Idiopathic Short Stature
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《新英格兰医药杂志》
This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author's clinical recommendations.
A healthy, active 12-year-old boy is in the first percentile for height (133.0 cm ; 2.25 SD below the mean for age and sex) and in the third percentile for weight (29 kg ) (Figure 1). He is the same size as his 10-year-old sister and is the shortest boy in his seventh-grade class. His father's height is 168.0 cm (66.1 in.; –1.28 SD), and his mother's height is 148.0 cm (58.3 in.; –2.25 SD). His physical examination is unremarkable, with normal proportions and no signs of puberty. His bone age is 10 years. His evaluation reveals no systemic disease (e.g., growth hormone deficiency or gastrointestinal or thyroid disorder) and no skeletal dysplasia. His midparental height is 164.5 cm (64.8 in.), and his predicted height is 163.8 cm (64.5 in.). Is growth hormone therapy indicated?
Figure 1. Growth Chart for Boys, Showing Height and Weight Data for the Patient and Height Data for His Parents.
The predicted height of the patient is 163.8 cm. The triangle denotes bone age. Data are adapted from the National Health and Nutrition Examination Survey.1
The Clinical Problem
Idiopathic short stature, also referred to as normal-variant short stature or short stature of undefined cause, is a diagnosis of exclusion. Implicit in the diagnosis is that systemic diseases — including growth hormone deficiency, intrauterine growth retardation, genetic or syndromic causes of short stature, and other factors compromising growth, such as depression or psychosocial deprivation — have been excluded.2 Until recently, growth hormone was considered an experimental therapy for children with idiopathic short stature,3,4,5 and discrimination between growth hormone deficiency and sufficiency was considered critical to identify children who were likely to respond to pharmacotherapy.3,4
This distinction has become blurred by recent studies demonstrating the efficacy of growth hormone for increasing adult height in children with idiopathic short stature.6,7,8,9 In the past, restriction of growth hormone to children with a documented deficiency reflected the scarcity of pituitary-derived growth hormone.5,10 The introduction of recombinant growth hormone, which was precipitated by the occurrence of Creutzfeldt–Jakob disease with pituitary growth hormone, made supply no longer a limiting factor.10,11 Recombinant human growth hormone therapy was approved by the Food and Drug Administration (FDA) in 2003 for idiopathic short stature; criteria for its use are listed in Table 1.12 The addition of this indication for growth hormone therapy rekindled a long-standing debate regarding ethical and economic ramifications of its use in otherwise healthy children.13,14
Table 1. Criteria for the Use of Growth Hormone in the Treatment of Idiopathic Short Stature.
Strategies and Evidence
Evaluation
The evaluation of a child with short stature requires attention to the family and medical history, longitudinal growth data, a detailed physical examination, and laboratory and imaging studies (including bone age) to rule out systemic disease and genetic conditions associated with short stature.10,15,16 An assessment of the child's psychological well-being, social stressors, and the family's concerns and expectations is also critical, both to ascertain the degree of psychosocial stress related to the child's short stature and to assess the possible role of nonorganic causes of poor growth.
Calculation of the midparental height — by taking the average of the parents' heights and adding 6.5 cm (2.5 in.) for boys or subtracting 6.5 cm for girls to account for sex differences in adult height — provides an estimate of the genetic target height (with 1 SD as 6.4 cm for women and 7.2 cm for men). Measurement of bone age (skeletal maturation), by comparing ossification centers of the hand with those of published standards,17 provides an estimate of predicted height on the basis of the proportion of adult stature achieved. Given a child's height, chronologic age, and bone age, the predicted adult height can be estimated with the use of Bayley–Pinneau tables, which are derived from normative data in healthy children who were followed serially. The precision of this method is dependent on the accuracy of the height measurement and the bone-age reading and tends to improve at older bone ages. At age 12, 1 SD for the prediction of height is 2.5 to 3.8 cm (1 to 1.5 in.). In boys with a constitutional delay in growth and development who have a bone-age delay of more than three years, this method has been shown to overpredict height by as much as 3.1 cm.18
Although it has been suggested that the severity of growth impairment should guide therapy,13,19,20 rather than an assessment of the growth hormone level, distinguishing growth hormone deficiency from idiopathic short stature remains important. Criteria for the institution of therapy differ for the two conditions, as may the magnitude of the growth response. Insulin-like growth factor 1 (IGF-1) and IGF-binding protein 3 (IGFBP-3) are two growth hormone–responsive growth factors that should be measured in serum as an initial screen for growth hormone deficiency, followed by provocative testing for growth hormone.10,15,16 Although these growth factors are relatively stable in the circulation, serum levels of growth hormone are variable, with the highest peaks occurring overnight; thus, a low random level of growth hormone is nondiagnostic.
