Noonan syndrome

Overview

Noonan syndrome is a genetic disorder that prevents normal development in various parts of the body. A person can be affected by Noonan syndrome in various ways. These include unusual facial characteristics, short stature, heart defects, other physical problems and possible developmental delays.

Noonan syndrome is caused by a genetic mutation and is acquired when a child inherits a copy of an affected gene from a parent (dominant inheritance). It can also occur as a spontaneous mutation, meaning there's no family history involved. Noonan syndrome belongs to a group of related conditions called the RASopathies. These conditions have some overlapping features and are all caused by genetic changes that disrupt the body's RAS pathway, affecting growth and development

There's no specific treatment for Noonan syndrome. Management focuses on controlling the disease's symptoms and complications. Growth hormone may be used to treat short stature in some people with Noonan syndrome.

Symptoms

Facial features:

The way a person's face looks is one of the key clinical features that leads to a diagnosis of Noonan syndrome. These features change with age:

  • Early infancy. A baby younger than 1 month old may have wide-set and down-slanting eyes, low-set ears, a deep groove and wide peaks in the upper lip, a short neck, and a low hairline on the back of the head.
  • Infancy. An infant may have prominent eyes with a downward slant and thickened lids, and a nose that's depressed at the top, with a wide base and bulbous tip.
  • Childhood. A child's face may appear expressionless, and his or her facial features may appear coarse or elongated.
  • Adolescence. An adolescent's face is typically wide at the forehead tapering to a pointed chin. The facial features become sharper and the eyes are less prominent, and the neck lengthens to reveal extra folds of skin (webbed neck) or prominent neck (trapezius) muscles.
  • Adulthood. When a child with Noonan syndrome reaches adulthood, the crease that runs from the edge of the nose to the corner of the mouth becomes prominent and the skin may be wrinkled and appear transparent.

Heart disease:

About 80 percent of people with Noonan syndrome have congenital heart disease, accounting for some of the key signs and symptoms. Pediatric cardiologists may be the first doctors to see children with Noonan syndrome. Some forms of congenital heart disease associated with this disorder include:

  • Valve disorders. Pulmonary valve stenosis is a narrowing of the pulmonary valve, the flap of tissue that separates the lower right chamber (ventricle) of your heart from the artery that supplies blood to the lungs (pulmonary artery). It's the most common heart problem seen with Noonan syndrome. The defect may occur by itself, or there can be additional associated defects.
  • Thickening of the heart muscle (hypertrophic cardiomyopathy). This is abnormal growth or thickening of the heart muscle that affects more than 20 percent of people with Noonan syndrome.
  • Other structural defects. People with Noonan syndrome often have structural defects of the heart. The defects involve a hole in the wall that separates the two lower chambers of the heart (ventricular septal defect), or a condition that causes a narrowing of the arteries that carry blood to the lungs for oxygen (pulmonary artery stenosis).

Growth issues:

  • Your child's birth weight will likely be normal, but some children with Noonan syndrome have difficulty with feeding. This can cause poor weight gain until about 18 months.
  • The growth spurt that's usually seen during adolescence may be delayed in your child, but because this disease causes bone maturity to be delayed, your child has the potential to continue growing into his or her late teens.
  • By adulthood, about one-third of people with Noonan syndrome have normal height, but short stature remains more common.

Musculoskeletal issues:

An unusually shaped chest often with a sunken sternum (pectus excavatum) or raised sternum (pectus carinatum) often occurs in those with Noonan syndrome. Wide-set nipples and a short neck, often with extra folds of skin (webbed neck), also are common.
Learning disabilities:

  • Intelligence isn't affected for most people with Noonan syndrome. However, there is an increased risk of learning disabilities.
  • Special education in school may be necessary for some people with Noonan syndrome. Still, it's usual for people with Noonan syndrome to finish high school, go on to college and have careers.

