Нунан синдромы: Жүзі, жүрегі және қаңқа ерекшеліктері

Genetic condition involving facial, heart, blood and skeletal features
[[File:InfantWithNoonan2. jpg|thumb|Abnormal features of Noonan syndrome at the age of 3 months: Note the low set, posteriorly rotated, and abnormally formed ear.

Some of the characteristic features of Noonan syndrome include a large head with excess skin on the back of the neck, low hairline at the nape of the neck, high hairline at the front of the head, triangular face shape, broad forehead, and a short, webbed neck. In the eyes, hypertelorism (widely set eyes) is a defining characteristic, present in 95% of people with Noonan syndrome. This may be accompanied by epicanthal folds (extra fold of skin at the inner corner of the eye), ptosis (drooping of the eyelids), proptosis (bulging eyes), strabismus (inward or outward turning of the eyes), nystagmus (jerking movement of the eyes) and refractive visual errors. The nose may be small, wide, and upturned. The development of the ears and auditory system may be affected in people with Noonan's syndrome. This can result in low set ears (in over 90%), backward rotated ears (over 90%), thick helix (outer rim) of ear (over 90%), incomplete folding of ears, chronic otitis media (ear infections), and hearing loss. Development of the mouth may also be affected in Noonan syndrome. This can result in deeply grooved philtrum (top lip line) (over 90%), micrognathia (undersized lower jaw), high arched palate, articulation difficulties (teeth don't line up) which can lead to dental problems. Similar to the muscular manifestations above, in the mouth, poor tongue control may be observed.

Skin signs and symptoms in Noonan syndrome include lymphedema (lymph swelling of the extremities), keloid formation, excessive scar formation, hyperkeratosis (overdevelopment of outer skin layer), pigmented nevi (darkly pigmented skin spots), and connective tissue disease.

Abnormalities in the limbs and extremities may occur in Noonan syndrome. This may manifest as bluntly ended fingers, extra padding on fingers and toes, edema of the back of hands and tops of feet, and cubitus valgus (wide carrying angle of the elbows). For short stature, growth hormone is sometimes combined with IGF 1 (or as an alternative, IGF 1 as a stand alone) can be used to achieve an increased height/final height quicker. The final adult height of individuals with Noonan syndrome is about 161–167 cm in males and 150–155 cm in females, which approaches the lower limit of normal. Spinal abnormalities may be present up to 30% of the time and this may require surgery to correct in over 60% of these cases. Other musculoskeletal manifestations in Noonan syndrome are associated with undifferentiated connective tissue disorders which can be associated with joint contractures (tightness) or joint hypermobility (looseness). Additional factors may present in the form of winging of the scapula, scoliosis, breast bone prominence (pectus carinatum), breast bone depression (pectus excavatum). Muscle abnormalities may present as hypotonia (low muscle tone), which may lead to lordosis (increased hollow in the back) due to poor abdominal muscle tone.

Noonan syndrome is the second most common syndromic cause of congenital heart disease. 50 70% of individuals with NS are born with some form of congenital heart defect, with pulmonary valvular stenosis being the most common (50–60%). Other heart defects include hypertrophic cardiomyopathy (12–35%), ventricular septal defects (5–20%), and atrial septal defects (10–25%).

Restrictive lung function has been reported in some people.

A number of diverse gastrointestinal (GI) symptoms have been associated with Noonan syndrome. These include swallowing difficulties, low gut motility, gastroparesis (delayed gastric emptying), intestinal malrotation, and frequent or forceful vomiting. These digestive issues may lead to decreased appetite, failure to thrive from infancy to puberty (75%), and occasionally the need for a feeding tube.

In some males with Noonan syndrome, testicles do not descend (cryptorchidism).

Lymphatic anomalies including Posterior cervical hygroma (webbed neck) and Lymphedema may present in people with Noonan syndrome. A number of bleeding disorders have been associated with Noonan syndrome, these include platelet dysfunction, Blood clotting disorders, partial deficiency of factor VIII:C, partial deficiency of factor XI:C, partial deficiency of factor XII:C, and an imbalance of plasminogen activator inhibitor type 1 (PAI 1) and tissue plasminogen activator (t PA) activity. It has been associated with Von Willebrand disease, Amegakaryocytic thrombocytopenia (low platelet count), prolonged activated partial thromboplastin time, combined coagulation defects. When present, these Noonan syndrome accompanying disorders can be associated with a predisposition to bruise easily, or hemorrhage.