For this reason, known growth hormone secretagogues, such as arginine and clonidine, are administered to stimulate the secretion of growth hormone. The gold standard has traditionally been to require two tests in order to optimize specificity and increase the predictive value.21,22 Despite this procedure, the reliability of provocative testing for growth hormone is hampered by poor reproducibility, variability in growth hormone assays, and inconsistent criteria for the diagnosis of growth hormone insufficiency, with cutoffs ranging from 5 to 10 mg per deciliter.23,24 When growth impairment is associated with a central-nervous-system injury or structural abnormalities, growth hormone testing may be unnecessary.19,25 On the other hand, the use of growth hormone testing in conjunction with serum IGF-1 and IGFBP-3 levels aids in the identification of children with defects downstream of growth hormone secretion who may benefit from more recently approved growth-promoting agents, such as IGF-1 and IGFBP-3.26,27,28
Growth Hormone Therapy
Gains in Height
Available data suggest that growth hormone therapy increases adult height between 3 and 6 cm in children with idiopathic short stature, but such growth requires long-term therapy. In studies demonstrating the efficacy of growth hormone therapy for this indication, the mean duration of therapy was four to seven years.6,8,9,29
A meta-analysis of the efficacy of growth hormone therapy in children with idiopathic short stature identified only four controlled studies and six uncontrolled studies with data regarding adult height.6 After growth hormone therapy (at doses of 0.25 to 0.40 mg per kilogram of body weight per week) or observation for a mean of 5.3 years in 118 patients in controlled studies, the adult height in the group that was treated with growth hormone was 5 to 6 cm greater than that of the untreated controls and 3.6 to 4.6 cm greater than the height predicted at baseline. In the eight uncontrolled studies with data regarding adult height for 246 patients, growth hormone treatment (at a dose of 0.14 to 0.33 mg per kilogram per week) for a mean of 4.7 years resulted in a gain of 3.8 to 4.5 cm in adult height above the height predicted at baseline. A subsequent study, sponsored by the National Institutes of Health (NIH), was a randomized, double-blind, placebo-controlled trial of growth hormone (at a dose of 0.22 mg per kilogram per week, divided into doses administered three times a week) in prepubertal children with idiopathic short stature. The study showed a mean gain in adult height of 3.7 cm in 22 patients who were treated with growth hormone (over a mean duration of 4.6 years), as compared with 11 patients who were treated with placebo.8
Short-term growth velocity increases during growth hormone therapy but is not predictive of final height outcome. However, if no increase in growth rate is observed with the use of adequate doses, adult height is unlikely to increase, and growth hormone therapy should be discontinued.
Higher doses of growth hormone may confer a greater benefit. A European study compared adult heights of 17 patients treated with growth hormone that was administered six times a week at a mean dose of 0.37 mg per kilogram per week for 7.0 years to that of 17 patients treated with a dose of 0.24 mg per kilogram per week for 6.1 years.9 In comparison with their baseline predicted adult height, the children who were treated with the higher dose had a significantly greater gain in adult height (7.2 cm, as compared with 5.4 cm for the group that received a lower dose). Moreover, daily administration of growth hormone has been shown to be more efficacious than administration three times per week.10
Despite the mean height gains associated with growth hormone therapy, there is individual variability in growth response, and some children have no increase in their adult height above the baseline predicted height.6,7,8,9,30,31,32 In the European study, although the SD of the mean height improved from –3.26 to –1.69±0.17 at the lower dose of growth hormone and from –2.88 to –1.12±0.18 at the higher dose, the ranges were –3.21 to –0.61 and –3.46 to 0.38, respectively.9 These data contrast with the more severe growth impairment but greater response to growth hormone therapy that is generally observed in children with classic growth hormone deficiency.5,10,33
A difficulty encountered with growth hormone therapy is the maintenance of a long-term regimen of daily injections. Trials of growth hormone frequently have high attrition rates. Of the 68 patients in the NIH study, 21 of 37 who were treated with growth hormone and 23 of 31 who were treated with placebo dropped out before the attainment of near-adult height despite an increase in growth velocity in the group treated with growth hormone.8 Outside of closely monitored studies, the issue of noncompliance and interruption of therapy is even more problematic. If injections are intermittent, suboptimal administration of the drug and growth deceleration when growth hormone is discontinued may compromise the expected gains in height and result in treatment failures.34
Psychosocial Outcomes
In addition to growth end points, psychosocial outcomes of growth hormone therapy are also relevant in the evaluation of the risk–benefit ratio of such therapy for children with idiopathic short stature. Early studies suggesting that children with short stature have maladaptive behavior and emotional problems related to teasing and low self-esteem have not been confirmed.35,36,37 Neither children with short stature who were referred for growth evaluation nor those screened in population studies had substantial emotional distress or impairment in psychosocial functioning, as compared with peers of normal stature or community norms.35,36,37 In the NIH trial of children with idiopathic short stature, baseline scores on behavior and self-competence fell within those in the general population.38 Overall psychosocial functioning and self-image were not substantially different in children treated with growth hormone from those in controls, except for the parental assessment of external behavior in years 3 and 4. Moreover, growth hormone therapy has not demonstrably improved measures of quality of life for children in limited studies.39,40,41
Although academic and social achievements have been shown to be correlated with adult height, population studies have found that socioeconomic factors exert the overriding influence on academic success and psychosocial health.35,42 Thus, the purported psychological benefits of achieving a taller stature are of questionable merit, and additional studies are needed to examine quality-of-life outcomes. Conversely, concerns about "medicalizing" healthy short children and perturbing psychological health with the long-term administration of growth hormone have been somewhat allayed by a recent report describing stable psychosocial functioning in children with idiopathic short stature who were treated with either growth hormone or placebo.38
Safety Concerns
On the basis of information from international databases and registries, a review of safety data on almost 100,000 children who were treated with growth hormone for a variety of indications found no increase above population norms for several potentially adverse effects of growth hormone therapy, such as diabetes mellitus, slipped capital femoral epiphyses, avascular necrosis of the femoral head, and cancer; idiopathic intracranial hypertension was observed in 1 of 1000 treated children, as compared with a rate of between 0.5 and 0.9 per 100,000 in the general population.43,44
In a study45 of 1848 patients with growth hormone deficiency who were treated with pituitary-derived growth hormone from 1959 to 1985 in the United Kingdom, concern was expressed about the potential risk of cancer. When patients at high risk for cancer were excluded, there were two cases of colorectal cancer and two cases of Hodgkin's disease among the 1352 remaining patients, which translates into an increase in the risk of colorectal cancer by a factor of 11 and of Hodgkin's disease by a factor of 3, as compared with the general population.45 The small size of this cohort study and the fact that no cases of colorectal cancer have been reported in the larger registry studies of patients treated with growth hormone make the significance of this observation questionable. However, the supraphysiologic concentrations of IGF-1 that are found with higher doses of growth hormone raise at least theoretical concern about an increased risk of neoplasia.
