Growth Hormone Deficiency Learning Zone
Transcript: Diagnosis and management in children
Professor Mehul Dattani, Dr. Charlotte Höybye, Professor Steven Simoens, Dr. Shankar Kanumakala and Dr. Robert Murray
Interview recorded Jul 2023. All transcripts are created from interview footage and directly reflect the content of the interview at the time. The content is that of the speaker and is not adjusted by Medthority.
So, maybe we should now think about moving on to the next presentation. Over to you, Rob. So, yeah. Okay, thank you, Mehul for the introduction. So, we're going to talk a little bit about growth hormone deficiency diagnosis in children and management. It's really an overview so that we can start discussions in it. So, disclosures. And I suppose the first thing is when we'd like to consider investigations for GHD and these really come from the time of the GRS meeting which was back in 1999, and seem to have been followed through ever since that time. They do seem quite marked in some of the degrees of growth hormone deficiency before they recommend it investigation. So, for height, itself being less than three standard deviations below the mean, it's obviously quite a long way down from what you'd expect or better though is if we've got a mid-parental height and less than 1.5 SDs below mid-parental height, but rather than height, height velocity seems a much better marker. But obviously, we need prospective data there to follow people and look at how fast they're growing really to get a better idea.
But seems to be a more accurate way of assessing growth auxologically. So, in that they recommend less than two standard deviations below the mean over one year or over two years less than 1.5 standard deviations. So, it's, it is quite a bit of follow up to really hit those height-velocity targets. Other things that help us in deciding who to investigate and obviously coming to a diagnosis earlier would be patients who have hypo, known hypothalamic-pituitary lesions where we know they're at risk of hypopituitarism Multiple pituitary hormone deficits. We know if you are deficient in a number of hormones, you're highly likely to be growth hormone deficient. Cranial irradiation of patients that a lot of the cohort that I would follow looking at regular tests to see if these patients develop growth hormone deficiency. And I feel in that cohort, you can pick up these people when they become growth hormone deficiency by prospective testing and before they've lost that height, making things easier to treat.
And then, there will be those who have neonatal symptoms when they present really early with growth hormone deficiency such as hypoglycaemia or the facial, mid-facial formations that malformation they get. And then, obviously, the people that Mehul has already mentioned in the craniofacial midline problems. So, diagnosis in children. Growth hormone deficiency is fairly rare still it's about 1 in 4,000 children, so we're not talking something that's common and other causes of growth hormone deficiency are probably a lot more common than growth hormone deficiency. So, we need to consider those first and simple things like hypothyroidism, whether they have a skeletal disease obviously, the Turner is maybe a little bit more obvious and those who have chronic illness obviously, all have a reduction in growth. So, the cancer survivors that I see again, they significantly reduce height velocity and height whilst they're unwell and soon as we put them into remission you see that catch up growth. They're not in the, a lot of them are not growth hormone deficiency and they pick up without us intervening.
Diagnosis as we've already mentioned has several criteria. We need the auxological criteria which we have in children, which is really important that we just mentioned. Clearly, we don't have that in adults and transition, but in children, it really is a great help in diagnosing growth hormone deficiency. We then need the biological testing which is the bit that is a little bit more tricky. We need a growth hormone provocative test and there's been plenty of those that have been used in the past and still used. And then, IGF-1 and BP-3 which we mentioned a little bit already about that being an additional helpful test at times but not others. Radiological evaluations, again, for bone age to look at skeletal maturity will help us if there's delay that will help us. Obviously, as we mentioned with the obese patients, if it's ahead of time, ahead of chronological age, that may be against the diagnosis of growth hormone deficiency. If we're thinking there's a cranial lesion then obviously, MRI scans to look at the hypothalamic-pituitary area and that would support our diagnosis of growth hormone deficiency as well. And then, genetic analysis which is something that's becoming more widespread in a lot of conditions within endocrinology now and the patients we should be doing in that, and it tends to be those who've got a family history or those with more severe disease either because it's of earlier onset or the provocative tests are particularly low or the IGF-1's particularly low to guide us that they may have a genetic cause. How do we confirm growth hormone deficiency?
