosine phosphatase SHP-2(src homology region2-domain phosphatase-2). SHP-2 is a component of several intracellular signal transduction pathways involved in embryonic development that control cell division, differentiation and migration. During embryonic development, the SHP-2 protein is critical in the development of the heart, blood cells, bones, and several other tissues.

This protein positively regulates the activation of the RAS-MAPK signaling pathway, suggesting that the overactivated SHP-2 can give rise to NS.

PTPN11 gene mutations account for approximately 50% of all cases of Noonan syndrome and there is a significant higher prevalence of PTPN11mutations among familial cases than sporadic ones.

More than 50 mutations causing Noonan syndrome have been identified in the PTPN11 gene. Most of them replace single amino acids in the SHP-2 protein. The vast majority of mutations changes amino acid residues located in or around the interacting surfaces of the N-SH2 and C-SH2 domains. All mutations are missense changes and cluster at the interacting portions of the amino-terminal src-homology 2 (N-SH2) and protein tyrosine phosphatase (PTP) domains.

The resulting proteins are continuously active or have prolonged activation. This increase in protein activity disrupts the regulation of the RAS-MAPK signaling pathway and this misregulation can result in heart defects, growth problems, skeletal abnormalities and other features of Noonan syndrome.

According to genotype-phenotype analysis pulmonary stenosis is more prevalent among who have PTPN11 mutations than patients without these mutations, whereas hypertrophic cardiomyopathy is less prevalent among those with PTPN11 mutations.

Furthermore people with Noonan syndrome due to PTPN11 gene mutations have an increased risk of developing juvenile myelomonocytic leukemia.

●NS-caused by mutation in the SOS1 gene (“son of sevenless homolog 1”)

The SOS1 gene encodes the protein SOS1( son of sevenless homolog 1) which is a positive regulator of RAS by promoting guanine nucleotide exchange.SOS1 binds to the inactive Ras-GDP complex, causing dissociation of the bound GDP. Because GTP is present in cells at a higher concentration than GDP, GTP binds spontaneously to “empty” Ras molecules, with release of SOS1. Therefore Ras activation is accelerated by SOS1 protein that functions as a guanine nucleotide-exchange factor, which helps convert inactive GDP-bound Ras to the active GTP- bound form.

SOS1 gene mutations account for 10-15% of Noonan syndrome cases.

More than 20 mutations causing Noonan syndrome have been identified in the SOS1 gene. These mutations change single amino acids in the SOS1 protein and cause a constitutively active protein with RAS-MAPK signaling pathway hyperactivation.

There is a documented correlation between type of mutation and phenotype. Genotype-phenotype analysis confirmed a high frequency of ectodermal anomalies and a low prevalence of cognitive impairment and reduced growth. Finally, mutation analysis performed on cohorts of individuals with nonsyndromic pulmonic stenosis, atrial septal defects, and ventricular septal defects excluded a major contribution of germline SOS1 mutations to the isolated occurrence of these cardiac anomalies.

●NS-caused by mutation in the RAF1 gene (“Raf-1 proto-oncogene, serine/threonine kinase.”).

The RAF1 gene encodes Raf1, a serine-threonine kinase which is part of the Ras-MAPK signaling pathway. Raf1 participates in the RAS-RAF-MEK-ERK signal transduction cascade.

Once activated by the active complex Ras-GTP, RAF-1 phosphorylates the MEK protein and activates it. MEK then phosphorylates and activates the ERK . ERK then also in turn phosphorylates and activates a variety of downstream molecules (nuclear components, transcription factors, membrane proteins and other protein kinases ) that control important cellular functions. Under ordinary circumstances, the cascade involving RAF1 leads to changes in gene expression and protein synthesis. A constitutive activation of RAF-1 kinase, as a result of genetic changes, disrupts the normal control of several important cell processes ( cell growth, differentiation and survival ).

RAF1 gene mutations account for 5-10% of pathogenic mutations associated with patients diagnosed with NS.

More than 10 mutations causing Noonan syndrome have been identified in the RAF1 gene. These mutations interrupt the normal activity of the RAF1 protein, causing problems with cell division, apoptosis, cell differentiation, and cell migration.

