Idiopathic Short Stature: Expert Perspectives
Although recombinant human growth hormone was approved by the FDA for certain children with ISS, treatment remains controversial given that ISS is not a diagnosis but a variant of normal growth.
Short stature is defined in children as a height 2 standard deviations (SD) or more below the statistical mean for the age- and sex-matched population. In the absence of evidence for pathologic causes, children at or below −2 SD can be considered to have idiopathic short stature (ISS).1 Recombinant human growth hormone was approved by the US Food and Drug Administration in 2003 for children with ISS who are 2.25 SD below the mean and unlikely to attain an adult height within the normal range, but treatment for ISS remains controversial given that ISS is not a diagnosis but a variant of normal growth. Guidelines from The Endocrine Society, updated in 2017, advocate a shared decision-making approach regarding growth hormone therapy and advise against routine treatment for all children with ISS.2
For clinical perspective on ISS and its treatment, Endocrinology Advisor interviewed pediatric endocrinologists Alan D. Rogol, MD, PhD, professor emeritus at the University of Virginia, and Molly Regelmann, MD, assistant professor of pediatric endocrinology and diabetes at the Children's Hospital at Montefiore, Bronx, New York. Dr Rogol is co-author of the Consensus Statement on the Diagnosis and Treatment of Children With Idiopathic Short Stature, issued in 2008 under the auspices of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology.1
Endocrinology Advisor: What is the rationale for treating children with ISS given the lack of conclusive evidence that treatment improves quality of life? Do the benefits outweigh the risk of adverse events?
Dr Regelmann: While it is true population studies indicate that most individuals with shorter stature are able to function within normal ranges, children with ISS are exceptionally short, and studies assessing function in those with heights >2.5 SD below the mean are lacking. In addition to the potential for psychosocial concerns, extreme short stature can limit employment opportunities. For example, branches of the military have height minimum requirements — 58 to 60 inches tall — and many cars and trucks cannot be operated by those <57 inches tall without modifications.
Dr Rogol: The rationale is quite simple: to make the adult height greater and to bring the children closer to their peers in height during therapy. The second part of the rationale is to make them psychologically better – whatever that means, considering the vast majority are psychologically okay. I do not believe the benefits of treatment typically outweigh the risk of adverse events, given that the benefits are small. Although physical adverse events are minor and infrequent, the major adverse event is unmet expectations. For example, if a child is made 6 cm taller in adult height by receiving 6 years of recombinant human growth hormone at perhaps $20,000 to $30,000 a year, that would statistically be a positive. However, if he started out at 5 feet and is now 5 feet 2 inches, he would still be considered quite small. The unmet expectation is that he failed to be of at least average height after daily injections for such a long time.
Endocrinology Advisor: What is the approach taken at your institutions to the treatment of children with ISS?
Dr Regelmann: As ISS — or as I prefer to call it, growth failure of unknown etiology — is a diagnosis of exclusion, my approach is to first do a full assessment for potential causes of growth failure or short stature. As I do for all patients with growth concerns, a thorough medical history — including but not limited to birth history, medical history, and family history — is an essential first step in the evaluation. A complete physical examination that includes assessments for genetic causes of growth failure and staging of puberty is the next step. I then typically perform screening laboratory tests and radiology studies, based findings from the history and physical examination, to assess for both endocrine and nonendocrine causes of growth failure. A bone age radiograph should also be performed to help better understand growth potential.
In children with no laboratory abnormalities on first assessment, extreme short stature, and a bone age that is not consistent with the potential for normal variant constitutional delay of growth and puberty, it is reasonable to consider referral to genetics or to conduct additional testing, particularly to rule out mild skeletal dysplasias. Prior to considering treatment, height velocity is typically monitored for at least 6 months and extensive discussions are had with parents or guardians and patients regarding the risks and benefits of treatment with recombinant human growth hormone. The diagnosis of idiopathic short stature is only concluded once all other causes of growth failure have been excluded and it is determined that the adult height is likely to be 2.25 SDs below the mean. Without a known diagnosis, patients and parents or guardians are counseled that treatment is optional. I also discuss that it is challenging to predict the benefit of treatment, but that on average, there is about a 2-inch height gain with about 5 years of treatment. I note that some patients respond exceptionally well to treatment, and others have no significant response. If a child is not demonstrating a response to treatment within the first 6 months of therapy, I typically recommend discontinuing treatment, although the Pediatric Endocrine Society Guidelines suggest that children can be given up to 12 months to respond to therapy.
Dr Rogol: Each of us has a different approach. Mine was honed over the few decades that recombinant human growth hormone has been available for this indication. I am retired now, but my approach was focused on what I call “butt time” – that is, my butt in a chair talking with the parents and the child or adolescent about the risks and benefits of treatment and also noting that a 6- or 12-month trial of medication is in order in a minority of children. The rationale for that is that growth beyond 6 to 12 months of therapy is well predicted by the growth during this period, so the usual contract is that the child grows 2.5 cm per year more than previously to continue on medication for the next year. In full disclosure, I am 5 feet tall. I use that to point out that one does not need to be tall to graduate from high school, go to college, and play sports. I, as an example, was a varsity athlete in high school and university – perhaps not a particularly good one! – and have had a long running career as an adult.
Endocrinology Advisor: What is the impact when children are treated with growth hormone therapy and fail to gain height? Are there harms or benefits to unsuccessful treatment?
Dr Regelmann: I think that setting expectations prior to starting therapy is extremely important. Most children with ISS have a modest response to treatment — an average of 2 inches with 5 years of therapy — but there are some who do not respond and others who have a response similar to children treated for growth hormone deficiency. These children most likely have an unidentified defect in growth hormone secretion. I often refer to the medication as a marathon, as it takes years of daily subcutaneous injections to see a few inches of height gain above what would have been expected without treatment.
Dr Rogol: The impact of unmet expectations is real. The child could say, “I did everything that my parents and the doctor said to do and yet I am unsuccessful in growing more – and it must be me who is bad or wrong.” I cannot conceive of a benefit to unsuccessful treatment. Harms likely are in the psychological sphere. It is important to note how the specialist got to see the patient. Statistically speaking, 2% to 3% of all children will be short. ISS is a variant of normal, not a disease. It is only a minority of short children who pester their parents and their pediatrician about this and an even smaller number who get referred to an endocrinologist. Even in that group, the psychological dysfunction is small, often still within the broad range of normal. Except in unusual circumstances, the rationale for treatment to dampen or fix the psychological issues is a nonstarter.
1. Cohen P, Rogol AD, Deal CL, et al. Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology workshop. J Clin Endocrinol Metab. 2008;93(11):4210-4217.
2. Grimberg A, DiVall SA, Polychronakos C, et al; on behalf of the Drug and Therapeutics Committee and Ethics Committee of the Pediatric Endocrine Society. Guidelines for growth hormone and insulin-like growth factor-I treatment in children and adolescents: growth hormone deficiency, idiopathic short stature, and primary insulin-like growth factor-I deficiency. Horm Res Paediatr. 2016;86(6):361-397.