Controversies persist in diagnosing, treating GH deficiency, short stature in children
Growth hormone deficiency, characterized by the inadequate secretion of GH from the anterior pituitary gland, is a rare disorder among U.S. children, with an estimated prevalence of 1 in 3,500.
The condition is distinct from idiopathic short stature, defined as a condition in which the height of an individual is more than 2 standard deviations (SD) below the corresponding mean height for a given age, sex and population, without evidence of systemic, endocrine, nutritional or chromosomal abnormalities. Idiopathic short stature is subcategorized according to parental heights and pubertal timing, in an effort to find evidence for a possible genetic or multigenetic component.
Both GH deficiency and idiopathic short stature are treatable with GH therapy; idiopathic short stature became an FDA-approved indication for GH therapy in 2003.
Nearly 2 decades later, controversy persists regarding the diagnosis of GH deficiency and who should receive treatment. Short stature is the most common reason for referral to a pediatric endocrinologist, according to the Growth Hormone Research Society.
The diagnosis of GH deficiency in childhood — whether congenital or acquired, idiopathic or organic — remains challenging, in large part due to the lack of a true gold standard and the relatively poor performance of available diagnostic testing, according to experts. In the U.S., a lack of relevant and consistent criteria for approval of GH therapy among insurance companies has made persistence with GH therapy more difficult.
Adding to the complexity are societal pressures surrounding desired height, particularly for boys; direct-to-consumer advertising targeted at parents asking whether their child is “growing normally” can play on such concerns.
“The tricky part becomes what constitutes GH deficiency when the child is absolutely short and does not have any other pituitary deficiency?” Nelly Mauras, MD, chief of the division of endocrinology, diabetes and metabolism at Nemours Children’s Health System in Jacksonville, Florida, and professor of pediatrics at Mayo College of Medicine, told Endocrine Today. “We rely on biochemistry for that — GH stimulation tests and bloodwork to help guide us in that diagnosis. There are two separate questions: Who is GH deficient in absolute terms? Quite another one is, who may benefit from GH treatment? Those are two different things.”
Controversies in testing, diagnosis
Outside the neonatal period — when a random GH measurement of less than 7 ng/mL identifies GH deficiency — measurement of random serum GH concentrations is of no clinical value in the evaluation of a short or poorly growing child. GH secretion is pulsatile with the majority of GH pulses occurring overnight, with very low GH concentrations between pulses, according to Sumana Narasimhan, MD, FAAP, a pediatric endocrinologist at Cleveland Clinic Children’s and associate professor of pediatrics at Cleveland Clinic Lerner College of Medicine.
“The problem with GH is measuring it is very difficult because of the nature of its secretion,” Narasimhan told Endocrine Today. “GH is secreted in a pulsatile way, almost like the beam light from a lighthouse. You see the beam hit, and before you can get it, it’s gone.”
Provocative tests of GH secretion using pharmacologic stimuli continue to play a key role in GH deficiency diagnosis; however, the measured GH concentration can vary substantially depending on the stimulation test and GH assay used, creating difficulties for diagnostic accuracy, Philip G. Murray, PhD, a researcher with the Manchester University NHS Foundation Trust, and colleagues wrote in a review published in 2016 in the Archives of Disease in Childhood. A peak stimulated GH of less than 10 ng/mL is the usual cutoff for GH deficiency in children in the U.S., whereas some countries employ cutoffs as low as 7 ng/mL, the researchers noted.
“The lack of any ‘gold standard’ test for GH deficiency diagnosis has led to the development of somewhat arbitrary cutoff levels,” Murray and colleagues wrote. “Attempts have been made to optimize the cutoff concentration using auxological criteria to define GH deficiency — predominantly height velocity — but these attempts have been hampered as other disorders can share similar auxology to GH deficiency.”
Pharmacologic agents used to stimulate GH production also vary across the U.S., Mauras said.
“There is a hodgepodge of secretagogues people use,” Mauras said. “Some use glucagon, some use L-arginine, L-dopa or clonidine. The tricky part is you may perform the same test on the same child 3 days in a row and get three different answers.”
