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Transcript: Recognizing syndromic and secondary causes of GHD
Lars Sävendahl, MD, PhD, Bradley S. Miller, MD, PhD
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- [Brad] Hi, my name is Brad Miller and I'm a pediatric endocrinologist at the University of Minnesota Medical School and M Health Fairview Masonic Children's Hospital. Today I'd like to introduce the podcast, "Bridging growth hormone deficiency gaps: From complexity to continuity". Today's topic is recognizing syndromic and secondary causes of growth hormone deficiency, and I'm joined by Lars Sävendahl.
- [Lars] Hi, I am Lars from Karolinska Institute in Stockholm, Sweden. I'm pediatric endocrinologist, and I'm also senior physician at Astrid Lindgren Children's Hospital at Karolinska University Hospital in Stockholm. Pleasure to meet you, Dr. Miller. - So great to talk to you tonight. What I'd like to start with is which clinical features should prompt clinicians to look beyond isolated growth hormone deficiency and consider syndromic or secondary causes? - To me, looking at the growth curve and losing growth percentiles between one and two years of age is to me a quite strong indication that there might be a syndromatic short stature. We all know that growth hormone deficiency rarely presents with growth failure before one year of age. And of course a familial short stature can also present second year of life. But a clear loss of growth precentiles during second year of life is suggestive of a syndrome. And if you look for example, at Turner Syndrome patients, most of them have lost growth potential during their second year.
- [Brad] Excellent. The other things that we think about as early warning signs, aside from the growth pattern, what are some of the other symptoms or physical changes that we would look for to identify those other conditions?
- [Lars] Of course, developmental problems, neurodevelopmental problems. We always look for any syndromic features, malformations, micro or macrocephaly for example. And of course all the syndromatic, we have full pediatric endocrinologist and geneticist. We have a quite systematic way of going through the patient. I usually go from top to down and starting with the hairline and then the forehead and the eyes and going down and ticking off. And I think if you do that systematically, you are quite likely to pick up any syndrome, even if you can't really point out what syndrome, if you have done this systematically in many patients, you are quite good at this.
- [Brad] When we think about the very early patients who have growth hormone deficiency, are there some key signs that we should be looking for for those congenital syndromes or genetic syndromes that have a growth hormone problem?
- [Lars] I mean, congenital growth hormone deficiency, which is often malformations, boys micropenis is what we look for. Symptom could be hypoglycemia, especially if there is a multiple pituitary hormone deficiency where you have both cortisol and growth hormone deficiency. So there are ways to diagnose based just on clinical signs and symptoms, pituitary deficiency including GHD, very early on in life and during first year of life, as I said, we cannot really rely on growth.
- [Brad] What are the family history diagnostic clues? Are there any connections we can make from the family related to growth hormone deficiency? And how often is that growth hormone deficiency itself a genetic condition that you see?
- [Lars] Yeah, of course if the patient grow much below the genetic height, we always calculate the mid parental target height. And if the patient has a growth trajectory, which is clearly below more than minus two standard deviation below the target, that suggests a problem, right, which could be syndromatic. Then of course if there is any history of a genetic disorder in the family is very important. It could be a recessive, it could be dominant, it could be X-linked, right? So you always should ask for this in your family history. And when taking family history, do it in three generations. I always plot a growth chart, three generation growth chart. And if you do that graphically, you can quite quickly pinpoint whether this is a genetic short stature or whether this might be an autosomal dominant disorder, for example. And other questions I usually ask because I also run a tall stature clinic is or a sudden death in any family member at a young age right? Which can indicate the syndrome when it's on the tall side is Marfan syndrome, but there're also other syndromes where you may die early on, right, from a syndrome.
- [Brad] No, I think, no, very good point. And I've definitely had families where I've seen the adult and then the child, who both have the same genetic cause for growth hormone deficiency. And so they weren't necessarily syndromic, if you will, but they had, as you mentioned, a genetic cause of a growth hormone problem. So when do you think genetics is necessary in our evaluation for children for growth in general and then more specifically growth hormone deficiency?
