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Editorial |
Lucile Packard Foundation for Children’s Health, Palo Alto, California 94304; Stanford University, Palo Alto, California 94305; and Oregon Health & Science University, Portland, Oregon 97239
Address all correspondence and requests for reprints to: Ron G. Rosenfeld, Lucile Packard Foundation for Children’s Health, 770 Welch Road, Suite 350, Palo Alto, California 94304. E-mail: ron.rosenfeld{at}lpfch.org
Despite the dramatic photographs of giants and dwarfs commonly found in textbooks of endocrinology or as entries in The Guinness Book of World Records, human growth is, in actuality, a tightly controlled phenotypic variable. In the United States, for example, the SD for adult height in both males and females is approximately 3 inches, representing only 4% of the mean adult heights of 69 and 64 inches, respectively (1). Nevertheless, extensive experience has shown that when children with short stature are treated with GH, at least with a standard weight-based dosing schedule, considerable variability in responsiveness to therapy has been observed (2, 3, 4). This, perhaps, may not be surprising in non-GH-deficient conditions, such as Turner syndrome, intrauterine growth retardation, or idiopathic short stature, where the underlying basis of growth failure is unlikely to be related to straightforward perturbations of the GH-IGF axis. It has been difficult, however, to understand why children with GH deficiency, in whom therapy is directed, presumably, at the straightforward replacement of an absence of GH, should vary so greatly in their clinical outcomes. A range of responsiveness to GH persists, in fact, even when factors such as statural deficiency before therapy, bone age, midparental height, and duration of treatment are taken into consideration.
Given that animal knockout (5) and human mutational analysis (6) have both supported a central role for the IGF system in postnatal growth and the mediation of GH actions on stature, the most likely candidates for variability in responsiveness to GH therapy would appear to be factors influencing IGF generation after GH administration or sensitivity to IGF action at the epiphyseal growth plate. Current knowledge supports the concept that the overwhelming majority of GH actions on growth are mediated through binding to the transmembrane GH receptor (GHR), followed by activation of JAK2, phosphorylation of STAT5b, and transcriptional regulation of IGF-I (7). GHR transcripts exist in several isoforms in humans, among which is the retention (GHRfl) or exclusion (GHRd3) of exon 3, which encodes a 22-residue sequence in the extracellular domain (8). This stretch of amino acids appears to be located away from the GH-binding interface of the GHR and, indeed, GHRfl and GHRd3 share similar binding properties for both pituitary and placentally derived GH (9). Furthermore, in studies of family members of a patient with GH insensitivity resulting from compound heterozygosity for nonsense mutations of exon 3 and exon 4 of the GHR, it was apparent that the presence of a single allele encoding either GHRfl or GHRd3 is sufficient for normal stature (10). Evidence to date supports the hypothesis that the loss of exon 3 is the consequence of an intrachromosomal recombination event between two similar primate-specific retroelements flanking exon 3, but the relative roles of the two isoforms in GH action remain elusive.
In western European populations, it has been estimated that 68–75% of GHR alleles are GHRfl, whereas 25–32% are GHRd3 (8, 11). Although several studies have indicated that adult stature of normal individuals is not affected by the GHR genotype, a recent investigation by Dos Santos et al. (11) reported that responsiveness to GH therapy was significantly impacted by GHR alleles. In that study of two cohorts of short children, either small for gestational age or idiopathic short stature, the homozygous or heterozygous presence of GHRd3 resulted in a significantly greater growth response in both yr 1 and 2 of GH therapy. Now, in a related study by Jorge et al. (12), these findings have been extended to studies in a GH-deficient population. Patients carrying at least one GHRd3 allele had a significantly greater first-year response and achieved a superior adult height on GH therapy than did patients homozygous for GHRfl. In both studies, the presence of one or more GHRd3 alleles was sufficient to impart superior GH responsiveness, consistent with a dominant effect of this allele.
