Noonan Syndrome

Noonan syndrome is a genetic condition that affects many parts of the body, causing distinctive facial features, heart problems, short stature, and other health challenges that vary widely from person to person.

Table of contents

• What Is Noonan Syndrome?
• How Common Is This Condition?
• What Causes Noonan Syndrome?
• Signs and Symptoms
• How Is It Diagnosed?
• Treatment and Management
• Outlook and Living With the Condition
• Related Conditions

What Is Noonan Syndrome?

Noonan syndrome is a genetic condition that stops typical development in various parts of the body^[1]. It can affect a person in several ways, including unusual facial features, short height, heart problems, and other physical problems^[1]. The condition is present from before birth, although milder cases may not be diagnosed until a child gets older^[7].

While some children born with this condition have mild symptoms, others can have more serious issues^[4]. The symptoms of Noonan syndrome can be mild to severe, and two children with the condition may have completely different symptoms and skills^[8].

How Common Is This Condition?

Noonan syndrome occurs in approximately 1 in 1,000 to 2,500 people^[2]. It is a relatively common genetic disorder that affects both sexes and all ethnic groups equally^[7]. This makes it one of the most common single-gene disorders in the world^[23].

What Causes Noonan Syndrome?

A changed gene causes Noonan syndrome^[1]. Noonan syndrome occurs most often due to changes, called mutations (alterations in genetic information), in certain genes that help your body’s tissues grow and develop^[4]. These mutated genes produce proteins that are active longer than they should be, interfering with proper cell growth and division^[4].

Mutations in multiple genes can cause Noonan syndrome. Mutations in the PTPN11 gene cause about half of all cases^[2]. SOS1 gene mutations cause an additional 10 to 15 percent, and RAF1 and RIT1 genes each account for about 5 percent of cases^[2][3]. At least 8 different faulty genes have been linked to the condition so far^[7]. Together, mutations in these genes account for 70-75 percent of Noonan syndrome cases^[3].

The condition may be inherited or occur as a new mutation^[1]. In some cases, the faulty gene associated with Noonan syndrome is inherited from one of the child’s parents. The parent with the faulty gene may or may not have obvious features of the condition themselves^[7]. A child inherits a copy of an affected gene from a parent in what is called dominant inheritance (when only one copy of a changed gene is needed to cause the condition)^[1]. Only one parent needs to carry the fault to pass it on, and each child they have has a 50 percent chance of being born with the condition^[7].

In other cases, the condition is caused by a new genetic fault that isn’t inherited from either parent, appearing as a spontaneous change with no family history involved^[1][7]. In these cases, the chance of the parents having another child with Noonan syndrome is very small^[7].

The underlying genetic mechanism involves a disruption of the RAS-mitogen-activated protein kinase (MAPK) pathway—a cell-signaling pathway that transmits signals from the cell membrane to the nucleus^[5]. This condition is part of a family of genetically related disorders affecting this pathway, known as the RASopathies^[5].

Signs and Symptoms

Symptoms of Noonan syndrome vary greatly and range from mild to severe^[1]. These symptoms may be related to the specific gene containing the change^[1]. Most symptoms start when the fetus is developing in the uterus or appear in children before age 11^[4].

Facial Features

How the face looks is one key feature that leads to a diagnosis of Noonan syndrome^[1]. People with Noonan syndrome have distinctive facial features such as a deep groove in the area between the nose and mouth (called the philtrum), widely spaced eyes that are usually pale blue or blue-green in color, and low-set ears that are rotated backward^[2]. Other facial features may include^[1][4]:

• Eyes that are wide-set, slant down and have droopy lids
• A tall forehead
• A flat nose with a wide base and bulbous (bulging) tip
• The inside roof of the mouth may be highly arched, and the lower jaw may be small
• Teeth may be crooked
• A deep groove between the nose and the mouth, with wide peaks in the upper lip

Facial features may be easier to see in infants and young children but change with age^[1]. These distinct features become less clear in adults, and the facial features can be more subtle and may be hardest to recognize in an adult with Noonan syndrome^[1][16].

