Chapters Transcript Video Diagnosis and Treatment of Growth Hormone Deficiency (GHD) in Childhood and Adolescence Hi, good morning, everybody, and thank you, Jay for the kind introduction. I'm Angel, one of the pediatric endocrinologists in Oakland, and thank you for having me today, um, to talk about one of the very common endocrine concern um that we see, which is short stature and particularly a touch on the growth hormone deficiency in children and adolescents and And talk about some updates in the current treatment with the growth hormone. So I will spend the next 35 to 40 minutes to um um talk about it and then we'll have the Q&A session in the end. So, So this is my uh talk is focused on the um diagnosis and treatment of growth hormone deficiency in children and adolescence. Uh, I have no disclosure. So a brief, um, you know, and a lot of my talk. So at the beginning, I will talk briefly about, you know, short stature evaluation and and specifically talk about the condition growth hormone deficiency, and then, and then we'll discuss um more on the treatment. Um, with various indications and what are the outcomes and the adverse side effects. And then lastly, I'll also, um, sort of touch upon that what we observed the disparities in the evaluation and also treatment. Uh, of children with growth hormone deficiency and um in the very end, I think it's also very important, it's like when, uh, you know, What are the concerning sign and features and when should we consider a referral to the pediatric and crinologist for further evaluation? So first of all, like normal regulation of our growth. So normal human growth can be divided into three overlapping stages, each under the control of different factors. So infancy accounts for about 15% of the eventual height, and which is largely under the um nutritional regulation, and by the age of 2 length is more predictive of final adult height than at birth. Which means either baby was born large or small for gestational age at birth. It's usually not predictive um for their adult heights. During childhood, it contributes about 40% of the final height. Growth hormone and thyroid hormone are important re regulating hormones during that period of time. Sometimes we observe like many growth spurt with endearing stasis could happen during this phase, and each phase lasting for several weeks. And lastly, it's pubertal growth spurt that adds an additional 15% to the final height. And during that period of time, growth hormone and sex steroids promote bone maturation and the growth spurt, and eventually the estrogen causes epiphysal fusion and the attainment of the final adult height. This is a graph kind of like picturing the difference determinants of growth in various stages. So as we note during as we can see, the most rapid growth is observed during infancy, and then it slows down. Until puberty. So what is short stature? So before we talk about, you know, growth hormone, obviously the first sign is the patients who are short. So what is the definition of short stature? So it is defined as the height more than 2 standard deviation below the mean for the age and the sex, and usually it's a C scores minus 2 standard deviation and that will ring a bell, and, and that usually corresponds to the height chart um roughly below the percentile. Excuse me. So when, when, when does growth become a concern or a problem? Obviously, if the patient have very significant severe, uh, short stature with the standard deviation way below the um the mean or really far off from the genetic potentials and um that is a concern. The other signs of showing, you know, concern for growth failure is if we observe like a normal linear growth velocity, um, for age and the sex, or when we track the growth curves that we start seeing a deviated downward, um, crossing to major centile curves, then that's the concern that there might be some suspicion of growth failure. Growth velocity is generally measured at least 4 to 6 months anval, and it's usually calculated as a centimeter per year. And growth, this is uh the the graph on the right side is a growth velocity chart that represents the age dependent changes in the growth velocity from birth to adulthood. And as you can see also like during infancy and early, you know, childhood, that's the period of more dramatic rapid growth. And then another growth but is around the pubertal stage and then And it was, it was slow down once the patient is getting close to complete uh completion of the puberty. So generally, some, you know, idea about so at what, you know, grow velocity that starts to be concerning. So for young kids, um, if a growth velocity is less than 5.5 centimeters in a year. Um, or around toddler, if it's less than 5, from 6 to puberty, if it's less than 4 in boys or 4.5 in girls, then it Then we should start, you know, um, to be, you know, concerned and then to have to consider like further events. Not the patient. Showing Uh normal linear velocity. So here are Hi, Doctor Nick. We see with Warren, you know, from television. It might not necessarily problem. Hi, Doctor Nick. I, I think we're having a little bit of connection problem. Can you hear me OK? Yes. Can, can you repeat that slide or or just the, the end of that because I think we're having a little bit of difficulty with you. I can hear you. OK, we're, we're just having some, the sound is breaking down just a little bit. Oh, I see. OK, so, uh, OK, so, yeah, so. OK Can you hear me OK right now? Yes, it's better now. Oh. OK. I think we're having a little bit of technical difficulties. We'll