Good afternoon. Thank you, Chairperson, for the kind introduction and many thanks to the organizing committee for the invitation to participate in this meeting. I was really looking forward to be with you in person. However, unfortunately, this was not possible. Here are my disclosures. Short stature is one of the most common reasons of referral for pediatric endocrinology clinics, and it accounts for approximately 40% of new patient referrals. Many families may actually present with the explicit question of whether growth hormone therapy should be administered to their child. However, most patients referred for short stature do not have organic disease. The majority of referrals fall within one of two categories, either familial short stature or constitutional delay of growth and puberty. In pediatrics, growth is considered a vital sign and pathologic short stature should not be missed. Here are some examples from my own clinic of patients who all presented with a chief complaint of short stature and ended up with a myriad of previously undiagnosed diseases. I picked a few for the purpose of this presentation from whom I learned some lessons that I would like to share with you. Let's start with Karim. The patient name is made up, but all the details are real. He presented at four years and 10 months of age with short stature, height plotting at the third percentile, past medical history, recurrent tonsillitis, underwent adenoidectomy and tonsillectomy, birth history, normal birth weight, no perinatal issues, on review of systems, no headaches, no polys, no vision issues, no fatigue, change in activity, appetite, sleep pattern or school performance. However, he seemed to be gaining weight more than height. In fact, his weight plotted at the 78th percentile and his body mass index at the 98th percentile. His family history was significant for thyroid disease on maternal side with a no history of short stature, no growth disorders, no puberty disorders. And his mid-parental height was 179.9 centimeters, plotting close to the 75th percentile. On physical exam, he did not have syndromic or cushionoid features. He was proportionate with normal upper to lower segment ratio. He had abdominal obesity, no goiter and no neurologic deficits. So let's start with some basic questions. Does Karim have a short stature that warrants evaluation? Do you need additional history and data? What would be on your differential and which labs and imaging would you order? So according to the Hormone Research Society International Consensus, children with any of the following characteristics should be considered for evaluation of pathology. First, if they have a short stature with a height below minus two standard deviations, that would correspond to the third percentile on the growth curves. Second, if they have a height that clearly deviates from the familial background, meaning a height that is more than one percentile, that is more than 1.5 standard deviation below the mid-parental height, that would be approximately 10 centimeter difference in adult height. This has to be taken with caution. First of all, you need to have accurate measurement of the parents' heights. And second, if let's say dad is 190 centimeters tall and mom is 155 centimeters tall, then the interpretation of mid-parental height deviation need to be taken with caution. And the third criterion is a significant deceleration in growth velocity that is not explained by the normal channeling that we see in infancy where a child may be born small and catch up to his genetic potential or may be born large and catch down to his genetic potential. And also a deviation in growth velocity not explained by the pre-pubertal growth deceleration or by pubertal delay. This is the formula commonly used to calculate mid-parental height, which is the expected height of an individual given their parents' heights. And it is corrected to plus or minus 6.5 centimeters or plus or minus eight centimeters depending on which formula you follow. Some points to consider. Always accurate measurements, whether you're using the newest electronic device or the oldest device, the positioning of the head of the child in the Frankfurt position and using a consistent technique is always important. Measure the parents if possible. If you have a small child and you're measuring them supine, this is length plotted on the curves for those below two years of age. There is always a debate on which growth curve to use, WHO or CDC or the local curves. Regardless of which curve you are using, be consistent in the curve that you're using and take into account that the mean height on the growth curve that you're using may not be the mean height for the population your patient is coming from and take that into account. And also it is important to use appropriate curve for age and sex and to do accurate plotting. It may seem trivial, but this is the same patient with heights we plotted. If you are using an electronic health record system, it is easy to make the accurate plotting. However, with old paper and pen, it is easy also to make mistakes. Another element