Noonan syndrome is a genetic disorder that is present from birth.  It is one of a group of related conditions known as RASopathies (pronounced “rass-op-athies”). These are conditions caused by mutations in genes that are part of a critical cell signaling pathway called the RAS/MAPK pathway.

To understand this, it is helpful to use an analogy. Think of the cells in a developing body as needing constant instructions on when to grow, divide, and differentiate into different tissues. The RAS/MAPK pathway is like a crucial “Go!” signal that relays messages from the outside of the cell to the nucleus inside, telling it to grow and divide. This signal is transmitted like a cascade of falling dominoes, with one protein activating the next in a precise sequence.

In Noonan syndrome, there is a mutation in one of the genes that makes one of these “domino” proteins. This mutation creates a faulty domino that is partially “stuck” in the “on” position. As a result, the “Go!” signal is slightly overactive all the time. This constant, low-level overstimulation disrupts the normal, orderly process of development, leading to the wide range of features seen in the syndrome, from the way the face is formed to how the heart valves develop.

Clinically, when I see a child with subtle facial changes, a heart murmur, and delayed growth, Noonan syndrome is always on my radar. Early recognition really helps with management.

Noonan syndrome is caused by  mutation in one of several different genes that are part of the RAS/MAPK signaling pathway. These mutations are changes or “spelling errors” in the genetic code that cause a protein in the pathway to be overactive.

While several genes can be involved, the most common one is:

• PTPN11: Mutations in this gene are responsible for approximately 50% of all cases of Noonan syndrome.

Other genes that are frequently involved include SOS1, RAF1, and KRAS. The specific gene that is mutated, and the location of that mutation, can sometimes influence the severity and pattern of symptoms a person experiences. For example, mutations in the PTPN11 gene are more commonly associated with pulmonary valve stenosis, while mutations in the RAF1 gene are more frequently linked to hypertrophic cardiomyopathy.

Families are often shocked because there’s no family history. I explain that while Noonan syndrome can be inherited, it often appears as a brand-new mutation in a child without any known risk.

Noonan syndrome is a genetic condition, but the way a person comes to have it can differ. It can be inherited from a parent or it can occur as a brand-new event in a family.

Sporadic (de novo) Mutation

In approximately 50-75% of cases, Noonan syndrome is sporadic. This means the genetic mutation is de novo, or “new.” It occurs by complete chance during the formation of the egg or sperm cell in a healthy parent, or very early in embryonic development. In these cases, the parents do not have the mutation, and there is nothing they did or did not do to cause the condition. The risk of these parents having another child with Noonan syndrome is very low.

Autosomal Dominant Inheritance

In the remaining cases, the condition is inherited from a parent who also has Noonan syndrome.

• The inheritance pattern is autosomal dominant. This means that an individual only needs to inherit one copy of the mutated gene from one parent to have the syndrome.
• An affected parent has a 50% chance of passing the gene mutation to each of their children.
• It is important to note that because Noonan syndrome has such a wide range of severity, a parent may have a very mild, undiagnosed case and only learn of their own diagnosis after their more obviously affected child is diagnosed.

I’ve seen children diagnosed without any family history, and it’s important to reassure parents that nothing they did caused it. It’s a genetic lottery they didn’t ask to play.

Symptoms of Noonan syndrome vary widely, but many features are recognizable during infancy or early childhood.

The most common signs and symptoms involve several key areas:

Characteristic Facial Features

Many individuals with Noonan syndrome share a recognizable, though often subtle, facial appearance that tends to change with age.

• In infancy: A high, broad forehead; widely spaced and often down-slanting eyes (hypertelorism); droopy eyelids (ptosis); and low-set ears that are rotated backward.
• In childhood: The facial features may appear less striking, but the eyes remain prominent.
• In adolescence and adulthood: The face may appear longer, with a more prominent jaw and a high-arched palate.

Congenital Heart Defects

Heart problems are the most common serious medical issue in Noonan syndrome, affecting up to 80% of individuals. The most common heart defects are:

• Pulmonary Valve Stenosis: A narrowing of the valve that controls blood flow from the heart to the lungs.
• Hypertrophic Cardiomyopathy (HCM): A thickening of the heart muscle, which can affect its ability to pump blood effectively.
• Atrial or Ventricular Septal Defects (ASD or VSD): A hole in the wall separating the heart’s upper or lower chambers.