In children treated with growth hormone for idiopathic short stature, no cases of peripheral edema, pancreatitis, or benign intracranial hypertension have been reported, and the incidence of other serious side effects has been low: slipped capital femoral epiphysis developed in 0.04 percent of patients, and 0.07 percent had an alteration in carbohydrate metabolism.32,46 Three cases of neoplasia have been reported, none of which were thought to be caused by growth hormone therapy. Although these data are reassuring, the numbers are relatively small and the studies are of short duration; therefore, long-term surveillance for rare side effects is imperative in children treated with growth hormone for idiopathic short stature.
Areas of Uncertainty
Among children classified as having idiopathic short stature, there is great variability in biologic factors such as serum concentrations of IGF-1 and IGFBP-3, the extent of bone-age delay, and the timing of puberty. The heterogeneity of this diagnosis suggests that there are diverse underlying mechanisms for growth impairment. Although the genetic determinants of growth and stature remain incompletely defined, identification of specific molecular defects in the growth hormone–IGF axis or other growth-related genes may better inform therapeutic decisions.26,47,48 The reasons for poor response to growth hormone in some children are unclear. Although some cases can be attributed to suboptimal dosing regimens or noncompliance and some are associated with discordant advancement of bone age in relation to linear growth,30,31 inherent genetic influences on growth or biologic factors affecting responsiveness may also play a role. Growth hormone therapy is typically discontinued when growth velocity declines to less than 2 cm per year or when a height within the normal adult range is achieved, but the optimal duration of therapy remains unclear.
In addition to the uncertainty about whether the beneficial outcomes of growth hormone therapy outweigh its potential risks and the difficulties of adhering to therapy, many observers have expressed concern about the ethical and economic ramifications of the expanding use of growth hormone.5,13,14,49 At the core of the controversy is the question about whether short stature is a disease state or a continuum of normal development and, therefore, whether growth hormone therapy is a therapeutic or a cosmetic intervention. A recent economic analysis, based on the approved dosing guidelines and published efficacy data regarding adult height, calculated that the current cost of growth hormone therapy for five years is $52,000 per incremental inch of height gained.50 Because of the exorbitant cost and the large number of children whose height falls below the 1.2 percentile who theoretically qualify for therapy, the use of growth hormone in idiopathic short stature generates questions about the equitable distribution of health care resources and the economic effect on the health care system.14,49,50
Guidelines
Guidelines from the American Academy of Pediatrics and the Growth Hormone Research Society, which were published before FDA approval of growth hormone for idiopathic short stature, urged the use of growth hormone for nonapproved indications only within controlled trials.3,4,16 More recently updated recommendations from the Lawson Wilkins Pediatric Endocrine Society make note of the FDA guidelines for the use of growth hormone in patients with idiopathic short stature but stress caution about the unknown long-term consequences of the drug and the difficulties of identifying rare side effects.51
Conclusions and Recommendations
For children with idiopathic short stature, such as the boy in the vignette, the decision to treat must be individualized and should be guided by consultation with a pediatric endocrinologist with expertise in childhood growth disorders. Other causes of growth failure should be excluded, and ideally, the child's growth should fulfill the stringent FDA criteria. Assessment of psychosocial stressors and dysfunction is important; psychological intervention should be recommended if any concerns are identified. If growth hormone therapy is recommended, determination of the baseline growth rate before treatment is helpful in order to assess the effect of growth hormone therapy on growth velocity. To ensure realistic expectations, patients and their families should be educated about the anticipated average height gain of 4 to 7 cm after several years of daily therapy and the potential for not achieving this goal; they should also be informed that a brief course of growth hormone therapy or interrupted therapy because of missed injections is unlikely to be effective. Finally, the lack of clear prognostic factors for response to therapy and the individual variability in response necessitate periodic reappraisal of the treatment plan.