to pay attention to is attention to growth velocity in context of age and pubertal status. In this graph over here, over this axis you have the growth velocity in centimeters per year and over this axis you have the age. During infancy, there is a rapid growth velocity up until two to three years of age. Then a growth velocity slows down to between four to six centimeters in childhood. And there is a pre-pubertal growth depth followed by an acceleration in growth velocity that happens a little earlier in girls and then in boys and followed by completion of linear growth. And whenever interpreting growth velocity, take into account the age and the pubertal status. You can use the height velocity curves and they do take into account the late bloomers. And you can see over here for a late bloomer with pubertal delay, the deceleration and growth velocity can be steep and usually they end up catching up. I cannot overemphasize how important it is to take a thorough history and clinical exam in the evaluation of a child with a short stature, looking at their birth history, at their overall medical history, taking details of the familial heights, their puberty timing, the nutritional status of the child, their psychological status, and very important if you can get their prior growth records to see their pattern of growth. For physical exam, in addition to the general detailed physical exam, pay attention if the child is proportionate, sitting height, arm span, head circumference, looking for midline defects, potential syndromic features. Skeletal changes and skin stigmata. And the laboratory evaluation and the imaging should be targeted to the clinical scenario. So back to our patients. His height at initial presentation was on the third percentile, so not below the two standard deviations. However, he had a clear deviation from the familial background and he plotted along a percentile significantly below the lower end of the familial height target range. And we were lucky to have a prior growth record from when he had his surgery at our hospital. And there was a clear deceleration in growth velocity. A year back, he plotted on the 11th percentile and now he is on the third percentile for height. And in addition, he had an increase in weight, no systemic symptoms, and no neurologic deficits. And the family history is positive for thyroid problems. What's on your differential and which labs or imaging would you want to order? Here's a list of what is commonly ordered for patients with short stature. For Karim, this is what we ordered. And I'll give you the results. Everything turned out to be normal, including the thyroid, which was actually the first on my differential, given his increase in weight and the deceleration in height and the positive family history of a thyroid disease. The IGF-1 was normal, the IGF binding protein was normal, and the bone age was normal. So what's your next step now? Would you reassure since all labs are normal? Would you follow up? Or would you go for growth hormone stimulation testing? For us, since it was the first time I see him in clinic and I wasn't a hundred percent sure whether the height taken at the time of surgery was accurate or not accurate, and all his labs were fine, and his clinical presentation was basically okay, we decided to follow up. And he returned a few months later. He had no new clinical signs by history, and his exam was still normal. His height actually was still tracking along the third percentile. We repeated the IGF-1 and the IGF binding protein three, and both of them were low. The TSH and the 3T4 by repeat were also normal. So what's your next step now? Now we went for the growth hormone stimulation test. And the results on two different stimulation tests were severe growth hormone deficiency with a peak growth hormone below three nanograms per mL, and a normal cortisol response during insulin-induced hypoglycemia, speaking of an intact pituitary-adrenal axis. So what's your next step? Would you start growth hormone treatment? Would you do an MRI of the cell lab brain? Or you do not believe the test results? So this is actually clear growth hormone deficiency, and we went for MRI imaging, and lo and behold, there was a 3.5 by 2.2 and 2.6 centimeter solid and cystic lesion occupying the superior cellular region and involving the pituitary stalk. And it turned out to be a craniofaryngeoma. So this was his first visit to our clinic. As soon as we diagnosed the craniofaryngeoma, he underwent surgical resection. Unfortunately, due to the location of the tumor, he ended up with multiple pituitary hormone deficiencies. And we started hydrocortisone treatment, tyroxin treatment, and desmopressin. And around a year later, we started growth hormone treatment. Very important point to make here that I'm sure you're all aware of. It's always very important to respect the order in pituitary hormone replacement, hydrocortisone replacement, then tyroxin replacement. Of course, for desmopressin, you can start from the get-go and later on growth hormone replacement. So growth hormone was started around this time, and