It has been documented that patients with Noonan syndrome caused by RAF1 mutations have a greater incidence of cardiac anomalies (especially hypertrophic cardiomyopathy ) than other people with Noonan syndrome with other mutations. In a recent study a specific RAF1 mutation ( p.Ser257Leu ) has been linked to the development of a severe pulmonary arterial hypertension. This specific mutation has been associated with dephosphorylation of a critical serine residue and constitutive activation of the Raf-1 kinase. This study suggests that abnormal activation of the Ras-MAPK pathway may play a significant role in the development of pulmonary vascular disease in the subset of patients with Noonan syndrome and a specific RAF1 mutation.

●NS-caused by mutation in the KRAS gene (“Kirsten rat sarcoma viral oncogene homolog”)

The KRAS gene encodes K-Ras protein, a monomeric membrane GTPase involved in cell growth, differentiation and apoptosis. It is a part of RAS/MAPK signaling pathway. The K-Ras protein is turned on and off by the GTP and GDP molecules. To transmit signals K-Ras must be activated by binding to a molecule of GTP, instead when K-Ras is bound to GDP the protein is inactive and it does not relay signals to the nucleus.

About only 2% of people with Noonan syndrome have mutations in the KRAS gene.

The KRAS gene mutations associated with this syndrome change single amino acids in a critical region of the K-Ras protein. The result is an overactive protein, with increased GTP-binding and a decreased ability to convert GTP to GDP. The abnormally active protein alters normal RAS/MAPK signaling and disrupts the development of organs and tissues.

There is a correlation between mutation and phenotype. Patients with mutations in the KRAS gene usually have a more severe or atypical form of Noonan syndrome. Furthermore intellectual disability is more common in people who have the syndrome with a KRAS gene mutation than in people with syndrome caused by a mutation in a different gene.

●NS-caused by mutation in others genes

PTPN11, SOS1, RAF1 and KRAS are the most frequently associated with this syndrome, but many other genes have been documented in a very small percentage of cases.

Recently a new gene called RIT1 has been discovered as one of responsible genes. In fact according to a recent study RIT1 is responsible for approximately 10% of the patients negative for mutations in the previously known genes associated with NS. Genotype- phenotype analysis display that RIT1 mutations correlate with a higher frequency of high birth weight, relative macrocephaly, left ventricular hypertrophy and ectodermal findings such us curly hair, hyperpigmentation and wrinkled palms and soles. According to this study, because of the relatively high frequency of mutations in RIT1 among patients with NS, it should be added to the list of genes included in panels for the molecular diagnosis of NS through target next-generation sequencing.


The diagnosis of Noonan syndrome is mainly based on clinical features (When to suspect Noonan Syndrome - Table 4) and a scoring system has been devised to help diagnose patients with this condition. (Diagnostic Criteria for Noonan Syndrome - Table 2) However clinical diagnosis can be difficult because some of the features associated with this disorder are subtle and can be hard to identify, so diagnosis may be missed in mildly affected patients. Sometimes this syndrome is not diagnosed until adulthood, only after a person has a child who is more obviously affected by the condition.

Noonan syndrome must be considered in differential diagnosis with Turner syndrome (karyotype analysis) and with the others RASopthaties. Because of the common underlying Ras-MAPK pathway dysregulation, the RASopathies have an overlapping phenotype, although specific clinical and molecular features can often be distinguished.

Molecular genetic testing can confirm diagnosis in 70-80% of cases. NS can be confirmed genetically by the identification of any of the known causative genes. However the absence of a known mutation will not exclude the diagnosis because the genetic cause of Noonan syndrome is still unknown in the remaining 20-30% of patients. Identifying the remaining genes associated with NS is important for accurate diagnosis, patient management, and delineating genotype/phenotype relationships. Larger studies characterizing the clinical conditions found in NS patients are needed to provide potential genotype-phenotype correlations that may aid in clinical management. A positive genetic diagnosis will help the clinician to be aware of possible anomalies specific to that certain gene mutation and this may aid risk assessment and patient management.

When molecular diagnosis is confirmed, it could be evaluated age-appropriate developmental assessment. Some patients may require multidisciplinary evaluation and regular follow-up care. Management guidelines were developed by American and European consortia recently. Management is optimized by adherence to age-specific guidelines that emphasize screening and testing for common health issues. (Guidelines for Management of Noonan Syndrome - Table3)

Referral to a clinical geneticist for assistance in the diagnosis and management of Noonan syndrome, including determining the appropriateness and sequence of genetic testing, may be helpful.

Also prenatal diagnostics (amniocentesis) and preimplantation genetic diagnosis can be provided if the disease-causing mutation has been identified in the family.


