The age at onset of puberty is often delayed and short stature is common in Noonan syndrome, although adult height is not always affected. In boys there may be problems with the testicles descending (cryptorchidism) and reduced fertility in adult life.

Puberty

The average age of the onset of puberty is delayed in people with Noonan syndrome compared with the general population:

• 35% of boys enter puberty after the age of 13·5 years
• 44% of girls enter puberty after the age of 13 years.

Fertility is not impaired in women with Noonan syndrome.

In a significant number of boys with Noonan syndrome one or both testes may fail to descend into the scrotum (cryptorchidism). This should be corrected by early surgery which helps to reduce the incidence of fertility problems with lower sperm counts later.

Growth

At birth, the baby’s weight and body length are usually normal. But as the growth spurt that comes with puberty is often delayed or longer, short stature is common during the age of normal puberty. The adult height of people with Noonan syndrome is not always affected – but on average it is reduced.

It is useful to monitor growth and refer to the growth charts for Noonan syndrome where possible. If growth is significantly delayed it may be helpful to have a referral to a specialist paediatric endocrinologist. Although the level of growth hormone is usually normal children with short stature in Noonan syndrome will usually respond to treatment with regular growth hormone injections. There is some controversy about this as the treatment will be required over several years and is expensive. Most children with Noonan syndrome will get an increase in height from the treatment which may be very helpful in boosting the child’s self-confidence. However there is still some debate about how effective the growth hormone treatment is in increasing the final height.

At the present time growth hormone is only available through a specialist paediatric endocrinologist. The NHS has not recommended growth hormone for all children with Noonan Syndrome but the position on this is currently under review. The presence of an underlying cardiomyopathy may be a contraindication for growth hormone as there have been reports of cardiomyopathy increasing on growth hormone treatment

Other growth-related issues include spinal deformity, chest deformities (‘pigeon chest’ or a sunken chest), widely spaced nipples, forearms that angle away from the body to a greater degree than normal when fully extended (cubitus valgus), and knock knees.

Hearing and vision

People with Noonan syndrome can suffer from hearing loss and eye problems.

Hearing

Problems with hearing are relatively common, but in many cases these are related to fluid in the middle ear (chronic otitis media) in childhood and are temporary. Severe hearing problems are rare but may be helped with hearing aids or cochlear implants.

Vision

Eye problems that may affect people with Noonan syndrome include:

Strabismus – a condition where the eyes do not point in the same direction. Also known as a squint, the condition causes one or both eyes to turn inward (‘crossed eyes’) or outward (‘wall eyes’).

Refractive errors – a type of visual problem that makes it hard to see clearly. They occur when the shape of the eye keeps light from focusing correctly on the retina (a light-sensitive layer of tissue in the back of the eye). It is corrected by glasses.

Amblyopia – also known as a ‘lazy eye’, amblyopia is a childhood condition where the vision does not develop properly because one or both eyes are unable to build a strong link to the brain. It usually only affects one eye, and means that the child can see less clearly out of the affected eye and relies more on the ‘good’ eye. It is treated by patching the eye.

Nystagmus – a condition of uncontrolled eye movement that causes the eyes to move or “wobble” constantly.

Lymphatic disorders are a well-recognised complication of Noonan syndrome. They can lead to swelling, due to the accumulation of fluid in the body.

The lymphatic system is a network of channels and glands throughout the body that helps fight infection and remove excess fluid. It drains extra fluid – lymph – that has passed out of the blood and into tissues and returns it back to the blood. Issues with the lymphatic system can lead to oedema – an excess of watery fluid collecting in the body’s tissues or cavities.

