I am a SENCo at a primary school and we have a child in year 5 with Noonan’s Syndrome. I was wondering if you could provide me with support or advice on how best to educate her on what to expect in puberty and teenage years?

We aren’t aware of any specially adapted resources in primary school in preparing for puberty (only the standard resources given to all children). In preparing for secondary school, if she has learning difficulties and/or autism and you feel she needs a more simplified version of puberty education, her mum could ask for this at the EHCP annual review and the school should be able to provide it. There are also sexual health charities who can support, such as Dhiverse, who have a programme for children (aged 11+) with learning difficulties or autism called ABC: https://www.dhiverse.org.uk/our-services/learning-disabilities-difficulties/. They produce a free booklet and a leaflet which is more simplistic with pictures and they run a workshop programme. You would need to search online to find something similar in your area. Mencap also produce a guide (Sexuality and Relationships Resources) which contains information and links that might be useful.
Girls with Noonan’s Syndrome tend to have delayed puberty and start their periods later. This is less so if they’re taking growth hormones, but even with those they will start their periods later than their peers, which could potentially cause stress if she doesn’t realise beforehand that this will most likely be the case. NS girls also tend to have heavy periods because of problems with blood clotting. There are options to deal with this that her mother could discuss with her GP if it causes issues with her school attendance and/or participation in activities.

My son’s paediatrician has suggested we get a WISC test for him. Please can you let me know if you have any recommendations for this.

The WISC test (Wescher Intelligence Scale for Children) is an intelligence test for children which generates an IQ score for the child. This is done by a clinical psychologist and can be used in evidence towards the Educational Health & Care Plan (EHCP) at school. Any consultant the child is seeing can make the referral, or the school might be able to organise an educational psychologist to do it. Our understanding is that it is best done in conjunction with other tests.

I need a bit of help as I have been tasked with writing a risk assessment and revised job description for a female employee with Noonan Syndrome working in a residential care home as a waitress. Is there anything specific I should include/ask that wouldn’t be apparent to someone unfamiliar with the condition?

Noonan Syndrome presents in different ways for different people, so risk assessing would need to be done on an individual basis. Talk to the employee to find out if there are any additional risks or requirements such as mobility issues and/or difficulties with fine motor control, which could present specific needs around lifting/carrying, or learning difficulties which might impact on how well the employee can understand instructions, express concerns, or ask questions of their employer. Many adults with NS have very few issues that would need additional risk assessment or changes to a job description.
There are charities that offer support—search online for ‘supported employment services’ to find organisations in your area who specifically work as a bridge between employer and employee, to support both parties where the employee has a long-term health condition or physical or learning disabilities. They will have lots of advice and information that you could find helpful, and they may also be able to step in and support this staff member during her employment too.

Is there an explanation for the muscle fatigue and the aches and pains post-exercise that seem to be associated with Noonan’s?

This is something that occurs across the whole Rasopathy pathway and it’s been very slow to come to the forefront of the medical community but it is the subject of ongoing research. People wonder if there’s intrinsic differences in the muscle and in the meeting we’re having in Milan in June there’s quite a big section on energy metabolism and muscle issues so I think we will get some understanding of it but all we can say now is that it’s real but we don’t yet understand the actual physiological basis for it. From the point of view of Neurofibromatosis Type 1 that is obviously different to Noonan Syndrome but another disorder of the Ras MAPK Pathway, we have a pilot study that’s just starting in Manchester about fatigue and we did a scoping exercise with a Google-based questionnaire and had a fantastic response very quickly. That’s been catalytic to us having an observational study of fatigue piloting an intervention about things that might improve muscle stamina in due course in a group of people who have NF1. If that’s successful it could have implications for other disorders of the pathway.

My son has mild scoliosis. Are there implications later in life regarding skeletal/muscular complications?

Generally speaking mild scoliosis will not cause any major problems but it may get worse if there is rapid growth at puberty. It is worth following up to puberty, but it is not usually progressive in Noonan syndrome.

I suffer from leg pains at night and I know it has been mentioned that vitamin D deficiency could be associated with this. Is there any more evidence that this is correct? Is it advisable to supplement vitamin D? What are the other possible treatments, for example massage or Calpol?

Low vitamin D levels are very common in the UK mainly because you need to spend at least 8 hours a day out in bright sunshine in order to have adequate vitamin D levels. Vitamin D levels are even lower as you go north, to Sweden and places like that. So, if your child is under the age of 5, they should really be taking some sort of vitamin supplement if they’re fussy and not eating well. Leg pains are very common in childhood so what I always recommend is that you go and try just going onto normal vitamin supplements. If leg pains persist, particularly if leg bones start looking bowed or bent, that sort of thing, then it’s worth getting Vitamin D levels checked. But your vitamin D levels really have to be quite low to get a high dose of vitamin D to bring them up again – it’s better in childhood to make sure you take your childhood vitamins. And then the other thing is to try to spend some time outside and then have a diet that’s got plenty of vitamin D in it – things like eggs, fish, vegetables – all those things that children like eating!

