特发性矮小治疗国际共识(2)（J Clin Endocrinol Metab. 2008年)

	Defining the Response to GH Treatment

Short-term auxological features that suggest a successful first-year response to GH treatment in individual patients include a change in height SDS of more than 0.3–0.5, a first-year height velocity increment of more than 3 cm/yr, or a height velocity SDS of more than +1. Restoration to a more normal height during childhood is an important consideration. Mathematical models can be used to estimate responses to therapy with the selected dose (25).

Biochemical features

Serial IGF-I measurements during GH therapy are useful to assess efficacy, safety, and compliance and have been proposed as a tool for adjusting the GH dose. No other biochemical tests are routinely recommended in GH-treated ISS patients.

Psychological features

An important rationale for treatment with GH is the assumption that it will improve quality of life. Validated instruments sensitive to the specific domains that are affected in short children and that are easily administered in the clinic are needed but are not currently recommended as part of routine care.

	Interpretation of Outcome Measures Assessing the Success of GH Treatment

Short-term outcome measures (i.e. <2 yr) must take into account the age, pubertal status, and degree of growth retardation of the individual patient. In most children with ISS, the change in height SDS will provide the best indicator of response, but height velocity, height velocity SDS, and the change in height velocity (centimeters per year or SDS) all have utility, and are sometimes superior, in assessing response when interpreted in light of the patient’s clinical situation. Long-term auxological parameters that define the success of therapy include adult height SDS, adult height SDS minus height SDS at start of GH, adult height minus predicted height, and adult height minus target height. Long-term psychosocial and metabolic outcomes should be evaluated in registries for these patients.

	Outcome of GH Therapy in Children with ISS

The mean increase in adult height attributable to GH therapy (average duration of 4–7 yr) in children with ISS is 3.5–7.5 cm compared with historical controls (26, 27), with patients’ own pretreatment predicted adult heights (28), or with nontreatment control or placebo control groups (29, 30).

Responses are highly variable and are dose dependent. Concern has been raised that higher GH doses (>53 µg/kg·d) may advance the bone age and the onset of puberty (31), but this has not been found in other studies (32).

Multiple factors affect the growth response to GH, many of which are unknown. Children who are younger or heavier, who receive higher GH doses, and who are shortest relative to target height have the best growth response. These factors account for approximately 40% of the variance in growth response. Adult height outcome is influenced negatively by age at start and positively by midparental height, height at start, bone age delay, and the first-year response to GH (23, 24). The utility of baseline and treatment-related biochemical data including IGF-I has not been validated in long-term studies, but 2-yr studies suggest that the rise in IGF-I correlates with short-term height gain (30).

	Monitoring for Efficacy and Safety in GH-Treated Children with ISS

Children treated with GH should be monitored for height, weight, pubertal development, and adverse effects at 3- to 6-month intervals. Regular monitoring for scoliosis, tonsillar hypertrophy, papilledema, and slipped capital femoral epiphysis should be performed as part of the regular physical exam during follow-up visits. We recommend that after 1 yr, the response to therapy be assessed by calculating height velocity SDS as well as the change in height SDS. Pubertal stage should be assessed regularly, and bone age may be obtained periodically to reassess height prediction and for consideration of intervention to modify the tempo of puberty. IGF-I levels may be helpful in guiding GH dose adjustment, but the significance of abnormally elevated IGF-I levels remains unknown. Thus far, no instances of elevated blood glucose in GH-treated patients with ISS have been reported, but there is controversy regarding the need for routine monitoring of glucose metabolism.

	GH Treatment Adjustment Strategies

Dosage is usually selected and adjusted by weight. If the growth response is considered inadequate, the dose may be increased. There are no definitive data concerning the long-term safety of doses higher than 50 µg/kg·d in children with ISS. The upper limit of GH dosage used in other pediatric conditions is approximately 70 µg/kg·d (28, 33), but the possibility of using such doses varies in terms of national health economics. In the United States, the current FDA-approved doses for GH in ISS are up to 0.3–0.37 mg/kg · wk (34). In the future, growth prediction models may improve GH dosing strategies. IGF-I levels may be helpful in assessing compliance and GH sensitivity; levels that are consistently elevated (>2.5 SDS) should prompt consideration of GH dose reduction. Recent studies on IGF-based dose adjustments in ISS demonstrated increased short-term growth when higher IGF targets were selected, but this strategy has not been validated in long-term studies with respect to safety, cost effectiveness, or adult height (31).