“For the provocation tests, the gold standard would be the insulin hypoglycemia test, which we don’t use anymore, especially for children,” Narasimhan said. “You are stuck with other pharmacologic stimuli, and none of them are perfect. There is a variability in the peak depending on the stimuli used.”
Assay issues also persist in GH stimulation testing, a continued frustration among endocrinologists, according to Adda Grimberg, MD, scientific director of the Diagnostic and Research Growth Center at Children’s Hospital of Philadelphia.
“One of our biggest handicaps is that the assays used to measure GH and insulin-like growth factor I are not harmonized or standardized,” Grimberg told Endocrine Today. “That is a big problem. As a clinician, you’re reading papers about these tests designed decades ago using assays that don’t even exist now, and you’re interpreting results of your patients with the assays of today that don’t necessarily translate. That was a major headache for us in writing guidelines for GH treatment for the Pediatric Endocrine Society. How do we integrate evidence when every paper had a different test, a different reference, and you can’t compare absolute values? That’s why some of these problems are persisting as long as they are.”
An MRI is warranted for a short or poorly growing child who has insufficient GH response to stimulation, according to Cheri Deal, PhD, MD, FRCPC, chief of endocrinology and diabetes and professor at Sainte-Justine Mother-Child University of Montreal Hospital.
“The finding of midline anomalies, such as an ectopic posterior pituitary, strengthens the case for growth hormone deficiency and makes continued surveillance of the other hormonal axes necessary,” Deal told Endocrine Today.
Which children to treat
“Being short or even being shorter than expected or shorter than you want to be can be very emotive,” Siobhan T. Pittock, MB, BCh, assistant professor of pediatrics in the department of pediatric endocrinology and metabolism at Mayo Clinic in Rochester, Minnesota, told Endocrine Today. “GH deficiency is not a prerequisite for responsiveness to GH therapy; GH treatment can promote growth in many children.”
In the 17 years since the FDA approved the use of GH for children with idiopathic short stature, use of the therapy has expanded, with at least seven companies marketing GH therapy for pediatric indications, Paul Kaplowitz, MD, PhD, former chief of endocrinology at Children’s National Medical Center in Washington, D.C., and colleagues wrote in a study published in Endocrine Practice in 2018. However, across the U.S., insurers vary in their willingness to approve GH therapy for short children without GH deficiency.
“We conclude that, at least concerning the insurance companies in the Washington, D.C., area, for children who do not test GH deficient, the decision as to who gets insurance coverage for GH and who does not is unrelated to either the degree of shortness or our prediction based on bone age as to how tall the child will be as an adult,” Kaplowitz and colleagues wrote. “The strict use of the cutoff of 10 ng/mL for deciding which short children would benefit from GH therapy denies treatment to many children who would benefit.”
In the study, Kaplowitz and colleagues proposed six points to be considered by the pediatric endocrine community to help decrease the overall cost of GH therapy while allowing approvals for treatment of very short children. These include a height cutoff of –2.5 SD or less (0.6 percentile) instead of –2.25 SD (1.25 percentile); a growth rate of less than 4.5 cm per year or less than the 25th percentile for age, except in very short children; a predicted adult height of no more than 64 inches for boys and 60 inches for girls; no GH testing in short children with normal IGF-I levels meeting the aforementioned criteria; a starting dose of 0.24 mg/kg per week (20% less than the “standard dose” of 0.3 mg/kg per week); and stopping treatment once the child reaches normal range in height for those children who are growing well after onset of puberty.
“Some of these, however, can be unnecessarily restrictive, and treatment should be individualized,” Mauras said.
“The treatment of idiopathic short stature with GH therapy has been controversial since the FDA approval,” Narasimhan said. “Increasing demand for GH therapy in non-GH-deficient children has led to an increased rate of insurance denials for treatment. It is time that the pediatric endocrine community revisit this issue so GH is still available for use in very short children who need it the most to help them get even closer to normal, functional adult height.”
Grimberg said more partnership is needed between insurance companies and the endocrine societies to allow more expert input into insurance regulations regarding who should be covered for treatment.