- [Lars] I think it is, you need to be very careful when performing genetics and I think it is good to follow algorithm when it comes to performing genetic workup. I strongly recommend the newly published international guidelines published in the European Journal of Endocrinology just a few months ago here in 2026 by Andrew Dauber and many international co-authors. And they give guidance on when to perform genetic testing and what genetic testing and an algorithm. So depending on what symptoms you have and likelihood to have a genetic course, you perform different testing and they classify patients into isolated short stature, those who might have skeletal dysplasia, those patients who might have defects in growth hormone IGF axis, and those who might have syndromic short stature. And as we discussed earlier, if you have for example, neuro developmental disorders or major malformations, then you should consider referring to clinical geneticist. And depending on them, whether it's recognized or unrecognized syndrome, we can do either targeted testing or consider referral to a medical geneticist to perform more advanced genetic testing.
- [Brad] I think it's an area where we as pediatric endocrinologists are becoming more involved and one of the challenges is access to that medical geneticist or genetic testing, whether it's because of insurance barriers or referral challenges. And so I think we as pediatric endocrinologists need to learn more and arm ourselves for interpreting the test, but continue to partner, as you said, with our genetics colleagues for phenotyping as well as interpretation and recommending of the proper testing. So definitely.
- [Lars] Testing becomes less and less expensive and we need to really be aware of the potential benefits and risks of performing a test. And we need to always involve the family and the patient in that decision-making, whether to perform the testing or not, because the false positive is quite high in these genetic testing when you can make a lot of secondary findings, which is irrelevant.
- [Brad] Yeah, let's transition now to secondary causes of growth hormone deficiency. And I know that you have been involved in caring for children who have developed a growth hormone problem because of their medical conditions that they've experienced. So what are the things that we need to focus on there?
- [Lars] Of course, secondary then we need that there's another cause, right? Like a damage or disorder of the pituitary or hypothalamus rather than a genetic, right? And this could be, for example, craniopharyngioma, it could be post-radiation for neuro brain tumor or post-surgery. In some cases also it could be post-traumatic, these secondary growth hormone deficiencies. And here of course we'll have a lot of help from just a medical history from neuroimaging of course and the physical exam and labs. But here often we need to include neuroimaging in evaluation.
- [Brad] Yeah, I think traumatic brain injury is an unrecognized potential cause I've taken care of a few children who had long-term growth failure after a significant traumatic event that wasn't recognized as related to growth hormone deficiency. The other piece, intrathecal chemotherapy has been recognized over time as being an a risk factor in some of our cancer survivors. And so in addition to radiation, I think those are key questions.
- [Lars] And one other important underlying cause is glucocorticoids. That's my research taught an area actually, negative consequences of glucocorticoid treatment on growth. And many of these patients have been treated on quite high doses of GCs, glucocorticoids. So always look at the medicines, whether there is any treatment that might affect growth negatively. Even inhaled steroids, even the asthma patients on high doses of glucocorticoids often present with the growth failure and sometimes end up in peds endo clinic. So that's of course one important differential.
- [Brad] Good question. When you're thinking about the diagnostic workup for syndromic or secondary growth hormone deficiency, what are the things that you should be focusing on?
- [Lars] Neuroimaging, as I said, is of course important there and then we need to do the labs as well, right? But of course if we have a history of brain surgery or radiation and we know based on the radiation dose, that is very likely that the patient will develop growth hormone deficiency and the patient present with short stature and low IGF1, we do not necessarily need to do full pituitary testing. So then diagnosis is quite easy.
- [Brad] What are some of the limitations of the tests that we use, particularly in individuals with secondary growth hormone deficiency? I find that sometimes our testing isn't as helpful as we'd like it to be.
- [Lars] I entirely agree. Entirely agree.
- [Brad] So the growth hormone deficiency stimulation tests sometimes is normal in children who have a clear damage to the hypothalamus and pituitary.
- [Lars] Correct.
- [Brad] Sometimes if they're overweight, their IGF1s aren't as low as we would expect them to be. So those I think are some of the things that I've noticed in my clinical experience.
- [Lars] I totally agree.
- [Brad] I mentioned earlier how we capture these patients and part of the challenge is how do we talk to our colleagues to make sure that these children are being referred, whether it's the geneticist, the neurologist, or the oncologist, and how can we make improve that process?
- [Lars] I think multidisciplinary team conference, we always have that actually every morning in our peds endo clinic, where we discuss new referrals and who to see the patient and what team to see the patient. So individualize and sometimes you need all these specialists, sometimes you do not need it. So individualize your team members.
