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Is idiopathic short stature a disease requiring treatment?
Some 2% of children will always be more than two standard deviation below the height mean for age and sex. A more appropriate definition of short stature for clinical purposes would be 2 SD below the mean parental standard deviation score. Because idiopathic short stature is a diagnosis of exclusion, it is necessary to clarify what it is not.
Nonorganic nutritional growth retardation is a common cause of growth failure and may be easily overlooked. Approximately one half of German children with ISS have been found to be poor eaters and to have lower body mass indices than normal.
Pediatric endocrinologists have traditionally considered constitutional delay in growth and maturation by far the most common cause of referral for short stature in the pediatric endocrine clinic, and familial short stature as separate entities from ISS.
Since the availability of unlimited supplies of rhGH beginning in 1985, the definition of growth hormone deficiency has been greatly liberalized and has led to the inclusion and rhGH treatment of large numbers of normal short children. This reflects the uncertainties of GH testing for the diagnosis of GH deficiency, including assay variability; intra-individual variability; the arbitrary definition of normal; the influence of age, sex, pubertal status, and BMI on response; and deficient responses in the absence of endocrine disease (eg with undernutrition) and during the preadolescent growth lag phase. Although 100% of normal adolescents at Tanner stage 4-5 pubertal development had normal response to aggressive GH stimulation testing, only 39% of prepubertal children “passed,” but following ethinyl estradiol priming, 100% “passed.” This phenomenon probably accounts for the ~70% of patients treated for isolated GH deficiency in childhood who have normal GH responses after adolescence.
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Commercial promotion of rhGH has included various mechanisms of rewarding pediatric endocrinologists and supporting professional and lay organizations. The FDA approved the use of rhGH for the treatment of ISS in 2003; the European Commission has rejected the industry’s request for approval.
The 2005 FDA and 2007 European Commission approvals of rhIGF-I for the treatment of very rare GH insensitivity disorders used a novel and non-specific diagnosis, “severe primary IGF-I deficiency.” This opened the door for off-label promotion for “primary IGF deficiency” based on the finding of a single low IGF-I for age and the observation that many ISS patients have low IGF-I levels. As with GH testing, however, IGF-I determinations are unreliable for a variety of reasons. Poor nutrition is associated with low IGF-1 concentrations.
The most important bias may come from the probability that the populations studied include a majority with constitutional delay in growth and maturation who have substantially delayed bone age while their IGF-I concentrations are interpreted for chronologic age. A delayed 14-year-old boy with 4 cc testes and a bone age of 11 years (a typical presentation) is not expected to have a normal testosterone level for a 14-year-old. The same logic should apply to interpreting his IGF-I measurement, which is also dependent on pubertal development. In this example, an IGF-I concentration at –2 SD would become –1 SD when corrected for bone age.
Idiopathic short stature |
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While it may be intuitive that short stature is a handicap, neither history nor clinical research support this notion. Normal English children with short stature have unimpaired self-esteem and behavior and normal IQ, but may underachieve related to their socioeconomic status. In a U.S. study of normal statured, short-referred, and short non-referred participants, no differences were found in intelligence or achievement using teacher, parent and child measures, but referred children had more externalizing behavior problems and poorer social skills, confirming referral bias. Other studies have failed to show clinically significant psychosocial morbidity, school achievement or quality of life differences from normal among children referred for short stature.
Treating ISS
Treatment of ISS with rhGH has generally not been shown to affect school achievement, psychosocial measures or quality of life when rhGH treated and untreated normal short children are compared.
With treatment for a period of ~five years, 4 cm to 5 cm of added adult height can be expected with wide individual variability. A recent meta-analysis of 10 randomized controlled trials of rhGH therapy in ISS showed none of the studies to be of good quality and only two to be of moderate quality in terms of randomization methods, blinding and the handling of withdrawals. The conclusion was: “Although treated individuals may be taller than nontreated individuals, they are still relatively short compared with peers of normal height. Therefore whether the small expected gain in height is substantial enough to merit frequent or daily injections for a number of years in children who do not have a disease is not clear. Additionally there is no evidence that GH treatment improves health-related quality of life or psychological adaptation.”