Although the current height of the patient in the vignette meets the criterion for the use of growth hormone to treat idiopathic short stature, his predicted height according to the Bayley–Pinneau tables is within the normal range and is consistent with his midparental target height (Figure 1). Given his delayed bone age, he most likely has familial short stature in conjunction with constitutional delay of growth and development. I would not recommend growth hormone therapy for this child on the basis of my assessment of the risk–benefit ratio, although some experienced pediatric endocrinologists would consider the treatment appropriate — a divergence of opinion that underscores the therapeutic challenges and lack of consensus in the management of idiopathic short stature. In either case, longitudinal monitoring of growth and development with periodic review of the management is essential.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Department of Pediatrics, University of Massachusetts Medical School, Worcester.
Address reprint requests to Dr. Lee at the Pediatric Endocrine Division, Department of Pediatrics, University of Massachusetts Medical School, 55 Lake Ave. N., Worcester, MA 01655, or at mary.lee@umassmed.edu.
References
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American Academy of Pediatrics Committee on Drugs and Committee on Bioethics. Considerations related to the use of recombinant human growth hormone in children. Pediatrics 1997;99:122-129.
Guyda HJ. Four decades of growth hormone therapy for short children: what have we achieved? J Clin Endocrinol Metab 1999;84:4307-4316.
Finkelstein BS, Imperiale TF, Speroff T, Marrero U, Radcliffe DJ, Cuttler L. Effect of growth hormone therapy on height in children with idiopathic short stature: a meta-analysis. Arch Pediatr Adolesc Med 2002;156:230-240.
Hintz RL, Attie KM, Baptista J, Roche A. Effect of growth hormone treatment on adult height of children with idiopathic short stature. N Engl J Med 1999;340:502-507.
Leschek EW, Rose SR, Yanovski JA, et al. Effect of growth hormone treatment on adult height in peripubertal children with idiopathic short stature: a randomized, double-blind, placebo-controlled trial. J Clin Endocrinol Metab 2004;89:3140-3148.
Wit JM, Rekers-Mombarg LTM, Cutler GB, et al. Growth hormone (GH) treatment to final height in children with idiopathic short stature: evidence for a dose effect. J Pediatr 2005;146:45-53.
Grumbach MM, Bin-Abbas BS, Kaplan SL. The growth hormone cascade: progress and long-term results of growth hormone treatment in growth hormone deficiency. Horm Res 1998;49:Suppl 2:41-57.
Fradkin JE, Schonberger LB, Mills JL, et al. Creutzfeldt-Jakob disease in pituitary growth hormone recipients in the United States. JAMA 1991;265:880-884.
Food and Drug Administration. FDA approves humatrope for short stature. Fed Regist 2003;68:24003-24004.
Allen DB, Fost N. hGH for short stature: ethical issues raised by expanded access. J Pediatr 2004;144:648-652.
Cuttler L, Silvers JB. Growth hormone treatment for idiopathic short stature: implications for practice and policy. Arch Pediatr Adolesc Med 2004;158:108-110.
Schwartz ID, Grunt JA. Growth, short stature, and the use of growth hormone: considerations for the practicing pediatrician -- an update. Curr Probl Pediatr 1997;27:14-40.
Growth Hormone Research Society. Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. J Clin Endocrinol Metab 2000;85:3990-3993.
Greulich WW, Pyle SI. Radiographic atlas of skeletal development of the hand and wrist. 2nd ed. Stanford, Calif.: Stanford University Press, 1959.
Bramswig JH, Fasse M, Holthoff ML, von Lengerke HJ, von Petrykowski W, Schellong G. Adult height in boys and girls with untreated short stature and constitutional delay of growth and puberty: accuracy of five different methods of height prediction. J Pediatr 1990;117:886-891.
Badaru A, Wilson DM. Alternatives to growth hormone stimulation testing in children. Trends Endocrinol Metab 2004;15:252-258.
Werther GA. Growth hormone measurements versus auxology in treatment decisions: the Australian experience. J Pediatr 1996;128:S47-S51.
Hindmarsh PC, Swift PG. An assessment of growth hormone provocation tests. Arch Dis Child 1995;72:362-367.
Reiter EO, Martha PM Jr. Pharmacological testing of growth hormone secretion. Horm Res 1990;33:121-126.
Carel JC, Tresca JP, Letrait M, et al. Growth hormone testing for the diagnosis of growth hormone deficiency in childhood: a population register-based study. J Clin Endocrinol Metab 1997;82:2117-2121.
Ghigo E, Bellone J, Aimaretti G, et al. Reliability of provocative tests to assess growth hormone secretory status: study in 472 normally growing children. J Clin Endocrinol Metab 1996;81:3323-3327.
Nagel BH, Palmbach M, Petersen D, Ranke MB. Magnetic resonance images of 91 children with different causes of short stature: pituitary size reflects growth hormone secretion. Eur J Pediatr 1997;156:758-763.
Attie KM. Genetic studies in idiopathic short stature. Curr Opin Pediatr 2000;12:400-404.
Blair JC, Savage MO. The GH-IGF-I axis in children with idiopathic short stature. Trends Endocrinol Metab 2002;13:325-330.
Rosenfeld RG. The molecular basis of idiopathic short stature. Growth Horm IGF Res 2005;15:Suppl A:S3-S5.