The main complications of Noonan Syndrome include:

- Severe intellectual disability
- Severe coagulopathy
- Lymphedema around vital organs ( heart and lungs )
- Infertility (in males)
- Renal anomalies that may increase the rate of urinary tract infections
- Malignant neoplasm: patients with Noonan syndrome have an increased risk of leukemia, in particular specific mutations in the PTPN11 gene can increase the risk of developing juvenile myelomonocytic leukemia. These mutations cause the SHP-2 protein to be continuously active and this overactivity disrupts the regulation of pathways that control the production of immature blood cells. As a result, certain white blood cells are overproduced, leading to this type of leukemia. JMML may regress spontaneously or evolve in acute myeloid leukemia.

2015-04-09T13:02:07 - giulia antoniol



Noona Syndrom is a common genetic disorder autosomal dominant with multiple congenital abnormalities.
It is characterised by congenital heart disease,short stature,a broad and webbed neck,sternal deformity,variable degree of developmental delay,cryptor-chidism,increased bleeding tendency and characteristic facial features that evolve with age.It was characterized by jacqueline Noonan in 1962.
(Noonan Syndrome,2013)


Noonan Syndrome is characterized by marked variable expressivity,which makes it difficult to identify mildly affected individuals.The incidence is one in 1,000 to 2,500 live births for severe phenotype,but mild cases may be as common as one in 100 live births.Familial recurrence is consistent with an autosomal dominant mode of inheritance,but de novo mutation are more common,accounting for 60% of cases.There is no known predilection by race or sex.
(Noonan Syndrome,2014)

Diagnostic criteria

Early, accurate diagnosis of Noonan syndrome is important because each patient requires an individual treatment regimen and has a different prognosis and recurrence risk.
Establishing the diagnosis can be very difficult,especially in adulthood.There is a great variability in expression and the phenotype becomes less pronounced with increasing age.Several scoring systems have been devised to help the diagnostic process.The most recent scoring system was developed in 1997.
(Noonan Syndrome,2007)

Scoring system for Noonan Syndrom:

1. Facial
Maior: Typical facial dysmorphology;
Minor:Suggestive facial dismorphologie
2. Cardiac
Maior:Pulmonary valve stenosis,Hipertrophic cardiomyopathy and/or electrocardiographic results typical of Noonan Syndrome
Minor:Other defects
3. Height
Maior:<3 centile
Minor:<10 centile
4. Chest Wall
Maior:Pectus carinatum/excavatum
Minor:Broad thorax
5. Family History
Maior:First degree relative with definite Noonan Syndrome
Minor: First degree relative with suggestive Noonan Syndrome
6. Other features
Maior: One of the following intellectual disability,cryptorchidism,or ialymphatic vessel dysplasia
Minor: One of the following intellectual disability,cryptorchidism,or ialymphatic vessel dysplasia

Noonan Syndrome is considered present if the patient has typical facial dysmorphology plus one feature from categories 2A through 6A or two categories from features 2B through 6B,or has suggestive facial dysmorphology plus two features from categories 2A through 6A or three features from categories 2B through 6B.
(Noonan Syndrome,2014)

Symptoms and signs

Characteristic facial features that change with age

In the postnatal period the forehead is broad and high, there is hypertelorism, epicanthic folds and downward slanting palpebral fissures, low-set posteriorly rotated ears with a thick helix, high arched palate, micrognathia, and a short neck with excess nuchal skin and a low posterior hairline. The contour of the face becomes more triangular with age and in childhood the face often appears coarse or myopathic, with prominent eyes and (unilateral or bilateral) ptosis, and thick lips with prominent nasolabial folds.
In the adolescent and young adult the eyes are less prominent and the neck appears less short. Sometimes there is marked webbing or prominent trapezius. Typically, older adults have prominent nasolabial folds, a high anterior hair line, thick hooded eyelids and wrinkled skin. The facial features can be subtle, especially at old age.
(Noonan Syndrome,2007)