Before birth (prenatal)

Abnormalities in development of the lymphatic system can become apparent during pregnancy. The prenatal issues for Noonan Syndrome are:

• Increased nuchal translucency Between 10 and 14 weeks of pregnancy, ultrasound is used to measure the size of the translucent space behind the neck of the foetus – the nuchal translucency. The size reflects the amount of fluid that has accumulated under the skin of the foetus. Nuchal translucency tends to be increased in Noonan syndrome, as well as in other chromosome disorders such as Down syndrome and Turner syndrome.
• Hydrothoraces: Accumulation of fluid in the pleural cavity (the space between the lungs and the walls of the chest) of the foetus.
• Hydrops fetalis: Abnormal fluid collections in the foetus, such as around the heart or lungs, in the abdomen, or in the skin and soft tissues.)

Children and adults

Swelling of the feet at birth is often described in Noonan syndrome, and some of the characteristics of this condition – webbed neck, low-set ears, low hairline and drooping of the upper eyelid (ptosis) – may be related to oedema in the womb.

Persistent lymphatic disorders are rare, however. When they do occur, they can affect:

• Legs: Lymphoedema is a long-term (chronic) condition that causes swelling in the body’s tissues. In Noonan syndrome it usually affects the legs, so is termed bilateral lower limb lymphoedema.
• Genitals: Swollen genitals can be caused by the backflow of chyle (a milky fluid containing fat droplets which drains from the small intestine into the lymphatic system during digestion). If the valves in the lymphatic system do not control the flow correctly, chyle can mix with lymph and be routed into the genitals and legs. This is called chylous reflux.
• Small intestine: Enlarged lymph vessels supplying the lining of the small intestine can lead to a range of problems, including

1. Swelling of the legs and abdominal discomfort
2. Loss of lymphatic fluid into the intestine
3. Leaking of albumin and other protein-rich materials into the         intestine (called protein-losing enteropathy)
4. Too little albumin in the blood
5. Reduced levels of antibodies
6. Immunodeficiency (called intestinal lymphangiectasia).

• Chest: Lymphatic fluid can leak into the space between the lung and chest wall. When this fluid builds up in the lungs, it can cause a severe cough, chest pain and difficulty breathing. The condition is termed chylothorax.

The age of onset of these problems varies – for some, swelling begins as a young child, for others as adults.

The causes of these issues in people with Noonan Syndrome are not fully understood. It is not clear whether the primary problem is an abnormality of the valves in the lymphatics and veins, or whether the reflux in the legs and genital region is a result of the chylous reflux from the intestines.

It is also not clear why this may present later in life – the triggers are not known.

Specialist Tests

A technique called lymphoscintigraphy is used to investigate lymphoedema. A radiolabelled tracer is injected, which then allows an image of the lymph drainage pathways to be created using a gamma camera.

Management and treatment

Compression garments and bandaging are used to help reduce swelling of the legs, and a low fat diet or cryotherapy may be effective in reducing swollen genitals.

In 2020, US doctors reported that a Noonan syndrome patient with severe lymphatic issues had been treated successfully with trametinib (an inhibitor of mitogen-activated protein kinase, a component of the Ras/MAPK pathway).

Musculoskeletal pain is a frequent and under-recognised clinical feature of Noonan syndrome.

A 2021 study found that 25% of people with Noonan syndrome suffered from musculoskeletal pain, and 14% had joint stiffness in the wrists, elbows, ankles, knees and hips.

A separate study, also in 2021, found that 62% of people with Noonan syndrome experienced chronic pain. This pain was present among both adults and children – in this study, 50% of the people with chronic pain were children, less than 16 years old – and was linked to hypermobile joints. Joint laxity is more common in people with Noonan syndrome – a 2012 study reported that it affected 49% of people with Noonan syndrome, a portion of whom had chronic pain. If joints are hypermobile, the abnormal range of motion can increase stress on adjacent muscles and tendons, causing pain.

Although hypermobility may be an important factor the pattern of joint involvement is different from that seen with hypermobility alone and it is not clear what other mechanisms may be involved with Noonan syndrome. On investigation there are no abnormalities of the inflammatory markers seen in other forms of arthritis and fortunately although the pain may be distressing there is no progressive joint damage.

