Evaluation and Treatment of Growth Failure in Children

CARLOS R. HAMILTON, JR., MD, FACE: Hello, I'm Dr. Carlos Hamilton. Welcome to AACE Clinical Conversations. In this program, we will be discussing the evaluation and treatment of growth failure in children.

Joining me to discuss this topic is Dr. Naomi Neufeld, practicing pediatric endocrinologist at the Neufeld Medical Group and Clinical Professor of Pediatrics at UCLA School of Medicine in Los Angeles. Also Dr. Paul Saenger, Professor of Pediatrics at the Albert Einstein College of Medicine in Bronx, New York. Thank you both for joining me today.

Dr. Saenger, tell us briefly about your evaluation of patients that are referred to you because of growth failure?

PAUL SAENGER, MD, MACE: The child is considered being short when he or she is more than two standard deviations below the mean for this population group or also taking into account the height of the parents.

Two standard deviations is generally the third percentile, so approximately 3% of children may be defined as having short stature.

CARLOS R. HAMILTON, JR., MD, FACE: And if there is a change in their growth curve, if they don't continue to grow, even though they may not be that short, do they still -- are they still considered growth failure patients?

PAUL SAENGER, MD, MACE: That is a very important point. The growth rate is an important point, an important tool in the assessment of short stature because growth rate changes may indicate some growth failure even before the child reaches a position of the third percentile on the growth curve.

CARLOS R. HAMILTON, JR., MD, FACE: I understand. And, in a general medical situation, there are many different situations that can cause this. Obviously, we're interested particularly in growth hormone and those factors, but there are other medical conditions that are considered, are there not?

PAUL SAENGER, MD, MACE: Indeed there are. There are many conditions that impact on growth. There are psychogenic reasons, psychological reasons. There are nutritional causes. There are other metabolic diseases, other systemic diseases like kidney disease, heart disease, lung function abnormalities that adversely affect the growth rate of a child. But some of the causes are, indeed, endocrine in nature, and this is what the endocrinologist then will investigate.

CARLOS R. HAMILTON, JR., MD, FACE: Naomi, who should have then growth hormone studies including stimulation tests and IGF measurements?

NAOMI NEUFELD, MD, FACE: Well, the clinical criteria for this, as Dr. Saenger alluded to, are clearly children whose heights are below the -- two standard deviations below the mean. Also children whose growth velocities have slowed, also children who are short given their mid-parental target height.

For all of those children, we would recommend an IGF-1 level, insulin-like growth factor 1 level and an IGF binding protein 3 level. And if those -- those vary by age and by sex, and they also vary depending on the quality of the laboratory, so you need to make sure that when you do the IGF-1 and IGF binding protein levels, that they're done by a reputable lab.

The reason that we choose those as the initial test is that those can be done at any time of day. They are independent of whether the child is -- has been fed or is fasting, and so they're a good clinical assessment tool that can be done in the initial evaluation.

CARLOS R. HAMILTON, JR., MD, FACE: And IGF, or somatomedin, as some people call it, is a readily available laboratory study that can be done without any special preparation?

NAOMI NEUFELD, MD, FACE: Exactly. Exactly. That -- that's absolutely correct.

CARLOS R. HAMILTON, JR., MD, FACE: And stimulation tests are...

NAOMI NEUFELD, MD, FACE: I reserve stimulation tests for those children whose IGF-1 levels are greater than two standard deviations below that mean for age and gender specifically. Some people have suggested that IGF-1 levels which are low in combination with low IGF binding protein 3 levels are suggestive of growth hormone deficiency. But that may narrow the field a bit too much, so stimulation tests are done generally for children.

CARLOS R. HAMILTON, JR., MD, FACE: But a random growth hormone is not very useful in these situations because it frequently is very low normally, is that not correct?

NAOMI NEUFELD, MD, FACE: That -- that's true. Growth hormone when it's secreted is eliminated from the system within 15 seconds or so, so you really need to perform a stimulation test with any of the well described medications, such as...

CARLOS R. HAMILTON, JR., MD, FACE: We understand that growth hormone is secreted episodically and it's often during the very late night or early morning hours when you're not likely to be drawing blood anyway.