I've been following him for all those years. He had an excellent response. At 12 years of age, he was at a percentile commensurate with his mid-parental height target. And then he seemed to be slowing down. Would you think why he slowed down during this period of time? Although he was taking growth hormone, appropriate IGF-1 levels, proper compliance. So the answer is he also has hypogonadotropic hypogonadism because of his pituitary deficiency, and he needed puberty induction. And this slowing down is due to puberty not starting. He, in fact, did not want to take an additional injection, and we agreed to give him a little bit of time. I saw him most recently at 14 years of age in July. He was 160 centimeters tall, and we initiated testosterone treatment for puberty induction. And we will be seeing him back in a few months, hopefully. So the key learning points from Karim's case is the importance of clinical follow-up and re-evaluation, and also that IGF-1 can be normal and newly acquired growth hormone deficiency. Bone age can also be normal despite growth hormone deficiency if there is obesity, because obesity leads to bone age advancement, or if there is newly acquired growth hormone deficiency. Another point to make in the case of Karim is that it is essential to do an MRI of the cell block brain when there is confirmed growth hormone deficiency. Another point that you may be asking in your head, how come he didn't have other symptoms? In fact, Karim only had short stature and obesity, no other symptoms, no neurological symptoms, no other deficits. This is a review of the manifestations of craniopharyngioma prior to diagnosis, and growth retardation can be an early manifestation in around 15% of patients. It's not clear whether in this study it was an isolated manifestation or together with other manifestations. And the median time from the appearance of growth retardation to diagnosis was around 24 months. So again, another lesson to be always thorough, even if there are no neurological symptoms to get actually an MRI once growth hormone deficiency is diagnosed. And to that point, the current guidelines recommends universal MRI imaging for any child with a diagnosis of growth hormone deficiency. There is a recent study that attempted to find a correlation between the severity of growth hormone deficiency and the yield of the MRI. So the researchers divided the patients into three groups based on the peak growth hormone response to stimulation, group A with a peak growth hormone response below five nanograms per ml, group B, five to 7.4 nanograms per ml, and group C, 7.5 to 9.9 nanograms per ml. In all groups, abnormal MRIs were detected in all severity levels with the highest frequency of around 37% in those with severe deficiency and in those with multiple pituitary hormone deficiencies. Here are the abnormalities that were detected. It's important to note that the majority had the normal pituitary even in group A with the severe deficiency, with the exception of those with multiple pituitary hormone deficiencies. And the abnormalities detected were ectopic posterior pituitary, interrupted pituitary stalk, hypoplastic adenohypophysis, septo-optic dysplasia spectrum. A tumor was detected in 8% of the patients with severe growth hormone deficiency, and four of those were craniopharyngiomas. So as a conclusion, there is no optimal cutoff of peak stimulated growth hormone level at which imaging was more likely to detect pathology. And as things stand right now, if you are sure of your diagnosis of growth hormone deficiency, it is better to get an MRI before starting treatment, especially if it is severe deficiency or definitely multiple pituitary hormone deficiencies. Let's move on to patient case two, and let's call him Tarek. So Tarek presented at 11 years, nine months of age. He was noted by his primary care physician to be short. A bone age was done, it was read at seven years, and this triggered a workup. IGF-1 was low, IGF-binding protein three normal, had had a normal CBC and normal baseline testing. A growth hormone stimulation test was recommended by his physician and an MRI, but the parents preferred to get a second opinion. So we obtained some more history. The parents did not note slowing down in his growth, but they say he is usually shorter than his peers. He is healthy, he had a benign murmur, and cardiac evaluation was normal, and he had no developmental delay, no perinatal issues, and negative review of systems with no noted puberty signs. Family history positive for short stature in parents. His brother is however tall, and he was a late bloomer. And there is also constitutional delay in his cousin as well. And on physical exam, he had a normal exam, and he had a soft murmur, and he was starting to have some enlargement of the testicles with no pubic or axillary hair appearance. So we obtained his oxology. His height at our first evaluation was 142 centimeters, plotting at the 21st percentile, and this is where his mid-parental height plots. So his height is well within the upper range of the mid-parental height target range. His weight