HOR MON E RE SE ARCH I N PÆDIATRIC S
Published online: September 7, 2011
Horm Res Paediatr 2011;76(suppl 3):1–2 DOI: 10.1159/000330131
Overview: Developments in Idiopathic Short Stature Jan M. Wit a , Leo Dunkel b a
Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands; b Department of Pediatrics, University of Kuopio and Kuopio University Hospital, Kuopio, Finland
Few topics in pediatric endocrinology provoke more discussion and dissent than idiopathic short stature (ISS). Differing opinions are held on virtually all aspects of the disorder and this is particularly true for its definition and management. Usually, the existence of differing opinions is a result of a paucity of observational and experimental data and, although ISS is no exception, some research findings are available. Following a consensus meeting held in 2007 [1] and subsequent publication of two large preparatory review articles [2, 3], several new reports have been published with an emphasis on the genetic and psychosocial aspects of ISS. Thus, an Expert Conference on Developments in ISS was convened in Barcelona, Spain, in October 2009 to facilitate discussion on recent developments and to debate the existing controversies. The conference was divided into six sessions. The first session focused on the definition and subcategorization of ISS, the diagnostic workup of the short child and spontaneous growth including adult height. The major topic of debate was whether the clinical syndromes of familial short stature (FSS) and constitutional delay of growth and puberty (CDGP) should be included or excluded in the definition of ISS. According to the majority vote at the consensus meeting in 2007, these conditions were considered subcategories of ISS; however, others wanted to restrict the term ‘ISS’ to describe children who were not typical representatives of FSS or CDGP. The diagnostic workup of the short child is critical since ISS is a diagnosis of exclusion. While there was wide agreement at the 2007 consensus meeting that a thorough medical history and physical examination are necessary, participants remained uncertain as to which additional investigations were relevant based on the presentation of the child. Because of the various definitions of ISS that have been used over the years, the categorization of FSS versus non-FSS and the limited number of longitudinal studies, there is no clear understanding of spontaneous growth in children with ISS. Without reliable data on the natural history of ISS, it is difficult to determine the efficacy of any treatment for it.
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The molecular background of ISS was discussed in the second session. New insights have been gained from genome-wide association studies (GWASs) and from single gene disorders; however, GWAS data have so far failed to translate into clinical utility. Adult height is associated with polymorphisms of hundreds of genes, more than 40 of which have been recently identified by GWAS. These new genetic data support the view that short stature may be an expression of an accumulation of ‘short’ alleles, which makes development of a functional algorithm for genetic testing of the short child difficult. Few clinicians would defend the statement that all children with ISS are appropriate candidates for drug treatment, but there is uncertainty about the most appropriate selection criteria. In the third session, participants debated the criteria for initiating treatment in children with ISS, specifically, auxology and laboratory findings, as well as psychological outcomes. Treatment options were discussed next. Growth hormone (GH) has been used in clinical trials for more than 20 years and was approved for use 7 years ago in the Unites States and some other countries. There is now a novel therapy available for use when the plasma insulin-like growth factor-1 level is low in the presence of normal, or even elevated, GH secretion. An alternative approach is to delay or diminish the biological action of sex steroids, particularly estrogens, through gonadotropin-releasing hormone analogs or aromatase inhibitors, or to add anabolic steroids. Since self-esteem and confidence issues may arise in a child with ISS, psychological intervention would seem beneficial; however, there are no published data on the effectiveness of this approach. The safety and efficacy of GH as a treatment for ISS were discussed in session five. Although GH has been used for a number of years in children with ISS, data remain scarce on the outcome in terms of efficacy, the relevant predictors and safety, particularly in the long term. More data are needed to reassure clinicians that the benefits of GH treatment outweigh any safety concerns. Session six focused on other possible benefits of GH therapy beyond longitudinal growth. Data were presented on quality-oflife (QoL) issues, potential effects on psychological functioning and impact on metabolism. To conclude, a roundtable discussion was held to elicit feedback on the cost-effectiveness of treating children with ISS. Clinical considerations and QoL research were featured. These proceedings, comprised of summaries of the various presentations, are intended to provide interested physicians and scientists with up-to-date reviews and expert opinions on various aspects of ISS.
Disclosure Statement
J.M.W. is a consultant to and has received consulting fees/honoraria from Ipsen and Pfizer, is a speaker/teacher for Ipsen, Pfizer and Lilly, serves on advisory committees/review panels for Ipsen, Lilly, Pfizer, Tercica and Pharming, has carried out contracted or funded research for Ipsen, Novo Nordisk, Pfizer and Ferring and is an investigator in clinical trials sponsored by Pfizer and Lilly. L.D. is a consultant to and has received consulting fees or honoraria from Pfizer, Ipsen and Novartis and serves on advisory committees/review panels for Ipsen.