Eye conditions:

  •  A common sign of Noonan syndrome is abnormalities of the eyes and eyelids. Differences in the shape and size of the eyes are hallmark features. Often the iris is pale blue or green.
  • Problems with the eye muscles (strabismus, or crossed eyes), refractive problems — astigmatism, nearsightedness (myopia), farsightedness (hypermetropia), rapid movement of the eyeballs (nystagmus) — and problems with the nerves of the eyes are common.

Bleeding:

  •  Most people with Noonan syndrome have a history of abnormal bruising or bleeding. Sometimes the bleeding condition isn't discovered until a person has surgery and experiences excessive bleeding (hemorrhage).

Lymphatic conditions:

  •  Noonan syndrome can cause problems with the lymphatic system, which drains excess fluid from the body and helps fight infection. These problems can show up before or after birth and can be focused in a particular area of the body or may be widespread. The most common problem is excess fluid (lymphedema) on the back of the hands or top of the feet.

Genital and kidney conditions:

  •  Many people, especially males, with Noonan syndrome can have problems with the genitals and kidneys. Kidney problems are generally mild and occur in a fairly small number of people with the syndrome.
  •  Puberty may be delayed in both boys and girls, but most females develop normal fertility. In males, however, fertility may not develop normally — often because of undescended testicles, a condition that's common in males with Noonan syndrome.

Skin conditions:

  •  Various problems that affect the color and texture of the skin are common. People with Noonan syndrome often have curly, coarse hair or sparse hair.

Many of the symptoms associated with Noonan syndrome are treated just as they would be for anyone else experiencing a health problem. Taken together though, the many problems this disorder can cause require coordinated management by your health care team.

Complications can arise that may require special attention, including:

  • Developmental issues. If your child is affected developmentally, he or she may have difficulty with organization and spatial sense. Sometimes the developmental challenges are severe enough to require a special plan to address your child's learning and educational needs.

  • Bleeding and bruising. Noonan syndrome can cause excessive bleeding and bruising. This can create problems during surgery or dental work.

    If excess bleeding and bruising affect you or your child, avoid aspirin or aspirin-containing products because aspirin can affect clotting of the blood. Children in general need to avoid aspirin because of its association with Reye's syndrome.

  • Complications from lymphatic conditions. Sometimes fluid can collect in the cavity around the heart and lungs, requiring a chest tube to drain. If the draining is prolonged or needs to be repeated, this can sometimes result in weight loss or infection.
  • Genital and urinary tract complications. Males may have a low sperm count and other fertility problems because of undescended testicles (cryptorchidism). Structural abnormalities in the kidneys may increase the rate of urinary tract infections.

Causes

The cause of Noonan syndrome is a mutation in a particular gene. Currently, scientists know of eight genes that can cause Noonan syndrome.

The mutation can be inherited from a parent who carries the defective gene (autosomal dominant), or it can develop because of a new mutation in children who don't have a genetic predisposition for the disease. Children who have one parent with Noonan syndrome have a 50 percent chance of developing the disorder.

Defects in these genes cause them to produce proteins that are continually active. Because these genes play a role in the formation of many tissues throughout the body, this constant activation of their proteins disrupts the normal process of cell growth and division.

Prevention

If you have a family history of Noonan syndrome, talk to your doctor about undergoing genetic counseling before you have children. Noonan syndrome is inherited in an autosomal dominant manner. This means that having one changed (mutated) copy of the responsible gene in each cell is enough to cause the condition. Each child of a person with Noonan syndrome has a 50% (1 in 2) chance to inherit the condition.However, because many of the cases of this disease occur spontaneously, there's often no known way to prevent it.

If  Noonan syndrome is detected early, it's possible that ongoing and comprehensive care may lessen some of its complications, such as heart disease.