Congenital heart defects

The most common heart defect is pulmonary valve stenosis with dysplastic leaflets(50%-60%).Hypertrophic obstructive cardiomyophaty(HOCM)with asymetrical septum hypertrophy is present in 20% of patients.Atrial septal defects occur in 6%-10% of cases.Ventricular septal defects occur in 5% of cases and persistent ductus arteriosus occurs in 3% of cases
More than 80% of patients with NS have an abnormality of the cardiovascular system.PVS is the most common. The valve may be dysplastic in 25% to 35% of those with PVS and is often associated with an ASD.Isolated ASDs and partial atrioventricular canal defects are also relatively common. Approximately 50% of patients with NS have an unusual electrocardiographic pattern characterized by left-axis deviation, an abnormal R/S ratio over the left precordial leads,and an abnormal Q wave.Many patients
have mild PVS that requires only periodic reevaluation. If the PVS is or becomes clinically significant, initial treatment is usually pulmonary balloon valvuloplasty, but it may be unsuccessful if the valve is dysplastic. With severe dysplasia, a pulmonary valvectomy or pulmonary homograft may be
needed in childhood. The other cardiac defects can be treated in the standard ways.HCM is present in 20% of patients with NS overall but is particularly frequent with RAF1 mutations,and it is variable in severity and natural history.In some infants with HCM the condition resolves, whereas in others it
becomes rapidly progressive and may have a fatal outcome. Others develop HCM after infancy. The course may be stable or progressive, or it may improve.Management is similar to that for any patient with HCM and may include the use of -blocker medications or surgical myomectomy to reduce outflow obstruction.It is important for adults with NS to have lifetime cardiac follow-up. Leftsided obstructive lesions may develop in adulthood.Pulmonary valve insufficiency and right ventricular dysfunction are potential problems after earlier pulmonary valve surgery. Cardiac arrhythmias have been rare in the limited reports available about long-term follow-up of adults.(Noonan Syndrome-clinical features,diagnosis and menagement guidelines)
(Noonan Syndrome,2007)

Characteristic chest deformities

Characteristic chest deformities consist of pectus carinatum superiorly and pectus excavatum inferiorly. These sternal abnormalities are present in 70%–95% of cases. The thorax is broad and the internipple distance is large. About 15% of patients develop thoracic scoliosis. The shoulders are often rounded with scapula alata. Other common orthopaedic features include cubitus valgus (50%), radioulnar synostosis (2%), clinobrachydactyly (30%), joint hyperextensibility (50%) and talipes equinovarus (12%). Giant cell lesions of the jaw, similar to those seen in cherubism, have been reported in several patients

Undescended testicles

Are common in male patient at birth(77%).High FSH levels and poor quality semen have been found in adults,suggesting a failure of spermatogenesis in patients with testicular maldescent.In both sexes,pubertal development is delayed.The mean age of menarche in female patients is 14,6 years.However,fertility is not impaired in females with NS.The average bone age is also delayed by two years.Mean adult height is 162,5 cm in males and 152,7 cm in females.Growth hormone(GH) levels are in the normal range.Somatomedin levels are elevated in some cases.
Cryptorchidism occurs in up to 80% of boys, and surgical orchiopexy is required.Recent evidence suggests sertoli cell dysfunction rather than cryptorchidism as the etiology of male gonadal dysfunction.
(Noonan Syndrome,2007)

Increased bruising or bleeding

Increased bruising or bleeding is frequent,especially in childhood.Up to 55% of cases have a mild-to-moderate bleeding tendency.Coagulation studies reveal prolonged bleeding times,factor VIII,XI and XII deficiencies,thrombocytopaenia and platelet function defects.Approximately 25% of individuals
with NS have partial factor XI deficiency.The bleeding symptoms do not correlate well with the degree
of deficiency. A number of other coagulation factors can be depressed, and low factor XII and factor VIII activity are the next most frequent depressions.It is important to note that
although factor XII deficiency can prolong the activated partial thromboplastin time, it does not result in clinical bleeding. Low factor VIII levels can be seen with von Willebrand disease,which is a common bleeding disorderin the general population; although both low factor VIII and von Willebrand factor have been reported in NS, an accurate estimate of the prevalence of von Willebrand disease in patients with
NS has not yet been determined.Less commonly, factor IX and factor II have also been reported to be deficient in patients with NS and can contribute
to bleeding risk.Both thrombocytopenia and platelet dysfunction have been described in patients
with NS. The etiology of the thrombocytopenia is probably multifactorialand can be associated with a
defect in platelet production caused by a decrease in megakaryocytes.Splenomegaly may also cause mild-tomoderate thrombocytopenia and is found by ultrasound in up to 52% ofpatients with NS.Splenomegaly may be isolated or associated with hepatomegaly. In some patients, hepatosplenomegaly
or splenomegaly may be caused by NS/myeloproliferative disorder(MPD).
(Noonan Syndrome-clinical features,diagnosis and menagement guidelines)
(Noonan Syndrome,2007)

