Autoimmune Diseases and Noonan Syndrome

Brett | May. 5, 2019

Noonan Syndrome (NS) is one of many RASopathies – a group of rare conditions caused by mutations in the RAS-MAPK pathway. The RAS-MAPK pathway is involved in many cellular processes so any mutation can have profound effects on many areas of the body such as heart function, circulation and clotting, fertility, cognition, digestion and immunity. It is the latter consequence we are exploring in this Blog. Unfortunately there are some auto-immune disorders associated with RASopathies and we will look at these in more detail below. 

What is an Autoimmune disease?

The immune system is a collection of special cells and chemicals that fight infection-causing agents such as bacteria and viruses. An autoimmune disorder occurs when a person’s immune system mistakenly attacks their own body tissues. There are around 80 different autoimmune disorders ranging in severity from mild to disabling, depending on which system of the body is under attack and the severity of the immune reaction. Autoimmune diseases are diagnosed by a number of assessments but the primary indicator is the presence of autoimmune antibodies – proteins made by the immune system that mistakenly target normal, healthy cells, organs and tissues.

Autoimmune diseases occur in approximately 7-9% of all individuals. Research has shown that clinically diagnosed autoimmune diseases occur in 14% of people with RASopathies; approximately twice the rate of the non-RASopathy population. However recent studies have shown that autoimmune antibodies occur in 52% of people with RASopathies! This discrepancy between clinical diagnosis and blood pathology is not surprising as many people may not seek medical investigation and treatment for their symptoms.

For example someone with NS may downplay their joint pain as ‘growing pains’ or ‘soreness after exercise’ and not realise it’s actually Systemic Lupus Erythematous (SLE) – a common autoimmune disorder in RASopathies. Another example may be someone with NS ignoring gastrointestinal complaints as ‘indigestion’ as poor gut motility is common in NS. Unfortunately those gastrointestinal symptoms may be Coeliac Disease – an autoimmune disorder that occurs at 10 times the rate in people with NS than the non-NS population. When you have a genetic syndrome such as NS it can be easy and understandable to blame or assign many symptoms and complaints to being part of the syndrome. However we encourage all individuals with NS to have all symptoms properly assessed especially those related to the autoimmune diseases that occur more frequently in people with RASopathies. We will explore these autoimmune diseases now so you can learn more about them and be aware of any associated symptoms in future if they occur to you or your loved ones.

Why do Autoimmune diseases occur more frequently in RASopathies?

The higher occurrence of autoimmune disease involvement could result from several underlying mechanisms within RASopathies.

First, a mutation of a gene involved in the function, regulation, or development of both the immune and non-immune systems could occur. Alteration of the activity or structure of immune proteins could cause dysfunction in both the immune system and another organ system. As the RAS-MAPK pathway is involved in many bodily functions including immunity this is likely to occur much more frequently than in an individual without RAS pathway mutations.

Second, a gene critical in the development of one of the involved systems could be closely linked to a gene important for the immune system. So even if the RAS pathway mutation isn’t directly affecting immune cell function it may be inhibiting an enzyme or other protein which in turn increases or decreases the function of an associated immune cell or organ.

Third, insults at crucial times in embryological development could affect more than one organ system if both were developing at that time.  RASopathies are germline mutations meaning they occur at very early stages of embryonic development. Unfortunately this means the RAS pathway mutation can affect organ systems as they are growing and developing and this may influence immune organs such as the Thymus, Spleen or bone marrow.

Last, exposure to acidosis or toxic metabolites, as may be found in some inborn errors of metabolism, could affect function of the immune system. Many RASopathies are associated with metabolic, circulatory and inflammatory issues which may ‘alert’ the immune system and trigger the creation of autoimmune antibodies that attack healthy tissues.

Which Autoimmune diseases are associated with RASopathies?

The main autoimmune diseases occurring in greater frequency in RASopathy syndrome individuals are Systemic Lupus Erythematous (SLE), Coeliac Disease (CD), Autoimmune Thyroiditis, Primary Antiphospholid Syndrome (PAPS), Autoimmune Hepatitis and Vitiligo.

Systemic Lupus Erythematous (SLE)

Lupus Rash

SLE is often referred to as the ‘great imitator’ because it mimics many illnesses. Common initial and chronic complaints include fever, malaise, joint pains, muscle pains, and fatigue. Because these symptoms are so often seen in association with other diseases, these signs and symptoms are not part of the diagnostic criteria for SLE. When occurring in conjunction with other signs and symptoms, however, they are considered suggestive.