and BMI were on the 7th percentile. And I was lucky enough to have prior growth data from his growth records from the primary care physician. And it was clear, we plotted them, we entered the data on our curves, and it was clear that he's following his own curve with no deceleration and growth velocity. So what we have is a normal height for age and sex, normal height for genetic background, normal growth velocity, no syndromic features, no systemic disease, no developmental delay, but a low IGF-1 for age and Tanner stage. I also reviewed the bone age and it turned out to be normal 10 years, six months within two standard deviations for age. So what is your next step? Would you proceed with growth hormone stimulation testing because the IGF-1 is low? Would you get an MRI cell law? Or would you look for other causes of low IGF-1? Or would you repeat the IGF-1 in a different lab? A reminder that he had a normal thyroid test, negative celiac screen, normal CBC, and normal baseline testing. So we decided to repeat the IGF-1 in our laboratory and the value came back normal, 137 nanogram per ml. And actually it was in line with his clinical picture. So I felt comfortable to tell him, we don't need to do anything right now and let's just keep a close clinical follow-up and see you back in a few months. I saw him back last week actually, and his height is still tracking along the same percentile and we're repeating an IGF-1 TFTs and we will keep a close follow-up. So what's the point of this case? The point of this case is to point out the variability in the IGF-1 assay between laboratories. This is actually worldwide known. And in fact, in 2009, there was an international standardization for IGF-1 immunoassays by the WHO. And the IGF-1 variability in the assay could be due to several factors, from poor antibody specificity, to the method of calibration, to the reference range establishment. There is a recent study that actually compared the IGF-1 results on four different platforms and using three different immunoassays and one mass spectroscopy assay, and both actually using the WHO standards. And still there was a variability between different laboratories. So the key point, another, sorry, before that, another point to take into account when interpreting IGF-1 and IGF binding protein three levels is to look at the reference range for age and to make sure that the lab is providing a proper reference range for age. And also to take into account the Tanner stage. So if you have an adolescent who is, let's say a female who is 12 years old and who has not started to have any pubertal signs yet, you have to take into account that you would compare the IGF-1 to Tanner stage one, not only to her age. Otherwise it would look falsely low. So the key points to take from this case presentation is that you need to use a reliable assay and reliable reference data for IGF-1 and IGF binding protein three levels. And the ranges will differ based on age, sex, and pubertal status. Also very important that the levels can be affected by malnutrition or undernutrition, by chronic illness, they can be low, by liver disease, they can be low, and thyroid disease also, they can be low. There is limited value in children below three years of age. So I don't usually order it unless I'm looking for something. And it's not very reliable in survivors of childhood cancer. If the IGF-1 level is above standard deviations at any age, usually growth hormone deficiency is unlikely. And IGF binding protein three may be more reliable in children less than three years of age, but is less sensitive than IGF-1 after three years of age. The combination of how IGF-1 and IGF binding protein three can be indicative of some genetic defects. And an elevated IGF-1 level in patients with short stature may indicate mutations in the IGF-1 receptor or the PapaA2 genes. This is specifically in the IGF-1 receptor, it would be a severe short stature. So the conclusion is treat the patient, not the labs, and reconsider the diagnosis, and reconsider testing when things do not add up. Another point to make and why I did not proceed with growth hormone stimulation testing. Growth hormone stimulation tests have their limitation. First of all, they're not 100% sensitive and specific. You need two tests, they are invasive. Several agents are used. We're trying away from insulin due to the potential side effects with hypoglycemia, but sometimes I end up doing it. There is always a debate whether to prime or not to prime children who are at an adolescent age group and who have not yet started puberty. And the consensus right now among most people is to do priming for boys and girls if they are at an age where they're supposed to be in puberty and they haven't started puberty before going for a growth hormone stimulation testing. Always consider the obesity effect on testing. Patients who are obese will have a paradoxical, will, the obesity will affect the results of growth hormone stimulation testing and also very important to respect the order in testing. And what I mean by this, make sure that you have ruled out hypothyroidism, you