Constitutional Delay of Growth & Maturation |
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Intense off-label promotion of rhIGF-I since 2005 is based on the conjecture that most ISS is due to primary IGFD, which requires that clinicians “replace what’s missing.” The manufacturer has recruited clinicians to promote the outrageous estimate of 60,000 affected children in the United States and Europe and to present case histories as indicative of patients who should receive IGF-I, but which do not meet approved criteria, including straightforward constitutional delay in growth and maturation.
Endocrine IGF-I is inadequate and may not even be necessary for normal growth. In patients with GH receptor deficiency treated with rhIGF-I, growth responses are much less than with rhGH treatment of GH deficiency. Thus, injections of rhIGF-I do not “replace what’s missing,” emphasizing the importance of GH effects beyond GH dependent hepatic production of IGF-I, ie GH stimulation of chondrocytes and autocrine/paracrine production of IGF-I. The hepatic GH receptor knockout mouse, in which 95% reduction occurs in circulating IGF-I, has normal growth. Treatment with rhIGF-I in GH sufficient individuals might be counterproductive because of feedback suppression of GH secretion with diminution of the effects of GH on local growth plate and IGF-I secretion.
Familial short stature |
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The most frequent reason for referral to pediatric endocrinologists after diabetes management is for evaluation and treatment of short stature. Most have constitutional delay in growth and maturation and, if treatment is indicated, can be given a three-month course of testosterone to accelerate adolescence without compromising final height, or a longer course of oxandrolone. There is no rationale for treating this normal variation with rhGH on the basis of GH stimulation testing without sex steroid priming, and certainly not with rhIGF-I, as has been proposed. Familial short stature and ISS are characterized by deviant height for bone age and likelihood of adult short stature, which can be modestly, at best, altered by pharmacologic and costly rhGH treatment. There is no scientific rationale or evidence basis to suggest that rhIGF-I would be more effective than rhGH in promoting growth in children with ISS, and reason to suspect that it might be counterproductive, suppressing endogenous GH effects on growing bone.
Arlan L. Rosenbloom, MD, is an Adjunct Distinguished Service Professor Emeritus in the Department of Pediatrics at the University of Florida College of Medicine, Gainesville, Fla.
Dr. Rosenbloom has summarized several important issues relating to the treatment of children with short stature of various etiologies. These issues concern many thoughtful pediatric endocrinologists and serve to provide caution for the appropriate use of currently available therapies. Although all may not agree with some of the positions taken by Dr. Rosenbloom, all would agree that it is important to discuss them openly for the benefit and long-term safety and efficacy of therapy for the children for whom this therapy is prescribed.
– Mark A. Sperling, MD
Endocrine Today Editorial Board member
For more information:
- Bryant J, Baxter L, Cave CB, et al. Recombinant growth hormone for idiopathic short stature in children and adolescents (Review) The Cochrane Library 2007, Issue 3. Art. No.: CD004440. DOI:10.1002/14651858.CD004440.pub2.
- Lee MM. Idiopathic short stature. N Engl J Med. 2006;354:2576-2582.
- Marin G, Domené HM, Barnes KM, et al. The effects of estrogen priming and puberty on the growth hormone response to standardize treadmill exercise and arginine insulin in normal girls and boys. J Clin Endocrinol Metab. 1994;79:537-541.
- Rosenbloom AL, Guevara-Aguirre J. Controversy in clinical endocrinology: Reclassification of IGF-1 production and action disorders. J Clin Endocrinol Metab. 2006;91:4232-4234.
- Rosenbloom AL. Is there a role for recombinant insulin-like growth factor-I (rhIGF-I) in the treatment of idiopathic short stature? Lancet. 2006;368:612-616.
- Wudy SA, Hagemann S, Dempfle A, et al. Children with idiopathic short stature are poor eaters and have decreased body mass index. Pediatrics. 2005;116:52-57.