NOONAN SYNDROME
DEFINITION
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.
EPIDEMIOLOGY
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.
CLINICAL FEATURES
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:
-hypertelorism
-ptosis
-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
-micrognathia
-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 - http://www.ncbi.nlm.nih.gov/pubmed/24444506
Clinical manifestations of Noonan syndrome - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3232501/
PATHOGENESIS AND GENTICS
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.
http://ghr.nlm.nih.gov/condition/noonan-syndrome
http://en.wikipedia.org/wiki/Noonan_syndrome
● 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.
DIAGNOSIS AND MANAGEMENT
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.
COMPLICATIONS
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.