Bryant J, Cave C, Milne R. Recombinant growth hormone for idiopathic short stature in children and adolescents. Cochrane Database Syst Rev 2003;4:CD004440-CD004440.
Kamp GA, Waelkens JJJ, de Muinck Keizer-Schrama SM, et al. High dose growth hormone treatment induces acceleration of skeletal maturation and an earlier onset of puberty in children with idiopathic short stature. Arch Dis Child 2002;87:215-220.
Kawai M, Momoi T, Yorifuji T, Yamanaka C, Sasaki H, Furusho K. Unfavorable effects of growth hormone therapy on the final height of boys with short stature not caused by growth hormone deficiency. J Pediatr 1997;130:205-209.
Kemp SF, Kuntze J, Attie KM, et al. Efficacy and safety results of long-term growth hormone treatment of idiopathic short stature. J Clin Endocrinol Metab 2005;90:5247-5253.
Blethen SL, Baptista J, Kuntze J, Foley T, LaFranchi S, Johanson A. Adult height in growth hormone (GH)-deficient children treated with biosynthetic GH. J Clin Endocrinol Metab 1997;82:418-420.
Lampit M, Hochberg Z. Prevention of growth deceleration after withdrawal of growth hormone therapy in idiopathic short stature. J Clin Endocrinol Metab 2002;87:3573-3577.
Downie AB, Mulligan J, Stratford RJ, Betts PR, Voss LD. Are short normal children at a disadvantage? The Wessex growth study. BMJ 1997;314:97-100.
Sandberg DE, Voss LD. The psychosocial consequences of short stature: a review of the evidence. Baillieres Best Pract Res Clin Endocrinol Metab 2002;16:449-463.
Zimet GD, Owens R, Dahms W, Cutler M, Litvene M, Cuttler L. Psychosocial outcome of children evaluated for short stature. Arch Pediatr Adolesc Med 1997;151:1017-1023.
Ross JL, Sandberg DE, Rose SR, et al. Psychological adaptation in children with idiopathic short stature treated with growth hormone or placebo. J Clin Endocrinol Metab 2004;89:4873-4878.
Sandberg DE, Colsman M. Growth hormone treatment of short stature: status of the quality of life rationale. Horm Res 2005;63:275-283.
Theunissen NCM, Kamp GA, Koopman HM, Zwinderman KAH, Vogels T, Wit J-M. Quality of life and self-esteem in children treated for idiopathic short stature. J Pediatr 2002;140:507-515.
Wheeler PG, Bresnahan K, Shephard BA, Lau J, Balk EM. Short stature and functional impairment: a systematic review. Arch Pediatr Adolesc Med 2004;158:236-243.
Wilson DM, Hammer LD, Duncan PM, et al. Growth and intellectual development. Pediatrics 1986;78:646-650.
Critical evaluation of the safety of recombinant human growth hormone administration: statement from the Growth Hormone Research Society. J Clin Endocrinol Metab 2001;86:1868-1870.
Clayton PE, Cowell CT. Safety issues in children and adolescents during growth hormone therapy -- a review. Growth Horm IGF Res 2000;10:306-317.
Swerdlow AJ, Higgins CD, Adlard P, Preece MA. Risk of cancer in patients treated with human pituitary growth hormone in the UK, 1959-85: a cohort study. Lancet 2002;360:273-277.
Quigley CA, Gill AM, Crowe BJ, et al. Safety of growth hormone treatment in pediatric patients with idiopathic short stature. J Clin Endocrinol Metab 2005;90:5188-5196.
Goddard AD, Covello R, Luoh SM, et al. Mutations of the growth hormone receptor in children with idiopathic short stature. N Engl J Med 1995;333:1093-1098.
Kant SG, Wit JM, Breuning MH. Genetic analysis of short stature. Horm Res 2003;60:157-165.
Voss LD. Growth hormone therapy for the short normal child: who needs it and who wants it? The case against growth hormone therapy. J Pediatr 2000;136:103-106.
Lee JM, Davis MM, Clark SJ, Hofer TP, Kemper AR. Estimated cost-effectiveness of growth hormone therapy for idiopathic short stature. Arch Pediatr Adolesc Med 2006;160:263-269.
Wilson TA, Rose SR, Cohen P, et al. Update of guidelines for the use of growth hormone in children: the Lawson Wilkins Pediatric Endocrinology Society Drug and Therapeutics Committee. J Pediatr 2003;143:415-421.(Mary M. Lee, M.D.)
A healthy, active 12-year-old boy is in the first percentile for height (133.0 cm ; 2.25 SD below the mean for age and sex) and in the third percentile for weight (29 kg ) (Figure 1). He is the same size as his 10-year-old sister and is the shortest boy in his seventh-grade class. His father's height is 168.0 cm (66.1 in.; –1.28 SD), and his mother's height is 148.0 cm (58.3 in.; –2.25 SD). His physical examination is unremarkable, with normal proportions and no signs of puberty. His bone age is 10 years. His evaluation reveals no systemic disease (e.g., growth hormone deficiency or gastrointestinal or thyroid disorder) and no skeletal dysplasia. His midparental height is 164.5 cm (64.8 in.), and his predicted height is 163.8 cm (64.5 in.). Is growth hormone therapy indicated?