Symptoms and Diagnosis

The symptoms of lupus can vary and may include:

  • Skin rashes (both on the face and body)
  • Hair loss
  • Mouth and nose ulcers
  • Chest pain (as a result of inflammation of the lining of the heart or lungs)
  • Joint swelling
  • Anaemia (a deficiency in the number or quality of red blood cells), leukopenia (low white blood cell count), or  lymphophenia (low platelet count)
  • Poor kidney function
  • Seizures or visual disturbances (resulting from inflammation of the nervous system)

It’s unlikely that one person will experience all of these symptoms but if an individual is experiencing 4 or more this can be considered highly suggestive of SLE.  At times the symptoms experienced as a result of lupus (such as rash, pain, fatigue) will become more intense. These periods are called a ‘flare’. Flares are unpredictable and can seem to come out of nowhere. They’re often triggered by stress, illness and exposure to ultraviolet (UV) light. Blood tests can confirm SLE; primarily ANA and anti-ENA counts.


Medication can help manage your symptoms and assist in controlling your overactive immune system. Because people with lupus experience different symptoms, and to varying degrees, there is no ‘one size fits all’ treatment. You might need to take a combination of different medications that could include:

  • Pain-relieving medication (analgesics) – medications such as paracetamol can provide temporary pain relief
  • Non-steroidal anti-inflammatory drugs (NSAIDs) – for example, naproxen and ibuprofen help control inflammation and provide temporary pain relief
  • Corticosteroids such as prednisolone are used to quickly control or reduce inflammation. They are used in the early days of your condition, or if you’re going through a flare, to get the inflammation under control. They do have side effects if used for long periods, so your doctor will closely monitor you while you’re taking them
  • Hydroxychloroquine medications such as Plaquenil are referred to as ‘anti-malarials’ because they were originally used to treat malaria. We now know that they’re very effective at controlling immune system activity in chronic conditions such as lupus. Hydroxychloroquine is effective in treating skin and joint problems associated with lupus. People who take hydroxychloroquine are less likely to have flares, so many people with lupus will take these medications long term
  • Disease modifying anti-rheumatic drugs (DMARDs) – this group of medications works on controlling your overactive immune system. They help relieve pain and inflammation, and can also reduce or prevent joint damage
  • Immunosuppressants – these medications including azathioprine, mycophenolate mofetil, cyclosporine, leflunomide, methotrexate, and cyclophosamide modify unwanted activity of the immune system. Each of these medications has particular effects on lupus and particular side effects, so your specialist will closely monitor the effects they have on you.

All medications can have side effects and it’s important the decision to begin treating SLE is discussed with a doctor or Rheumatologist.

There are some other ways to independently treat and manage SLE. Some of these methods include:

  • Limiting exposure to ultraviolet (UV) light. UV light, especially sunlight, can cause a flare. This can include skin rashes in sun-exposed areas.
  • Exercise – regular physical activity has general health benefits and can help manage the symptoms of SLE. Exercising regularly improves sleep quality, increases energy levels, reduces fatigue, and improves overall strength and fitness. Exercise can also help prevent long-term consequences of SLE such as heart disease and osteoporosis.
  • Pain management – there are many things you can do to manage pain and different strategies will work for different people and different situations. For example, heat packs can help ease muscle pain, cold packs can help with inflammation and gentle exercise can help relieve muscle tension.
  • Manage your stress – stress can aggravate SLE symptoms. Things that can help reduce stress include planning and time management techniques, using relaxation and mindfulness techniques such as going for a walk, meditating or listening to relaxing music and avoiding people and situations that cause you stress.
  • Balance rest and activity – planning activities to make the most of energy levels by alternating periods of activity with rest. Breaking large jobs down into small achievable tasks can prevent fatigue.
  • Eat well – eating a balanced diet can help provide better energy levels, help to maintain weight, and create a greater sense of wellbeing.
  • Stay at work – being productive is good for health and wellbeing. It’s important to prevent SLE symptoms from limiting your participation in meaningful life roles such as working.

Coeliac Disease

Normal intestinal villi and damaged villi post-Coeliac Disease

Coeliac Disease (CD) is an autoimmune disease in which the immune system attacks the small intestine creating both gastrointestinal and systemic symptoms such as bloating, diarrhoea, constipation, malabsorption, anaemia and poor growth. We covered CD extensively in a previous Blog Post so for more information please see here:

Autoimmune Thyroiditis

Autoimmne Thryoiditis is as the name suggests a disease in which the immune system attacks and causes inflammation within the Thyroid gland. The Thyroid produces hormones which influence metabolism, circulation, development, sexual function and sleep. This state of impaired and lowered thyroid function is called hypothyroidism.