All in all, these are stunning observations and would appear to support GHR isoforms as the first pharmacogenomic biomarkers with predictive value for GH responsiveness. To some extent, however, one has an inescapable sense of these observations being almost "too good to be true," and to point out the deficiencies that characterize the two studies: 1) neither investigation is prospective and is, consequently, stigmatized by issues that confront any retrospective analysis of data obtained for other reasons; 2) the absence of an effect of genotype on normal adult stature is somewhat puzzling, although it has been proposed (but never proven) that individuals with a genotype conferring decreased GH responsiveness compensate by increasing their GH production; 3) neither study provided data on IGF generation characteristics of the study groups, nor, for that matter, were serum IGF-I levels followed systematically during the course of GH treatment (13); and 4) no mechanism to explain differential responsiveness to GH based upon the presence or absence of exon 3 of the GHR has been established.
Despite such caveats, these are exciting observations and are clearly worthy of serious consideration and carefully designed prospective studies. These should include both clinical studies with discrete populations of GH recipients (i.e. GHD patients should not be intermixed with other causes of short stature, which are worthy of their own independent studies), as well as biochemical investigations directed at the mechanism of action of each GHR isoform. Does, for example, the GHRd3 isoform result in greater activation of the JAK/STAT system, with enhanced transcription of IGF-I, or does it, perhaps, influence other GH signaling mechanisms that contribute to growth in a manner independent from the IGF system? Because knockout studies have suggested that the GHR may facilitate growth, at least to a limited extent, through mechanisms independent of the IGF system, such studies of the influence of GHR isoforms on various postreceptor signaling mechanisms may be of particular value.
Whether or not the GHRd3 isoform really, in the end, contributes significantly to GH responsiveness, these studies play an important role in directing our attention to the wide and largely unexplained variability in GH responsiveness among pediatric (and, perhaps, adult) patients receiving GH treatment. This is an area that is particularly well-suited to a pharmacogenomic approach, as the clinical effectiveness of therapy should be readily quantifiable. Candidate genes include not only the GHR, but the entire GHR-dependent signaling cascade, as well as genes that impact IGF responsiveness at the growth plate. A recognition of the wide range of clinical responsiveness to GH, and its molecular basis, should also serve to strongly challenge the traditional, weight-based GH dosing that has been in use for over 40 yr (14). The ultimate outcome should be the recognition of the importance of individualized GH dosing, based on each patient’s specific genomic characteristics and therapeutic goals. This would constitute a major improvement in a therapy that has been historically dominated by a "one size fits all" approach.
Footnotes
Abbreviation: GHR, GH receptor.
R.G.R. is a consultant for the following: Genentech, Tercica, Novo Nordisk, DSL, LG, and Lilly; and has received grant support from Genentech and Tercica.
Received January 5, 2006.
Accepted January 12, 2006.
References
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  B. Raz, M. Janner, V. Petkovic, D. Lochmatter, A. Eble, M. T. Dattani, P. C. Hindmarsh, C. E. Fluck, and P. E. Mullis Influence of Growth Hormone (GH) Receptor Deletion of Exon 3 and Full-Length Isoforms on GH Response and Final Height in Patients with Severe GH Deficiency J. Clin. Endocrinol. Metab., March 1, 2008; 93(3): 974 - 980. [Abstract] [Full Text] [PDF]
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B. Bakker, J. Frane, H. Anhalt, B. Lippe, and R. G. Rosenfeld Height Velocity Targets from the National Cooperative Growth Study for First-Year Growth Hormone Responses in Short Children J. Clin. Endocrinol. Metab., February 1, 2008; 93(2): 352 - 357. [Abstract] [Full Text] [PDF]
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J. Baron Growth Hormone Therapy in Childhood: Titration Versus Weight-Based Dosing? J. Clin. Endocrinol. Metab., July 1, 2007; 92(7): 2436 - 2438. [Full Text] [PDF]
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