Growth and Skeletal Issues

• Short stature is a very common feature. Babies are often born at a normal length but their growth slows over time.
• Pectus carinatum (protruding chest bone) or pectus excavatum (sunken chest bone).
• A short neck, sometimes with webbing.

Other Common Medical Issues

• Feeding difficulties in infancy.
• Bleeding disorders: Easy bruising or abnormal bleeding due to clotting factor deficiencies or low platelets.
• Cryptorchidism (undescended testicles) in males.
• Lymphatic issues, causing fluid collection.

Developmental and Learning

• Most individuals with Noonan syndrome have normal intelligence.
• However, mild learning disabilities are common, and developmental milestones like walking and talking are often delayed due to low muscle tone (hypotonia) in infancy.

What stands out is the mix of subtle signs. Many kids are diagnosed when multiple small concerns come together: short stature, a soft murmur, and maybe a speech delay. Connecting the dots makes all the difference.

Diagnosis of Noonan syndrome is based on physical exam, family history, and genetic testing.

• Prenatal Diagnosis: The syndrome may be suspected before birth if a prenatal ultrasound reveals signs like increased fluid at the back of the neck (nuchal translucency), excess amniotic fluid (polyhydramnios), or a heart defect. A definitive prenatal diagnosis can be made through genetic testing on samples from amniocentesis or chorionic villus sampling (CVS).
• Postnatal Diagnosis: After birth, the diagnosis is suspected based on the physical exam.
• Definitive Genetic Testing: The diagnosis is confirmed with a molecular genetic test using a blood sample. Doctors will typically order a Noonan syndrome gene panel, which uses next-generation sequencing to test for mutations in the many different genes known to cause the condition. A positive test confirms the diagnosis. However, it is possible to have a clinical diagnosis of Noonan syndrome even if a mutation is not found in one of the currently known genes.

Once a diagnosis is made, a child will undergo a comprehensive baseline evaluation to screen for all the potential associated health issues. This always includes a full evaluation by a pediatric cardiologist with an echocardiogram, a hearing test, an eye exam, a renal ultrasound, and a hematology consultation.

A good physical exam often tells the story, but confirming the gene mutation gives families a clearer picture and allows us to plan better for the child’s future.

There is no cure for Noonan syndrome, but symptoms can be managed with a multidisciplinary care team. Early intervention helps improve quality of life.

The key management strategies include:

• Cardiac Care: Many children will require open-heart surgery in infancy to repair congenital heart defects. Lifelong follow-up with a cardiologist is essential.
• Growth and Endocrine Management: An endocrinologist will monitor growth using specialized Noonan syndrome growth charts.
  • Growth Hormone (GH) Therapy: GH therapy is often used in children with Noonan syndrome and short stature. It has been shown to increase growth velocity and can lead to an improved final adult height (NORD, 2023). This is a long-term therapy involving daily injections.
  • Puberty may be delayed, and some males may require testosterone replacement therapy in adulthood.
• Developmental Support: Early intervention is the cornerstone of helping a child with Noonan syndrome reach their full potential. This includes:
  • Physical therapy to help with low muscle tone and motor skills.
  • Speech therapy to address language delays.
  • Occupational therapy to help with fine motor and daily living skills.
  • An individualized education plan (IEP) to support the school.
• Management of Other Medical Issues:
  • Feeding Support: In infancy, a feeding specialist or dietitian may be needed to manage feeding difficulties.
  • Hematology: Screening for bleeding disorders before any surgery.
  • Routine Screenings: Regular hearing and vision checks.

What I always emphasize is that the earlier we start support, therapy, heart care, growth monitoring, the better the child’s long-term outcome. These kids are full of potential.

Noonan syndrome is a common genetic disorder that can affect the body in a multitude of ways, from a child’s facial features and heart structure to their growth and development. The condition is highly variable, and while some individuals face significant medical challenges, many others have milder features. While there is no cure, a proactive and coordinated multidisciplinary team approach is essential to manage the complex needs of an individual with Noonan syndrome. With early diagnosis and consistent support, individuals with Noonan syndrome can lead full, healthy, and productive lives.

National Organization for Rare Disorders (NORD). (2023). Noonan Syndrome. Retrieved from https://rarediseases.org/rare-diseases/noonan-syndrome/

National Institutes of Health, Genetic and Rare Diseases Information Center (GARD). (2021). Noonan syndrome. Retrieved from https://rarediseases.info.nih.gov/diseases/7233/noonan-syndrome

The Noonan Syndrome Foundation. (n.d.). What is Noonan Syndrome?. Retrieved from https://www.teamnoonan.org/