The MEN1 Mosaic

#57 - Before You Go For Genetic Testing, Listen To This (UK Consultant Clinical Geneticist)

• Lizzie Dunn • Season 2 • Episode 7

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What if your genetic test revealed something you weren't prepared for? – Season 2, Episode 7

Dr Fiona Lalloo is one of the UK’s leading Consultant Clinical Geneticists—and the first genetics expert to join me on the podcast. In this episode, Fiona explains why testing isn’t always as straightforward as we think, where private patients fall into nasty traps, and how the NHS approach to MEN1 can offer crucial long-term support.

Tune in to find out:

• The potential dangers of rushing into private genetic testing
• Why genetic counselling is NOT therapy (but many get confused)
• How gene inheritance works—and what it means for your family
• Why MEN1 is an unpredictable disease unlike many others
• How to take advantage of the NHS support you may not know exists

ABOUT OUR GUEST:
Dr Fiona Lalloo is a consultant in Cancer Genetics. She qualified from Newcastle University in 1990 and trained in adult medicine before moving into Genetics in 1994. Her MD was undertaken on the genetics of breast and ovarian cancer. She was appointed consultant in 2001. She has been involved at a national level with the recruitment of trainees into clinical genetics and is currently Chair of the Cancer Genetics Group. Dr Lalloo is involved with teaching of both undergraduates and postgraduate medicine devising, instigating and running the first national course on cancer genetics. She has maintained her research interest in breast and ovarian cancer and is the author of “Genetics for Oncologists”. Her clinical interests include breast, ovarian and bowel cancer and endocrine malignancies. She is currently Clinical Lead for Genetic Medicine.

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Disclaimer
I share my personal experience as a MEN1 patient. Nothing in this episode, including the opinions of my guests, is intended as medical or holistic advice. Please consult a qualified professional before making changes to your care.

Be very careful about what tests are being done. A lot of the private tests are really big panels of lots of different genes. What you want to look at is the MEN1 gene. They might find something in another gene that's completely unrelated that you then need to have to consider as well.  In the States anybody can ask for a genetic test, any physician, so you won't necessarily get a genetic counselor. Some of the companies will say, we've done this diagnostic test. If your family get tested by us quickly, we'll give you half price. A completely different mindset in a private healthcare setting than within the public healthcare setting.  You can give people an idea of what can be seen and what the most common features of MEN1 are, but you can't say what any individual is going to develop or when. They say, I need to know whether I've got the gene change or not. 'Cause it'll give me certainty. And I say, well, yes, but I can give you certainty about that. I can't give you certainty about what's going to happen. You need to be able to deal with that uncertainty. And that can be really difficult.

  Dr. Fiona Lalloo happens to be the first medical genetics expert I've had on this podcast so far. Fiona helps me understand what the MEN1 diagnosis will likely mean for me or my family as patients, how someone with MEN1-like symptoms should best secure themselves genetic screening or counseling, and why the UK's NHS is so well set up to support patients through the diagnosis process, unlike other systems worldwide. Let's dive back in.

Fiona, can you explain to those of us listening what's your role in the diagnosis process? How are you involved?

Two ways we get involved. So the first one is being asked to give an opinion on someone who's got clinical features. So we will be referred patients by endocrinologists or surgeons just to say they've got a clinical suspicion. This might be MEN1. And then we'll be asked to review the patient, look at the clinical features, get the appropriate information, decide whether we think that is likely clinical diagnosis, and then we'll organize the genetic testing, and get back to the patient once we've got the results. The other way of diagnosing or seeing patients is the same scenario you found yourself in. It's a family where there's known to be MEN1 in relatives and then we already know the gene change in the MEN1 gene and we can offer that as a test to unaffected relatives to make sure they get into the appropriate screening that they need.

It sounds to me when I hear from patients who come via the clinical route of diagnosis, it can be quite stressful to actually get the diagnosis in the first place because there are some very specific symptoms, but sometimes they're not, sometimes they're mistaken for other conditions. If a patient is suspicious of MEN1 but doesn't necessarily have the genetic variation in their family. I understand It's very difficult going through the GP route 'cause the GP isn't necessarily  familiar with MEN1. How is it in your experience that it's most successful for a patient to get to see someone like you if they don't have the genetic variant, but they're suspicious of the mutation?

