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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-1641
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 11 4235-4236
Copyright © 2006 by The Endocrine Society

CONTROVERSY IN CLINICAL ENDOCRINOLOGY

Problems with Reclassification of Insulin-Like Growth Factor I Production and Action Disorders

Pinchas Cohen

Mattel Children’s Hospital, and David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095-1752

Address all correspondence and requests for reprints to: Pinchas Cohen, M.D., Professor and Chief of Pediatric Endocrinology, University of California, Los Angeles, 10833 Le Conte Avenue, MDCC 22-315, Los Angeles, California 90095-1752. E-mail: hassy{at}mednet.ucla.edu.


   Abstract
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 Abstract
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Context: Recent developments in the IGF field have raised questions on whether this is the right time to redefine IGF deficiency.

Objective: In this controversy, arguments are made against the need for redefining IGF deficiency at this moment, suggesting instead to wait for further clinical developments.

Case: Although a number of rare case reports of IGF deficiency with precise molecular etiologies have been described, the vast majority of the cases remain clinically defined and without a genetic diagnosis.

Interventions: Because IGF products are now available for clinical use in IGF-deficient patients, we are still using GH stimulation and static IGF levels as our only clinical diagnostic and classification tools.

Positions: We need to develop additional clinical tools, side by side with molecular tools, for the diagnosis and subclassification of IGF deficiency. Chief among these are the IGF-generation test for identification of GH-insensitive patients and genetic panels of polymorphic changes in relevant genes.

Conclusions: Until further progress is made in the clinical classification of IGF deficiency, we should not change the current classification, and, when we do, it should be the responsibility of the relevant societies in the field to conduct a consensus statement on the topic first.

OVER THE LAST decade, our understanding of human growth disorders has advanced dramatically. Multiple new molecular defects accounting for short stature have been identified, including new mutations in the GHRH-GH pathway, the GH-secretagogue pathway (1), new mutations in the GH receptor, mutations in the effector pathway of the GH receptor including Stat-5b (2), mutations in the IGF gene (3), as well as the IGF-I receptor (4). Additionally, mouse models of these human conditions have emerged as useful tools in the study of these disorders (5). All of these examples involve reductions in the circulating levels of IGF-I, either as a consequence of decreased GH action or as a direct result of decreased IGF production in the liver and other tissues. This ever-expanding body of knowledge underscores the importance of IGF in growth and of IGF deficiency in growth disorders (6).

In 2005, the Food and Drug Administration (FDA) officially recognized IGF deficiency as a treatable condition and approved two products (Increlex or IGF-I and Iplex or IGF-I complexed with IGF binding protein-3) for the management of patients with severe short stature and IGF deficiency. The clinical approach to the diagnosis of IGF deficiency is therefore a practical issue with clear implications to the management of patients, and thus, a useful and clinically relevant classification of IGF deficiency should be a welcome addition to the literature. Unfortunately, genetically defined IGF deficiency disorders constitute less than 1% of the short patients evaluated by U.S. physicians, whereas a full one third to one half of short patients are IGF deficient (7). Therefore, a molecularly driven classification adds little to the flow of decision making regarding the work up of short stature in real-life situations. A major reason for this may be that, rather than defined discrete mutations, combinations of several polymorphisms in relevant genes may lead to the clinical phenotype. At the current time, diagnostic tools to assess this possibility are unavailable.

Instead, the clinician is left with a small arsenal of simple tools, including the ability to measure IGF-I as well as the levels of stimulated GH in the sera of short children (8). These tools divide the population of short children into three groups, as shown in Fig. 1Go, which is a Venn diagram of individuals with growth disorders, including those who are GH-deficient, those with IGF deficiency, and those who can be classified as displaying idiopathic short stature. These are the actual diagnostic categories currently used. This paradigm will certainly change in the near future. Additional tools are emerging to serve clinicians involved in caring for short children. These tools include possible genetic testing panels, additional biochemical markers, and new dynamic diagnostic tools; chief among these is the IGF-generation test (9). The latter test is critical in its ability to differentiate IGF deficiency that is responsive, unresponsive, or partially responsive to GH therapy (10). Obviously, such a test will have to be validated with corresponding growth data on GH treatment. Therefore, future classifications of short children should incorporate existing and emerging clinical tools that will assist clinicians in daily patient management.


Figure 1
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  		FIG. 1. A Venn diagram delineating idiopathic short stature (ISS), IGF deficiency (IGFD), and GH deficiency (GHD).