work with uh Doctor Niff to get her presentation back, but just hang with us for a second. Hi. Hi. Hi, Jay, sorry, I don't know what's going on. Yeah, no worries. Can you hear me OK right now and can you also see my slide? Yes, we can, we can see your slide. OK, so I'll just go back here. Where we stop. Sorry, um, there's some disconnect uh connection problems. So, um, so basically I think some of the concerns concerning features is when we particularly look at the growth velocity. At various stages. And here are some of the sort of like the references at what point um for different ages that we should start to think about, you know, growth failure or some concern in the growth issues. So for younger kids, if it's less than 5.5 centimeters or older kids from sex to puberty, so before puberty, obviously for kids, they are. In, uh, they're having good pubertal growth spurt, then it will be a different number, but what we're talking about here is from 6 to close to at the onset of puberty, it's usually less than 4 centimeters for boys and then 4.5 um for girls. Um, so here are some examples of, uh, you know, something normal growth patterns or growth charts that we see in the clinic that which warrants, you know, further evaluation and obviously as I mentioned, you know, slowing down of the growth velocity or crossing major center. Curves as shown in graph A and C. Um, here, it's something, you know, that, you know, we should. Be concerned and especially the patient have a generic, you know, um. Potential with the mid at the middle, the current height, the patients really deviated from the parental height, so this can be something, you know, like pathologic. Um The difference between the graph, excuse me, graph A and C are actually look at the weight. So it's also very important when we talk about growth. We're not just focusing on the stature, the height, but the weight also give us, you know, important information as shown here, that's, you know, there's what we're talking about two different disease processes because You know, for this one, we also worry about any, you know, weight issues that are causing the, um, you know, growth deceleration. All right, so in terms of like evaluation, of course, I mean, of history and physical examination provide lots of information even before any blood work or any imaging, um, specifically, you know, family history, parents' height, no birth histories, whether the patient was born small, IEGR or any complication during pregnancy. And other medical problems to understand the risk factors for growth failure. Then the best next steps to evaluate a child whichual stature is by doing a bone age, which is in the X-ray of the left hand. Um, it is an indicator to skeletal uh maturation, and based on the maturation, we can estimate the temple of growth and also what's the remaining growth potential. And the traditional method of doing it is it's actually to compare the plane radiograph of the left hand to a database of the norm, so kind of really a pattern recognition and looking at the the database and then find the which which is the like the closest to the patient's X-rays, and a bone age that this more than 2 standard deviation away from the mean for the age is likely to uh due to like a pathology. Laboratory tests, so baseline blood tests are considered. To rule out, you know, some other medical problems. For example, we do a celiac screening of the patient also have like, you know, poor weight gain or weight loss, um, like CBC we screen for anemia, liver, and renal, you know, function. We often do a thyroid function test to rule out thyroid, you know, dysfunction either hypo or hyperthyroidism. Karyotypes is recommended in girls with short stature um to Roe Turner syndrome. Growth factors, specifically IGF-1 and IGFBP3, are the surrogate markers as a screening for the growth hormone deficiency. So as we know, a random growth hormone level, it's never reliable due to the postal secretion and especially during sleep. So that's the reason why we use the surrogate markers with the IGF-1 and IGFBP3 and never, you know, use like a random growth hormone because it's not, you know, the, the result that's not interpretable. And IGF one, however, are nutritionally dependent and so what it means is that it can be low due to malnutrition, independent of the growth hormone status. So first we need to interpret the result carefully, especially in underweight children. And um again, with worrisome or very, very low IGF1 and IGF BP3 on the screening test, plus the evidence of like growth failure can be evaluated further by growth hormone stimulation test. The provocative growth hormone stimulation test remains the subject of much controversy. And there are significant issues concerning the validity and the reproducibility of the growth hormone testing. Even though it's flawed, growth hormone stimulation tests remain part of the comprehensive evaluation of growth and it is essential for the diagnosis of growth hormone deficiency. There are several agents that utilize in the growth hormone stimulation test, and often will use to provocative tests agents um to minimize any false abnormal responses. Because these provocative tests are secretory dynamics, we usually will use a combination of two agents for the test. Um, right now the current agree a point cutoff level it's 10. It is to use to diagnose form of deficiency, but more and more studies showing a lower cutoff can actually be employed uh because there's multiple different like studies to try to test like the, the um the cutoff, especially