We've touched on that a little bit. So, the provocative tests are the mainstay and there's some I've mentioned there like the insulin, the arginine, the glucagon, clonidine tests. But there's been plenty of different ones in the past like exercise tests, Bovril tests many of which have very little in the way sensitivity and specificity for the diagnosis and fortunately, we no longer use. If we have a patient who has isolated growth hormone deficiency they ideally should have two tests though, in people as, again, as we've mentioned if you've got multiple pituitary hormone deficiencies because the risk of growth hormone deficiency is so high then one test would be adequate. And there's several things like that similar if you've got a anatomical lesion of the HP axis or a history of radiation where we think one test would therefore be adequate. Diagnostic cutoffs, I think most of us now have settled on a diagnostic cutoff of somewhere around seven really, for where we would consider patients to be children to be growth hormone deficient. And that seems to tie in with the auxological data that we have or certainly is the best cutoff for the auxological data.
But that's still a matter of debate. And obviously, there may be that in transition where we are considering a, in puberty where we're considering a slightly higher cutoff value or where all the other data seems to suggest patients are growth hormone deficient and if they've got a level between 7 and 10 that may be worth trying growth hormone replacement. IGF-1 and BP-3, if they're below the normative range at less than minus two standard deviations, again, may well be a help in our diagnosis. Our goals of management really are in children predominantly to optimise our growth of our children to that which we think is similar to mid-parental height and try to optimise that. To date, we are not generally achieving that and there may be a number of factors to discuss later like adherence which are factors in that, but also the fact that by the time we have growth, diagnosed growth hormone deficiency, we have less time to treat the patient and bring their growth up before puberty fuses the epiphysis. The goals are different obviously in children where we're thinking of growth to where we're thinking of adults which is more quality of life and improving the metabolic sequelae and in transition where we're trying to optimise bone and muscle mass to that genetically which the patient should have. Mehul also touched on the assessment of growth hormone deficiency and we generally do that at the end of growth to look at whether a patient still requires growth hormone replacement. The idiopathics that Mehul mentioned are the commonest ones.
There's about 30% of those through the studies that seem to have no longer have growth hormone deficiency. But there was some work done with Steve Shalet's group in Manchester which also showed some of the irradiation ones which had had two tests during childhood to show that growth hormone deficiency also recovered. So, it's probably, unless people are pan hypo pit and if it's isolated growth from deficiency, we probably should be retesting in many of the pathologies. Management, management is growth hormone replacement. We give back what the child is missing. We should be starting it as soon as we make the diagnosis due to that limited period for treatment and growth, we have both the single once-daily growth hormone replacements and we now have once-weekly preparations which, again, will be discussed a little bit later as a new option. Changing doses generally, that's has been weight-based so that when a child is assessed every three to four months then the dose can be adjusted if necessary to the right amounts. So, a little bit more different with the long actings which we can chat about. And also IGF-1 is used a lot more.
When I first started doing endocrinology 20 years ago, we used very little of IGF-1 as a guide to doses in childhood growth hormone replacement but it's now much more commonly used as a safety marker and monitoring response is clearly by height auxology and looking at increases in height velocity really our best marker and using growth charts which will have that data on to see what's normal for age and gender are also very important to use. In the long term, as I say this is predominantly looking at effectiveness which will be our height velocity of the child and in, at the end, obviously, final height, and obviously, we are looking through this at safety and making sure the adherence to our medications is upheld because otherwise, they're not going to be effective. We've discussed discontinuing treatments in that transition time to adulthood. My feeling is we should be treating children in transition but many of them, after years of growth hormone replacement therapy like a break. So, we often let the adolescents stay off of growth hormone little while and discuss it at further appointments. But interesting to see what other people do. And I think now we're open to the discussion.
I would like to ask you about growth hormone testing because some of the tests are quite cumbersome and maybe not that pleasant for the children and also as you said, they're tested maybe too late, we would like them be tested earlier. Now, macimorelin is registered for the diagnosing growth hormone treatment. Do you think that would be an advantage in children as well? It would be, I'm not aware that macimorelin is yet been tried in the paediatric population all the data I'm aware of is in adults. But I mean it's a simple test for adults. It's something I'm incorporating into our routine pituitary follow-up for the adults and my cancer survivors. So, it's something we're going to do there. So, I think it would be good but I think I suspect it's going to need clinical trials before the paediatricians go into that kind of area. I don't know which tests Mehul and Shankar are using currently, or Steven in their patients predominantly. I think we predominantly use glucagon. Most of our patients probably only get one test, so. Yeah, yeah. I think, Shankar, do you want to make a point and then I'll run in? Yeah, I mean we use glucagon and I also have one question which we'll touch on what Mehul said earlier and we had about obesity. When we adjust the dose based on weight, obviously, obesity will have an impact.