Acute leukaemia and myeloproliferative disorders

MPD have been described in some patients.The mutation in PTPN11 gene is associated with a predisposition to an MPD,which most often resolve spontaneously.In rare cases,individuals with NS can develop fatal MPD,typically juvenile myelomonocyticleukaemia(JMML).
NS/MPD is a condition seen in infants with NS that is characterized by leukocytosis with monocytosis, thrombocytopenia,and hepatosplenomegaly. Although the clinical picture of NS/MPD resembles that of juvenile myelomonocytic leukemia, infants with NS/MPD seem to have a favorable prognosis.Although some infants with NS/MPD have been reported to develop aggressive leukemia, the majority with this
condition present in the first few months of life and will remain stable or improve by 1 year of age without specific therapy.Despite the role of somatic PTPN11 and KRAS mutations in the development of
malignancies, the incidence of cancer in older children and adults with NS has not been shown to be increased over that of the general population.However, additional studies are needed to accurately assess the risk of malignancy in individuals with NS.
(Noonan Syndrome-clinical features,diagnosis and menagement guidelines)
(Noonan Syndrome,2007)

Lymphatic vessel dysplasia,hypoplasia or aplasia

These disorders are common findings in NS.They lead to generalized lymphoedema,peripheral lymphoedema,pulmonary lymphangiectasia or intestinal lymphangiectasia.The most common manifestation is dorsal limb lymphoedema,which usually disappears during childhood.
Varying degrees of oedema or hydrops are present during intrauterine life.Ultrasound examination may reveal cystic hygroma in early pregnancy.Foetal pads on fingers and toes are common(67%).
Other types of lymphatic involvement that have been described in patients with NS include hydrops, chylous pleural effusions, chylothorax, pulmonary lymphangiectasis, intestinal lymphangiectasia,
hypoplastic leg lymphatics,anomalous lymphatic vessels in the thoracic cage and aplasia or absence
of the thoracic duct, hypoplastic inguinal and iliac lymphatic vessels,and testicular lymphangiecta.
(Noonan Syndrome-clinical features,diagnosis and menagement guidelines)
(Noonan Syndrome,2007)

Gastointestinals and feeding issues

Most infants (75%) with NS have feeding difficulties; poor suck with prolonged feeding time (15%), very poor suck and slow feeding with recurrent vomiting (38%), and severe feeding problems that require tube-feeding for 2 weeks (24%) have been described.Investigation of some children with poor feeding has revealed immaturity of gut motility and delayed gastrointestinal motor development.Gastroesophageal reflux is common,and there have been a few reports of malrotation. Typically, the period of failure to thrive is self-limited, although poor weight gain may persist for up to 18 months.
(Noonan Syndrome-clinical features,diagnosis and menagement guidelines)

Neurologic,cognitive and behavioral issues

The neurologic, cognitive, and behavioral aspects of individuals with NS are poorly understood and extremely variable.There is an increased incidence of cognitive issues and learning disabilities, an increased incidence of brain abnormalities, and a wide array of other neurologic problems. In a
study of 151 subjects with NS, 76% had feeding difficulties, 94% had ocular problems, 50% had hypermobility of joints/hypotonia, 13% had recurrentseizures, 3% had hearing loss, and 3%
had peripheral neuropathy.There was also a general delay in the mean age of motor milestones; sitting alone occurred at 10 months, walking occurred at 21 months, and speaking 2-word sentences occurred at 31 months.Another study revealed that 84% had some type of neurologic problem.Structural malformations and deformations of the central nervous system and spinal cord are found at relatively
low frequency. The most common defects are Arnold-Chiari malformation type I and hydrocephalus. The mean head circumference is at the 50th percentile;however, some individuals with NS can be microcephalic or macrocephalic.Most people with NS have normal intelligence,but 10% to 40% require
special education.Even among those of normal intelligence, IQ has been shown to be 10 points less than
unaffected family members or 1 SD below that of the general population.The observed heterogeneity
in cognitive abilities in syndromes of the Ras/MAPK signaling cascade including NS can be at least partially
ascribed to the individual affected genes and the type of mutation.For example, SOS1 mutations and
specific PTPN11 mutations have been associated with no or mild cognitive delays.Children with NS have a higher rate of clumsiness, poor coordination, stubbornness,and irritability.Bodyimage problems and poor self-esteem, depression, and social inadequacy have been noted to occur in adults with NS.Limited data are available on the psychological and psychiatric characteristics of patients with NS. Psychiatric
problems are rarely found, and qualitative data in a study of 112 adults with NS revealed their reporting
an inability to fit in but an overall good or satisfactory quality of life. In addition, the majority of adults with NS finished high school and had paying jobs.
(Noonan Syndrome-clinical features,diagnosis and menagement guidelines)