- [Brad] For us, the oncology team is one of the key partners. And personally I am in the clinic with them every week as part of watching children as they're going through their therapy early in the diagnosis and then continuing to follow them afterwards. But it's interesting, that seems to work for our brain tumor patients, but less so for our leukemia patients. And so sometimes I'm not there on the day that the leukemia patients are there. And so I think it's really important to develop those workflows with the teams to make sure that we're catching everybody.
- [Lars] Yeah we have a similar setup here, regular conferences with our oncologists and I think that is really advisable to have.
- [Brad] The bigger challenge is the primary care provider who's seeing patients in the community, what has worked for your system in terms of educating and communicating with them to make sure the patients come to see us when they should.
- [Lars] Either by regular meetings, where we invite primary care physicians and importantly local regional guidelines. So how to work up the patient in primary care and when to refer the patient to the specialist. Such written guidelines, I feel is very beneficial. And if you have those guidelines, you can ensure that the patient always arrives in your clinic with quite complete growth chart, for example. And the medical history information that you need. And also some basic workup that we stress the primary care physicians to do prior to referring to exclude other causes of short stature. I mean many chronic disorders we know including family psychological problems may present as with short stature. And they, I personally believe should not end up in peds endo specialist clinic. They should be handled by primary care.
- [Brad] When you think of the children with syndromic causes of growth hormone, hormone deficiency, they often have other associated genetic or birth defects. How does your team partner with trying to make sure that they're seeing all of their specialists in a coordinated way?
- [Lars] We have clinical guidelines for each of these syndromes detailing how often and when to meet these different specialists. So it's kind of an algorithm and an Excel sheet. So not to miss anything. And this is also shared with the families and patients. So they are also aware and I think to involve the families is important because then we reduce further the risk that we miss something.
- [Brad] Yeah how do you, in your system, is that, is the nurse in charge of that? Is there a complex scheduler that keeps track of that or is that more on the families? What's worked in how your system tries to coordinate that care?
- [Lars] So for each, I mean for this guidelines, each specialist clinic have their own system to ensure that you have the ophthalmology checkup every year. They have the cardiology every year, et cetera. But we have always one kind of primary specialist who take care of the patient. Often it's the peds endo to ensure that these, all these other specialist visits take place at the right time point. But often it works very well because everyone is aware of these guidelines and automatically call the patient back. I think it works pretty well.
- [Brad] I think that is a challenge in different systems to figure out who is in charge of those pieces and making sure, you know, as a pediatric endocrinologist, I think of myself as a complex pediatrician for, you know, the quarterback for many of the children with rare diseases. And so I find myself referring them back to the cardiologist because they haven't been to see them for some time, et cetera. So I think it's an important thing to decide who is that person for each individual condition.
- [Lars] Agree.
- [Brad] Are there any other key points that you would wanna bring up for either helping that long-term monitoring or the initial diagnosis or the acquired growth hormone deficiency? Any other thoughts that you'd like to share?
- [Lars] I think we have covered this quite well, Dr. Miller today and to you who listened to this podcast, I really encourage you to look into this clinical guidelines by Andrew Dauber in European Journal of Endocrinology, published earlier this year, 2026, the international guideline on testing of children with short stature genetic testing and follow the algorithm there, which is very much in line of what we have discussed today in our podcast, Dr. Miller.
- [Brad] Absolutely. No, I think that the genetics of all of our conditions is gonna be really important. We, as pediatricians, sub-specialists, et cetera, are going to be learning how we incorporate the genetic tests into the care, individualized care of our patients over time. So I think it's a really key topic and an excellent consensus group that came together specifically related to growth.
- [Lars] What I should also mention, Dr. Miller, is that artificial intelligence, there are ways now to diagnose syndromes. There are legal aspects there to be cleared out and which is often a problem. But if you can solve this and use, there are commercial tools and also free tools to diagnose syndromes just based on pictures. Geneticists use this quite frequently. I've tried that in my own clinic with quite good success.
- [Brad] Well, thank you very much Dr. Sävendahl for this conversation today and look forward to talking again.
- [Lars] Very nice talking to you, Dr. Miller, and have a nice day today. Bye.
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