with the newer, you know, essays for testing the growth hormone, and some studies suggest like the cutoff of like 6 or 7 can actually be employed instead of using the You know, the original um cut off at 10. All right, so I cover, you know, a little bit on short stature evaluation and the test, and so here is a summary. So what are the causes for short stature? So. There's many, many different, like on the differentials can be physiological, meaning that's actually not a disease, it's just like the patient is genetically defined to be short because of the family, um, but also like, you know, some other disease entity, um, including, you know, systemic illnesses, nutrition, malnutrition, and specifically like, you know, for endocrine disorder, then growth hormone deficiency, thyroid dysfunction. And diabetes can, you know, cause like short stature. And so in the following slides, I'll cover, um, kind of like, you know, talk about growth hormone deficiency specifically and the growth form of treatment. So, growth hormone deficiency by the name means the patient has problem of like making the growth hormone. It can be congenital, it can be acquired or idiopathic, which means there's no identifiable like reason. So congenital form usually due to some gene differences like gene mutations or structural abnormalies of the pituitary gland because we know pituitary gland. Is the gland of making growth hormone. Growth hormone deficiency due to underlying pituitary abnormally may be accompanied by some, you know, clinical features, for example, line defects, including cleft lip or palate, central incisor associated with some syndrome or associated with like structural defect of the brain, for example, sub septal optic dysplasia. Halorosencephaly, hydrocephaly, or agenesis of the corpus callosum. For acquired, meaning, you know, any pathologies involving the CNS, including CNS tumor, uh, you know, commonly in children it's a cranopharynioma or any CNS trauma, irradiation, infections or inflammations that involve the brain can put the patient at risk of hormone deficiency slash other hormone deficiency. Majority of the cases up to 70% are actually idiopathic, uh, and isolated, um, growth hormone problem. Clinical features, um, so again, it depend on the clinical presentations varies depending on the age of onset. So during the period neonatal period, um, There's increased incidence of hypoglycemia and prolonged like uh conjugated hyperpoeic anemia causing jaundice, specifically boys with growth hormone deficiency can also present with micro penis. In children, um, with growth hormone deficiency, um, as we discussed. And the uh previous slides that they can have some midlined defect, like, you know, features like midface hypoplasia, dental crowding, central incisor, um, or disproportionately small hands and feet, and, uh, typically children's with growth hormone deficiency present with growth deceleration after a period of normal growth during infancy. And it start presenting like, you know, slowing down of the growth after the age of like 3 or 4, and, and which is consistent with the uh like very, very first lines to talk about the normal regulation of the growth because during infancy, nutrition is the major drive of the growth and the growth hormones start to kick in after the age of like 2 or 3. So once the patient, you know, starts showing growth hormone, uh, you know, short stature or failure role, we will, you know, evaluate and once they are confirmed, then. There's a treatment. We, we, you know, um, we can, you know, offer treatment with the growth hormone, um, recombinant human growth hormone first received approval from the FDA back in 1985 for uh treating pediatric growth hormone deficiency. And it was originally designed as like intramuscular injection, but then subsequent, you know, study showing like subcutaneous injection is, um, you know, showing the same effect. And so now, you know, it's a commonly used as like a daily administration as aOU injection. And below is kind of like the slide of showing the development of the growth hormone, um recomb recombinant growth hormone since the 90, um, you know, 85 and then Subsequently, there have been multiple different brands and pharmaceutical companies and also recently, um, this development of the longer acting types of the growth hormone. Indication. So there are so far currently 8 FDA approved indications for growth hormone use. Uh, in pediatrics, um, including patients have confirmed for formal deficiency. Idiopathic short stature, meaning that there's like no identifiable like cause, patients usually have like normal birth weight, normal body pro uh proportion, normal response to the stimulation, and their high standard deviations correspond to the parental standard deviation and and they're really short with the height standard deviations minus 2.25. Another indication is small for gestational age without any catch up growth by 2 to 4 years. And then couple syndromes are also indicating, uh, indicated, including Turner syndrome, Prader-Willi syndrome, Noonan syndrome, and also the so gene um have deficiency, and lastly is the chronic renal insufficiency. So these are the current FDA approved indications. You probably are aware there are actually other possible or experimental use of for hormone in various clinical situation, uh, you know, some other syndromes with like short stature, for example, Russell Silver syndrome, um, you know, there's like, you know, very small study kind of like look at the um. The response of usedtri growth hormone in RSS and this