Noonan Syndrome: Pathophysiology, Causes, Symptoms, Complications, Diagnosis and Treatment

It is a genetic disorder that is present from birth. It includes a variety of distinctive features and health problems.

It is often associated with congenital heart diseases, short stature and unusual facial features.

According to the National Organization of Rare Disorders, it is believed that Noonan syndrome affects approximately 1 in 1,000 to 1 in 2,500 people.

Some reports suggest that it may be more common than this, but misdiagnosis or underdiagnosis makes it difficult to determine the true prevalence.

Noonan syndrome was first recognized as a unique entity in 1963 when Noonan and Ehmke described a series of patients with unusual facies and multiple malformations, including congenital heart disease.

Previously it was thought that these patients had a form of Turner syndrome , with which Noonan syndrome shares numerous clinical characteristics.

The observation that patients with Noonan syndrome have normal karyotypes was important to allow the distinction between the Turner and Noonan syndromes.

The cardinal features of Noonan syndrome include unusual facies (ie, hypertelorism, oblique eyes down, webbed neck), congenital heart disease, short stature, and chest deformity.

Approximately 25% of people with Noonan syndrome have mental retardation. Hemorrhagic diathesis is present in up to half of all patients with Noonan syndrome.

Skeletal, neurological, genitourinary, lymphatic, ocular, and cutaneous findings may be present in varying degrees.

Pathophysiology

The pathophysiology of Noonan syndrome is not completely understood, but it is associated with mutations in genes that are part of the signal transduction pathway RAS / RAF / MEK / ERK, an important regulator of cell growth.

Approximately 50% of patients have genetic mutations in PTPN11, with mutations SOS1 and RAF1 identified in another 13% and 5-17% of patients, respectively. Mutations have also been identified in KRAS, NRAS, BRAF and MAP2K1, but in a smaller number of patients.

Morbidity and Mortality

The main source of morbidity and mortality in patients with Noonan syndrome depends on the presence and type of congenital heart disease.

Noonan syndrome is also characterized by a slight increase in the risk of certain cancers.

In a review of the literature covering 1937-2010, Kratz et al found the most commonly reported cancers in Noonan syndrome, as diagnosed in a total of 1051 patients, who were neuroblastoma (8 cases), acute lymphoblastic leukemia ( 8 cases).

Also low grade glioma (6 cases) and rhabdomyosarcoma (6 cases); Like Noonan syndrome, all these cancers are associated with mutations of the RAS signaling pathway.

Juvenile myelomonocytic leukemia and myeloproliferative disorder have also been associated with Noonan syndrome.

A study by Jongmans et al also showed an elevated risk of cancer in patients with Noonan syndrome. Twelve of the 297 patients with a PTPN11 mutation developed a malignancy, a risk 3.5 times higher compared to healthy individuals.

Hematological malignancies occurred more frequently, while 2 malignancies not previously observed in Noonan syndrome were detected: a malignant mastocytosis and a malignant epithelioid angiosarcoma.

Noonan syndrome occurs sporadically or autosomally dominant. In any case, males and females are equally affected.

The disorder is present from birth, but age affects the facial phenotype. Babies with Noonan syndrome can be difficult to recognize just because of the facial appearance.

The phenotype becomes more striking in early childhood, but with advancing age, it can become quite subtle. Careful examination of the parents of an affected child can in fact reveal that they are mildly affected.

Causes of Noonan Syndrome

Noonan syndrome is caused by an abnormality or mutation in one of several genes.

The defective gene associated with Noonan syndrome can be:

  • Inherited from a father: Approximately 50 percent of people with the condition have an affected father. The father who carries the genetic abnormality may or may not have obvious characteristics of the disorder.
  • A new mutation that occurs randomly in children without any genetic predisposition.

Having a father with Noonan syndrome is the biggest risk factor for the development of the disease. The risk of passing the defective gene from parents to children is 50 percent for each pregnancy.

Signs and Symptoms of Noonan Syndrome

The signs and symptoms associated with Noonan syndrome vary greatly from person to person. They can be mild, moderate or severe and may vary depending on the gene in question. However, there are a number of common signs and symptoms.

Unusual Facial Traits

This is one of the most obvious signs of Noonan syndrome, and this is a key consideration in the diagnosis.

Facial features tend to be more obvious in children, but they become more subtle as people move into adulthood. The most common characteristics of Noonan syndrome are:

  • Large eyes.
  • Fallen eyelids.
  • Iris pale.
  • Big head.
  • Wide forehead.
  • A short and wide nose.
  • Falling face that seems to lack expression.
  • A small jaw.
  • A short neck.
  • Excess skin on the neck.
  • Ears low and turned towards the back of the head.
  • Problems with growth and development.

People with this condition can:

  • Have a normal birth weight, but experience a delay in growth over time.
  • Show low levels of growth hormones.
  • Go to puberty a few years later than the average.
  • Fail to experience normal growth during puberty.

Some people with Noonan syndrome reach normal height in adulthood, but the average height is 5 feet and 3 inches for men with this condition, and 5 feet for women.