Figure 1. Growth Chart for Boys, Showing Height and Weight Data for the Patient and Height Data for His Parents.
The predicted height of the patient is 163.8 cm. The triangle denotes bone age. Data are adapted from the National Health and Nutrition Examination Survey.1
The Clinical Problem
Idiopathic short stature, also referred to as normal-variant short stature or short stature of undefined cause, is a diagnosis of exclusion. Implicit in the diagnosis is that systemic diseases — including growth hormone deficiency, intrauterine growth retardation, genetic or syndromic causes of short stature, and other factors compromising growth, such as depression or psychosocial deprivation — have been excluded.2 Until recently, growth hormone was considered an experimental therapy for children with idiopathic short stature,3,4,5 and discrimination between growth hormone deficiency and sufficiency was considered critical to identify children who were likely to respond to pharmacotherapy.3,4
This distinction has become blurred by recent studies demonstrating the efficacy of growth hormone for increasing adult height in children with idiopathic short stature.6,7,8,9 In the past, restriction of growth hormone to children with a documented deficiency reflected the scarcity of pituitary-derived growth hormone.5,10 The introduction of recombinant growth hormone, which was precipitated by the occurrence of Creutzfeldt–Jakob disease with pituitary growth hormone, made supply no longer a limiting factor.10,11 Recombinant human growth hormone therapy was approved by the Food and Drug Administration (FDA) in 2003 for idiopathic short stature; criteria for its use are listed in Table 1.12 The addition of this indication for growth hormone therapy rekindled a long-standing debate regarding ethical and economic ramifications of its use in otherwise healthy children.13,14
Table 1. Criteria for the Use of Growth Hormone in the Treatment of Idiopathic Short Stature.
Strategies and Evidence
Evaluation
The evaluation of a child with short stature requires attention to the family and medical history, longitudinal growth data, a detailed physical examination, and laboratory and imaging studies (including bone age) to rule out systemic disease and genetic conditions associated with short stature.10,15,16 An assessment of the child's psychological well-being, social stressors, and the family's concerns and expectations is also critical, both to ascertain the degree of psychosocial stress related to the child's short stature and to assess the possible role of nonorganic causes of poor growth.
Calculation of the midparental height — by taking the average of the parents' heights and adding 6.5 cm (2.5 in.) for boys or subtracting 6.5 cm for girls to account for sex differences in adult height — provides an estimate of the genetic target height (with 1 SD as 6.4 cm for women and 7.2 cm for men). Measurement of bone age (skeletal maturation), by comparing ossification centers of the hand with those of published standards,17 provides an estimate of predicted height on the basis of the proportion of adult stature achieved. Given a child's height, chronologic age, and bone age, the predicted adult height can be estimated with the use of Bayley–Pinneau tables, which are derived from normative data in healthy children who were followed serially. The precision of this method is dependent on the accuracy of the height measurement and the bone-age reading and tends to improve at older bone ages. At age 12, 1 SD for the prediction of height is 2.5 to 3.8 cm (1 to 1.5 in.). In boys with a constitutional delay in growth and development who have a bone-age delay of more than three years, this method has been shown to overpredict height by as much as 3.1 cm.18
Although it has been suggested that the severity of growth impairment should guide therapy,13,19,20 rather than an assessment of the growth hormone level, distinguishing growth hormone deficiency from idiopathic short stature remains important. Criteria for the institution of therapy differ for the two conditions, as may the magnitude of the growth response. Insulin-like growth factor 1 (IGF-1) and IGF-binding protein 3 (IGFBP-3) are two growth hormone–responsive growth factors that should be measured in serum as an initial screen for growth hormone deficiency, followed by provocative testing for growth hormone.10,15,16 Although these growth factors are relatively stable in the circulation, serum levels of growth hormone are variable, with the highest peaks occurring overnight; thus, a low random level of growth hormone is nondiagnostic.
For this reason, known growth hormone secretagogues, such as arginine and clonidine, are administered to stimulate the secretion of growth hormone. The gold standard has traditionally been to require two tests in order to optimize specificity and increase the predictive value.21,22 Despite this procedure, the reliability of provocative testing for growth hormone is hampered by poor reproducibility, variability in growth hormone assays, and inconsistent criteria for the diagnosis of growth hormone insufficiency, with cutoffs ranging from 5 to 10 mg per deciliter.23,24 When growth impairment is associated with a central-nervous-system injury or structural abnormalities, growth hormone testing may be unnecessary.19,25 On the other hand, the use of growth hormone testing in conjunction with serum IGF-1 and IGFBP-3 levels aids in the identification of children with defects downstream of growth hormone secretion who may benefit from more recently approved growth-promoting agents, such as IGF-1 and IGFBP-3.26,27,28
Growth Hormone Therapy
Gains in Height
Available data suggest that growth hormone therapy increases adult height between 3 and 6 cm in children with idiopathic short stature, but such growth requires long-term therapy. In studies demonstrating the efficacy of growth hormone therapy for this indication, the mean duration of therapy was four to seven years.6,8,9,29
A meta-analysis of the efficacy of growth hormone therapy in children with idiopathic short stature identified only four controlled studies and six uncontrolled studies with data regarding adult height.6 After growth hormone therapy (at doses of 0.25 to 0.40 mg per kilogram of body weight per week) or observation for a mean of 5.3 years in 118 patients in controlled studies, the adult height in the group that was treated with growth hormone was 5 to 6 cm greater than that of the untreated controls and 3.6 to 4.6 cm greater than the height predicted at baseline. In the eight uncontrolled studies with data regarding adult height for 246 patients, growth hormone treatment (at a dose of 0.14 to 0.33 mg per kilogram per week) for a mean of 4.7 years resulted in a gain of 3.8 to 4.5 cm in adult height above the height predicted at baseline. A subsequent study, sponsored by the National Institutes of Health (NIH), was a randomized, double-blind, placebo-controlled trial of growth hormone (at a dose of 0.22 mg per kilogram per week, divided into doses administered three times a week) in prepubertal children with idiopathic short stature. The study showed a mean gain in adult height of 3.7 cm in 22 patients who were treated with growth hormone (over a mean duration of 4.6 years), as compared with 11 patients who were treated with placebo.8
Short-term growth velocity increases during growth hormone therapy but is not predictive of final height outcome. However, if no increase in growth rate is observed with the use of adequate doses, adult height is unlikely to increase, and growth hormone therapy should be discontinued.