do show some increase in the height standard deviation again. Most of these are very small trials, so the data is still kind of like inconclusive. Um, you know, growth hormone has been, you know, um, experimentally using treating patients with hypophosphp rickets, you know, there's data for treatment of of of cystic fibrosis. Um, again, it lacks of long term, you know, data on the benefits of this treatment. Uh, as I mentioned, the growth hormone has been used on a once a day injection, and there's so many different brands, and they are, you know, equivalent, and, uh, usually it's a self-injected, um, administration, either by parents or that by the patient themselves if they are old enough. And so these are the sites and areas that we, you know, they usually do the injection and um. Because of the need of the daily injections, individual adherence to the growth hormone has been shown to decrease over time with the concomitant reduction in the kite velocity and also the IGF1 levels in the short term. And so that leads to the development of the longer acting, which is the once weekly injection, and then now there's a couple um long acting growth hormone. Specifically, the Sky rover has been approved for treating pediatric uh growth hormone deficiency. So this is just like a very, uh, you know, pulling one of the data supporting that the long acting growth hormone is as effective as the daily injection, and in terms of the safety profiles and the tolerability profiles are similar and actually indeed showing increased compliance. So they have similar growth velocity when compared to the once daily versus the um once weekly injection. So treatment responses, um, so the the average dose for the growth hormone for growth hormone deficiency is from 0.7 mg per kilogram per week to 0.24 mg per kg per week. Uh, definitely. We see increase in adult height with the changes in the height standard deviation scores, and most of the patients while they're on formal, majority of them actually be able to get close to their adult heights. Um, and, and in addition to the height benefits, there are also a lot of non-height benefits with the growth hormone treatment. Um, study shows that a patient being treated with growth hormone have improved quality of life, better social integration and self-esteem because of the improvement in the stature. They're also showing improved body composition with a decrease in the fat mass and increase in muscle mass. And improve their exercise capacity and have improvement in the bone mineral density and formal deficiency. So what are the side effects of Gerol? Is it 100% safe? Um. It, so here are the list of the side effects that we, you know, always discuss with the family and we wanted to, you know, be comprehensive, so we kind of like that's really a long list, but obviously, you know, some of the side effects are more common, some of like real like. and only reported in a few cases. Um, and the most commonly associated is usually the injection itself, like including swelling of the injection site, rashes or some mild like rea uh allergic reaction. Um, skip slip capital femoral epiphysis or skivvy, it's also associated with growth hormone therapy. Um, but the incident is really rare between like 2240 cases per 1000 per 100,000 patients. Uh, the other is the benign intracranial hypertension has been reported in growth form of treated patients as well, and it might develop within months after treatment starts, or even as long as like 5 years into the course. The mechanism is unclear, but it may reflect changes in the fluid dynamics within the CNS within the brain. Um, it is rare, but, you know, we always like, you know, get alert to, you know, patients complain about headache or vision changes or any neurological signs. We recommend to stop the growth of hormone and then evaluate. Some other side effects including, you know, the worsening of the scoliosis, worsening of the adenotonsiar hypertrophy, and they're also like temporary increasing your blood sugars, causing insulin resistance and, you know, risk of like, you know, diabetes, cardiovascular risks. So specifically, what about cancer? So whether there's any risk association with, you know, development of like cancer. So this concerned um About the risk of cancer in children treated with growth hormone was first raised for the first time by, you know, case reports as right being children who developed leukemia during or following growth hormone treatment um with uh the diagnosis of growth hormone deficiency. And then subsequently because of the The concern, a lot of like, you know, long term studies, big trials in different parts of the country, um, to try to really like follow up those patients on hormone treatment and to understand the, you know, the associations of secondary cancer. And one of the big sort of like group um in 2009, the conception from like the eight European countries or the stage. A group was established with the purpose to evaluate the long term safety of growth hormone therapy and childhood. And they divide a patient into slow, low risk category, high risk, and intermediate risk depending on the etiology for low risk of those patients treated for isolated growth hormone, for idiopathic doctor or small for just gestational age versus high risk patients or those with history of cancer, they're like cancer survivors. Uh, and then intermediate risk are including patients with like other, you know, conditions like Turner syndrome, Nuna syndromes, or non-isolated growth hormone, non-cancer diagnosis. Studies show like both the