Our son gets leg and foot pain in bed, which is relieved by Calpol and hot water bottles. Could this be connected to problems in the lymphatics?

Lymphoedema is not usually painful – you may get a bit of discomfort particularly if you’re on your feet all the time, but as a general rule it’s not going to cause pain so if there’s no swelling, it’s just pain so I don’t think so. We do get quite a number of children who seem to get joint pains in the teenage years and we’ve often puzzled about that. There are various theories but it doesn’t seem to be progressive and damaging arthritis and it does seem to improve with time and to be resolved with local treatments and with things like Calpol and paracetamol. At the American meeting in Seattle in July, support groups – CFC, Costello, NS – made presentations and all raised this issue of pain so I think it’s very common across the pathway and I think it’s very poorly understood but an American research group has recently got a small amount of funding to start looking at it.

Our 4-year-old son has pains in his legs and arms, and can wake up screaming in the night because of this—but the medical response was that they were just ‘growing pains’. Is this the case?

This was a fairly common issue, especially in adolescence when there could be a lot of muscle and joint pain. A small study in the past didn’t show that there was any underlying problem which would cause long term damage. In most cases, the symptoms respond to normal analgesics such as Calpol or paracetamol or sometimes even a physical thing like a hot water bottle eases the local pain. It does tend to get better with time. It’s a question which needs more research but at the moment the specific cause can’t be pinpointed. There is a suggestion that many people with the condition are vitamin D deficient although in at least one case, treating this didn’t seem to alleviate the problem.

Just out of the blue, a few days ago, our 5-year-old grandson had what we thought was a seizure. He had three or four on that day. He’s been booked in for an EEG as they are suspecting epilepsy. Because he has Noonan Syndrome, are there any other possible causes for the seizures? Is it different to the general population? Should we be considering other causes?

We certainly have seen a slight increase in seizures with Noonan Syndrome. They don’t seem to have a particularly different pattern from some of the other epilepsy we have but maybe we could have some general points about how we diagnose and treat epilepsy. It is important to note that sometimes it can be difficult to distinguish a seizure from a fainting episode that’s caused by an abnormal heart rhythm. It’s unlikely to be that but a heart rhythm abnormality is one of the things that need to be thought about and having an ECG should be part of the investigation. The ECG would look at the electrical activity in the heart, the EEG is looking at the electrical activity in the brain in an identical manner and seeing if there are any sporadic intermittent changes that we would associate with the seizure activity.

Sometimes we need a prolonged EEG to pick up those episodes and if he’s only just presented, perhaps with a little cluster of these funny episodes, it’s not unusual that perhaps we miss them with an isolated EEG. It’s useful if we can capture the clinical episode with the electrical changes that we see. Sometimes imaging of the brain will be helpful as well as there are some different brain structures that can contribute to epileptical activity.

There are lots of things that being under a general paediatrician with an interest in neurology or a paediatric neurologist would be very helpful from that point of view. They would need to look at what the movements are like, how they present; there’s a lot of information they can pick up from that as well. Structural, electrical, all need to be looked at but don’t forget other causes for the fits, faints and funny turns, as we call them. One of the things that we found useful, and it doesn’t sound a very pleasant thing to have to do, but OK if you do it in the privacy of your own home, was to take a short film of what was happening because an experienced epilepsy consultant can tell a lot from that. So if the circumstances allow and the person is being looked after well, if someone else can take a film on their phone, that can be very valuable to an epilepsy consultant.

Our daughter suffers from spontaneous chylothorax as well as pulmonary stenosis and ASD. She’s had open heart surgery, which was very successful. I was wondering if in the medical world there is any more research being done on whether there is any connection to the chylothorax issues within her lungs to cardiac issues, or if they are totally separate situations?

There’s certainly association with chylothorax and cardiac surgery with individuals who have had open heart surgery who then develop chylothorax. We also know there is an increased prevalence of lymphatic problems in Noonan Syndrome. There is a lot of research going on in terms of the work Sahar is doing and the fact that we can now image lymphatics in a better way. We’ve talked about Noonan’s having some implications for growth and potentially over-growth, over-thickening of vessels. There’s a possibility that certain situations lead to over-growth of lymphatic vessels which then don’t do their job very well. There’s an excellent link now with Philadelphia with Professor Max Itkin who is an expert in interventional radiology to actually get a picture of the whole lymphatics of the body, not just the lower part of the body and then ways to intervene in certain circumstances.

I understand that hydrops is quite common in Noonan’s children. Our daughter’s 5 and had hydrops when I was pregnant. I just wondered if there’s a high chance of those that did suffer with hydrops of developing lymphoedema problems later in life?