have ruled out any other conditions before proceeding to growth hormone stimulation testing because it will give you a false positive result. And in certain situations, it's not necessary. If you have a clear cut multiple pituitary hormone deficiencies with a clear cut pituitary problem, you may not need it. Also another point of continuous debate is which cutoff to use, seven nanograms per ml or 7.5 nanograms per ml or 10 nanograms per ml. It depends on which country you practice in and which assays you are using. But this is also another point that is being considered. The more current guidelines cite seven or 7.5 nanogram per ml as the cutoff for normal peak growth hormone during stimulation. And the one important point to make is not to rely on growth hormone stimulation testing as the single diagnostic criteria for diagnosis. It has to be with other clinical features that do add up. And I'll give you an example also from clinic. This is a patient who presented to us for a second opinion regarding the need for growth hormone treatment. She was tested at six years of age and apparently she failed growth hormone stimulation testing and received six month treatment of growth hormone. I'm not gonna bore you with the details but she had a normal evaluation and upon questioning, she never really had short stature. She never really had a poor growth velocity and she was growing at a percentile appropriate for her genetic background. So it took some courage to stop treatment but I actually told her let's stop treatment and see what happens. And we've been following her up and she's following the same percentile. So again, following growth velocity over time and considering the whole picture is extremely important. Growth hormone stimulation testing is very important but when done in properly chosen patients and do not use it as the only indication to diagnose growth hormone deficiency. Let's move on to the third patient case. This will be a little bit faster. This is a nine-year-old girl, Serena with short stature and developmental delay. She presented to my clinic at nine years of age and she had growth delay starting five years of age. She was followed for a long time by neurology for developmental delay and speech delay. No seizures, normal birth history, normal birth weight and no recurrent illnesses. She actually had seen pediatric endocrinologist before coming to our clinic and she underwent a stimulation test that were normal. She had a normal bone age. She had an MRI brain as part of evaluation of her developmental delay and it didn't show any pituitary abnormalities. Her family history, some short stature on that side and nothing really pertinent except for paternal cousins that are receiving growth hormone treatment but we didn't have further details on them. The most important part of her presentation was her physical exam. So she had almond shaped eyes. The ears were not low set. Her neck was slightly short with no webbing, no goiter, no murmur and a normal cardiac exam. She had a short fourth metacarpal and peculiar hands and she had a shorter lower segment and she was standard stage one for puberty. This is her growth curve, short stature below the first percentile and below the lower range of the mid-parental height target range. And I was reviewing her labs and her imaging and I looked at her bone age and the bone age gave away the diagnosis. So can you guess the diagnosis? So yes, I'm sure you guessed right. Those radiologic findings are indicative of shocks insufficiency. And what you're looking at over here is the X-ray of Serena and over here is the X-ray of Malak, another patient of mine also with shocks insufficiency. You can see the triangularization of the distal radial epiphysis and both of them, the dorsal subluxation of the ulnar head, the looseness of the ulnar border of the distal radius, the pyramidalization of the carpal bones. You can see it in both of them as well. And more so in Malak, you can see an enlarged radius with the bowing. So Serena turned out to have a deletion in XP22.2 and by fish for the shocks region, she had one hybridization signal indicating that there is a shocks deletion. Shocks haploinsufficiency actually accounts for two to 5% of idiopathic short stature. And it is an approved indication for growth hormone treatment. And the shocks gene defects can vary in the severity of the phenotype. For those who have homozygous mutations, they have a very severe phenotype with a longer mesomalic displacement or a mesomalic dysplasia. Those with less severe phenotype are the Larry-Wilde dyschondrosteosis. And there is a much milder phenotype like our patient, Serena, who would present with only short stature. It's important to note that those patients have normal intellect. And in the case of Serena, the developmental delay was related to the deletion of the XP22.2 region. And this region actually contains the shocks gene and shocks gene refers to the short stature homeobox containing gene. And it is present on the pseudoautosomal part of the X and the Y chromosome. The predictive auxologic indicators for shocks