So if they think they have clinical features of MEN1, then they need to see their GP as a first port of call 'cause that's what everybody should do with clinical symptoms. And if the GP is then concerned about some endocrine abnormalities, they'll refer them to see an endocrinologist for further investigation. And if that collection of features, when the endocrinologist sees them is suggestive of MEN1 then they'll refer into the genetic service. Sometimes, the endocrinologist will do the genetic tests themselves, and then refer the patient in once a clinical diagnosis with a confirmed genetic status has been made into the genetic services. But certainly if anybody's got any features that that they think are due to an endocrine basis, they need to be seen by an endocrinologist. So they should see their GP first.

I think I've heard from many patients who get stuck at the step before that process, if that makes sense. They're struggling to get to see the endocrinologist. I know it can be quite, quite a stressful situation for a lot of different people.

I think the initial diagnosis is often quite difficult because, pituitary lesions are pretty common and so if you ever seen by an endocrinologist suit and you've got pituitary lesion, it's not until you develop another feature that people would think about MEN1 because actually MEN1 is really not common. But the other features in isolation are pretty common. High calcium levels are common feature within the general population.

I didn't know that for a very long time. It was only until I started being contacted by patients who didn't have MEN1, but they had similar symptoms, might have been hyperparathyroidism, and they were going in for surgery, they listened to the podcast, for example. They listened to Professor Fausto [Palazzo] speaking and they said, I'm not MEN1, but this is what I'm experiencing. It's a very interesting condition. I've always loved it because to able say to a medic, oh, I have MEN1, it's not quite like saying, oh, I have diabetes, or I have heart disease. It's quite curious. it evokes a lot of interest. That happens in endocrinology anyway. I'm sure it happens under genetics as well. Maybe it's just a little bit more of the slightly less common and therefore more exciting perhaps is a way of looking at it.

It's not that uncommon if you're a geneticist 'cause actually we end up seeing most patients who've got MEN1, they come through genetic services at some point in their lives.

It made me want to ask, at what point does the geneticist leave the process and do they leave the process entirely and shift over to endocrinology, or is there always a kind of point of contact?

So I think it depends on which service you in. Each service runs things slightly differently. In Manchester, we will see patients to make that initial diagnosis and then do the sort of family testing. But when someone has a genetic diagnosis, we will then refer them to endocrinologist for long term surveillance. If it's a child, we will then we will talk to them around the time of transition and when they're getting into the adult services, we would also try and talk to them in their late teens, early twenties, when they're thinking about family planning and say, come and talk to us when you're thinking about family planning. So there'll be touch points through an individual's life, but we don't see them on a regular basis.

The other component I wanted to talk to you about was genetic counseling, which I am not hugely familiar with myself. I didn't have genetic counseling. I can't say I wasn't offered it. I was quite young and I just don't remember. Is this something that is offered to all patients and how does the process work? Do patients need to seek it out themselves?

Genetic counseling happens in a genetic service. Whether you're seeing a clinical geneticist or a genetic counselor, you'll go through the counseling process. It's not like therapeutic counselling. It's completely different. What will happen is you will have, probably when you were a child, you will have seen a genetic counselor or a clinical geneticist to do the genetic test. But most children, when you are eight or 10, you can talk to a child about what's gonna happen, but you clearly can't have those in-depth consultations. But we need to do the genetic at that point in order to make sure that children get into the screening programs when necessary. What we would then aim to do is try and see that child when they're sort of 18, 19 to go through the condition again with them as a geneticist so they understand what the concept of MEN1 is and what the potential problems are, but also then to talk to them about what their options would be if they're getting to the stage where they're thinking about family planning, or just remind them that we're there in case of thinking about family planning. So it's those discussions and it's all the discussions around your options around reproduction is where you would then end up seeing a genetics professional, whether that's clinical geneticist or genetic counselor.

Right, so you've just said something, which is quite new to me, and that's that genetic counseling differs completely from therapeutic counseling. I think maybe I was just conflating the two. Is genetic counseling that process of understanding the process better of being a patient. It's not necessarily the emotional support that we might get from therapeutic counseling.

 So it is a emotional support but you don't do six weeks of counselling like you would do for some therapeutic sessions. The aim of genetic counseling is to make sure that the patient you're seeing, irrespective of what the genetic condition is, aware of what the condition is and informed about, is supported to come to terms with the diagnosis, if they are struggling with that, you will then have a number of sessions to try and help them understand it, but then also help them understand the wider implications in terms of themselves, but other family members.