Higher doses of growth hormone may confer a greater benefit. A European study compared adult heights of 17 patients treated with growth hormone that was administered six times a week at a mean dose of 0.37 mg per kilogram per week for 7.0 years to that of 17 patients treated with a dose of 0.24 mg per kilogram per week for 6.1 years.9 In comparison with their baseline predicted adult height, the children who were treated with the higher dose had a significantly greater gain in adult height (7.2 cm, as compared with 5.4 cm for the group that received a lower dose). Moreover, daily administration of growth hormone has been shown to be more efficacious than administration three times per week.10
Despite the mean height gains associated with growth hormone therapy, there is individual variability in growth response, and some children have no increase in their adult height above the baseline predicted height.6,7,8,9,30,31,32 In the European study, although the SD of the mean height improved from –3.26 to –1.69±0.17 at the lower dose of growth hormone and from –2.88 to –1.12±0.18 at the higher dose, the ranges were –3.21 to –0.61 and –3.46 to 0.38, respectively.9 These data contrast with the more severe growth impairment but greater response to growth hormone therapy that is generally observed in children with classic growth hormone deficiency.5,10,33
A difficulty encountered with growth hormone therapy is the maintenance of a long-term regimen of daily injections. Trials of growth hormone frequently have high attrition rates. Of the 68 patients in the NIH study, 21 of 37 who were treated with growth hormone and 23 of 31 who were treated with placebo dropped out before the attainment of near-adult height despite an increase in growth velocity in the group treated with growth hormone.8 Outside of closely monitored studies, the issue of noncompliance and interruption of therapy is even more problematic. If injections are intermittent, suboptimal administration of the drug and growth deceleration when growth hormone is discontinued may compromise the expected gains in height and result in treatment failures.34
Psychosocial Outcomes
In addition to growth end points, psychosocial outcomes of growth hormone therapy are also relevant in the evaluation of the risk–benefit ratio of such therapy for children with idiopathic short stature. Early studies suggesting that children with short stature have maladaptive behavior and emotional problems related to teasing and low self-esteem have not been confirmed.35,36,37 Neither children with short stature who were referred for growth evaluation nor those screened in population studies had substantial emotional distress or impairment in psychosocial functioning, as compared with peers of normal stature or community norms.35,36,37 In the NIH trial of children with idiopathic short stature, baseline scores on behavior and self-competence fell within those in the general population.38 Overall psychosocial functioning and self-image were not substantially different in children treated with growth hormone from those in controls, except for the parental assessment of external behavior in years 3 and 4. Moreover, growth hormone therapy has not demonstrably improved measures of quality of life for children in limited studies.39,40,41
Although academic and social achievements have been shown to be correlated with adult height, population studies have found that socioeconomic factors exert the overriding influence on academic success and psychosocial health.35,42 Thus, the purported psychological benefits of achieving a taller stature are of questionable merit, and additional studies are needed to examine quality-of-life outcomes. Conversely, concerns about "medicalizing" healthy short children and perturbing psychological health with the long-term administration of growth hormone have been somewhat allayed by a recent report describing stable psychosocial functioning in children with idiopathic short stature who were treated with either growth hormone or placebo.38
Safety Concerns
On the basis of information from international databases and registries, a review of safety data on almost 100,000 children who were treated with growth hormone for a variety of indications found no increase above population norms for several potentially adverse effects of growth hormone therapy, such as diabetes mellitus, slipped capital femoral epiphyses, avascular necrosis of the femoral head, and cancer; idiopathic intracranial hypertension was observed in 1 of 1000 treated children, as compared with a rate of between 0.5 and 0.9 per 100,000 in the general population.43,44
In a study45 of 1848 patients with growth hormone deficiency who were treated with pituitary-derived growth hormone from 1959 to 1985 in the United Kingdom, concern was expressed about the potential risk of cancer. When patients at high risk for cancer were excluded, there were two cases of colorectal cancer and two cases of Hodgkin's disease among the 1352 remaining patients, which translates into an increase in the risk of colorectal cancer by a factor of 11 and of Hodgkin's disease by a factor of 3, as compared with the general population.45 The small size of this cohort study and the fact that no cases of colorectal cancer have been reported in the larger registry studies of patients treated with growth hormone make the significance of this observation questionable. However, the supraphysiologic concentrations of IGF-1 that are found with higher doses of growth hormone raise at least theoretical concern about an increased risk of neoplasia.