NAOMI NEUFELD, MD, FACE: Absolutely.

CARLOS R. HAMILTON, JR., MD, FACE: So that by the middle of the day when the child is in your office, their growth hormone is oftentimes very, very low anyway.

NAOMI NEUFELD, MD, FACE: It's very low

CARLOS R. HAMILTON, JR., MD, FACE: So measuring IGF-1 and then if that is low doing a stimulation test is clearly in order. And the stimulation test that pediatricians usually use is?

NAOMI NEUFELD, MD, FACE: Generally, the ones that pediatricians use in the office are -- well, pediatric endocrinologists would use in the office are clonidine and L-dopa. And some...

CARLOS R. HAMILTON, JR., MD, FACE: And these are given orally?

NAOMI NEUFELD, MD, FACE: These are oral medications. Some people will use an arginine infusion. There are very few other medications that are used.

CARLOS R. HAMILTON, JR., MD, FACE: And the insulin infusion is not used in children like it is in many adult situations.

NAOMI NEUFELD, MD, FACE: There's -- there is a cause for concern to use insulin infusion, unless you're doing it within a hospital setting...

CARLOS R. HAMILTON, JR., MD, FACE: I understand.

NAOMI NEUFELD, MD, FACE: ...with a crash cart available.

CARLOS R. HAMILTON, JR., MD, FACE: Dr. Saenger, what treatments are available for the treatment of growth hormone deficiency or growth hormone failure in these patients?

PAUL SAENGER, MD, MACE: Well, we have had growth hormone available since the 60s. First, it was the growth hormone extracted from pituitary glands obtained at autopsy.

CARLOS R. HAMILTON, JR., MD, FACE: Yes.

PAUL SAENGER, MD, MACE: And since 1985, recombinant DNA-generated growth hormone is available, and that has really changed the field. Because for the first time, we had enough growth hormone available to treat all the children with growth hormone deficiency, whereas before we couldn't really do this.

So growth hormone is the cornerstone in the treatment of children with growth hormone deficiency, but it's also been approved and has been successfully used in a number of other conditions that go along with profound short stature and impaired growth but are not associated with growth hormone deficiency, such as Turner Syndrome, the short stature associated with chronic kidney failure, and also in children who are born small for gestational age, but fail to show appropriate catch-up growth by age three years.

And with this therapy that is long-term therapy, we have been able to achieve excellent growth rates. For children with growth hormone deficiency, we have been successfully achieving heights at the end of therapy that are close to the normal average height.

CARLOS R. HAMILTON, JR., MD, FACE: Really? And this is beginning at what age?

PAUL SAENGER, MD, MACE: Clearly, duration of treatment as well as compliance and appropriate dosing of the therapy are paramount. So average treatment duration in growth hormone deficiency is at least four to five years -- in many children even longer. So it is clearly a long-term treatment and short-term gains will not lead to successful improvement of adult height.

CARLOS R. HAMILTON, JR., MD, FACE: But if you -- if you can make these diagnoses by the time a child is 4 or 5 or 6-years-old, there is a very good chance that they would reach, say, the 50th percentile for their -- what you would expect.

PAUL SAENGER, MD, MACE: That is correct. In some cases of growth hormone deficiency, the diagnosis is made already in the newborn age because they have other problems such as low blood sugar, prolonged jaundice and it's made right away and treatment is initiated then.

In other children, yes, the pediatrician should refer these children to an endocrinologist as early as possible.

CARLOS R. HAMILTON, JR., MD, FACE: Now these treatments are obviously effective in patients who have growth hormone deficiency. Are they equally as effective in patients that have growth failure due to some of these other causes that you alluded to?

PAUL SAENGER, MD, MACE: They are effective. However, they're not as effective as in growth hormone deficiency, and we have to clearly say this. However, for example, in Turner Syndrome, we are successful to get these courageous young girls to a height of about five feet, which in most instances is quite satisfactory.

CARLOS R. HAMILTON, JR., MD, FACE: That's very good. Dr. Neufeld, tell us what other therapies are available to improve growth rates?