Symptoms and Diagnosis

  • Fatigue
  • Depression
  • Modest weight gain
  • Cold intolerance
  • Dry, coarse hair
  • Constipation
  • Dry skin
  • Muscle cramps
  • Increased cholesterol
  • Decreased concentration
  • Vague aches and pains
  • Swelling of the legs

As hypothyroidism becomes more severe, there may be puffiness around the eyes, a slowing of the heart rate, a drop in body temperature, and heart failure. In its most profound form, severe hypothyroidism may lead to a life-threatening coma (myxedema coma). In a severely hypothyroid individual, myxedema coma tends to be triggered by severe illness, surgery, stress, or traumatic injury. This condition requires hospitalization and immediate treatment with thyroid hormone.


Autoimmune thyroiditis can be easily treated with thyroid hormone replacement, if it is diagnosed properly. This is why it is important that people with Noonan Syndrome don’t dismiss these symptoms as being just ‘part of having NS’.  It’s advised that anyone with these symptoms seek medical assessment and testing as soon as practicable.

Primary Antiphospholid Syndrome (PAPS)

Primary Antiphospholipid Syndrome (PAPS) – also called Hughes’ syndrome – is an autoimmune condition that makes blood more likely than normal to clot (a thrombophilia). This can lead to unwanted blood clots (called thromboses) forming within blood vessels. In PAPS the individual’s antibodies attack a normal substance called phospholipid (which is why the antibodies are called antiphospholipid). The presence of the antiphospholipid antibodies causes the increased tendency of the blood to clot – they can trigger the coagulation cascade. The coagulation cascade is a chain reaction of events or chemical reactions that occur in the blood, leading to the formation of a blood clot. The antibodies can also cause inflammation which further increases the likelihood of the blood to clot.

In most people a certain event, such as pregnancy, stress or an infection provides a trigger for this chain of events in PAPS. Pregnancy itself (even without PAPS) makes a blood clot more likely to develop.

Symptoms and Diagnosis

PAPS can cause disability, serious illness and even death in a pregnant woman or her unborn baby if untreated. Unfortunately, it is a disease that is often under-recognised and under-diagnosed. This is probably because it can cause so many different problems, many of which have other, more common causes. Early diagnosis is important to try to prevent serious complications. Some common symptoms are:

  • Blood clots in veins (venous thromboses). Veins are blood vessels that bring blood back to the heart. They carry deoxygenated blood (blood without much oxygen left in it). After reaching the heart, the blood is sent to the lungs to get more oxygen. Venous means anything relating to the veins.
  • Blood clots in arteries (arterial thromboses). Arteries are blood vessels that take blood away from the heart. They carry blood containing oxygen (oxygenated blood) around the body. Arterial means anything relating to the arteries.
  • Blood clots in the placenta (thromboses in the placenta).
  • Kidney (renal) problems. A blood clot can occur in a blood vessel within a kidney. This can affect the kidney function and may lead to chronic kidney disease (CKD). 
  • Heart (cardiac) problems. This includes problems with the valves in the heart which can also increase the risk of stroke. An inflammation of the lining of the heart (endocarditis) can occur because of blood clots forming on the heart valves. Heart attack (myocardial infarction, or MI) due to a blood clot in one of the blood vessels that supply the heart muscle itself (the coronary arteries) can occur in PAPS. About 3 people in 100 with PAPS have an MI as their first sign of the disease.
  • Brain (cerebral) involvement. As well as stroke and TIA, PAPS is associated with other problems in the brain. These include migraine, seizures, memory loss and abnormal movement disorders.
  • Skin problems. A lace-like, purple mottled rash called livedo reticularis can occur – usually on the legs. It is caused by swelling of medium-sized veins in the skin. This can also have a totally innocent explanation and is common during winter in young women without PAPS.
  • Other blood problems. For example, a low level of platelets, which can cause easy bruising and a type of anaemia called haemolytic anaemia.
  • Avascular necrosis of the bone (also called osteonecrosis). Bones are a living part of the body and need a blood supply. The blood supply brings oxygen and other nutrients to the bone cells. Interruption of this blood supply (by a blood clot, for example) can lead to death of the bone – called avascular necrosis. It can lead to pain and arthritis.
  • Eye problems such as retinal blood clots. This can lead to permanent sight problems.
  • Budd-Chiari syndrome. This is a rare condition where a blood clot occurs in a vein in the liver. It can cause an enlarged liver, yellowing of the skin and of the whites of the eyes (jaundice) and tummy (abdominal) swelling due to fluid.
  • Infertility. Antiphospholipid antibodies are associated with infertility and testing for them is becoming more routine in investigations to find the cause of infertility.