mortality and morbidity for cancer were not increased for low risk category, but it's increased in high risk group, um, I mean, uh, because of the Risk factor of the history of like, you know, previous cancer. Um, there's no relationship between cancer risks and the duration of the cumulative dose of the growth hormone use in the low risk, um, group. Another study is called the Genesis. Um, it's another observational study and conducted more than on more than, you know, 20,000 growth hormone treated patients, again, with various diagnosis include, you know, that we talked about, and showed no significant increase in cancer mortality and morbidity observed in the low risk population. The only caveat of this study is um it's, it's relatively short, so it's only been about 4 to 5 years of follow up. Versus the uh the stage one has like more longer term follow up duration. What about risk for diabetes because uh one of the side effects we counsel family is also, it can also increase sugar. So we know growth hormone play a role in glucose metabolism and it isn't counter regulatory hormones. So it increases glucose neurogenesis and reduce insulin sensitivity. Um, studies show the incidence of type one diabetes or autoimmune diabetes was not increased. However, the incidence of type 2 diabetes was sixfold higher than expected. And, you know, for some patients diabetes actually persists even after discontinued hormone treatment. But It's um the study also kind of like concluded, um, you know, the increased risk, there's increased risk in patient already with like, you know, underlying risk factors, for example, Obesity, strong family history, genetic predisposition, and patients who are like, you know, have a very inactive lifestyle. So, so it's hard to tease out because for those patients with um diabetes, they already have some other risk factor that can put them at risk of like, you know, developing diabetes in addition to the use of hormone. Um, and many other, you know, um, and growth hormone can also surface like an accelerator and development, developing of diabetes with the predisposition diabetes, like sorry, disease, for example, Turner syndrome itself, um there's actually an increased association with like diabetes, regardless of the use of the growth hormone. Um, cardiovascular and cerbrovascular risk, I think it's less of like the discussion, but um, it's more kind of looking at like long term in adults that have been treated with profo in the past and some of the studies saying that's actually slightly higher risk of cardiovascular and cerbrovascular diseases. And again, in those patients, they also have like, you know, underlying risk factors. So this is kind of like the summary of um uh the current available evidence um about, you know, the different like risks. So for cancer, there's no evidence that's increased risk in the low risk group. For cardiovascular, there's some evidence in patients who have already have the risk factors and same as the type 2 diabetes. So duration of treatment, so how long do we usually treat patient uh with growth hormone? So as long. As the patients the grow place is still open, we usually will continue the treatment, um, and usually until, you know, the bone age of 16 in boys or 14 in girls, and also when they're like reaching near the final height. Um, and when also when we start seeing patients have like slowing down the growth velocity of less than 22 centimeters per year, that's the time we should discuss with the family about, you know, just um stopping the growth hormone. And depending on the starting age and also like the various, you know, indication, generally we're talking about, you know, treatment for 5 or more years. Lastly, the cost, so. We all know growth hormone is very expensive and and it may cost up to 20, you know, um, 000 per year depending on which brand. So here are kind of like, you know, showing you some costs for these two of the longer acting uh once weekly preparation and give an idea, it costs up to like, you know, 1600. 16, 1000 a year, um, and so these are the more commonly used like once daily preparation. Again, the cost varies, but we're talking about roughly like $20,000 per year, and And it's and it's I, you know, mentioned depending on the The the cause and some patients may be on growth hormone for at least like 5 to 6 years as a course of treatment. So, um, I just want in the following couple like briefly, I just want to briefly touch upon like the treatment for growth hormone for the other indications and what are the benefits and what's the, you know, the outcomes, um. For SGA and ISS, um. The dose as we see here, um, it tends to be a much higher dose when compared to the growth hormone deficiency because we know these patients, they're actually not deficient in growth hormone. So in order to have the effects, they needs to be on a higher dose, what we call the super physiological dose of the growth hormone to try to like promote the growth. Um, but study do shows like, you know, increase in adult height and also Uh, you know, improve in the quality of, um, quality of life. And, um, as we discussed, you know, studies show that it does not really alter the risk of developing metabolic syndrome or like type 2 diabetes, cancer risk in SGA and ISS like category. Girls with Turner syndrome, um, again, we need to use like a much higher dose up to like 0.47 mg per kg per week, and the mean high gain is roughly about 5 to 6 centimeter when compared to the untreated girls with Turner syndrome. And given the underlying conditions, putting the