Intellectual Development, Behaviour & Education

People with Noonan syndrome show a wide range of intellectual development, but some children may be slower in their developmental milestones and need extra help at school

The majority of people with Noonan syndrome have an IQ within the normal range but more children fall into the low-average range than the general population. In some cases, especially where there is an overlap with the CFC syndrome, there may be moderate to severe intellectual disability.

In both children and adults, difficulties with language are more common than in the general population. These can include problems with reading and spelling (dyslexia), and so some children with Noonan syndrome perform more poorly in tests of verbal ability than in tests of non-verbal ability. They can also have difficulties in explaining the meaning of words – which relies on overall reasoning ability and on vocabulary. In addition there may be problems with numeracy.
Behavioural and emotional problems
Children with Noonan syndrome are more likely to display social and emotional problems than their peers. In particular, they can tend to be inattentive. Some can find it difficult to express emotions verbally, and other issues such as mood disturbances, communication difficulties, attention deficit/hyperactivity disorder, and difficulties with social interaction have also been reported (e.g autism). The teenage years may be difficult for any child but especially so in Noonan syndrome as they may have difficulty fitting in with their peer group as they are shorter, later in entering puberty and may have some educational problems.
Motor coordination
Parents often report that their children are ‘clumsy’, and children with Noonan syndrome do have a higher incidence of suspected developmental coordination disorder than their peers.

Older children tend to have fewer problems than younger ones – clumsy children learn to adapt and manage their clumsiness but the underlying motor difficulties remain. Referral to physiotherapy and practice in specific skills, such as writing, might lead to improvements.
Self-esteem
As children with Noonan syndrome are usually of shorter stature than their peers, it might be proposed that this would affect their self-esteem – in the same way that it seems to in other disorders with short stature. However, this is not always the case and some children with Noonan syndrome can be very self-confident. Strong parental support will help to improve the child’s confidence.
Education
Educational achievement varies. Many gain a GCSE or equivalent qualification, but a significant proportion with more marked difficulties do not attain a qualification.

A study in 2007 found that:

• 43% gained a GCSE
•  8% gained an A Level
• 16% had a higher educational qualification
• About a third of adults had attended a school for children with learning difficulties.
• 20% attended a mainstream school but needed extra help.
• Of those adults who were no longer in school, 60% had a full-time job.

It is important that any affected child with delay in development should have an educational assessment at the start of their schooling. This will help families find the best placement for their child and may bring additional input from a speech therapist or classroom assistant.

Genetics

Noonan Syndrome is a genetic disorder – a change in a gene causes disruption in one of the pathways that guides the development and growth of the body.

Noonan syndrome is caused by a fault in one of several genes. The commonest gene involved is called PTPN11 but there have now been around 15 genes discovered which may cause Noonan syndrome or a related disorder. Genetic testing can be used to confirm the diagnosis of Noonan syndrome and also to test for the condition in pregnancy.

History

The first clinical description of what we now term Noonan Syndrome is thought to have been published by Estonian student Oskar Kobyliński in 1883. While a student at the University in Dorpat (now Tartu, Estonia), he reported on a patient with a webbed neck, which he termed ‘flüghautige Verbreitung des Halses’ (wing-like extension of the neck). This was followed by descriptions of similar cases in 1902 and 1930.

In 1962, at the Midwest Paediatric Research Meeting, Dr Jacqueline Noonan presented a clinical study of nine children who had congenital heart disease as well as other anomalies. The nine patients – six males and three females – shared distinctive facial features and had a short stature, pulmonary stenosis (problems with a major heart valve) and significant chest deformities. She published her research on these nine and an additional ten patients in the American Journal of Diseases of Children in 1968.

As Dr Noonan was the first to indicate that this condition occurs in both sexes, can be inherited in certain cases, includes congenital heart defects and is associated with a normal number of chromosomes, the eponym Noonan syndrome was proposed.

Thickening of the heart muscle (hypertrophic cardiomyopathy), which occurs in some patients with Noonan syndrome, was first described in 1972.