	Consideration of Adding Puberty Modulators

If height prediction is below –2.0 SDS at the time of pubertal onset in either sex, the addition of GnRHa may be considered as discussed above (35, 36). Alternatively, in males, aromatase inhibitors may be an option (22). However, long-term efficacy and safety data are not available for either of these interventions. Also, the impact of delayed puberty on somatic and psychological development is not known. We do not recommend aromatase inhibitors for girls.

	Duration of GH Treatment

There are two schools of thought about the duration of treatment. One is that treatment should stop when near adult height is achieved (height velocity <2 cm/yr and/or bone age >16 yr in boys and >14 yr in girls). Alternatively, therapy can be discontinued when height is in the normal adult range (above –2 SDS) or has reached another cutoff for the reference adult population (for example, in Australia, the 10th percentile; elsewhere, the 50th percentile). Stopping therapy is influenced by patient/family satisfaction with the result of therapy or ongoing cost-benefit analysis or when the child wants to stop for other reasons.

	Possible GH Side Effects

The possible side effects in GH-treated children with ISS are similar to those previously reported in children receiving GH therapy for other indications (37). However, the frequency of adverse events is generally less (38). No long-term adverse effects have been documented. Posttreatment surveillance with focus on cancer prevalence and metabolic side effects is recommended, but the feasibility of such studies is unclear.

	Cost/Benefit Analysis

The average ultimate height gain attributable to GH treatment in children with ISS, as well as the cost, are known (10,000–20,000 dollars/cm), but the short- and long-term benefits for the individual and society are unclear (26). It is presently not known whether, and how, a gain in height relates to change in quality of life. Therefore, GH treatment for children with ISS should be put in the context of the health budget for the specific country. At the current time, data demonstrating improved quality of life, better psychological health, etc. have not yet been collected in well-controlled studies. Therefore, recommendations for treatment that increases adult height should be balanced with the high cost of these therapies.

	The Definition of GH Nonresponsiveness

The expected result of GH treatment in ISS is an increase in height SDS and height velocity resulting in increased adult height. Because there is a continuum of GH responses, the definition of nonresponsiveness is arbitrary. Suggested criteria for poor first-year response include height velocity SDS less than +1 or change in height SDS less than 0.3–0.5, depending on age. Emerging tools for the definition of GH treatment failures include prediction modeling and age- and gender-specific growth-response charts (39). If the growth response is lower and compliance is assured, among the options considered may be increasing the dose of GH. IGF-I values can be used to assess compliance and sensitivity to GH. If after 1–2 yr and higher doses of GH, the growth rate is still inadequate, GH treatment should be stopped and alternative therapies could be entertained.

	Future Studies

Future studies on the management of children with ISS should involve three major areas. The first is improvement in diagnostic tools to categorize the different subpopulations who fall within the definition of ISS and their response to therapy. These would include molecular genetics, proteomics, and pharmacogenomics, better measures of GH and IGF-I sensitivity, and improved prediction models. The second area should involve psychosocial instruments, interventions, and outcomes. A third area is the conduct of well-controlled studies on the use of adjunctive pharmacological interventions such as the combination of GH and GnRHa, aromatase inhibitors, or IGF-I.

	Conclusions

ISS represents a significant clinical entity within the pediatric endocrinology practice, and multiple therapeutic interventions may be considered for these patients after appropriate evaluation has been conducted. Further clinical research and development is warranted to optimize the management of these children and to ensure that treatments are safe and beneficial.