Right I'm smiling 'cause it's like, oh my goodness me, how long I've been running this podcast and doing what I do. Somethings still stay new to me. So thank you very much for sharing that and for explaining the difference. I think that's gonna be quite useful for people listening back because it's not necessarily always clear coming into the process, into the diagnosis of what's involved, what's included. You mentioned family planning. I guess for someone who's listening back who's maybe newly diagnosed and not quite sure how MEN1 might look in the future for them or their family, can you take us a little bit through just very simply how that process works? Family planning?

It entirely depends on the age at which you've diagnosed it. So actually if you're a known family, you'd be diagnosing MEN in a child. So you know that the initial discussions you have with a child about doing a blood test to see whether they've got a condition, which means we need to look after them long term. They're currently well, and we want them to stay that way. So that's the sort of level of conversation you have with a 10-year-old. By the time you get to see an 18-year-old, you're just talking about what MEN is, what the inheritance is, how it's autosomal dominant. If they have children, the child will have a one in two or 50% chance of inheriting that condition from them but then there will be options. And then usually, depending on where they are in their life and relationships, they'll either want to get more information or they'll just smile and say, yeah, I'm off to university. And then we will say, but you need to come back and see us when you are in a relationship. Come back and see us when you've got a partner, 'cause we can explain to your partner what MEN1 is and what the risks are to your children. And then once you see the individual or the couple again, you then go through what their options are in terms of choosing to have a pregnancy and testing a child at 10, choosing to have a pregnancyand thinking about prenatal diagnosis, choosing to go through preimplantation genetic testing. So there are a number of different options But when an individual's thinking about that, they should be seen by a genetic counselor who will talk to them about what's available, what their options are, and then we'll guide them through their process if they've decided that's what they wanna do.

You mentioned there MEN1 being an autosomal dominant disease and there being 50% chance of any child inheriting the gene mutation. If someone inherits a gene mutation, are they then guaranteed to present with symptoms? Or do we not really know? Or is there a way of telling that someone's gonna necessarily become unwell?

It's very variable between families and within families, so you don't necessarily get what your parent had. But the stats would be that most people who have MEN1 will develop problems with their calcium levels. If you look at the data, it's something like 40% of people have a problem by the time they're 20, about 95% by the time they're 40. So you would expect people to go on to develop problems, but trying to predict, and that's one of the difficulties about counseling is actually, it's not a very predictable condition. You can give people an idea of what can be seen and what the most common features of MEN1 are, but you can't say what any individual is going to develop, or when. So whilst you can say you've definitely got MEN1, we can't say you're going to develop hypercalcemia by the age of X, or you are definitely going to have a pituitary lesion, which is going to produce prolactin, for example. You can say that on average, most people, if you have a pituitary lesion, the most likely thing you get is a prolactinoma. If you have a pancreatic lesion, one of the most common ones is a gastrinoma and you therefore have problems with stomach ulcers. So you can give ideas of what the problems are, and you can give ideas of what the likelihood of developing more, but you can't say to someone, well, you are definitely gonna develop it because it's a really variable condition and we don't understand that variability.

I feel like that's such an important point you've just made because it is variable, as you say, and it's unpredictable, and yet I think as human beings, we love certainty and we love predictability, so I think it's massively difficult for patients to manage because we want to be given black and white answers. I know, in my experience anyway, I've just wanted the the practitioner, whomever it might be, to make the decision for me 'cause I'm thinking, oh my goodness me, it's so much responsibility and I just don't know and I want to be absolutely certain. How do you help patients in that case, if you're involved, at those stages in terms of navigating uncertainty with something that really is unpredictable, MEN1.

I think navigating is really difficult, so certainly. In my experience, when you end up counseling slightly older adults, they say, well, I want to know for sure 'cause it'll give me certainty. I need to know whether I've got the gene change or not. And I say, well, yes, but I can give you certainty about that. I can't give you certainty about what's going to happen. And you need to be able to deal with that uncertainty. And that's like anxiety every time you go and get all your bloods done as to whether anything's gonna happen or not. I think the only certainty is you will go into a screening program. The aim of that screening program is to make sure that if anything's going wrong, we pick it up at an early enough stage that we can deal with it. But I think everybody manages uncertainty in different ways, and that's one of the roles of the genetic counselor come in. If you've got people who are really struggling with a diagnosis, we can ask them to be seen. We also have had patients who we then signpost to psychological support and therapeutic counseling to manage their anxiety around all of that. It's really difficult.