deletion that you can actually detect on physical exam are an increased fatigue to height ratio, a decreased arm span, and of course, the radiologic signs. And if the patient has the severe form, you can even see the medullary deformity. Some points to consider with the bone age. Accurate reading and interpretation is always key. And it is typically delayed in patients with growth hormone deficiency. However, it may not be the case with the recently acquired growth hormone deficiency. It's not very helpful if the child is below two years of age. Actually, most experts would say, obtain it after five years of age. But it can be helpful in identifying some subtle signs of skeletal dysplasia, like in our patient. And in advanced, in one of the mutations that was a few years, described a few years back, a bone age can be advanced with short stature. It may suggest a mutation in the aggrecan gene. And remember that it can be advanced despite growth hormone deficiency and severe obesity like our first patients. I will end up with this quick case. This is an 11-year-old girl who presented to clinic for short stature and obesity. And over the one year prior to presentation, she had only grown one centimeter. And she had a low birth weight, 2.6 kilos, recurrent abdominal pain, a history of frequent otitis and tonsillitis. And her family history is actually significant for tall stature rather than short stature in both her mom and her dad. Some short stature, but still within acceptable limits in aunts, and no puberty or growth disorders. On physical exam, almond-shaped eyes again with short neck, long lashes, no goiter, low arched palate, the ears were low-set. She had multiple nevi, no short fourth metacarpal, but had a boxy phenotype and slightly wide carrying angles at the elbows. And she had tanner one breast development, nipples not wide spaced, and no pubic or axillary hair. Laboratory evaluation, normal CBC, normal celiac screen, IGF-1. LH and FSH were high with a low estradiol. And yes, you guessed the diagnosis, Turner syndrome, 45XO. And she had a full evaluation. Echocardiography was normal. All the evaluation for Turner syndrome was normal with the exception of the primary ovarian failure. I'm presenting this case in particular to remind myself and remind you that Turner syndrome is a common diagnosis that is frequently missed. And for this particular patient, because her parents are tall, she did not manifest as much of a severe short stature early on. However, she had the typical deceleration and growth velocity that starts around five years of age and grows with Turner syndrome. And it became more manifest around the time of puberty because she wasn't able to go to a spontaneous puberty. And this brings us to the role of genetic testing in short stature. In general, for patients with identifiable phenotype, it would be better and more cost-effective to do a targeted genetic testing. Nowadays, with the presence of whole exome sequencing and chromosome microarrays, there are several studies that looked at whole exome sequencing for patients with idiopathic short stature, short stature where they couldn't find a diagnosis or as a first tier. And in a systematic review that was done recently, the yield of whole exome sequencing was 27% and of chromosome microarray, 13% in diagnosing a genetic cause of short stature. However, this has to be taken with caution because in most studies, the patients who were included were suspected to have a real cause of short stature. It is a tool that can be used whenever needed. With that, I will close by saying that the evaluation of short stature encompasses a holistic approach to the patient and aims to identify pathology and the diagnosis of growth hormone deficiency remains a clinical one where one synthesizes the auxology, the anatomy, the laboratory data to arrive at a diagnosis. And this is a slide that I like to share because it kind of quantifies the causes of short stature. This is another one looking at pathologic short stature by dysmorphic features being proportionate or disproportionate. No dysmorphic features with increased weight pointing more towards endocrine problems or with a normal or decreased weight pointing towards other disorders. And as a reminder, these are the FDA-approved indications for growth hormone treatment, growth hormone deficiency, SGA with poor catch-up growth, Turner syndrome with poor growth, chronic renal failure, Prader-Willi syndrome, Sjock's deficiency, and only in the U.S., Noonan syndrome and idiopathic short stature. Those two are not approved in most countries in Europe. And idiopathic short stature also is very specific, meaning a height, a projected final height that will be below minus 2.25 standard deviation for the population. So below 160 or 158 centimeters for males and below 150 or 148 centimeters for females. And treatment of idiopathic short stature is another whole topic with lots of discussion and controversy.

short stature

pediatric endocrinology

growth hormone deficiency

clinical evaluation

diagnostic tests

genetic considerations

individualized treatment