Ophthalmic abnormalities

Ophthalmic abnormalities are strabismus(48%-63%),refractive errors(61%)and amblyopia(33%)

In general,children with NS demonstrate mild motordelay,which may be partly attributed to the muscularhypotony that is often present in early childhood.Articulation abnormalities are frequent(72%).
Mental retardation is present in 15%-35% of cases and is usually mild.
(Noonan Syndrome,2007)

Characteristic's of Noonan Syndrome in the newborn

Characteristic's of Noonan Syndrome in the infant

Characteristic's of Noonan Syndrome in the child adolescent

Characteristic's of Noonan Syndrome in the adult

Genetics and Patogenesis

The RAS–MAPK pathway is a well-studied, widely important signal transduction pathway through which extracellular ligands—such as some growth factors, cytokines, and hormones—stimulate cell proliferation, differentiation, survival, and metabolism. Cell surface receptors are phosphorylated at sites within their cytoplasmic region after ligand binding. This binding leads to recruitment of adaptor proteins (eg, GRB2), which form a constitutive complex with guanine nucleotide exchange factors (eg, SOS) that convert inactive, GDP-bound RAS to its active GTP-bound form. Activated RAS proteins then activate the RAF–MEK–ERK cascade through a series of phosphorylation events, ending with activated ERK entering the nucleus to alter gene transcription and modulating the activity of cytoplasmic targets to cause the appropriate short-term and long-term cellular response to the stimulus. All the genes implicated in Noonan syndrome encode proteins integral to this pathway and disease-causing mutations usually enhance signal flow through this pathway.

History of molecular genetic testing and genetic research

In 2001, Tartaglia and co-workers21 identified missense mutations in the protein tyrosine phosphatase non–receptor type 11 gene (PTPN11) as the first molecular causes of NS. This discovery was enabled by the observations that PTPN11 resided within the NS1 critical region and that studies with a mouse model of PTPN11 defi-ciency revealed that its protein product,SHP-2, was critical for the embryologic development of the semilunar cardiac valves.Because pulmonary valve stenosis (PVS) is a prominent
feature of NS, these investigators reasoned that PTPN11 was a leading positional candidate gene in NS1. In addition,Tartaglia and co-workers recognized that SHP-2, a protein tyrosinephosphatase with largely positive regulatory roles in Ras/MAPK signaling,participated in signaling downstream from several ligand-receptor complexes with possible relevance to the pleiomorphic abnormalities observed in NS (eg, fibroblast growth factor for bone development, growth hormone[GH] and insulin-like growth factor for
somatic growth). The reasoning of these investigators proved correct, because they observed PTPN11 missense mutations in 2 medium-sized families inheriting NS in a pattern consistent with linkage to NS1 and then additional mutations in approximately half of a small number of sporadic cases or small families with NS.Subsequent molecular discovery indicated that other genetic syndromesthat resembled NS phenotypically,Costello and CFC syndromes, proved not to be allelic.LEOPARD syndrome,on the other hand, proved to beallelic with PTPN11; mutations account for 90% of cases, and specific mutations,
particularly Y259C and T468M,are prevalent only in LEOPARD syndrome.Other Ras/MAPK genes
were then considered as candidate genes that might be mutated in patients with NS that is not explained byPTPN11. HRAS mutations were shown to cause Costello syndrome, and 4 Ras/MAPK genes (KRAS, BRAF, MEK1, andMEK2) were mutated in CFC sydrome.By using this candidate gene approach, 6 additional Ras/MAPK candidate genes were identified from 2006 to the present: KRAS, NRAS, SOS1,
RAF1, BRAF, and SHOC2.(Noonan Syndrome-clinical features,diagnosis and guidelines)