 
It is important to realize that IGF deficiency can exist in a two-dimensional universe of abnormalities in either GH secretion (also referred to as secondary IGF deficiency) or GH responsiveness (sometimes called primary IGF deficiency). In many cases, combinations of subtle defects of both genetic and environmental origin can affect either or both axes of this equation. This paradigm is shown in Fig. 2Go. As noted, the more defined groups of GH deficiency and Laron syndrome have clear defects in GH secretion or action, whereas IGF deficiency encompasses a broader range of abnormalities, and the group of children classified as idiopathic short stature could fall almost anywhere within this diagram.


Figure 2
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  		FIG. 2. A two-dimensional diagram of GH secretion and GH sensitivity and short stature disorders.

 
The recognition of IGF deficiency as a distinct clinical diagnosis has led to the development of clinical trials using both IGF-I and GH for the treatment of this disorder (11). It makes sense that classification of IGF deficiency will be focused on defining clinically relevant, therapy-related algorithms that can be based on phenotypic features, biochemical markers, and genetic testing (12). This classification must be able to address all children with IGF deficiency, not just those with defined molecular syndromes. Obviously, this will be a challenging task that cannot be undertaken by one or two individuals. It will be the responsibility of the learned societies, including The Endocrine Society, the Lawson Wilkins Pediatric Endocrine Society, the Growth Hormone Research Society, the IGF Society, and the European Society of Pediatric Endocrinology, all of which have all addressed the challenge of creating similar documents (13), to come up with the desired document that will define and classify IGF deficiency in a practical, relevant manner that will assist clinicians in patient care.


   Footnotes
 
Disclosure summary: P.C. is a consultant to Tercica and Novo Nordisk and has received grant support from Genentech, Pfizer, Eli Lilly & Co., and Serono.

First Published Online September 5, 2006

Received July 31, 2006.

Accepted August 9, 2006.


   References
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  1. Pantel J, Legendre M, Cabrol S, Hilal L, Hajaji Y, Morisset S, Nivot S, Vie-Luton MP, Grouselle D, de Kerdanet M, Kadiri A, Epelbaum J, Le Bouc Y, Amselem S 2006 Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature. J Clin Invest 116:760–768[CrossRef][Medline]
  2. Kofoed EM, Hwa V, Little B, Woods KA, Buckway CK, Tsubaki J, Pratt KL, Bezrodnik L, Jasper H, Tepper A, Heinrich JJ, Rosenfeld RG 2003 Growth hormone insensitivity associated with a STAT5b mutation. N Engl J Med 349:1139–1147[Free Full Text]
  3. Woods KA, Camacho-Hubner C, Savage MO, Clark AJ 1996 Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N Engl J Med 335:1363–1367[Free Full Text]
  4. Abuzzahab MJ, Schneider A, Goddard A, Grigorescu F, Lautier C, Keller E, Kiess W, Klammt J, Kratzsch J, Osgood D, Pfaffle R, Raile K, Seidel B, Smith RJ, Chernausek SD; Intrauterine Growth Retardation (IUGR) Study Group 2003 IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med 349:2211–2222[Abstract/Free Full Text]
  5. Cohen P 2006 Overview of the IGF-I system. Horm Res 65(Supp 1):3–8
  6. Rosenfeld RG 2003 Insulin-like growth factors and the basis of growth. N Engl J Med 349:2184–2186[Free Full Text]
  7. Ranke MB 2006 Defining insulin-like growth factor-I deficiency. Horm Res 65(Suppl 1):9–14
  8. Park P, Cohen P 2005 Insulin-like growth factor I (IGF-I) measurements in growth hormone (GH) therapy of idiopathic short stature (ISS). Growth Horm IGF Res 15(Suppl A):S13–S20
  9. Rosenfeld RG, Buckway C, Selva K, Pratt KL, Guevara-Aguirre J 2004 Insulin-like growth factor (IGF) parameters and tools for efficacy: the IGF-I generation test in children. Horm Res 62(Suppl 1):37–43
  10. Blair JC, Camacho-Hubner C, Miraki Moud F, Rosberg S, Burren C, Lim S, Clayton PE, Bjarnason R, Albertsson-Wikland K, Savage MO 2004 Standard and low-dose IGF-I generation tests and spontaneous growth hormone secretion in children with idiopathic short stature. Clin Endocrinol (Oxf) 60:163–168[CrossRef][Medline]
  11. Cohen P, Bright GM, Rogol AD, Kapplegaard AM, Rosenfeld RG; American Norditropin Clinical Trials Group 2002 Effects of dose and gender on the growth and growth factor response to GH in GH-deficient children: implications for efficacy and safety. J Clin Endocrinol Metab 87:90–98[Abstract/Free Full Text]
  12. Clayton PE, Ayoola O, Whatmore AJ 2006 Patient selection for IGF-I therapy. Horm Res 65(Suppl 1):28–34
  13. Growth Hormone Research Society 2000 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 85:3990–3993[Free Full Text]



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