patient at actually higher risk of developing skiffy, heart problem, intracranial hypertension when compared to those receiving growth hormone for other indications, and we believe that's probably secondary to the higher risk due to the Turner syndrome itself. Uh, for Prader-Willi syndrome, again, in addition for the growth and uh adult height gain, I think the most important benefits is actually improving body composition is shown to decrease the fat mass and increase the muscle mass and also improve the motor function. The motor development as well as the muscle tone. So this is one of the indication that we, we treat babies with the Prader-Willi syndrome once they are diagnosed. So not necessarily for the height, but more so for the motor development and muscle function. Nuna syndrome, which is similar to the uh Turner syndrome in girls against similar, you know, you know, gain in height, uh the only um Precautions as we know that patients with Nuna syndrome are at slightly increased risk of developing solid tumors. So we need to be, you know, careful about considering growth horing these um patients. So, um, yeah, I think I have uh 5 more minutes. So in the next few slides, I want to cover briefly on, you know, disparities in diagnosis and treatment of pro hormone deficiency and pro hormone treatment. Um, so racial and ethnic disparities are seen in the evaluation and treatment of a childhood short stature and evaluating patient with growth hormone deficiency. And interestingly, I mean, this pattern actually already described were described over the past 30 years and in the first US growth hormone registry reports, so highlighting it's a persistent patent. That we're seeing, you know, racial and ethnic disparities. Um, studies show non-Hispanic white is 1.4 times more likely than the non-Hispanic black children. And 1.7, 1.7 times more than Hispanic children to undergo. Growth hormone evaluation. And for those who received the growth hormone treatment, non-Hispanic black had actually a lower high score, meaning that they are like, you know, much shorter than the non-Hispanic white, and they also have a rated height deficits from their mid parental height, so they're like even further away from their mid parental height before they get evaluated. And subsequently get treated. And this is another graph to show you, so it's a meta-analysis just to pull like different paper to show you what are the Gender disparity in terms of like, you know, the percentages of referral for male and female. And you can see, apparently, you know, height is always some more a concern for boys than girls, and social bias and parental willingness to accept shortstat more in girls should also be responsible for the gender disparity in growth hormone. You know, um, therapy and short start your evaluation. And here these are the papers showing, you know, the white versus the black, like the percentage of referral you can see, we're seeing more of the white, you know, um, kids being eva refer for evaluation when compared to the black. Um, this is another, you know, um, summary of various data to show you the percentages between the white and the black uh percentage received for form of treatment. You can see the significant discrepancy and the percentages. And um And also like the baseline height C score, and you can see for the white population they have a slightly higher. Height And the maximum peak growth and also for those like who under the um underwent. Evaluation. The growth hormone level actually peak higher for the white population when compared to the black. So essentially meaning that they have a lower threshold of getting the white kids being evaluated and treated for growth hormone. OK, so, uh, finally, When, when should we, you know, consider a referral? When do we need to refer a patient for further evaluation or, um, obviously, if you have any concern that the patient's not showing. An optimal linear growth velocity, um, or the patient is really, really short for their family and have severe short stature. So children with small for gestational age who do not catch up to the growth curve by the age of 2. Warrants evaluation, it might, the patient might not have any, you know, pathologies, but it's, it's an indication for, you know, grow hormone treatment, so it warrant a referral for discussion. If the patient had um severe short stature, it's below the 3rd, like, you know, the 3 standard deviation below the mean it's really, really significant of the growth chart and it also warrant um a workout. Again, we grow velocity over time, and if the projective height, it's more than 2 standard deviation below the mid parental height, and also all the diagnosis uh we discussed above that's approved for growth hormone deficient, the growth hormone therapy warrant a referral for discussion. And some findings that support, you know, investigations for growth hormone, if there's any signs indicative of like an intracranial lesion, neonatal symptoms that we discussed like hypoglycemia, micro penis in boys, uh. Those could be signs of former deficiency and then importantly is the, you know, Um, the growth parameters that we already discussed, and also in patients who are showing signs of other pituitary hormone deficiency that also warrant a more thorough comprehensive evaluation for the pituitary function. So, uh, I think I believe this is my, uh, very last line, so I think, um. Just like some tips, is when we talk about stature, height, uh, I think it's very important that, you know, to get accurate height and weight measurements. Again, have