Diagnosis involved blood test and clinical findings. An individual would need to have positive blood test results and relevant clinical symptoms.

The blood tests for APS involve detecting antiphospholipid antibodies. Blood testing in PAPS or suspected PAPS is a complicated process. Antiphospholipid antibodies are found in between 1 and 5 people in every 100 people without APS. So, a single positive test for any or all of the antiphospholipid antibodies does not mean you have PAPS. This is why it is important that only certain people should be tested (as we will explain).

There are three antiphospholipid antibodies: Lupus anticoagulant, Anticardiolipin antibodies and Anti-beta glycoprotein I antibodies. If you have a positive blood test for any of the antiphospholipid antibodies, it will need to be repeated after 6-8 weeks. This is because many people have these antibodies in their blood for a short period of time, without any harm being caused (called transient positivity). Transient positivity can occur in healthy people, harmlessly, after infections or some medications.

It is also possible that a first positive test has been a false positive. False positive tests are common (up to 1 in 4) in tests for antiphospholipid antibodies. This is because different laboratories have different techniques for measurement and different thresholds for a positive result. Persistent positive blood tests in the absence of APS are rare. So, if you test positive on a second, later occasion, the chances are that the test is correct (but this doesn’t necessarily mean you have PAPS).

Antiphospholipid antibodies are more likely to be found in your blood the older you are and if you take certain medications. They are also more likely if you have cancer, other long-term (chronic) diseases or infections. In these cases, the tests tend to be only weakly positive and they are not associated with an increased risk of blood clot or pregnancy problems. So, two positive tests, at least 6-8 weeks apart, are needed for diagnosing PAPS. However, some people have the antibodies and no problems. So, to diagnose PAPS you need a combination of a positive blood test for one of the antibodies AND one of the clinical criteria.

Relevant clinical symptoms are:

  • A blood clot. This can be arterial or venous, in any organ of the body. It is important that this has been proved – for example, with a scan.
  • A pregnancy-related problem. This includes either:
  • Repeated miscarriage. Three or more miscarriages before 10 weeks of pregnancy. Other causes of miscarriage (such as chromosomal abnormalities) have to be excluded.
  • Miscarriage after 10 weeks of pregnancy or stillbirth after 24 weeks of pregnancy. Again, other causes have to be excluded.
  • Premature birth before 34 weeks of pregnancy, due to eclampsia or severe pre-eclampsia. Eclampsia is a seizure in pregnancy caused by pre-eclampsia. Pre-eclampsia is a pregnancy-related problem with high blood pressure, protein in the urine and swollen legs.


People with PAPS are often referred to and managed by a specialist. This is usually a blood specialist (a haematologist) who will prescribe anti-clotting medication and compression garments to prevent thromboses forming in the first place. PAPS is regularly managed successfully without major complications but as always early diagnosis is crucial. Unfortunately many symptoms of PAPS & NS overlap – particularly sight, kidney, infertility problems and headaches. Again this is why these symptoms should be investigated thoroughly.

Autoimmune Hepatitis

Autoimmune hepatitis is liver inflammation that occurs when your body’s immune system turns against liver cells. The exact cause of autoimmune hepatitis is unclear, but genetic and environmental factors appear to interact over time in triggering the disease. Untreated autoimmune hepatitis can lead to scarring of the liver (cirrhosis) and eventually to liver failure. When diagnosed and treated early, however, autoimmune hepatitis often can be controlled with drugs that suppress the immune system.


Signs and symptoms of autoimmune hepatitis vary from person to person and may come on suddenly. Some people have few, if any, recognized problems in the early stages of the disease, whereas others experience signs and symptoms that may include:

  • Fatigue
  • Abdominal discomfort
  • Yellowing of the skin and whites of the eyes (jaundice)
  • An enlarged liver
  • Abnormal blood vessels on the skin (spider angiomas)
  • Skin rashes
  • Joint pains
  • Loss of menstrual periods

Increased risk factors for autoimmune hepatitis are:

  • Being female. Although both males and females can develop autoimmune hepatitis, the disease is more common in females.
  • A history of certain infections. Autoimmune Hepatitis may develop after you’re infected with the measles, herpes simplex or Epstein-Barr virus. The disease is also linked to hepatitis A, B or C infection.
  • Heredity. Evidence suggests that a predisposition to autoimmune hepatitis may run in families.
  • Having an autoimmune disease. People who already have an autoimmune disease, such as celiac disease, rheumatoid arthritis/SLE or hyperthyroidism (Graves’ disease or Hashimoto’s thyroiditis), may be more likely to develop autoimmune hepatitis. Unfortunately as previously discussed these autoimmune conditions have higher prevalence within the Noonan Syndrome community thus increasing the risk of autoimmune hepatitis for those with NS.