Cardiac Defects

Most people with Noonan syndrome have some form of congenital heart disease. Some examples of the types of heart defects that can have are:

Pulmonary stenosis : a narrowing of the pulmonary valve, which helps control blood flow from the heart to the lungs. The heart is under greater pressure to ensure that blood is pumped to the lungs. This can occur only in those with Noonan syndrome or with other heart defects.

Hypertrophic cardiomyopathy : the muscles of the heart enlarge and put pressure on the heart.

Septal defects : a hole in the heart that separates the two lower chambers of the heart. Small defects do not cause symptoms, but larger defects make the heart and lungs work harder.

Irregular heartbeat: This occurs in most people with Noonan syndrome, with or without abnormal heart structures.

Other Signs and Symptoms of Noonan Syndrome

A variety of other problems may arise. Some children experience feeding difficulties because it is harder for them to suck and chew.

Eye problems can include strabismus or crossed eyes, where the eyes point in different directions, lazy eye , where one eye is less able to focus, and slightly blurred vision.

Hearing problems can arise due to structural abnormalities or nerve problems.

Learning difficulties sometimes occur. Intelligence is usually not affected, but some people may have learning difficulties or mild intellectual disabilities. Problems with hearing and sight can contribute to this.

Feeding problems can affect babies, who may have difficulty chewing and chewing or may vomit shortly after eating.

Bruising and bleeding can be the result of blood clotting or platelet problems.

Behavioral problems can occur, including difficulties with attention and emotional challenges. A child may appear immature compared to his peers.

Decreased muscle tone can cause developmental milestones to be reached later than expected. People with Noonan syndrome report decreased muscle strength and clumsiness.

Male infertility may occur, particularly if one or both testicles do not fall into the scrotum, and this is not corrected at an early age. Female fertility is generally not affected.

Lymphatic conditions can occur if excess fluid accumulates in the lymphatic system. This can be noticed on the backs of the hands or the top of the feet.

Problems can develop in the bone marrow, such as an abnormal white blood cell count. This is unusual. It can resolve on its own or it can cause leukemia or cancer of the blood cells.

Sometimes renal affections arise, but these are rare and mild.

Complications of Noonan Syndrome

Other complications that may need special attention and medical or other interventions include:

Increased risk of cancer : According to the National Cancer Institute, people with Noonan syndrome have an increased risk of certain cancers, including soft tissue tumors, cancer of nerve cells and some forms of leukemia.

Developmental delays : If learning difficulties, intellectual disability or other developmental problems are important, children with Noonan syndrome may need a special plan to meet their educational and developmental needs.

Bleeding problems : Excessive bleeding may be common, but may not be discovered until dental work or surgery is performed. It is important to know this risk before any procedure.

Excess fluid accumulation : excess fluid that accumulates in lymphatic conditions can accumulate around the heart and lungs, and this can be dangerous.

Diagnosis

A doctor will diagnose Noonan syndrome based on the main signs and symptoms. Diagnosis can often be difficult due to the subtlety of some of the characteristics associated with the condition.

In some cases, the disorder is not diagnosed until someone with Noonan syndrome has a child with more obvious signs and symptoms. A diagnosis can be confirmed through molecular genetic testing.

The sooner Noonan syndrome is diagnosed, the earlier prevention and treatment strategies can be implemented, leading to better outcomes for patients.

Treatment

Since Noonan syndrome comes from a genetic defect, there is no cure. The goal of treatment is to control the symptoms and associated complications, so it varies for each individual.

Children with Noonan syndrome may need treatment for heart problems. Potential treatments include:

Heart conditions : medications or surgery, or both, may be necessary to treat heart defects. Regular check-ups can also be recommended.

Growth issues : height and weight should be controlled routinely during childhood and adolescence. Blood tests may be ordered and growth hormone therapy is suggested as a treatment option.

Learning difficulties : programs of child stimulation, physiotherapy, speech therapy and educational interventions may be necessary to address learning problems in childhood.

Excessive bleeding and bruising : Medications may be prescribed to help blood clot, and aspirin and products that contain it may be recommended.

Undescended testis : Surgery may be required if one or both testicles can not be moved into position.

Problems with the eyes and the ear : regular examinations of the sight and the hearing of the ocular health and the hearing can be recommended. Glasses, contact lenses and hearing aids will be recommended as appropriate.

Prevention and Perspectives of Noonan Syndrome

As many cases of Noonan syndrome occur randomly, there is currently no known way to prevent the development of the disease.

Those with a family history of the condition should talk with their doctor or a genetic counselor before trying to conceive.

According to the National Center for the Advancement of Translational Sciences, people with Noonan syndrome have a mortality rate three times higher than the general population.

However, symptoms vary widely from person to person, and perspectives vary accordingly. The long-term prognosis tends to depend on the presence and severity of heart defects.

The Information Center on Genetic and Rare Diseases advises that, with early intervention and adequate treatment of symptoms, most people with Noonan syndrome reach adulthood and lead independent lives.