Noonan syndrome belongs to the group of RASopathies. These syndromes are caused by the disruption of the signal transduction controlled by the Ras subfamily and Mitogen-activated protein (RAS/MAPK pathway).
The syndrome is relatively common. It was estimated that about 1 in 2500 newborn children in the world are affected. The features of the disorder include facial and skeletal abnormalities, heart defects and many others.
Mutations in one or several genes may cause Noonan syndrome. They may be inherited in an autosomal dominant pattern.
Typically (50% of cases) the defect in the PTPN11 (protein tyrosine phosphatase, non-receptor type 11) gene is detected. In 10-15% of cases SOS1 (SOS Ras/Rac guanine nucleotide exchange factor 1) gene mutations are found. 5% of cases are caused by the mutations in the RAF1 (Raf-1 proto-oncogene, serine/threonine kinase) and RIT1 (Ras like without CAAX 1) genes.
All of these genes are involved in the regulation of cell proliferation (growth and division) and differentiation (cells carry out specific functions), especially during the embryonic period and the development of the tissues of the body.
However, in 15-20% of cases the cause of the disease is unknown.
If one of the parents is affected the child has a 50 % risk of inheritance of the disorder. In some cases the disease may develop spontaneously due to a new mutation in children without genetic predisposition.
As long as the Noonan syndrome is a genetic disorder anyone with a family history of the disease is at risk. This means that the main method to prevent the disease is a genetic counseling that should be provided for the couples whose families are positive for the condition, if previously children with birth defect or abnormalities were born, or in case of infertility and miscarriages. Testing enables women and couples to prepare for pregnancy, find out the reasons of infertility or miscarriages, to make a decision as to whether or not to continue with their pregnancy, and helps provide information about the genetic diseases and raising an affected child, treatment and future pregnancies.
Symptoms of Noonan syndrome vary from mild to severe among the individuals with this syndrome.
Affected people have very distinctive craniofacial features. These hallmarks are more characteristic during infancy and change as the child grows.
Facial features may include:
- Wide-set eyes (ocular hypertelorism), down-slanting with droopy eyelids (ptosis) with skin folds that cover inner corners of the eye (epicanthal folds). Pale blue or green irises;
- Ears are low-set and rotated backward (pinnae);
- Nose is depressed at the top, with a wide base and bulbous tip;
- A deep groove between the nose and the mouth called philtrum and wide peaks in the upper lip. The crease that runs from the edge of the nose to the corner of the mouth becomes deeply grooved with age;
- Teeth are crooked, the roof of the mouth on the inside (palate) is highly arched (high-arched palate) and the lower jaw is small (micrognathia);
- The face may appear expressionless;
- Head is large with a prominent forehead and a low hairline on the back of the head (low posterior hairline);
- As the person ages, skin may appear thin and transparent.[Read also: Menkes disease]
Up to 85% of people with Noonan syndrome have some form of congenital heart disease, although some heart problems can occur later in life. Some forms of congenital heart disease associated with this disorder include:
- Valve disorders. Pulmonary valve stenosis – a narrowing of the pulmonary valve, is the most common heart problem in individuals with Noonan syndrome (50-60% of cases);
- Abnormal thickening of the heart muscle (hypertrophic cardiomyopathy) is present in 12-35% of cases;
- Other structural defects of the heart include ventricular septal defect, pulmonary artery stenosis, or aortic coarctation;
Restrictive lung function is present in some cases;
The abnormal function of gastrointestinal tract includes:
- Failure to thrive and loss of appetite;
- Digestive problems;
- Frequent vomiting;
- Decreased motility of the intestines and gastroparesis;
- Difficulties swallowing;
Noonan syndrome in 50-70% of cases affects normal growth. Issues may include:
- Birth weight may be normal, but growth slows over time;
- Poor weight gain due to eating difficulties;
- Growth hormone levels may be insufficient;
- Delayed growth spurt, although growth sometimes continues into the late teens as long as the growth is delayed;
- Average adult height is 5 feet 5 inches in males and 5 feet in females, but in some cases the height may be normal;
Some common issues can include:
- An unusual shape of the chest – a sunken (pectus excavatum) or raised sternum (pectus carinatum);
- Joint and muscle pain of different severity;
- Joint contractures or hypermobillity;
- Wide-set nipples;
- Short neck, often with excessive neck skin (webbed neck/pterygium colli) or prominent neck muscles (trapezius);
- Deformities of the spine (scoliosis or lordosis);
Intelligence isn’t affected for most people with Noonan syndrome.
Some individuals may have:
- Mild intellectual disability;
- A wide range of mental, emotional and behavioral issues that are usually mild;
- Hearing and vision deficits complicate learning;
- Speech-language pathology;
These may include:
- Cross-eye (strabismus);
- Refractive problems, such as astigmatism, nearsightedness (myopia) or farsightedness (hyperopia);
- Rapid movement of the eyeballs (nystagmus);
Noonan syndrome can cause hearing deficits because of the nerve issues or abnormalities of the inner ear bones in 50% of people with Noonan syndrome.
Noonan syndrome can cause excessive bleeding and easy bruising due to clotting defects, partial deficiency of Factor VIII, partial deficiency of Factor XI, partial deficiency of Factor XII, platelet dysfunction, combined coagulation defects or having too few platelets.
Noonan syndrome can cause problems with the lymphatic system, which drains excess fluid from the body and helps fight infection. These problems may occur before or after birth or develop in the teenage years or adulthood, can be focused in a particular area of the body or widespread. Most common is the excess fluid (lymphedema) on the back of the hands or top of the feet.
Neurologic problems in individuals with Noonan syndrome include:
- Hydrocephalus and Arnold-Chiary malformation;
Genital and kidney conditions
Individuals with Noonan syndrome may have problems with the genitals and kidneys:
- Undescended testicles (cryptorchidism) are common in males;
- Delayed puberty in both boys and girls;
- In males fertility may not develop normally;
- Kidney problems occur rarely;
People with Noonan syndrome may have skin conditions, which most commonly are:
- Various problems that affect the color and texture of the skin;
- Keloid formation;
- Curly, coarse hair or sparse hair
The main complications of the disease are:
- Mental retardation;
- Excessive bleeding;
- Pleuritis, pericarditis;
- Infections of urinary tract;
- Risk of developing cancer (especially leukemia);
- Individuals with Noonan syndrome have been reported to suffer from Malignant Hyperthermia and respiratory difficulties from anesthetics;
Genetic counseling is necessary to evaluate the diagnosis. Precise examination of the whole body is performed to estimate the function of the every organ.
The treatment of Noonan syndrome requires the administration of symptomatic therapy to avoid complications and comfort lives of affected individuals.
Growth hormone may be administered to accelerate the growth of the skeleton. Infant stimulation programs are recommended to help the child develop mentally.
Congenital heart defects in some cases should be treated surgically. Males with cryptorchidism should undergo surgery between 12 and 24 months of age.