Individuals with NS exhibit a broad range of cognitive abilities, typically ranging from mild intellectual disability to completely normal intelligence. Most patients have normal IQ levels (70 120), while around 20% may have cognitive impairment (IQ<70). Occasionally, Chiari malformation (type 1), may occur, which can lead to hydrocephalus. Seizures have also been reported.

Individuals may experience bleeding disorders of various types, often associated with thrombocytopenia, low levels of clotting factors, impaired platelet function, and more.

Several genes are involved in the genetic etiology of NS, with the key ones being PTPN11 accounting for 50% of genetically diagnosed cases, SOS1 responsible for 10 13% of cases, and RAF1 or RIT1 each contributing to an additional 5% of cases. Correlations between phenotype and genotype exist, and identifying the genetic cause can shed light on expected symptoms. For example, mutations in the PTPN11 gene are associated with an increased tendency for pulmonary stenosis or leukemia, while mutations in the SOS1 gene are linked to relatively normal development and stature compared to other NS cases. About 15 20% of NS cases remain genetically undiagnosed. Type Online Mendelian Inheritance in Man database Gene Year found Locus % of cases Description Refs. NS1 PTPN11 2001 12q24.1 50% The PTPN11 gene encodes the protein tyrosine phosphatase SHP 2. This protein is a component of several intracellular signal transduction pathways involved in embryonic development that modulate cell division, differentiation, and migration, including one mediated by the epidermal growth factor receptor, which is important in the formation of the semilunar heart valves. Duplication of the chromosome region containing PTPN11 can also result in NS. NS2 Unknown; autosomal recessive NS3 KRAS 2006 12p12.1 <5% NS4 SOS1 2006 2p22 10% Activating mutations in SOS1 can give rise to NS. SHP 2 and SOS1 positively regulate the Ras/MAP kinase pathway, suggesting that its dysregulation mediates NS development. NS5 RAF1 2007 3p25 3–17%

Heterozygous mutations in NRAS, HRAS, BRAF, SHOC2, MAP2K1, MAP2K2, and CBL have also been associated with a smaller percentage of NS and related phenotypes. A condition known as "neurofibromatosis–Noonan syndrome" is associated with neurofibromin.

Diagnosing of NS is based on the clinical symptoms presented by the individual, accompanied by attempts to confirm the diagnosis through molecular genetic tests to identify the specific genetic change leading to the condition. However, despite identification of 14 causative genes, the absence of a known mutation will not exclude the diagnosis, as more, as yet undiscovered genes can cause NS. Thus, the diagnosis of NS is still based on clinical features. In other words, it is made when a physician feels that a person has enough of the features to warrant the label. The principal values of making a genetic diagnosis are that it guides additional medical and developmental evaluations, it excludes other possible explanations for the features, and it allows more accurate recurrence risk estimates. With more genotype phenotype correlation studies being performed, a positive genetic diagnosis will help the clinician to be aware of possible anomalies specific to that certain gene mutation. For example, an increase in hypertrophic cardiomyopathy is seen in people with a mutation of KRAS and an increased risk of juvenile myelomonocytic leukemia exists for a mutation of PTPN11. In the future, studies may lead to a targeted management of NS symptoms that depends on what genetic mutation a person has.

There is no single treatment tailored to alleviate all possible symptoms of NS. Instead, the treatment varies depending on complications but tend to be quite standard, reflecting the treatment of the general population. Specifically, treatment of cardiovascular complications resemble that of the general population and treatment of bleeding diathesis is guided by the specific factor deficiency or platelet aggregation.

The lifespan of people with Noonan's syndrome can be similar to the general population, however, Noonan syndrome can be associated with several health conditions that can contribute to mortality. The greatest contributor to mortality in individuals with Noonan syndrome is complications of cardiovascular disease. This described nine children who in addition to congenital heart disease had characteristic facial features, chest deformities and short stature. Dr. John Opitz, a former student of Noonan's, first began to call the condition "Noonan syndrome" when he saw children who looked like those whom Dr. Noonan had described. Noonan produced a paper titled "Hypertelorism with Turner Phenotype" in 1968 where she studied 19 patients who displayed symptoms indicative of Noonan's Syndrome. In 1971, at the Symposium of Cardiovascular defects, the name "Noonan syndrome" became officially recognized.