Diagnosis

A diagnosis of Noonan syndrome is usually made after a doctor observes some of the key signs of the disease, but this can be difficult because some of the features associated with this disorder are subtle and can be hard to identify. Sometimes, Noonan syndrome isn't diagnosed until adulthood, only after a person has a child who is more obviously affected by the condition. Molecular genetic testing may help make a diagnosis.

If there's evidence of heart problems, your doctor will likely recommend an:

  • Electrocardiogram (ECG). The ECG involves placing electrodes on your chest. An ECG records the electrical impulses that travel through your heart to assess problems.
  • Echocardiogram. An echocardiogram uses sound waves to create a moving image of your heart working so that your doctor can see where there may be problems.

These tests can be used to assess the type and severity of the condition. These tests are usually done by a doctor who specializes in heart conditions (cardiologist).

Prognosis

There is a wide range in the nature and severity of signs and symptoms that may be present in people with Noonan syndrome, so the long-term outlook (prognosis) and life expectancy may differ among affected people. Studies generally suggest that long-term outcome depends largely on the presence and severity of congenital heart defects. Death in affected people has been frequently associated with the presence of complex left ventricular disease. Studies have indicated that people with Noonan syndrome have a 3-fold higher mortality rate than those in the general population.

Some affected people have ongoing health problems due to congenital heart defects, lymphatic vessel dysplasia, urinary tract malformations, blood disorders, or other associated health issues. However, with special care and counseling, the majority of children with Noonan syndrome grow up and function normally as adults. Signs and symptoms tend to lessen with age, and new medical problems associated with the condition are generally not expected to appear in adulthood.

Treatment

Treatment of the symptoms and complications that occur with Noonan syndrome depends on their type and severity. Many of the health and physical issues associated with this syndrome are treated just the way they are in the general population.

The treatment approach that your doctor may recommend to address various aspects of Noonan syndrome may include:

  • Heart treatment. Certain drugs may be effective in treating some kinds of heart problems. If there's a problem with your heart's valves, surgery may be necessary. Your doctor also may recommend that your heart function be evaluated periodically.
  • Treating low growth rate (short stature). Somatropin is approved for the Treatment of short stature in patients with Noonan syndrome

Your doctor will likely be checking your child's blood chemistry, thyroid function, bone growth and hormone levels. If your child's growth hormone levels are insufficient, growth hormone therapy may be a treatment option.

  • Addressing learning disabilities. A wide range of mental and behavioral issues can occur with this condition. Fortunately, there are many successful ways of coping with what are usually mild symptoms.

If you discover early that your child has developmental delays, ask your doctor about infant stimulation programs. Physical and speech therapies may be helpful for addressing a variety of possible symptoms. In some cases special education or individualized teaching strategies may be appropriate.

  • Vision treatments. Because vision problems are common with Noonan syndrome, your child will need eye exams at least every two years. Most eye issues can be treated with glasses alone. Surgery may be needed for some conditions, such as cataracts.
  • Treatment for bleeding and bruising. If you or your child has a history of easy bruising or excessive bleeding, avoid aspirin and aspirin-containing products. In some cases, doctors may prescribe drugs that help the blood to clot.
  • Treatment for lymphatic problems. Although lymphatic problems are a less common symptom, the many ways in which they can occur can make finding the problem and then treating it a challenge. Complications usually involve excess fluid that gets stored in various places in your body.

Sometimes fluid can collect in the space around your heart and lungs. If this happens, your doctor may want to insert a tube into your chest to drain the fluid. To prevent this problem, your doctor may suggest you modify your diet. Sometimes surgery is necessary if swelling around the heart and lungs persists.

  • Treatment of genital and urinary tract problems. If your son has undescended testicles at birth, your doctor will likely refer you to an experienced surgeon to consider whether surgery is appropriate. It's best for your child to receive such treatment before he enters school.

Another common problem in males with Noonan syndrome is that their testicles don't function properly, in which case testosterone replacement may be an option.

If a urinary tract infection occurs, treatment includes antibiotics.

Resources

Refer to Research Publications.