“There is this pushback — and some of it is appropriate — because there is that slippery slope,” Grimberg said. “There definitely needs to be limit setting. The problem is when the limit setting is arbitrary. Diagnosing growth problems really is a gestalt of multiple clues. As clinicians, we know there can be a lot of noise in those clues. Yet often people with no medical knowledge or training are deciding whether to approve or disapprove GH therapy because of a checklist in front of them.”
That situation may be changing as genetic testing begins to unravel some of the many causes behind what is called “idiopathic,” Mauras said.
Mauras said anthropometry — not only GH response to stimuli —is critical in determining which children to treat.
“Idiopathic does not mean an absolute lack of pathology,” Mauras said. “Idiopathic means we have not figured out what the pathology is. That is a very important distinction. As we get better at genetic diagnoses, ‘idiopathic,’ in the future, may become a term of the past, as we can better nail down where these deletions or mutations are in the complex pathway that regulates growth.”
Daily GH therapy continues to present multiple challenges to adherence and persistence. In an invited mini-review published in The Journal of Clinical Endocrinology & Metabolism in June, Bradley S. Miller, MD, PhD, professor in the department of pediatrics at the University of Minnesota Medical School, and colleagues cited device limitations, the inconvenience of required dose frequency, a lack of perceived benefit, insurance issues and cost. In the U.S., a lack of relevant and consistent criteria for approval of GH therapy among insurance companies has made persistence with GH therapy more difficult, the researchers wrote.
“Poor adherence to recombinant human GH reduced efficacy in children and adults, and recent publications suggest that as few as 30% of patients demonstrate good adherence (missing < 1 dose per week) to daily recombinant human GH therapy,” Miller and colleagues wrote. “Adherence is particularly poor in teenagers, which may explain why near-adult height outcomes in children remain below the mid-parental target height and the population mean.”
Multiple long-acting GH preparations are proceeding through clinical development, with some showing promising evidence of short-term clinical efficacy and safety in children with GH deficiency. However, more information is needed to guide individualization of the long-acting GH dose, Miller told Endocrine Today, including how to individualize the dose based on weight, growth response and IGF-I levels.
“After years of waiting, we are close to having commercially available growth hormone products that can be given weekly instead of daily,” Miller, also a pediatric endocrinologist at M Health Fairview University of Minnesota Masonic Children’s Hospital, said. “The clinical trial results have shown that long-acting GH given to children and adults has similar short-term efficacy and safety to daily GH. If compliance improves with long-acting GH, long-term outcomes could be better than daily GH.”
Data from one of those phase 3 trials, presented at ENDO Online in June, demonstrated that children with GH deficiency assigned the long-acting recombinant GH analogue somatrogon (Opko Health and Pfizer) for 12 months experienced an increase in height velocity similar to children assigned daily injections.
Somatrogon contains the amino acid sequence of human GH and three copies of the carboxy-terminal peptide derived from human chorionic gonadotropin, which extends the half-life of the drug and supports weekly administration, according to Deal.
“This long-acting growth hormone gave the expected robust catch-up growth for these children while maintaining a comparable safety profile,” Deal said. “Importantly, when estimated mean insulin-like growth factor I SD score (SDS) values during the week were examined, they were found to be within the normal range of plus or minus 2 SDS in more than 95% of the patients.”
Deal and colleagues analyzed data from 224 prepubertal children with GH deficiency and naive to GH therapy randomly assigned once-weekly somatrogon (0.66 mg/kg; n = 109; mean age, 7.8 years; 75.2% boys) or once-daily somatropin (0.24 mg/kg; n = 115; mean age, 7.6 years; 68.7% boys) for 12 months. The primary endpoint was annualized height velocity at month 12; secondary endpoints were annualized height velocity at month 6, change in height SDS at months 6 and 12, change in bone maturation after 12 months, absolute IGF-I levels and estimated mean IGF-I SDS. Safety endpoints included adverse events, site reactions, immunogenicity and hematologic, metabolic and hormonal changes.
At month 12, mean height velocity was 10.12 cm per year for children in the somatrogon group and 9.78 cm per year for children in the somatropin group, with the treatment difference of 0.33 cm per year favoring somatrogon, Deal said.
“Presumably, less injections will translate to better adherence to treatment, which is the goal of all pediatric endocrinologists,” Deal said.