	Acknowledgments

Consensus Workshop participants include David Allen, University of Wisconsin School of Medicine and Public Health, Madison, WI; Ivo Arnhold, Universidade de Sao Paulo, Sao Paulo, Brazil; Peter Bang, Karolinska Institute, Stockholm, Sweden; Fernando Cassorla, University of Chile, Santiago, Chile; Stefano Cianfarani, Tor Vergata University, Rome, Italy; Steven Chernausek, University of Oklahoma Health Sciences Center, Oklahoma City, OK; Jens Christiansen, Aarhus University Hospital, Aarhus, Denmark; Pinchas Cohen, UCLA, Los Angeles, CA; Leona Cuttler, Case Western Reserve University, Cleveland, OH; Paul Czernichow, Necker Enfants Malades University Hospital, Paris, France; Peter Davies, University of Queensland, Herston, Australia; Université de Montréal, Montreal, Canada; Yukihiro Hasegawa, Tokyo Metropolitan Kiyose Children’s Hospital, Tokyo, Japan; Chris Kelnar, University of Edinburgh, Scotland UK; Sandro Loche, Ospedale Regionale per le Microcitemie, Cagliari, Italy; Louis Low, University of Hong Kong, Hong Kong, China; Nelly Mauras, Nemours Children’s Clinic, Jacksonville, FL; Meinolf Noeker, University of Bonn, Bonn, Germany; John Parks, Emory University School of Medicine, Atlanta, GA; Moshe Phillip, Schneider Children’s Medical Center of Israel, Tel-Aviv University, Petah Tikva, Israel; Michael Ranke, University Hospital for Children and Adolescents, Tubingen, Germany; Sally Radovick, Johns Hopkins University School of Medicine, Baltimore, MD; Edward Reiter, Tufts University School of Medicine, Springfield, MA; Alan Rogol, University of Virginia, Charlottesville, VA; Stephen Rosenthal, UCSF, San Francisco, CA; Judy Ross, Thomas Jefferson University, Philadelphia, PA; Paul Saenger, Albert Einstein College of Medicine, Bronx, NY; David Sandberg, University of Michigan, Ann Arbor, MI; Martin Savage, London School of Medicine and Dentistry, London, UK; Lars Savendahl, Karolinska Institutet, Stockholm, Sweden; Jan-Maarten Wit, Leiden University Medical Center, Leiden, The Netherlands; and Susumu Yokoya, National Center for Child Health and Development, Tokyo, Japan.

Industry nonvoting participants included Eli Lilly and Co.; Barbara Lippe, Genentech; Ann-Marie Kappelgaard, Novo Nordisk A/S; Mireille Bonnemaire, Ipsen, Ltd.; George Bright, Tercica, Inc.; and Jose Cara, Pfizer Global Pharmaceuticals.

	Footnotes

The Consensus Workshop was organized and supported by the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society of Pediatric Endocrinology and supported in part by unrestricted education grants from Eli Lilly and Co., Ferring, Genentech, Ipsen, JCR Pharmaceuticals, Novartis, Novo Nordisk, Pfizer, and Tercica.

Endorsements: The Consensus document was endorsed by the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society (LWPES), the European Society of Pediatric Endocrinology (ESPE), the Latin American Society of Pediatric Endocrinology (SLEP), the Japanese Society of Pediatric Endocrinology (JSPE), the Canadian Pediatric Endocrine Group (CPEG), the Asia Pacific Pediatric Endocrine Society (APPES), and the Australasian Pediatric Endocrine Group (APEG).

Disclosure Statement: P.C. is a consultant to Tercica and Novo Nordisk and received grant support from Pfizer, Genentech, and Eli Lilly and Co. A.D.R. is a consultant to Tercica, Novo Nordisk, Genentech, Serono, and Pfizer. C.L.D. is a consultant to Serono and Eli Lilly, and Co. and a speaker for Novo Nordisk. P.S. is a consultant to Sandoz. E.O.R. is a consultant to Pfizer and a speaker for Genentech. J.L.R. is a consultant to Eli Lilly and Co. S.D.C. is a consultant for Tercica. M.O.S. is a consultant to Ipsen. J.M.W. is a consultant to Ipsen, Eli Lilly, and Tercica and received grant support from Pfizer, Novo Nordisk, Ferring, and Ipsen.