the, you know, accurate height and measurement and sometimes in the clinic, we usually will measure patient at least 2 or 3 times just to, just to make sure to minimizing any measuring errors. Because, um, and also like be consistent in order to compare the growth velocity. And also be able to calculate the met parental height, uh, based on, you know, their genetic potential to help to assess that the patient has appropriate growth for their genetic potential. And I spend, you know, a lot of time focusing on the stature, the height, with various, you know, cut off and standard deviation, but when we assess like somebody's growth, weight and the BMI is also, you know, equally important and they should also be, you know, assessed because as I show, there's like various, you know, differentials for patients who are short, so. Uh, one bucket is nutrition, malnutrition or other systemic illnesses that can affect both the weight and the height. These are the references, uh, I, I think, um. I have like about 10 minutes left for the Q&A. I hope that I managed the time. Well, I'm happy to take any question. I mean, again, this is a really big topic. There's so many things to cover, so I try to like, you know, something is more interesting. But yeah. We already have a lot of uh questions rolling in, so we'll get to it. Sure. Um, so we have a question from the chat. Uh, how frequently do you use growth hormone stimulation tests to verify a diagnosis of growth hormone deficiency versus just uh Relying on the IGF one and the binding protein and if there's imaging, this is something that I ask myself often and also discuss among ourselves. To be honest, I think it's actually, you know, going out of flavor of like you doing it now versus in the past. And you're right. I mean, in, in cases, you know, the patient already clearly showing evidence of like grow failure with evidence of like low. IGF-1, IGF BP3, you know, those like, you know, screening markers. Sometimes, I personally, I don't do the growth hormone stimulation test because we already have clinical evidence about chemical evidence. And, and then, uh, if the patients are already very short, um we can offer treatment and oftentimes the reason that we need to do the stimulation test one, again, is because practically we might need to meet some insurance criteria because from time to time, depending on the patient's insurance, will uh growth hormone can get like denial. If they don't have a proper growth hormone stimulation test. And the reason that, you know, we don't do growth hormone tests that often because as I mentioned, it has a lot of like problem with that because it is, I mean, in the past, it's, it's still the gold standard when we look at the literature and the textbooks, they still say it's a gold standard. But we know that it's like not reliable. It varies. And we are, and it's also a very tedious, you know, um, test that the patient has to be in the hospital at least for a half day, and we put in the IV and then do the frequent blood draw. So it's from the patient's standpoint, it's not something, you know, comfortable. And it's also. So the growth hormone stimulation test isn't necessary for diagnosis, but it would be beneficial and could help in insurance aspects of it. Gotcha. OK. Um, that was going to be my follow-up question of what does the growth hormone stimulation test look like practically for families and so that we can provide any sort of um guidance and counseling for what they might see, uh, when they see endocrine. But you already answered that too. Yeah, yeah, so it's usually like a half day, you know, in that hospital and often like we also discuss and then we'll provide, you know, some instruction, but mostly it's like the blood draw for kids, yeah. Gotcha. And then uh I have a couple of questions regarding the age of growth hormone therapy and when the optimal age is. So once we made the diagnosis, I mean, obviously the younger the age will, they will have, you know, a longer duration of the therapy, so they will have, you know, the The better outcome in terms of the high gait. So, I mean, that's definitely not like a minimal age cutoff for treating growth hormone. So for example, depending on the indication, so as I mentioned for Prader-Willi, we treat infants with Prader willy even. Um, from like 6 months. Um I see. For growth hormone, as I mentioned, usually the patients start presenting around the age of like 3 or 4. By then they will start showing like growth deceleration. And once we confirm that's usually the time that we initiate treatment, I will continue treatment until they achieve puberty. Gotcha. And so that's the, the follow-up question that uh someone asked is also what age or tanner stage is there a fall off in terms of like the benefits of using growth hormone? Yeah, I mean, if it's the older and also getting closer to the end of the puberty, then obviously we You're narrowing the winter treatment window. As I mentioned, by the time the growth places are closed or you know closing, there will be like less response to the growth hormone. And so that's the reason why we don't offer growth hormone treatment for kid or, you know, young adults if they are short, because we know that the growth plates are closed. I see. For the, for the height. So because there's another topic is like the use of growth hormone in adult population, but that's not for the heights. I see, I see. Yeah, so that's why if we have a bone age, it's already indicating it's, you know, the growth plates are closing. That we do not offer growth hor