Research on the genetics of Noonan syndrome often looked at the X chromosome, as people with Turner syndrome – which results from a single X chromosome only, rather than the usual XX or XY chromosomes – and Noonan syndrome have some similar physical characteristics. (Indeed, in 1938 the term ‘male Turner syndrome’ had been proposed, causing some confusion.). But in 1994, a link between Noonan syndrome and chromosome 12 was found.

In 2001, this link was narrowed down to a genetic change – a mutation – in the PTPN11 gene on chromosome 12, present in about half of patients with Noonan syndrome. Since then, other genes have been found to be associated with Noonan syndrome.
Inheritance
In the majority of people with the condition – about 60% – Noonan syndrome is caused by a new genetic change in the egg or sperm and so there is no family history. In this case, the chance of the parents having another child with Noonan syndrome is very small. This is termed ‘sporadic’ as it is caused by a ‘new mutation’.

In some people, however, the faulty gene associated with Noonan syndrome is inherited from one parent – who may or may not have obvious features of the condition themselves. Only one parent needs to carry the fault to pass it on, and each child they have has a 50% chance of being born with the condition. This type of inheritance is called ‘autosomal dominant’.

There is a very rare ‘autosomal recessive’ form of Noonan syndrome. This involves two parents who do not have the condition each having a particular faulty gene (LZTR1). In this case, Noonan syndrome may occur if a child inherits two copies of the faulty gene – one from each parent.

The genes

The most common genetic cause of Noonan syndrome is a mutation in a gene called PTPN11. This was discovered in 2001 and, since then, other genes have been linked to the condition.

• A mutation in PTPN11 occurs in about 50% of people with Noonan syndrome.
• SOS1 is the second most common causative gene, with variants occurring in 16–20% of individuals without PTPN11 variants.
• Mutations in other genes – RAF1, RIT1, KRAS, NRAS, BRAF, MAP2K1, RRAS, RASA2, SOS2, LZTR1 – are less common causes.
• In about 5–10% of cases, the genetic cause of Noonan syndrome is still not known.

The genes associated with Noonan syndrome play a crucial role in the Ras-mitogen-activated protein kinase (Ras/MAPK) pathway, which is involved in the development and growth of cells in the body. Several other syndromes are also associated with the Ras/MAPK pathway; collectively, the group of syndromes are known as the RASopathies [link to page on RASopathies] and they share many similar features.

Feeding difficulties

Many infants with Noonan syndrome have feeding difficulties which tend to improve with age.

Most infants with Noonan syndrome have feeding difficulties. This can include poor sucking, longer feeding times, or repeated vomiting. About a quarter of infants need to be fed by a tube for 2 weeks or longer. Reflux is also common. A speech therapist is the best person to assess and treat the feeding difficulties. X rays may be taken to observe the swallowing but the cause is likely to be a problem with the development of swallowing rather than any mechanical blockage. The feeding problems usually resolve by the age 15 months, but in a few cases feeding difficulties may persist for longer.

Feeding difficulties in infancy can also be an indication of delayed language development and lower educational achievement in the long-term.

Facial features

People with Noonan syndrome have characteristic facial features, particularly during childhood, which change with age and may be insignificant in adult life. In early childhood, ptosis (drooping eyelids), low set ears, short neck, and low hairline are characteristic.

The facial features include:

All ages

• Eyes: May be strikingly blue eyes with arched or diamond-shaped eyebrows
• Ears: Low set, posteriorly rotated, thick helices

A 2017 study used facial analysis technology to examine 161 people with Noonan syndrome from 5 different global populations – Caucasian, African and African American, Asian and Latin American. They found that the facial features were very similar across all the populations, and the technology could diagnose patients from all population groups with a sensitivity and specificity of 88% and 89%, respectively. The researchers proposed that the technology could support clinicians in making accurate Noonan syndrome diagnoses, helping with earlier detection and increased recognition of the syndrome throughout the world.

Cancer

People with Noonan syndrome have a small increased risk of several blood-related (haematological) cancers.