Physical Features

Many children with Noonan syndrome have a short neck, and both children and adults may have excess neck skin (also called webbing) and a low hairline at the back of the neck^[2]. Between 50 and 70 percent of individuals with Noonan syndrome have short stature^[2]. At birth, they are usually a normal length and weight, but growth slows over time^[2]. It is common for height and weight to be below the third percentile on a typical growth chart^[16].

Individuals with Noonan syndrome often have either a sunken chest (called pectus excavatum) or a protruding chest (called pectus carinatum)^[2]. Some affected people may also have an abnormal side-to-side curvature of the spine (called scoliosis)^[2]. Other physical symptoms include bulging toes or finger pads and nails that are abnormally shaped or discolored^[4].

Heart Problems

Most people with Noonan syndrome have some form of critical congenital heart disease (heart defects present from birth)^[2]. It is estimated that 50-80 percent of individuals with Noonan syndrome have a congenital heart defect^[16]. The most common heart defect in these individuals is a narrowing of the valve that controls blood flow from the heart to the lungs, called pulmonary valve stenosis^[2][16]. Some have hypertrophic cardiomyopathy, which enlarges and weakens the heart muscle^[2]. Other types of congenital heart defects are also seen in patients with Noonan syndrome, including septal defects (“hole in the heart”)^[16].

Bleeding and Clotting Problems

A variety of bleeding disorders have been associated with Noonan syndrome^[2]. Some individuals are found to have bleeding disorders, mainly problems with the way their blood clots^[16]. Some affected individuals have excessive bruising, nosebleeds, or prolonged bleeding following injury or surgery^[2]. Mild symptoms may include easy bruising or heavy menstrual cycles in women^[16].

Development and Learning

Most children diagnosed with Noonan syndrome have normal intelligence, but a few have special educational needs, and some have intellectual disability^[2]. Delay in reaching early developmental milestones is common for individuals with Noonan syndrome^[16]. Around 25 percent of individuals have learning disabilities, and some require a special education classroom setting^[16]. The average IQ tends to be lower than other family members who do not have Noonan syndrome^[16].

Puberty and Reproductive Issues

Adolescent males with Noonan syndrome typically experience delayed puberty^[2]. They go through puberty starting at age 13 or 14 and have a reduced pubertal growth spurt that results in shortened stature^[2]. Most males with Noonan syndrome have undescended testes (also called cryptorchidism, when the testicles remain in the belly rather than moving into the scrotum), which may contribute to infertility (inability to father a child) later in life^[2]. Females with Noonan syndrome can experience delayed puberty but most have normal puberty and fertility^[2].

Other Features

Noonan syndrome can cause a variety of other signs and symptoms^[2]. Some affected individuals have vision or hearing problems^[2]. Most individuals with Noonan syndrome have some type of eye and/or vision problem, and a much smaller percentage may have some degree of hearing loss^[16]. Affected infants may have feeding problems, which typically get better by age 1 or 2 years^[2]. Feeding difficulties are also common during infancy^[16].

Infants with Noonan syndrome may be born with puffy hands and feet caused by a buildup of fluid (called lymphedema), which can go away on its own^[2]. Older individuals can also develop lymphedema, usually in the ankles and lower legs^[2].

Around 10 percent of individuals have a kidney anomaly^[16]. These are typically mild and have little clinical significance, though having a structural kidney problem may make urinary tract infections more likely^[16].

Cancer Risk

Some people with Noonan syndrome develop cancer, particularly those involving the blood-forming cells (leukemia)^[2]. It has been estimated that children with Noonan syndrome have an eightfold increased risk of developing leukemia or other cancers over age-matched peers^[2].

How Is It Diagnosed?

A doctor typically diagnoses Noonan syndrome after seeing some key signs^[10]. Doctors usually notice the features of Noonan syndrome at birth or soon afterward and suspect the diagnosis^[8]. However, this can be difficult because some features of the condition are not easily seen and are hard to find^[10]. Sometimes Noonan syndrome is not found until adulthood, after a person has a child who is more clearly affected by the condition^[10].

The doctor will ask about the family history of genetic conditions, do an exam, and consider other genetic disorders with similar symptoms^[8]. Based on the results of these steps, the doctor will decide if a child may have Noonan syndrome^[8].

