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

Division of Endocrinology (A.L.R.), Department of Pediatrics, University of Florida College of Medicine, Gainesville, Florida 32608; and Instituto Endocrinologia, Metabolismo y Reproduccion (J.G.-A.), Quito, Ecuador

Address all correspondence and requests for reprints to: Arlan L. Rosenbloom, Children’s Medical Services Center, 1701 Southwest 16th Avenue, Gainesville, Florida 32608. E-mail: rosenal{at}peds.ufl.edu.

	Abstract

Top Abstract Introduction Previous Classifications A New Perspective References

 
Context: The need for the least ambiguous terminology for disorders affecting IGF-I production and action has become necessary with identification of defects at various steps in the GH-IGF-I axis and the promotion of new indications for and modalities of growth therapy. No generally agreed-upon or consensus-derived classification exists.

Objective: Our objective was to designate all disorders affecting IGF-I production and action by their discrete location, as is already done with the defects in pituitary differentiation factors, avoiding imprecise and ambiguous terminology.

Conclusions: We propose a pragmatic classification that is a precise listing of specific disorders sequentially following the GH-IGF-I axis, using their accepted designations, and the abolition of nonspecific or ambiguous terminology. This concept permits ready insertion of new discoveries.

	Introduction

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A RATIONAL AND specific classification for disorders affecting the GH-IGF-I axis is needed for scientific precision appropriate to contemporary knowledge and understanding of the control of growth and for ease of classification of newly discovered abnormalities. Accurate classification is also needed to avoid ambiguity and the use of vague terms for promotion of specific diagnostic or therapeutic endeavors. Reconsideration of classification of disorders resulting in IGF-I deficiency and resistance has become necessary with identification of defects at various steps in the GH-IGF-I axis and the emergence of new indications for and modalities of growth therapy (1, 2). Thus, the accuracy of the nomenclature is important both for investigators elucidating mechanisms of growth and for the perspective clinicians will have when considering diagnosis and therapy of growth problems.

	Previous Classifications

Top Abstract Introduction Previous Classifications A New Perspective References

 
A classification put forth in 1993 by Laron and other international experts was a simple separation of GH insensitivity (GHI) into primary and secondary groups; primary GHI encompassed typical Laron syndrome (clinical phenotype of severe GH deficiency with elevated circulating GH, low IGF-I, and unresponsiveness to exogenous GH) resulting from GH receptor (GHR) deficiency, postreceptor signal transduction abnormalities, and primary defects of synthesis of IGF-I (3). The latter had not yet been described, but there have now been two reports of defective IGF-I synthesis from deletion or mutation of the IGF-I gene (4, 5, 6). Considering such primary IGF-I defects also to be primary GHI is confusing and inconsistent with the definitions of primary and secondary (7). Secondary GHI, as proposed in 1993, included the development of GH-inhibiting antibodies in patients with GH gene deletion treated with recombinant human (rh)GH, antibodies to the GHR, diabetes, malnutrition, liver disease, and renal disease, disorders that are not consistently associated with elevated serum GH concentrations or low levels of IGF-I, which should be requirements for classification as GHI. The imprecise terminology reflected in this classification provides opportunities for subjective interpretation and application.

Subsequently, two of the authors of the classification above defined primary GHI to include a broader range of hereditary defects, adding to those previously listed as primary GHI (GHR defects, GH signal transduction defects, and IGF-I synthetic defects), IGF-I transport defect, IGF-I receptor defect, and bio-inactive GH molecule (8, 9). Secondary GHI was defined as acquired defects, as noted above. At the same time, Laron was referring to Laron syndrome as both primary GH resistance and primary IGF-I deficiency interchangeably (10).

Because of the imprecision and ambiguity of the 1993 classification, which persisted in its subsequent permutation, we proposed a classification based on the fundamental role of IGF-I, rather than one step in the GH-IGF-I pathway, GHR abnormality, as consistent with classifications used for other target hormone deficiency states (11). In this classification, primary IGF-I deficiency applied only to defects in IGF-I synthesis. Secondary IGF-I deficiency was considered to be congenital, caused by GHR deficiency or GH-GHR signal transduction defects, or acquired as a result of catabolic conditions such as chronic disease or undernutrition. Tertiary IGF-I deficiency included congenital and acquired GH deficiency. Unfortunately, the terms primary, secondary, and tertiary are sufficiently removed from such precise meanings that they obscure rather than enhance understanding and communication.

	A New Perspective

Top Abstract Introduction Previous Classifications A New Perspective References

 
In Dorland’s Illustrated Medical Dictionary, primary is defined as "first in order or in time of development; principal," and secondary is defined as "second or inferior in order of time, place, or importance; derived from or consequent to a primary event or thing" (7).

The terms primary and secondary are commonly used but are too general and imprecise for most scientific use, leaving room for confusion and communication errors. These terms were carried over from a time when medical science was unable to specifically pinpoint a given defect; with scientific advances, the terms primary and secondary have become archaic and should be avoided. As an example, it is apparent that primary IGF-I deficiency is an inappropriate designation for those with Laron syndrome secondary to GHR deficiency or post-GHR signal transduction abnormalities, and this term cannot rationally be applied both to such abnormalities and to defects in the IGF-I gene (2, 11). This dissonance reflects the traditional use of primary to indicate congenital conditions and secondary for those that are acquired, as noted above (8, 9). Some ambiguity may also arise from the perception of IGF-I as the principal, i.e. primary, growth effector. Thus, a clinical pathological state that is primarily the result of IGF-I deficiency devolves into primary IGF-I deficiency. Contemporary knowledge and the need for clarity in scientific communication must dismiss terminology that is subject to such variable and subjective interpretation.

We propose to evade this ambiguity by classifying abnormalities involving the GH-IGF-I axis according to their discrete locations (Table 1). This is already the practice for defects in pituitary differentiation factors, and there is no reason why archaic nomenclature should be used further along in the GH-IGF-I pathway. The defects in pituitary differentiation factors are detailed in the table for illustrative purposes; expansion of several of the other designations, particularly other causes of isolated GH deficiency (IGHD) and multiple pituitary hormone deficiencies (MPHD), congenital and acquired, and GHR deficiency, would be appropriate for a particular scientific endeavor or communication. Such an approach to classification is consistent with knowledge of existing defects at each level of the GH-IGF-I cascade and is adaptable to new discoveries in growth mechanisms, identification of new defects, and development of new therapies. There is little to justify continuation of nonspecific, imprecise, or misleading terminology given our current knowledge of the molecular and physiological aspects of growth.

	Footnotes

 
Disclosure statement: The authors have nothing to declare.

First Published Online September 5, 2006

Abbreviations: GHI, GH insensitivity; GHR, GH receptor; IGHD, isolated GH deficiency; MPHD, multiple pituitary hormone deficiencies; rh, recombinant human.

Received January 5, 2006.

Accepted August 1, 2006.

	References

Top Abstract Introduction Previous Classifications A New Perspective References

 

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