The genes involved in Noonan syndrome are part of the RAS/MAPK pathway, which controls cell growth. Mutations in these genes which are present at birth and occurred in egg or sperm (germinal mutations) such as in Noonan Syndrome are not usually associated with cancer. However when they occur due to a genetic error in the body after birth (somatic mutations) they may lead to a local cancers. Because somatic mutations of these genes may cause cancer they have been studied extensively by the pharmaceutical industry and there are many drugs in the pipeline which block the RAS/MAPK pathway and could potentially have application for treatment in Noonan syndrome.

As has been said cancer is very rare in Noonan syndrome but one specific form of leukaemia has been reported

• Juvenile myelomonocytic leukaemia is a very rare childhood blood cancer that occurs when immature blood cells (called blasts) make too many myelocytes and monocytes (two types of white blood cells) and cause a form of leukaemia. Fortunately there is now good treatment for this condition in specialised centres.

There are long term follow up studies being carried out to investigate whether people with Noonan syndrome have a higher incidence of other cancers in later life, but at present there is no evidence for this.

Cardiology – heart issues

Cardiac or heart abnormalities are often associated with Noonan syndrome. These can include problems with the heart valves, holes in the walls separating the chambers of the heart, and thickening of the heart muscle.

People with Noonan syndrome can be affected by a wide range of heart-related disease, which fall into two main categories:

• Congenital heart disease affects about 80% of patients
• Thickened heart muscle (hypertrophic cardiomyopathy) is found in about 20% of patients.

Heart problems in Noonan syndrome

Common:

Pulmonary valve stenosis
The pulmonary valve (the valve between the right ventricle and the pulmonary artery that goes to the lungs) is too small, narrow, or stiff.

Moderate risk:

Hypertrophic cardiomyopathy
The heart muscle becomes abnormally thick (hypertrophied).

Rare:

Atrial septal defect
A hole in the wall (septum) that divides the upper chambers (atria) of the heart.
Ventricular septal defect
A hole in the wall (septum) that separates the two lower chambers (ventricles) of the heart
Atrioventricular septal defect
A large defect in the centre of the heart that can be a combination of:

• atrial septal defect
• ventricular septal defect
• abnormalities of the valves, often resulting in one large valve instead of two separate valves

Mitral abnormalities
A problem with the valve located between the left heart chambers (left atrium and left ventricle)

Aortic coarctation
Part of the aorta – the large artery that carries oxygen-rich blood to the rest of the body – is narrower than usual.

Patent ductus arteriosus
A persistent opening between the two major blood vessels leading from the heart. The opening, a normal part of a baby’s circulatory system in the womb, usually closes shortly after birth.

Tetralogy of Fallot
Complex abnormality with four defects of the heart:

• Ventricular septal defect;
• Pulmonary stenosis;
• Enlarged and abnormal aortic valve;
• Ventricular hypertrophy – the muscular wall of the lower right chamber of the heart (right ventricle) is thicker than normal.

Pulmonary valve stenosis

Affecting about 40% of people with Noonan syndrome, pulmonary valve stenosis is the most common heart problem. It occurs when the pulmonary valve (the valve between the right ventricle and the pulmonary artery that goes to the lungs) is too small, narrow, or stiff.

The severity varies:

• Mild cases (about 60%): these cases are similar to patients with pulmonary valve stenosis who do not have Noonan syndrome – the stenosis tends not to progress (and often improves without treatment) and may not need surgical treatment. However, in some cases there may be an additional heart problem such as an atrial septal defect.
• Moderate (about 10%) or severe (about 30%) cases: in these cases, the rates of surgical treatment are higher – about 50% and 100%, respectively.

Atrioventricular septal defects

An atrioventricular septal defect (AVSD) is a large defect in the centre of the heart that can be a combination of:

• atrial septal defect
• ventricular septal defect
• abnormalities of the valves, often resulting in one large valve instead of two separate valves

A partial atrioventricular septal defect is the most common form of this problem, but complete defects, while rare, do occur.