References 1 Cohen P, Rogol AD, Deal CL, Saenger P, Reiter EO, Ross JL, Chernausek SD, Savage MO, Wit JM; 2007 ISS Consensus Workshop participants: 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;93:4210–4217. 2 Wit JM, Clayton PE, Rogol AD, Savage MO, Saenger PH, Cohen P: Idiopathic short stature: definition, epidemiology, and diagnostic evaluation. Growth Horm IGF Res 2008;18:89–110. 3 Wit JM, Reiter EO, Ross JL, Saenger PH, Savage MO, Rogol AD, Cohen P: Idiopathic short stature: management and growth hormone treatment. Growth Horm IGF Res 2008;18:111–135.
Horm Res Paediatr 2011;76(suppl 3):2 DOI: 10.1159/000330132
Chairman’s Summary: Definition of Idiopathic Short Stature
relatively sizable effects on growth, but minor effects on other organ structure or function; [potentially] multiple gene polymorphisms with minor effects on growth; and/or genes that affect the tempo of development by which height is an indirect target. Professor Anita Hokken-Koelega, Rotterdam, The Netherlands, then discussed the complexity of the diagnostic workup of the short child. Based on the fact that ‘idiopathic’ requires the exclusion of obvious organic, endocrine, nutritional and systemic disorders, the diagnostic path has to be broad, but also directed by clinical judgment. In particular, Professor Hokken-Koelega emphasized new findings about the GH-insulin-like growth factor (GH-IGF) pathway that could affect growth and development [3, 4]. Therefore, it is necessary to comprehensively investigate GH secretion and factors of the IGF system (IGF-I, IGF-II, IGF binding protein-3, acid labile subunit, etc.). In addition, genetic abnormalities in the GH-IGF-signal transduction pathways are currently observed in patients diagnosed with ISS. The technology that is rapidly emerging to observe genetic variations in these patients could lead to specific diagnoses that, eventually, could lead to tailored therapies. Professor Jürgen Brämswig, Münster, Germany, reviewed the literature on spontaneous growth and adult height in ISS. The literature is quite limited and the criteria for inclusion of patients have not been homogenous. Generally, children with FSS grow to about 0.5 SDS below mean target height, while those with non-FSS grow to about 1.0 SDS below mean target height [5, 6]. Thus, a sizable fraction of children with ISS will remain short into adulthood. So far, the methods to predict individual adult height outcomes are fairly inaccurate. Height, parental height, bone age and gender appear to affect height prognosis. Professor Brämswig pointed out that individual growth of both parents needs to be considered. Disclosure Statement
University Children’s Hospital, Universitätsklinikum Tübingen, Tübingen, Germany
M.B.R. is a consultant to and an advisory committee/review panel member for Pfizer and a speaker/teacher for Pfizer, Novo Nordisk, Ipsen and Lilly; he receives consulting fees from Pfizer and honoraria from Pfizer, Novo Nordisk, Ipsen and Lilly.
Professor Jan-Maarten Wit, Leiden, The Netherlands, led a discussion about the current definition of idiopathic short stature (ISS) including the ‘hypothetical’ pathophysiologies of ISS. The current most widely accepted definition of ISS is: ‘…a condition in which the height of the individual is more than 2 standard deviation scores (SDS) below the corresponding mean height for a given age, sex and population group, without evidence of systemic, endocrine, nutritional or chromosomal abnormalities. Specifically, children with ISS have normal birth weight and are growth hormone (GH) sufficient’ [1, 2]. The definition includes a subcategorization into familial short stature (FSS) and non-FSS based on the height of the patient in relation to the familial target range. Based on new data analyzing groups of children classified as having ISS or those born small for gestational age, Professor Wit pointed out that the borders between these descriptive diagnoses of short stature are blurred. He also noted the ongoing discussion about whether the terms FSS and constitutional delay of growth and puberty are separate from ISS. This debate has not yet come to a conclusive ending. Based on the present concept, Professor Wit argued that ISS could be the result of genetic factors involving single genes with
1 Ranke MB: Towards a consensus on the definition of idiopathic short stature. Horm Res 1996;45(suppl 2):64–66. 2 Cohen P, Rogol AD, Deal CL, Saenger P, Reiter EO, Ross JL, Chernausek SD, Savage MO, Wit JM; 2007 ISS Consensus Workshop participants: 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;93:4210–4217. 3 Walenkamp MJ, Wit JM: Genetic disorders in the growth hormoneinsulin-like growth factor-I axis. Horm Res 2006;66:221–230. 4 Wit JM, Clayton PE, Rogol AD, Savage MO, Saenger PH, Cohen P: Idiopathic short stature: definition, epidemiology, and diagnostic evaluation. Growth Horm IGF Res 2008;18:89–110. 5 Rekers-Mombarg LT, Wit JM, Massa GG, Ranke MB, Buckler JM, Butenandt O, Chaussain JL, Frisch H, Leiberman E: Spontaneous growth in idiopathic short stature. European Study Group. Arch Dis Child 1996;75:175–180. 6 Ranke MB, Grauer ML, Kistner K, Blum WF, Wollmann HA: Spontaneous adult height in idiopathic short stature. Horm Res 1995;44:152– 157.
Michael B. Ranke
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Horm Res Paediatr 2011;76(suppl 3)
References
Developments in Idiopathic Short Stature