NAOMI NEUFELD, MD, FACE: Since the year 2006, IGF-1, also known as somatomedin-C, has become commercially available. It's now approved for children who have what is called IGF-1 deficiency, children who have resistance to the action of growth hormone at the level of the tissue and who are unable to generate within themselves normal levels of IGF-1.

CARLOS R. HAMILTON, JR., MD, FACE: And this is effective for which categories of patients?

NAOMI NEUFELD, MD, FACE: Well currently, the evidence supports the use of IGF-1 only in children with this classical IGF-1 deficiency.

CARLOS R. HAMILTON, JR., MD, FACE: This is the so-called Loran dwarfism pattern.

NAOMI NEUFELD, MD, FACE: The Loran dwarf, right.

NAOMI NEUFELD, MD, FACE: And these are -- there are very few children in whom this diagnosis is made. But in those children, IGF-1 has been successful in enhancing growth rates.

At the first year, we see a quadrupling of growth rate, and then subsequently after years two through five, the growth rate decelerates some, but it still remains above the pretreatment levels. And these children get to a better height than they would without therapy.

CARLOS R. HAMILTON, JR., MD, FACE: Has there been any experience with using this IGF-1 treatment in patients that have growth hormone deficiency itself, or other types of growth failure?

NAOMI NEUFELD, MD, FACE: There are current trials of this medication in other situations than pure IGF-1 deficiency, but those are ongoing and we don't have the evidence yet...

CARLOS R. HAMILTON, JR., MD, FACE: There are no comparisons as to whether one would be more effective in certain situations...

NAOMI NEUFELD, MD, FACE: That's a very intriguing question, and it's one that all of us would like to see the answer to, so...

CARLOS R. HAMILTON, JR., MD, FACE: Because relative resistance to the effects of hormones is something that we all begin to appreciate more and more. It makes you wonder if there is a spectrum of relative deficiency of action of growth hormone or perhaps of IGF-1 in certain cases.

NAOMI NEUFELD, MD, FACE: Well, absolutely. And there are circumstances in which children who have been getting growth hormone will suddenly experience a decrease in growth rate, and that needs to be investigated. So IGF-1 in that situation has also been used, and...

CARLOS R. HAMILTON, JR., MD, FACE: Very interesting.

NAOMI NEUFELD, MD, FACE: That is one circumstance other than the pure IGF deficiency.

CARLOS R. HAMILTON, JR., MD, FACE: Dr. Saenger, these treatments, especially treatments with growth hormone, also raise the IGF-1 level. Describe that process for us and tell us a little bit about how that works.

PAUL SAENGER, MD, MACE: Growth hormone after it's administered as a subcutaneous injection will stimulate the production of IGF-1. Predominantly it's made in the liver. That’s where also the binding protein for the IGF-1 is made, but it's also made at other sites, probably also in the periphery right at the site of growth hormone action. So we also have local IGF-1 generation.

We can measure that rise in IGF-1 in the bloodstream after growth hormone administration, and many physicians use this as a measure of growth hormone sensitivity. You could also use it as an assay or as a test for compliance with the growth hormone therapy and for its efficacy because the IGF-1 level is bound to rise. It has to double or quadruple on growth hormone therapy.

CARLOS R. HAMILTON, JR., MD, FACE: So if a patient was being treated with growth hormone injections, which are usually given every evening, if I'm not mistaken.

PAUL SAENGER, MD, MACE: Yes.

CARLOS R. HAMILTON, JR., MD, FACE: If -- if they did not have the expected rise in IGF-1 that you were anticipating, that might indicate a relative insensitivity and you might try some other -- the IGF-1 supplementation. That's very interesting information.

PAUL SAENGER, MD, MACE: That is indeed what clinicians do. So if there is no rise in IGF-1, I mean, you can also expect that there won't be much of a change in growth rate, and that's really what you're looking for

You have to go back to the drawing board and think about it. What other modalities of therapy can I employ, and then clearly IGF-1 moves into center stage.

CARLOS R. HAMILTON, JR., MD, FACE: It's very interesting. Well, there are obviously lots of areas for further investigation in this, and we're looking forward to hearing more about those in the future.

Thank you very much for joining us this morning, and we appreciate all of you watching and thank you. And once again, I’m Dr. Carlos Hamilton.