In children treated with growth hormone for idiopathic short stature, no cases of peripheral edema, pancreatitis, or benign intracranial hypertension have been reported, and the incidence of other serious side effects has been low: slipped capital femoral epiphysis developed in 0.04 percent of patients, and 0.07 percent had an alteration in carbohydrate metabolism.32,46 Three cases of neoplasia have been reported, none of which were thought to be caused by growth hormone therapy. Although these data are reassuring, the numbers are relatively small and the studies are of short duration; therefore, long-term surveillance for rare side effects is imperative in children treated with growth hormone for idiopathic short stature.
Areas of Uncertainty
Among children classified as having idiopathic short stature, there is great variability in biologic factors such as serum concentrations of IGF-1 and IGFBP-3, the extent of bone-age delay, and the timing of puberty. The heterogeneity of this diagnosis suggests that there are diverse underlying mechanisms for growth impairment. Although the genetic determinants of growth and stature remain incompletely defined, identification of specific molecular defects in the growth hormone–IGF axis or other growth-related genes may better inform therapeutic decisions.26,47,48 The reasons for poor response to growth hormone in some children are unclear. Although some cases can be attributed to suboptimal dosing regimens or noncompliance and some are associated with discordant advancement of bone age in relation to linear growth,30,31 inherent genetic influences on growth or biologic factors affecting responsiveness may also play a role. Growth hormone therapy is typically discontinued when growth velocity declines to less than 2 cm per year or when a height within the normal adult range is achieved, but the optimal duration of therapy remains unclear.
In addition to the uncertainty about whether the beneficial outcomes of growth hormone therapy outweigh its potential risks and the difficulties of adhering to therapy, many observers have expressed concern about the ethical and economic ramifications of the expanding use of growth hormone.5,13,14,49 At the core of the controversy is the question about whether short stature is a disease state or a continuum of normal development and, therefore, whether growth hormone therapy is a therapeutic or a cosmetic intervention. A recent economic analysis, based on the approved dosing guidelines and published efficacy data regarding adult height, calculated that the current cost of growth hormone therapy for five years is $52,000 per incremental inch of height gained.50 Because of the exorbitant cost and the large number of children whose height falls below the 1.2 percentile who theoretically qualify for therapy, the use of growth hormone in idiopathic short stature generates questions about the equitable distribution of health care resources and the economic effect on the health care system.14,49,50
Guidelines
Guidelines from the American Academy of Pediatrics and the Growth Hormone Research Society, which were published before FDA approval of growth hormone for idiopathic short stature, urged the use of growth hormone for nonapproved indications only within controlled trials.3,4,16 More recently updated recommendations from the Lawson Wilkins Pediatric Endocrine Society make note of the FDA guidelines for the use of growth hormone in patients with idiopathic short stature but stress caution about the unknown long-term consequences of the drug and the difficulties of identifying rare side effects.51
Conclusions and Recommendations
For children with idiopathic short stature, such as the boy in the vignette, the decision to treat must be individualized and should be guided by consultation with a pediatric endocrinologist with expertise in childhood growth disorders. Other causes of growth failure should be excluded, and ideally, the child's growth should fulfill the stringent FDA criteria. Assessment of psychosocial stressors and dysfunction is important; psychological intervention should be recommended if any concerns are identified. If growth hormone therapy is recommended, determination of the baseline growth rate before treatment is helpful in order to assess the effect of growth hormone therapy on growth velocity. To ensure realistic expectations, patients and their families should be educated about the anticipated average height gain of 4 to 7 cm after several years of daily therapy and the potential for not achieving this goal; they should also be informed that a brief course of growth hormone therapy or interrupted therapy because of missed injections is unlikely to be effective. Finally, the lack of clear prognostic factors for response to therapy and the individual variability in response necessitate periodic reappraisal of the treatment plan.
Although the current height of the patient in the vignette meets the criterion for the use of growth hormone to treat idiopathic short stature, his predicted height according to the Bayley–Pinneau tables is within the normal range and is consistent with his midparental target height (Figure 1). Given his delayed bone age, he most likely has familial short stature in conjunction with constitutional delay of growth and development. I would not recommend growth hormone therapy for this child on the basis of my assessment of the risk–benefit ratio, although some experienced pediatric endocrinologists would consider the treatment appropriate — a divergence of opinion that underscores the therapeutic challenges and lack of consensus in the management of idiopathic short stature. In either case, longitudinal monitoring of growth and development with periodic review of the management is essential.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Department of Pediatrics, University of Massachusetts Medical School, Worcester.
Address reprint requests to Dr. Lee at the Pediatric Endocrine Division, Department of Pediatrics, University of Massachusetts Medical School, 55 Lake Ave. N., Worcester, MA 01655, or at mary.lee@umassmed.edu.
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