If untreated Autoimmune Hepatitis can cause enlarged veins in the esophagus, fluid accumulation in the abdomen, liver failure and liver cancer. This is why it’s imperative any of the aforementioned symptoms are investigated as soon as possible to exclude hepatitis. Diagnosis can be made by blood tests and a liver biopsy to confirm and evaluate the level of liver damage.


The goal of treatment is to slow or stop the immune system attacking the liver. This may help slow the progression of the disease.

Doctors will prescribe medications that lower immune system activity. The initial treatment is usually prednisone. A second medication, azathioprine (Azasan, Imuran), may be recommended in addition to prednisone. Prednisone, especially when taken long term, can cause a wide range of serious side effects, including diabetes, thinning bones (osteoporosis), broken bones (osteonecrosis), high blood pressure, cataracts, glaucoma and weight gain. Doctors typically prescribe prednisone at a high dose for about the first month of treatment. Then, to reduce the risk of side effects, they gradually reduce the dose over the next several months until reaching the lowest possible dose that controls the disease. Adding azathioprine also helps you avoid prednisone side effects. Most people need to continue taking the prednisone for at least 18 to 24 months, and many remain on it for life. Although you may experience remission a few years after starting treatment, the disease often returns if the drug is discontinued.

When medications don’t halt the progress of the disease or an individual develops irreversible scarring (cirrhosis) or liver failure, the remaining option is a liver transplant. During a liver transplant the diseased liver is removed and replaced with a healthy liver from a donor. Liver transplants most often use livers from deceased organ donors. In some cases, a living-donor liver transplant can be used. During a living-donor liver transplant, you receive only a portion of a healthy liver from a living donor. Both livers begin regenerating new cells almost immediately.


Vitiligo is a disorder in which white patches of skin appear on different parts of the body. This happens because the cells that make pigment (color) in the skin are destroyed by the immune system. These cells are called melanocytes. Vitiligo can also affect the mucous membranes (such as the tissue inside the mouth and nose) and the eyes.


White patches on the skin are the main sign of vitiligo. These patches are more common in areas where the skin is exposed to the sun. The patches may be on the hands, feet, arms, face, armpits, groin, genitals and lips. Diagnosis is made via blood tests and a skin biopsy.


Treatment aims to help make the skin look more even in colour. The choice of treatment depends on the number of white patches, how widespread the patches are and personal preference.

Current treatment options for vitiligo include medical, surgical, and other treatments. Medical treatments include topical medicines (such as creams) put on the skin and oral medications with or without ultraviolet A (UVA) light treatments. Some medical interventions will aim to remove the colour from other areas so they match the white patches.

Surgical treatments include skin grafts from a person’s own tissues or tattooing small areas of skin.

Other treatments include sunscreens, cosmetics such as makeup or dye, to cover the white patches and counselling. The latter is most important – counselling services are crucial for people with Vitiligo as the change in appearance can trigger depression and other mental health issues which will inhibit quality of life.


People with Noonan Syndrome (and all the RASopathies) have a higher risk of autoimmune diseases than the general population. When someone has a genetic disease such as Noonan Syndrome it can be very easy to dismiss symptoms as ‘part of the NS journey’. As we have detailed in this Blog many of the autoimmune diseases feature symptoms commonly mentioned by people with NS (fatigue, pain, poor growth, fluid accumulation etc.). For this reason we encourage everyone with NS (and their carers) to have any of the aforementioned symptoms thoroughly assessed by the relevant health professionals. Thankfully most of the autoimmune diseases that are more common in NS can be detected with simple blood tests. We will be releasing new Clinical Management Guidelines for Noonan Syndrome this year and they will feature ANA and other autoimmune blood test recommendations at certain life stages. It is also important to remember that most autoimmune diseases can be very successfully treated once diagnosed.

Remember: ‘Be Aware, Not Alarmed’


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