Hypertrophic cardiomyopathy

About 10 – 20% of people with Noonan syndrome suffer from hypertrophic cardiomyopathy, where the heart muscle becomes abnormally thick (hypertrophied). This can become evident early in life, with more than half diagnosed by six months of age (much earlier than other childhood forms of hypertrophic cardiomyopathy, which on average become evident at the age of 8 years). Obstructions of the outflow from the left ventricle are common, and children with Noonan syndrome and hypertrophic cardiomyopathy are more likely to have congestive heart failure than other children with hypertrophic cardiomyopathy.

Genetics

A mutation in the PTPN11 gene is the most common cause of Noonan syndrome but there are now up to 15 genes which may be involved. The gene affected can also influence the likelihood and type of congenital heart disease.

PTPN11 mutation

• More likely to have pulmonary valve stenosis or an atrial septal defect
• Less likely to have hypertrophic cardiomyopathy

RAF1 mutation

• Less likely to have pulmonary valve stenosis
• More likely to have hypertrophic cardiomyopathy

RIT1 mutation

• More likely to have hypertrophic cardiomyopathy and valve abnormalities

SOS1 mutation

• More likely to have pulmonary valve stenosis

Treatment

About a third of patients with pulmonary stenosis needed surgery or a repeat procedure.

A balloon can be used to open a stiff valve, through a procedure termed ‘percutaneous balloon valvuloplasty’. If this fails or is deemed not feasible, surgical valvotomy – an open-heart procedure to open up a valve – can be carried out.

Other structural heart defects may require invasive treatment. Some may be amenable to catheter intervention (e.g. percutaneous balloon valvuloplasty, stent insertion or device closure) but others may require cardiac surgery. Treatment of other structural heart defects – these may require cardiac surgery

Treatment of hypertrophic cardiomyopathy is primarily directed at treating symptoms. This is usually with medication (e.g. beta blockers), although rarely cardiac surgery to relieve left ventricular outflow tract obstruction or to repair or replace the mitral valve may be required. Very rarely, individuals with Noonan syndrome and hypertrophic cardiomyopathy may be at an increased risk of potentially life-threatening abnormal heart rhythms and treatment with an implantable cardioverter-defibrillator (ICD) may be recommended. More recently, a new class of drugs (MEK inhibitors such as trametinib) has been reported to improve the features and symptoms of hypertrophic cardiomyopathy in some children with Noonan syndrome and related conditions presenting with very severe forms in the first few months of life. Further studies to investigate the use of these drugs are ongoing.

The most common blood disorders are abnormalities of bleeding caused by coagulation defects.

A history of abnormal bruising or bleeding is common in people with Noonan syndrome, and some may have deficiencies of clotting factors in the coagulation pathway that leads to appropriate clotting and stopping blood loss. The reason for this is unclear.

A study of 72 people with Noonan syndrome found:

• 65% had a history of abnormal bruising or bleeding
• 40% took longer for blood clots to form
• 50% had a single deficiency in the coagulation pathway
• 17% had multiple deficiencies in the coagulation pathway

People with Noonan syndrome have also been found to have von-Willebrand disease – another condition where blood clots do not form correctly – and disorders related to platelets, which are cells in the blood which clump together at the start of clotting.

Although problems rarely occur, before an operation it is important that the surgical team is aware of the potential to bleed. This should lead to a careful coagulation scree before major surgery and in the case of minor day surgery the child may be kept overnight or at least until it is clear that any post operative bleeding has stopped.

I am a 56-year-old adult male with Noonan Syndrome. What, if any, effect might the condition have on me as I get older?

In general terms, the main issue is the narrowing of the pulmonary valve in the heart in childhood which may recur again after treatment later in life. There are a number of rarer complications that may occur, but as you have mentioned no symptoms they are unlikely. The rare complications include swelling of the legs, problems with the gut, weight loss, and disturbances in the heart pumping or heart rhythm.