Grimberg, who called less-frequent injection therapy “the holy grail of the GH world,” said long-acting treatment will be particularly useful for adolescents in the transition period.
“Let’s be honest, who wants to take daily shots for years and years?” Grimberg said. “It is certainly everyone’s hope that weekly therapy improves adherence, though that remains to be seen and proven. My only caution with long-acting GH is safety. Anytime something becomes less physiologic, the potential for adverse effects increases. That is something we will have to keep an eye on.”
Narasimhan said patients, their families and referring clinicians must be made aware that not all short stature is hormonal; other causes could lead to a child not growing.
“Education of the parents and referring clinicians sets up a different expectation, and that is that GH deficiency is more of an exclusion process,” Narasimhan said. “It should not be the first thing one thinks of when you see a very short person, unless they are extremely short and definitely not growing.”
“We need to reframe expectations,” Grimberg said. “We are seeing a lot more people coming in saying, ‘My kid is short and wants to be taller, give me GH.’ The expectation is you can give any child GH and get them to a height that you choose. The reality is it just doesn’t work that way.”
Pittock said that parents and children need to understand the difference between being short due to an underlying condition and being shorter than they would like to be.
“In an effort to ensure availability and insurance coverage for those children with FDA-approved indications causing significant short stature, we need to set boundaries on when GH should be used,” Pittock said. “We need to resist the temptation to treat healthy children who are shorter than they want to be simply because their GH level falls below an arbitrary cutoff value.”
Moving forward, the increased capability and availability of genetic and epigenetic testing in clinical practice has the potential to enhance the diagnostic process and inform appropriate treatment, Deal said.
“If we do decide to treat a very short child with [idiopathic short stature], we must work, as much as possible, to know what we are actually treating,” Deal said. “Whether it is through additional genetic tests, epigenetic tests, or whether it is simply through a better understanding of the family environment the child is growing up in, we have to know what we are treating. I don’t want to see drugs thrown out simply because when testing was done, there were subcategories of patients that might be more at risk for side effects. As you increase the patient population you are going to treat, you may be bringing in patients more at risk.”
Mauras said it is important for any child who is not growing as expected to be seen by a pediatric endocrinologist.
“There is a lot of apprehension and anxiety from parents, but I think any child who is 2 SD below the mean or shorter, or who is growing poorly, deserves an endocrine evaluation,” Mauras said. “Growth hormone is not a panacea. It is not a free-for-all. However, we have learned a lot during the last 20 years about who can and cannot respond to GH therapy, and it is still the most potent growth-promoting agent that we have.”
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- Deal CL, et al. Somatrogon growth hormone in the treatment of pediatric growth hormone deficiency: results of the pivotal pediatric phase 3 clinical trial. Presented at: ENDO Online; June 8-19, 2020 (virtual).
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- Grimberg A, et al. Horm Res Paediatr. 2016;doi:10.1159/000452150.
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- For more information:
- Cheri Deal, MD, PhD, FRCPC, can be reached at Sainte-Justine Mother-Child University of Montreal Hospital, 3175 Côte Ste-Catherine, Montréal, Québec H3T 1C5; email: firstname.lastname@example.org.
- Adda Grimberg, MD, can be reached at the Diagnostic and Research Growth Center, Children’s Hospital of Philadelphia, 3500 Civic Center Blvd., 12th Floor Buerger Center, Philadelphia, PA 19104; email: email@example.com.
- Nelly Mauras, MD, can be reached at Nemours Children’s Health System, Division of Endocrinology, Diabetes and Metabolism, 807 Children’s Way, Jacksonville, FL 32207; email: firstname.lastname@example.org.
- Bradley S. Miller, MD, PhD, can be reached at the Division of Endocrinology, Department of Pediatrics, University of Minnesota, 2450 Riverside Ave., 8952D, MB671 East Building, Minneapolis, MN 55454; email: email@example.com.
- Sumana Narasimhan, MD, FAAP, can be reached at Cleveland Clinic Children’s, 8950 Euclid Ave., Cleveland, OH 44106; email: firstname.lastname@example.org.
- Siobhan T. Pittock, MB, BCh, can be reached at Pediatric Endocrinology, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905; email: email@example.com.