What Is Noonan Syndrome?
Noonan syndrome is a genetic condition that affects the development of various parts of the body6. First described in the 1960s by American cardiologist Dr102. Jacqueline Noonan, it is one of the more common genetic syndromes, estimated to occur in 1 in every 1,000 to 2,500 births worldwide10. While its features can differ greatly from person to person, the condition is always caused by a change in one of several genes that regulate how cells grow and develop10.
Characteristic Physical Features
People with Noonan syndrome often share certain physical traits, though these can be quite variable and may change with age6. Common features include a distinctive facial appearance with wide-set, down-slanting eyes, low-set ears, and a short or webbed neck. Many individuals also have a shorter stature compared to their family members and may have a chest deformity, such as a sunken or protruding breastbone3. These features are often most noticeable in childhood and can become less apparent in adulthood8.
Heart and Circulation Issues
Heart conditions present from birth are very common, affecting a majority of individuals5. The most frequent issue is pulmonary valve stenosis, a narrowing of the valve that controls blood flow from the heart to the lungs3. Other heart problems can include a thickening of the heart muscle, known as hypertrophic cardiomyopathy3. Additionally, many individuals may have a tendency to bleed or bruise easily3. This can show up as frequent bruising or bleeding for longer than usual after an injury or surgery, often due to how the body's platelets and clotting factors work3.
Developmental and Other Health Concerns
The syndrome can impact development and other body systems in various ways. While intellectual ability varies, some individuals may have learning disabilities or delayed developmental milestones3. Feeding difficulties are very common in infancy and may require tube feeding, but these issues typically improve as the child gets older61. Other potential health concerns include lymphatic problems causing fluid retention (lymphedema), vision or hearing problems, undescended testicles in boys, and delayed puberty4.
The Genetic Causes of Noonan Syndrome
At its core, Noonan syndrome is caused by a gene change, or mutation, that disrupts a vital communication network within our cells6. This network controls fundamental processes like cell growth, division, and specialization4. When a mutation occurs, this pathway becomes overactive, leading to the developmental differences seen in the condition4.
The Ras/MAPK Pathway: A Stuck "On" Switch
The cellular communication network at the heart of Noonan syndrome is called the Ras/mitogen-activated protein kinase (Ras/MAPK) pathway4. You can think of this pathway as a series of switches that turn cell growth signals on and off at precisely the right times9. In individuals with Noonan syndrome, a mutation in one of the pathway's genes causes it to get stuck in the "on" position9. This continuous "grow" signal disrupts the normal development of the heart, facial features, bones, and other tissues, resulting in the characteristic features of the syndrome3.
Noonan syndrome belongs to a group of related conditions called "RASopathies," which all share this common mechanism of an overactive Ras/MAPK pathway4.
The Key Genes Involved
Researchers have identified several different genes along the Ras/MAPK pathway that can cause Noonan syndrome when mutated42. The specific gene involved can influence the type and severity of symptoms10.
- PTPN11: This is the most common cause, found in about 50% of cases7. Mutations in this gene make its protein, SHP-2, overactive7. This is often linked to the classic facial features, short stature, and heart defects like pulmonary valve stenosis3.
- SOS1: As the second most common cause, mutations in this gene account for 10-15% of cases7. Individuals with SOS1 changes often have more prominent skin features, and their height may be closer to average5.
- RAF1: Found in about 5-10% of cases, mutations in the RAF1 gene are strongly associated with hypertrophic cardiomyopathy, a condition where the heart muscle becomes unusually thick7.
- RIT1 and KRAS: Together, these genes account for another 5-10% of cases71. KRAS mutations are sometimes linked to more significant developmental delays41.
- Other Genes: A growing number of other genes, including BRAF, NRAS, and SHOC2, are responsible for a smaller percentage of cases71. Despite advances in genetic testing, in about 20% of individuals with a clinical diagnosis of Noonan syndrome, a specific gene mutation cannot be identified, suggesting that more causative genes are yet to be discovered61.
How Noonan Syndrome Is Acquired
A diagnosis of Noonan syndrome naturally leads to questions about where the genetic change came from62. The mutation can either be passed down from a parent or it can happen for the first time in a child with no family history of the disorder10.
Spontaneous (De Novo) Mutation
In about 60% of cases, Noonan syndrome is the result of a new, or "de novo," mutation4. This means the genetic change occurred randomly for the first time in the child and was not inherited from either parent10. The change typically happens in the egg or sperm cell before conception or very early in the embryo's development10. For parents of a child with a confirmed de novo mutation, the chance of having another child with the syndrome is very low, generally estimated to be less than 1%6.
Inherited from a Parent
In the remaining cases, Noonan syndrome is passed down from a parent to a child through an "autosomal dominant" inheritance pattern7. This means that only one copy of the altered gene—inherited from just one parent—is needed to cause the condition6. A parent who has Noonan syndrome has a 50% chance with each pregnancy of passing the gene change on to their child6. Because the features of Noonan syndrome can be very mild, it is not uncommon for a parent to be diagnosed only after their child receives a diagnosis with more obvious characteristics81.
The Importance of Genetic Counseling
To understand how Noonan syndrome occurred in a family and the risks for future pregnancies, genetic counseling is essential62. A genetic counselor can review the family's medical history and coordinate testing for the parents62. This can determine whether the gene change was inherited or occurred de novo, providing clarity on the recurrence risk10. This process ensures that families receive the most accurate information, support, and guidance tailored to their specific situation62.