It is very difficult and you mention a word anxiety, which is, profuse among MEN1 patients anyway and I'm sure to be honest, any patient managing health or illness. I know that there is through the genetic testing process, it can sometimes feel slow and a lot of patients say, well, would it be quicker if I went privately, for example, if that's accessible to them. I wanted to ask you, in your capacity, do you think that's necessarily a good idea? Do you think that there are benefits to going private or do you think the NHS is the better route?

For genetic testing, doing predictive testing, so if you know the mutation is in the family, I don't think there's any point in going privately. You might as well and see a genetic service 'cause you'll see a genetic counselor and you'll get the ongoing support whereas if you go and do the private testing, if you've got the gene change, you won't get the ongoing support without individual unit referred into an NHS service anyway. So I would think if you're doing predictive testing, certainly I would suggest that you go into the NHS service in most places, even if they've got really long waiting lists because they prioritize patients for predictive genetic testing. The private diagnostic testing, again, I think it's a little bit more tricky. It depends on who you're seeing. If you're going to see someone privately, needs to be someone who understands the genetics and is someone who ideally understands the genetics of MEN1 as opposed to someone who does different genetics. I would also be very careful about what tests are being done. A lot of the private tests are really big panels of lots of different genes. Well, actually what you want to look at is the MEN1. gene Or the hypercalcemia genes, if that's what you're being investigated for. Whereas if you have a big panel, they might find something in another gene that's completely unrelated that you then need to have to consider as well. And that can be really difficult.

It is interesting talking to you about this because. I think in the moment, to a lot of people, they want to get genetic screening done for themselves or for children. It might seem like a long wait. It's very nerve wracking and I think sometimes the private option, because it's quicker, can be quicker, that it just seems like the best response, or put it this way, it's probably a knee jerk response and not necessarily the best moving forwards. I think MEN1 is very much a long term game. This is not a short term thing and yes, if private genetic testing is accessible, I can so understand why patients want to do it. And if they choose to do it, then that's their choice. But for example. I had no idea about what you've just explained about the gene panel. You're gonna be potentially tested for so much more and you know you're gonna find out things and maybe things that you wouldn't have found out otherwise or weren't necessarily problematic in the first place, and then they become a problem. So what wasn't a problem is now a problem, and we're not even talking about MEN1 anymore. So it's a really valid point you've just made and I'm very grateful that we've touched on this definitely.

I think the other thing is that the system in the NHS is very different than other systems in the world. So if you go elsewhere, you get very different approaches to genetic testing. The advantage of being in the NHS is that if I see your father, for example, and you rock up in a clinic in Exeter, then I can quite easily transfer that information through our network, that they need to do the test in Exeter. Whereas if you're in the private system, it becomes a little bit more difficult in terms trying to access the control samples and the test reports that you need. It can be done, but logistically it's just harder.

The NHS is brilliant for so many different things, and I know I've had to really remind myself that when you're reading headlines in the news about this, that, and the other. I think there are so many benefits to the system that we have and some things that really work and when they work, they work well. You talk about systems that they have in other countries. There are some US patients actually in this community and the country so huge. They have to travel so far, and I think a lot of them end up feeling like they have to settle just because of distance. They have to settle for lesser quality of care somehow. There's a sort of rush to get through the process or they take the first available option. Obviously you are UK based, but if you were looking in on this situation in the US where it's a very different system, what would be your advice to patients who don't have this kind of structural support that's already existing in the UK that we have under the NHS?

I think it's very difficult. I think if you're gonna have a genetic test in the states, go and see a genetic counselor in the States because anybody can ask for a genetic test, any physician, so you won't necessarily get a genetic counselor for a lot of testing. So I think you should do that. I think the whole healthcare costs and insurance are so different that the system is so different. So for example, we would be much more, in terms of predictive testing, we take it much more slowly, we'll talk to patients about it. Whereas in the States, some of the companies will say, well, we've done this diagnostic test. If your family get tested by us quickly, we'll give you half price. So there's none of this let's discuss whether these people want it, whether, let's discuss what your views about it are, it's, you know, get it done quickly 'cause it's cheaper. A completely different mindset if you're working in a private healthcare setting than within the public healthcare setting, I think.

Wow. See, I had no idea about this and I'm grateful again that you've shared it. The people listening about to this podcast, if they're MEN1 patients are likely to have already gone through the genetic screening process, so this may or may not be relevant to them, but for their children, for example, most of MEN1 patients I talk to are more bothered about their children's experience with MEN1 than their own, and I can completely understand that. I'm not a parent, but I can understand exactly why that is, and I think it's so important to have guidance as you've given it. That's incredibly helpful.