Genotype/Phenotype correlations

Among the mutated genes that account for NS, many different genotype/phenotype correlations have been made. No phenotypic features are found exclusively among 1 genotype,probably because of genetic and epigenetic factors that influence both penetrance and expressivity.PTPN11 mutations have been consistently associated with the presence of a pectus deformity, easy bruising, the characteristic facial appearance, and short stature.Children with SOS1-associated NS are more likely to have CFC syndrome–like skin findings (keratosis pilaris, sparse hair, curly hair,sparse eyebrows) and less likely to have short stature or impaired cognitive functioning. Patients with NS caused by missense mutations in PTPN11 are more likely to have PVS and atrial septal defects (ASDs) and less likely to have hypertrophic cardiomyopathy(HCM) than people with NS without a PTPN11 mutation.Those with a pathogenic SOS1 mutation are more likely to have PVS than those with NS who have neither an SOS1 nor a PTPN11 mutation.It is remarkable that 80% to 95% of children with RAF1 mutations have HCM.Patients with the SHOC2 S2G mutation have a distinctive phenotype, initially termed Noonan-like syndrome, with loose anagen hair.In addition to the hair findings, the phenotype may include mitral valve and cardiac septal defects,GH deficiency, ectodermal abnormalities with darkly pigmented ichthyotic skin,hypernasal voice, and developmental issues with hyperactivity.In a study of patients with NS, both bleeding diathesis and juvenile myelomonocytic leukemia were found exclusively in patients with specific PTPN11 mutations. Familial cases of NS are more likely than sporadic cases to becaused by a PTPN11 mutation.NS attributable to KRAS mutations seems to confer a more severe phenotype with more significant learning issues and developmental delays.
(Noonan Syndrome-clinical features,diagnosis and menagement guidelines)

Diagnostic method

Until recently,diagnosis was made solely on the basis of clinical features,but molecular genetic testing can provide confirmation in 70% of cases.Noonan Syndrome is caused by mutations in RAS/MAPK pathway,which is essential for cell cycle differentiation,growth,and senescence.Approximately one-half of the known mutation are in PTPN11 gene.
Most cases are sporadic. In familial cases, autosomal dominant inheritance is confirmed. The risk of Noonan syndrome developing in the sibling of an affected person is 50% if the parent is affected, but is less than 1% if the parent is unaffected. Risk of transmission to the offspring of an affected individual is 50%. Preimplantation genetic diagnosis can be offered in familial cases with known mutations.

Antenatal diagnosis:

NS should be considered in all foetuses with polyhydramnion,pleural effusions,oedema and increased nuchal fluid with a normal kayotype.If there is clinical evidence of NS in the foetus or a first-degree relative has NS,obstetric ultrasound is indicated at 12-14 and 20 weeks gestation and again in the third trimester.Foetal echocardiography is indicated at 18-20 weeks'gestation.If NS is suspected in the unborn child,physical examination of the parents for features of the syndrome is indicated.A DNA test for mutation analysis can be carried out on blood,chorionic villi and amniotic fluid samples.

Genetic Testing for NS

The currently available commercial tests use different technologies (dideoxynucleotide sequencing, denaturing,high-performance liquid chromatography,and oligonucleotidebasedmicroarray sequencing) that fundamentally are based on the presence of missense or small insertions/deletions in the coding regions and flanking intron boundaries of genes that cause NS. Although gross chromosomal abnormalities (interstitial deletions,duplications, and balanced translocations) have rarely been identified
in patients with phenotypes that closely resembled (or were) NS,routine karyotyping or copy-number analysis is not recommended at this time for typical NS cases. It may be considered for atypical cases or when there is particularly severe neurocognitive involvement.

(Noonan Syndrome-clinical features,diagnosis and menagement guidelines)
(Noonan Syndrome,2014)

Differential Diagnosis

There are a number of conditions with phenotypes strikingly similar to NS. The first to mention is Turner syndrome (45, X0), a well known chromosomal abnormality in girls. Then there are a group of distinct syndromes with partially overlapping phenotypes in which causative mutations are found in genes of the RAS-MAPK pathway. These include Cardio-Facio-Cutaneous (CFC) syndrome, Costello syndrome , Neurofibromatosis type 1(NF1) and LEOPARD syndrome(multiple lentigines, ECG conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth and deafness). Individuals with LEOPARD syndrome may have distinct mutations in PTPN11 wich lead to a diminished catalytic activity of these SHP-2 mutants. Costello syndrome is caused by mutations in HRAS, NF1 by mutations in Neurofibromin and CFC syndrome by mutations in BRAF, KRAS and MEK1/2
(Noonan Syndrome,2007)

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