We’ve only seen about 15 people with Noonan’s and lymphoedema and some of those had hydrops but not all – and then I’ve seen many children with hydrops who haven’t developed lymphoedema so there’s no clear correlation at the moment.

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.

How open are doctors now to screening embryos for something like Noonan’s?

This is very much a question of personal choice. The GP can talk through the options with the person. The normal test is 9 or 10 weeks into pregnancy but even though it can indicate the gene is there it can’t always tell how severe the Noonan’s is going to be, and even in multi-generational cases, there may be differences between one generation and another. This needs to discussed sympathetically by the GP with the person in question.

What research is going on for adults aged over 30 with Noonan Syndrome, and where can they get help and advice?

A study with a cohort of families started in 1985 and most of them are now young adults in their twenties. Hopefully the group can continue to be followed up so that we’ll really know what’s happening later in life. There was also a collaborative effort across Europe to try to understand the natural history of the cardiac complications of Noonan Syndrome. Also, clinically, there are a number of specialised centres for example cardiomyopathy expert centres in the UK, which have a lot of experience of looking after adults with Noonan Syndrome-related congenital heart disease. It is important to remember however that Noonan Syndrome was not progressive. There could be complications later in life but many people remain in good health with no further problems.

With the advent of cell and gene therapies that’s started to emerge—we see more and more about that on the media—is there any prospect for genetic disorders to be treated per se rather than treatments being focused on the ailments that result from the syndromes themselves?

There is some interest in whether certain classes of mutation might be amenable to treatments that might modify the expression of the abnormal gene, but I think we really are a long way from gene-based therapy in developmental disorders because the diagnosis isn’t made until many of the manifestations are present so I think in the short term we are looking at treatments that might be directed at manifestations of the condition. I spoke to a professor who was interested in gene therapy and he looked into Noonan’s and because it’s very heterogeneous and he’s not completely understanding what the proteins are doing so he’s not really sure what kind of gene therapies are doing and he’s also – if you look at NS it’s not really deadly – it’s not that severe so they’re first of all looking for gene therapies that are very deadly at a young age so probably it will be in the future but as I understand now at the moment it is not a focus of interest.

One possible exception is the Novartis Study which is looking at targeting in particular proteins within the pathway and I think it’s still very early days but it’s possible for these sorts of drugs might potentially halt the progression of the thickening of the muscle in the heart and potentially in some cases may even reverse it. There’s animal data on this and some anecdotal reports of these drugs being used in children with disorders of the RAS pathway so it’s possible there might be some progress – it’s not gene therapy as such but it’s gene guided therapy that might improve some of the features we see in the heart but I think we’re still some way from this being seen as a routine treatment.
Because this is a pathway which is so important in cancer – this pathway was first recognised in 1982 and there’s been tremendous work done on modifiers of this pathway but the difficulties when you realise changes in this gene causes developmental disorders is that the side effect profile of what you would accept with someone with cancer is completely different to the side effect profile of someone – a child – with developmental disorder. We’re still very much at the stage of understanding the inter-relationships of the pathway and there’s a lot to be learned about just how it functions in the cell normally but then of course you have on top of that, mutational genes but people are very positive about this group of disorders that there will be treatments and the work that’s going on is directed at that but it’s just that it’s going to take some time.

My daughter’s mutation is MAP2k1. Quite often, when I see pictures of the pathway, that only comes under CFC Syndrome and Noonan’s isn’t mentioned on that mutation—I just wondered why?

There is a definite overlap between Noonan Syndrome and CFC Syndrome and where the lines are drawn is not clear at all. Often, it’s relatively historical about in which group of patients the gene changes were identified first, and so for MAP2k1, that was one of the original genes described as being a cause of CFC Syndrome and that then got its label as a CFC gene. As testing has been extended, there are more and more people with what looks clinically like a Noonan Syndrome phenotype who pop up as having a change in a previously CFC described gene. There has always been a few people known to have MAP2k1 gene changes in a fairly mild phenotype and they are in the literature here and there, and this degree of overlap is sufficient such that the way some labs now report their testing is “This result is consistent with a Rasopathy” which is fine as long as all of you guys who have Noonan Syndrome as part of your family know that Noonan Syndrome is the archetypical Rasopathy. We’ve had issues where paediatricians have sent for genetic testing and the result says “consistent with a Rasopathy” but the paediatrician nor the family have never heard of a Rasopathy and things become very difficult until we’ve been able to catch up with them and explain that it all makes sense. So, there are people with mild patterns of difference who have MAP2k1 mutations that were more characteristically described in people with a more severe CFC phenotype. The dilemma is do you define diagnosis by the gene or do you define it by the clinical features? I think probably we’re defining it by the clinical features first and then looking at the gene, but it’s an ongoing discussion. The best known and most widely used diagnostic criteria for Noonan Syndrome were done nearly 20 years ago before we had much gene testing at all. At the meeting in Milan we’re having a session on what should be the diagnostic criteria for Noonan Syndrome. Originally it was about the face, your stature, and whether or not you had congenital heart disease or a relative affected. I think they’ll be very different now and they will somehow have to incorporate a gene change.

