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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).

References

  • Joyce S, Gordon K, Brice G, et al. The lymphatic phenotype in Noonan and Cardiofaciocutaneous syndrome. Eur J Hum Genet. 2016;24(5):690-696.
  • Dori Y, Smith C, Pinto E, Snyder K, March ME, Hakonarson H, Belasco J. Severe Lymphatic Disorder Resolved With MEK Inhibition in a Patient With Noonan Syndrome and SOS1 Mutation. Pediatrics. 2020 Dec;146(6)
Lymphatic Disorders Factsheet

Is watching and waiting the best treatment for mild Lymphoedema or is it worth using compression garments early on to prevent it getting worse?

Lymphatic problems are very common – hydrops, swelling of the feet at birth, web neck, they’re all lymphatic, so they’re all very common. I think some children with Noonans and adults may have lymphoedema and not realised that that might be the problem or even their intestinal problems. If there’s some Lymphoedema, once it starts there is the possibility of it increasing and, some centres tend to treat people at an early stage with light garments – we don’t want to make life unbearable so they should be comfortable and easy to put on and we work with the patient to try to optimise that because if they don’t like wearing it, especially a child, they won’t comply so there is an in-between round for it but we would advocate early use of compression garments. It doesn’t cure it; it doesn’t stop it progressing but it may slow down and stabilise it.

My son is eight and we’ve identified everything he has an issue with medically. I was wondering if any other medical problems can arise with Noonan’s later on in childhood or into adulthood, other than maybe delayed puberty?

A lot of these syndromes are described in childhood and we get most of the information in childhood but what we want to do is follow it through so we have answers to that question. As a general rule most of the things that we predict in childhood are carried through but we don’t see other things developing. But in some cases, lymphoedema has developed in adult life, which we didn’t predict, so I think we need to do further studies to answer that in the longer term.

Our baby was born with extreme hydrops (increased fluid around the pregnancy). The obstetrician basically did a quick “Google” search as he had no guidelines for pregnancies for Noonan Syndrome and didn’t find anything that could go wrong but we wondered if there were plans to write any guidelines?

The problem is that hydrops occurs in a lot of different conditions so the problem for the obstetrician is what the underlying cause is. They may look for a number of causes – infections for example – and Noonan Syndrome comes a long way further down the line and sometime doing the test can take some time in getting the results. Certainly, a number of labs will offer the PTFN11 test for Noonan Syndrome if they think that’s a possible diagnosis in the womb. Hydrops is due to lymphatic problems so there have been a number of examples where Noonan Syndrome cases have presented with hydrops. Hopefully there a paper will be produced on this and particularly regarding prognosis and what’s best to do in the prenatal period.