 I had a question about the MEN1 gene mutation, and just for people like me who are a bit nerdy and want to know all the details about everything, how does the gene mutate and how does the mutation behave? What is it about the mutation that then provokes symptoms in a patient?

I'm not an expert on molecular biology, so I can't tell you that. We've all got gene mutations at the point of conception. DNA replication doesn't work properly. If you looked at anyone's genome, they've got hundreds of genetic variants. That's why what would account for de novo mutations, which you see, but they're not very common. Once you've got an individual who's got an a de novo mutation, then clearly their children are at risk. But de novo mutations happen in all genes at the point of conception. It's just whether it's an important gene or whether it's a dominant gene or not that makes a difference.

Right. This is fascinating for me. So MEN1, the genetic mutation, how does that differ to genetic predisposition to a certain condition? They talk a lot about being genetically predisposed to Alzheimer's.

So there are conditions where you have a clear Mendelian inheritance. So that will be things like MEN1 or the breast cancer predisposition genes. So those are genes where you can predict to a degree that someone who's inherited that gene change or has a genetic variant will develop some form of disease. Now, the likelihood is often variable. And that's what we've talked about in terms of Not everyone will develop every problem. So repenetrance of each condition is different. That's different to people who have almost like you have an increased risk, but it's not a particularly high increased risk if you have certain, gene variant. So if you've got ApoE you have a slightly increased risk of developing Alzheimer's, so there's different levels of variation. For example, if you look at breast cancer, you can see that some people have a very clear Mendelian inheritance. But some people, if you take a whole load of different variants within different genes, if you get the adverse allele for all of them, then you increase your risk. Then that's almost like polygenic risk score. It's an increased risk, which is confirmed by lots of different gene changes, but that are not necessarily inherited as a block from each person. So the sort of genetic preposition is we can say someone's at increased risk and you can get that information from a family history as much as genetic testing. But then there are some families where there's clear mendelian inheritance. You know exactly what the risks of inheriting that gene trait are.

I've never heard this expression before. Mendelian inheritance. So that's something new to me.

Dominant autosomal recessive. So Gregor Mendel.

So would that apply, for example, to a condition like cystic fibrosis or Huntington's.

Yes. So they're all clear cut. But then you've got people who know there's a lot of the autoimmune disorders, you've got an increased risk because there's autoimmune things in the family, and so you probably have an increased risk, but actually there's nothing very clear cut in most cases.

Ah, now, this is really interesting. Autoimmune. I'm glad you mentioned that, just because I think it's something that a lot of patients will be potentially suffering with alongside MEN1. Autoimmune seems to be all over the place, linked to the immune system. And I've always wondered how that differs to these more strictly genetic, I guess, disorders that we've just mentioned.

 On the subject of genetics, why not stay here? Does epigenetics play a part at all in MEN1? If that's something that you know?

I don't know the literature on that. There is likely to be some impact on why some people will develop one thing and not the other. Epigenetics often is involved in variability, but I don't know the literature on that.

Fiona, is there anything else that you want to talk about or think would be good to mention just while we're here?

I think the only thing that is worth people remembering is that the genetic services are there. If you've been seen by a geneticist in the past and you've got any questions, particularly when you're thinking about family planning or you've got children who haven't been tested and are the age at which they should be tested, then actually you should be reaching out to that genetic service just saying, I'd like another appointment. I need to come back and talk about it. That's what we're here for, that we're here to offer support to families, and make sure people get the testing that they need at the appropriate time.

Thank you for sharing that. I think that'll be really useful to hear. It's sometimes it's easy to see doors closing and then closed in healthcare. In the grand scale of my MEN1 experience so far, genetics has honestly accounted for about this much, but then it's so vital because without it, we might not know a lot of the cases that we do. It's very exciting to have, as I say, have my first geneticist guest and to have started down a conversation, which I hope will give any listeners a bit of inspiration or some wisdom that they might not have got elsewhere.  I think it's left only for me to say, Fiona, a huge thank you for sparing your time so generously and I look forward to potentially having you back on at some point in the future if it's something that you'd be willing to do.

 I thought I knew a lot about the MEN1 diagnosis, but this episode with Fiona has opened my eyes to a whole lot more. You can find out more about our wonderful guest in the description box below, and if you're an MEN1 patient after more empowering conversations like the one you've just listened to, click the Join my Community link so you never miss a new episode.