Now, is there a better parameter that we can use to adjust the growth hormone dose like body surface area or is height still one of the best parameters that we have to adjust the dose going forward? Yeah, I'm not sure we completely know the answer to that one, it sounds, I think, body-surface area would probably be better than weight. So, I would be an advocate for that. But beyond that, and monitoring response, I suspect there's not something we've got that's better and obviously, the safety aspect of things looking at IGF-1. So, I think incorporating those various aspects, I think was, is probably best. Yeah, but I'd agree, I mean we... I always tend to use surface area, Shankar, so, and I feel much more comfortable with that mainly because of the obese patients, I guess, yeah. And then, obviously, you are going to measure the IGF-1 maybe we'll come back to that in a little bit. And, Rob, in response to your question, we use glucagon in the younger children, and I also have an adolescent service at UCLH where we use an ITT, which actually, you know, given the bad press is very well-tolerated if it's done in the right way, I guess, and you know most of the problems previously were around correction of the hypoglycaemia and overcorrection. So, I think, you know, those tests have stood us in good stead generally, so, yeah. And we've also touched I guess, previously, on the issue of priming. So, I think we've covered that, but that is, that can be a bit of a challenge as well if people don't use that. So, any other points that people want to make in relation to Rob's presentation?
Well, what strikes me about the two presentations so far is that from a health economic perspective, the time to diagnosis plays a very important role because it'll have an impact on the clinical and economic burden of GHD throughout the lifetime of the patients. So, I was wondering are there any strategies that we could suggest put forward in order to reduce the time to diagnosis. So, I mean I think you are right, and I think it's probably going to vary from country to country in terms of the time to diagnosis. The earlier you diagnose and the earlier the children start on treatment, the better it is. Because if you lose out on growth in the early years, then it's very difficult to catch up on that later. And even in the UK, I've just saw someone in the clinic two days ago, who actually presented at the age of 10 with a height of minus five standard deviation scores, highly articulate intelligent patients, their parents rather, somehow they just did not pay any attention to the height of this child and she's going to have lost a lot of height. She's responded beautifully to start with, but you know, we're never going to makeup what she's lost.
So, I think, you know, it is difficult and I think it comes to screening and people's awareness of what is abnormal and when do you refer to start with. And also, and I think on the health economics side of things, the converse is true that maybe we readily diagnosed growth hormone deficiency in some cases, and that is really a piece of work that we are looking at now. ie, you know, children may test GH insufficient at one point in their life but that may not be the case later on. And Rob's already touched on the reversibility at the end of transition, but now, a number of papers both from Belgium and from Italy have suggested that early reversal, so if you test just in early puberty, they might reverse at that stage so you save money and the child having daily injections for at least three or four years maybe. So, that might be a route moving forwards. And the last point I wanted to make was the importance of an MRI. So, Rob, years ago when I started, people weren't doing it much and thought it wasn't helpful but actually, now I do it in every child that tests GHD or GH insufficient. Because that really gives you a good insight on the pathology.
Do you end up doing much in a way genetic testing based on things like findings of EPP, Ectopic Posterior Pituitaries and things like that? Yeah, so that mean that, yeah, that will take ages to answer completely but what we find is the yield is low at the moment, but it's increasing. We're now moving to gene discovery using a whole exome, the whole genome sequencing and that is certainly shedding more light. Currently, it's about 10% of children that we test will turn out to have a genetic defect. And as you say a family history or say, a type-two growth hormone deficiency which is a dominant form are not uncommon. So, you know, if you look you'll find it, but, you know, ectopic posterior pituitary has septo-optic dysplasia. The yield is extremely low at the moment but I think it will increase as our knowledge of genetics increases.
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