Genetic testing can confirm a diagnosis^[10]. A geneticist (a doctor who specializes in genetic disorders) will order a genetic test to see which mutation the child has^[8]. Knowing which gene changed can help doctors get a better idea about which symptoms will be most challenging for the child^[8]. Genetic testing can find an abnormality in almost 80 percent of people with Noonan syndrome^[4].

If there’s evidence of heart problems, a cardiologist can find out the type and how serious it is^[10]. The doctors may also order imaging tests such as magnetic resonance imaging (MRI), computed tomography (CT) scan, ultrasound, or echocardiogram (an ultrasound of the heart)^[8].

Treatment and Management

Although there’s no cure for Noonan syndrome, treatments can help decrease its effects^[10]. The earlier a diagnosis is made and treatment begins, the greater the benefits^[10]. Treatment for Noonan syndrome depends on the symptoms and complications and how serious they are^[10].

Doctors manage Noonan syndrome by controlling the symptoms and complications^[1]. Many of the health and physical issues are treated the same as they would be for anyone else^[10]. Given the many problems with this condition, a coordinated team approach is best^[10]. Your child may initially need quite a lot of treatment and support to help manage the various problems they have. However, they’ll typically need much less care as they get older^[11].

Heart Treatment

A full assessment of your child’s heart function should be carried out when Noonan syndrome is diagnosed^[11]. Certain drugs may treat some kinds of heart problems^[10]. If there’s a problem with the heart’s valves, surgery may be needed^[10]. The treatment your child needs will depend on the type of heart defect they have and how severe it is^[11]. Regular tests to check heart function will usually be carried out into adulthood^[11].

Treating Low Growth Rate

A health care professional should measure height three times a year until age 3 and then once a year until adulthood to make sure your child is growing^[10]. To find out if there is a problem with nutrition, blood tests may be ordered^[10]. If your child’s growth hormone levels are not high enough, growth hormone therapy may be a treatment option^[10]. They may use a growth hormone to treat short height in some people with Noonan syndrome^[1]. Treatment usually starts at around 4 or 5 years of age and continues until your child stops growing^[11].

Managing Learning Disabilities

For early childhood developmental delays, ask your doctor or health care professional about infant stimulation programs^[10]. If your child is diagnosed with a learning disability, an Education, Health and Care (EHC) plan may need to be drawn up to ensure your child gets the support they need^[11].

Feeding and Speech Problems

In children with Noonan syndrome, weak muscles in the mouth can sometimes cause speech and feeding problems^[11]. They may be referred to a speech therapist for help and support^[11]. In particularly severe cases of poor feeding, your baby may need a feeding tube for a few months^[11].

Undescended Testicles

If you have a baby boy with an undescended testicle, or testicles that don’t descend naturally within a few months of birth, corrective surgery is usually recommended^[11]. This is normally carried out before 2 years of age, because treating the problem early on should increase the chances of fertility being unaffected^[11].

Bleeding Disorders

Identification of bleeding disorders is important, as issues with clotting should be recognized before any surgical procedure^[16].

Outlook and Living With the Condition

Noonan syndrome can range from being very mild to severe and life-threatening^[7]. In many cases, the problems associated with the condition can be successfully treated at a young age or become less prominent over time^[7]. Almost all children with Noonan syndrome reach adulthood and most are able to lead normal, independent lives^[7].

Most adults with Noonan syndrome can lead a normal life^[11]. Long-term outcomes typically depend on the severity of heart problems^[3]. However, problems such as heart defects can occasionally be severe and life-threatening^[7]. Some children may need emergency surgery to correct the problem as soon as possible, and most people with Noonan syndrome will need to have their heart monitored regularly throughout their life^[7].

Your healthcare provider can recommend guidance to keep your child as healthy as possible and will work closely with you to help prevent complications or catch them early, so your child can lead a full, active life^[4].

Related Conditions

Noonan syndrome belongs to a group of related conditions known as RASopathies^[4]. All of the conditions are due to the same type of abnormal cell growth and development and have similar symptoms^[4]. These conditions all have similar signs and symptoms and are caused by changes in the same cell signaling pathway^[2].

In addition to Noonan syndrome, the RASopathies include cardiofaciocutaneous syndrome, Costello syndrome, neurofibromatosis type 1, Legius syndrome, and Noonan syndrome with multiple lentigines (formerly known as LEOPARD syndrome)^[2][4].