We have a son in his 30s who has NS and was born profoundly deaf. Has there been any recent research into connection between the two?

Noonan syndrome with multiple lentignes or freckles (previously known as LEOPARD syndrome) has deafness as a feature and so we know that deafness may be associated with the PTPN11 gene. In most cases deafness in Noonan syndrome will simply be due to glue ear but it may be due to nerve deafness. There has not been much research on the nerve deafness in Noonan syndrome.

If a child was tested in the past when they couldn’t identify the gene, should she be retested? If so, and the child isn’t seeing a paediatrician, should this be arranged through the GP or direct with the genetic centre?

The number of genes identified keeps increasing so if tests were done some years ago it could be more specific results from a new test would be helpful. Paediatricians should be able to do the tests but, in this case,, the approach should be through her GP because that was the usual way it was organised in the Health Service and the GP can make a direct referral. To the regional genetic centres.

Have you found patients with more than one mutation on the RAS pathway?

Yes. But sometimes we only look for one gene like PTPN11; we weren’t systematically looking at all but now we run a panel of maybe 10 or 12 genes and we occasionally find one that’s got more than one gene fault. It is possible for example to have a child with both the Noonan gene and another genetic condition causing short stature. It’s going to happen by chance occasionally but probably relatively rarely but with increasingly accurate testing, there will be more identified. It does seem to be a chance event rather than any biological principle underlying it.

We’ve got three kids, all grown up now, but we also have a grandson who’s been diagnosed with Noonan’s. My youngest daughter is one of the 30% for whom they don’t know what caused the Noonan’s, but our grandson, her nephew, is under the 3D scheme being run by Cambridge University. The geneticist at Middlesborough who saw my daughter is waiting for the results of the 3D study to see whether there’s any links. How do we make sure all these studies are linked together and the results are correlated and we get the best benefit out of them?

The 3D Study was set up to look at 12,000 children that was later extended to adults across the UK who display intellectual disability. Enrolment has been really through genetic services. The study only stopped recruiting in April 2015 and it was a actually a much bigger task than people thought it was going to be to just deal with the sheer volume of samples in terms of new technology so the first few years – it lasted 5 years – were actually very much about getting the actual experimental processes to work. And we really only started to get a lot of results in the last 12 months. As part of that process, people can express an interest in research into particular genes and our intention is to take forward the rasopathy genes and to look at those patients who were identified through the 3D study as having one rasopathy disorder which would most commonly be Noonan Syndrome to see what we can learn because they would presumably be people who are less typical. We’ve already seen some people in Manchester through 3D and other studies who have been found to have Noonan Syndrome.

How common is profound deafness with PTPN11 mutation? Through the Genome1000 project the connexion 26 gene mutation was also picked up in my son, of which I am a carrier of the same gene but not my husband. Which gene is more likely to have caused my son to be born profoundly deaf in addition to all the other typical PTPN11 traits?

Connexin 26 should only cause deafness if the child has a double dose of the abnormal gene and therefore it is unlikely to be due to the connexin 26 in your son. Deafness does occur in Noonan syndrome especially when associated with multiple freckles or lentigines, but we still do not know why deafness only affects a few children with Noonan /PTPN11. In theory it may be when PTPN11 interacts with other genes but I have not seen any evidence to support this, so I think the connexin 26 is coincidental.

Hi, my child is 5 years old with a PTPN11 mutation. He has normal igf-1 growth factor. How effective and safe will growth hormone be for him? He has a short stature at 0.4 centile.

Growth hormone is now widely used in Noonan Syndrome, but it is best to have this managed by a paediatric endocrinologist.

When it doesn’t run in a family, is there any understanding of when the mutation occurs? Is it always pre-fertilisation or is there evidence that it can happen during development and then you get mosaicism?

Mosaicism has been recorded for RAS-MAPK pathway disorders but it is thought to be exceptionally rare, and where there is an enrichment for the spontaneous mutation is in the spermatogenesis where sperm are turning over all the time, there’s lots of cell division, there’s lots of DNA copying that needs to happen and therefore there’s a much greater chance that it happens in the sperm generation as opposed to the eggs that just sit there and don’t have to do lots of dividing. So, the evidence is that over 90% of new mutations will be of sperm origin. There are also emerging studies on older fathers whose sperm generating cells have had more cell divisions having a higher chance in actuarial terms, going from one in an extremely large number to one in a slightly less extremely large number as the decades pass. There is a study that’s just staring in Oxford looking at the origin of mutations which might be relevant in the future to understand that further.

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.