treatment in those cases. Gotcha. So in those scenarios, would a bone age be helpful in determining whether you want to do growth hormone treatment or not? Yeah, so the bone age will help us in the treatment potential. Uh, it's part of the discussion with the family. Gotcha. And then another question that uh they had was, uh, is there any patients uh or families who decline using growth hormone therapy based on those um side effects, um, what do you do? Is there any regrets? What's the counseling around that? Yeah, so absolutely. uh, I mean, as, as we discussed, there's like so many different, you know, indication, and it's you also look at the, those FDA approved indication, some of the indication that actually not like a pathology, like the idiopathic shots that, uh, or the SGA with like a catch up growth. So particularly for the idiopathic shots doctor in some family. Um, they are not very excited about growth hormones. So in terms of like counseling, obviously I think it's important to make sure they understand what are the benefits and what are the side effects and to help them to understand, to make the decision. And once they have all the informed information for them to make the decision, and if they choose to wait and see or like not doing a formal treatment. I think it's still, you know, the patient's choice, um, but I always kind of counsel them. I mean, as long as the growth place is still open, uh, if at any point, they think, you know, they want to revisit the conversation, then we can. I mean, even they decline at the beginning, some families, some patients might come back, you know, 6 months later. Wanted to, you know, you know, to try on the growth hormone. But I do, I do have patient that eventually they decline and especially depending on the patient's, you know, background. So here also brings like why we are seeing some disparity because I think not just like the provider, you know, um, bias. Well, I guess also like Family, you know, like, um, their, uh, social bias and what like the parental willingness of getting treatment. I see. OK. Um, and then that the previous question sparked a couple other questions about uh growth hormone treatments into adulthood. Um, what are the benefits there, what are the indications? Yeah, little bit of a can of worms I feel like we got into. So, I mean, this is another big topic. So it's like a growth hormone deficiency in adult. So again, you know, we use growth hormone treatment for pediatric growth hormone deficiency more mainly it's for the height benefit. But once they're done with the growth of the growthplace are completed, obviously, we do not expect any more like increase in the height. But studies now showing the use of growth hormone in adult growth hormone deficiencies more for the metabolic profile, more for the body compositions and Um, energy and also, you know, those are like non-height benefits that observed in patients with growth hormones, uh, in adults. So again, this is also a discussion with patient transition and whether they want to like continue with the growth hormone and it tends to be a smaller dose. Gotcha. Um. The other question, we talked about some different formulations of growth hormones that were available. Um, do you have any preferences or is there any indications on which one you use based on age or comfortability? No, so I think ultimately it's. Obviously, I mean, the insurance is actually the biggest uh barrier, whether we can choose the daily versus the weekly and also the weekly preparation now is only approved, um, you know, get covered by growth hormone deficiency. So for some of the indication, unfortunately, we need to stay with the one. Daily injection. And then for the different brands, they're actually pretty, you know, um, equal. So again, so from time to time again because of the supplies and also the changes to the insurance, patients actually have to like change from one brand to another. Gotcha. And then I think effective and obviously I, I mean just a follow up. I mean, I usually will prefer the longer acting one for the growth hormone deficiency kits because it definitely show improve compliance and less burden of injection. Got you. And then I think we have time for one more question, but for everyone else, we haven't gotten to the questions for, would it be OK if they email you or message you directly? OK. And I will also send, I send you the power like the slide, yeah, yeah. Um, could you, I know you talked about, uh, the bone age and how it goes into an algorithm and trying to figure out, uh, what the age is based on, uh, trying to match things up. Is there any way that the general pediatrician working outpatient can have any sense of that or can we learn to read it a little bit to help guide parents in the moment at least, or do we just wait for the read? Uh, well, we, I mean, because, yeah, but certainly that's like way to learn, but yeah, how we do it is actually really comparing with an outlets of the various pictures. So for the general pediatrician, if they have, you know, those pictures again, this is kind of like a pattern recognition. Yeah, I mean, that could also be um. Helpful, but yeah, I mean, I'm happy to talk about how to read the phone ages in a different, you know, session, if it's really something like of an interest. Gotcha. OK. Well, that brings us to 9 o'clock. Uh, unfortunately, we won't go through all the questions, but, uh, feel free to email uh Doctor Nip and thank you for joining us for Grand rounds today. All right, thank you very everybody. Have a good day. Bye. Created by
