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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 11 4489-4493
Copyright © 2007 by The Endocrine Society

BRIEF REPORT

Association of the Growth Hormone Receptor d3-Variant and Catch-up Growth of Preterm Infants with Birth Weight of Less Than 1500 Grams

Felix Schreiner, Sonja Stutte, Peter Bartmann, Bettina Gohlke and Joachim Woelfle

Pediatric Endocrinology Division (F.S., S.S., B.G., J.W.) and Department of Neonatology (S.S., P.B.), Children’s Hospital, University of Bonn, 53113 Bonn, Germany

Address all correspondence and requests for reprints to: Dr. Joachim Woelfle, Pediatric Endocrinology Division, Children’s Hospital, University of Bonn, Adenauerallee 119, 53113 Bonn, Germany. E-mail: joachim.woelfle{at}ukb.uni-bonn.de.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Background: Preterm infants with very low birth weight frequently exhibit impaired longitudinal growth during the first years of life. Recently, the d3-isoform (genomic deletion of exon 3) of the GH receptor (GHR) has been linked to an increased responsiveness to GH.

Objective: Our objective was to test whether the GHRd3 isoform is associated with postnatal catch-up growth in very low birth weight preterm infants.

Design and Patients: We compared the postnatal growth pattern of 77 otherwise healthy preterm infants (mean gestational age, 28.5 wk; range, 23–35 wk) with a birth weight below 1500 g (mean birth weight, 941 g) to their GHR exon 3 genotype, which was analyzed by multiplex PCR. On examination, mean age of the children was 6.0 yr (range, 4.2–8.0 yr).

Results: Children homozygous or heterozygous for the GHRd3 allele showed a significantly higher rate of postnatal catch-up, compared with those homozygous for the full-length allele.

Conclusions: Our results define the GHR exon 3 genotype as a predictor for the postnatal growth pattern of very low birth weight preterm infants. Those who carry at least one GHRd3 allele are more likely to catch-up.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
PRETERM INFANTS WITH very low birth weight frequently exhibit impaired longitudinal growth during the first years of life. Although the majority of these children show catch-up growth, some remain short. To date, the pathophysiology of poor postnatal catch-up growth is still incompletely understood, so that a prediction of whether an individual patient will demonstrate sufficient catch-up at a later age remains difficult (1, 2).

Recently, the d3-isoform (genomic deletion of exon 3) of the GH receptor (GHR) has been linked to an increased response signaling to GH (3). The efficiency of GH treatment in children born small for gestational age (SGA) or with idiopathic short stature or Ullrich-Turner syndrome and children with GH deficiency was reported to be increased when carrying at least one GHRd3 allele (3, 4, 5). However, other groups failed to find a significant influence of this genomic GHR variant on the responsiveness to GH therapy (6, 7, 8). Although not tested so far, a model of dose dependency with a more pronounced impact when using supraphysiological doses has been suggested to explain parts of this discrepancy (8).

Because catch-up growth can be defined biologically as a period of supraphysiological growth velocity, we hypothesized that the GHRd3 variant might play a crucial role by modulating the effects of endogenous GH on target genes involved in the postnatal growth pattern, such as IGF-I. By assessment of the postnatal growth pattern of 77 preterm infants with a birth weight of less than 1500 g and analysis of their respective GHR exon 3 genotype, we found evidence for a role of GHRd3 in supporting catch-up growth.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
In this cross-sectional study, we surveyed 77 children (47 girls) who had been born prematurely (mean gestational age, 28.5 wk; range, 23–35 wk) as very low birth weight (VLBW) infants with a birth weight of less than 1500 g (mean birth weight, 941 g; range, 350-1500 g). All children were participants of the preterm follow-up program at our University Children’s Hospital Bonn. Between 1999 and 2002, 356 children with a birth weight of less than 1500 g were born in the Department of Obstetrics and Gynecology of our University Hospital. Of these, 292 survived the neonatal period. At the time of this study, 173 were still followed in the preterm follow-up program. Of these, 122 lived within 1 h driving distance of our hospital, and 101 agreed to participate in this study. Nineteen children were excluded due to a history of periventricular hemorrhage, severe necrotizing enterocolitis, or a known syndromal disorder. Furthermore, we did not include five children who were born after assisted reproduction techniques, because those are considered to be more prone to epigenetic alterations that might also affect growth. Our final study cohort consisted of 77 children. We compared recorded patient data from the initial 173 children with the final cohort after children suffering from severe cerebral hemorrhage or severe necrotizing enterocolitis were excluded. There were no significant differences between the remaining nonparticipants and the final study cohort regarding gestational age or auxological birth parameters. The study was approved by the ethics committee of the University Hospital Bonn.

After standardized measurement of the children’s and parents’ auxological data, SD scores (SDS) for height and parental target height were calculated (9). Children were classified as SGA if birth weight and/or birth length was less than –2 SDS (10); otherwise, the birth parameters were classified as appropriate for gestational age (AGA). Because the intent of this study was to analyze whether the different isoforms of the GHR exert an influence on the growth pattern of VLBW children with a simultaneous consideration of their respective genetic growth potential, we used a target height-corrected definition of catch-up growth. Catch-up was defined as height of at least –1 SDS, corrected for target height (SDScorrTH), at the time the child was examined. Mean age on examination was 6.0 yr (range, 4.2–8.0 yr).

DNA for the GHR exon 3 genotyping was extracted from buccal swabs using Chelex 100 chelating resin (Bio-Rad, Hercules, CA) (11) and was analyzed by multiplex PCR as described by Pantel et al. (12). As recommended by Audi et al. (13), an additional PCR amplification using only the full-length (fl)-spanning primers (G1 and G3) was run with all d3/d3 samples to confirm homozygosity.

Serum IGF-I and IGF-binding protein 3 (IGFBP-3) were measured by a commercial RIA (Mediagnost, Tübingen Germany), and SDS were calculated based on the reference data from the manufacturer. Normative values for this assay were obtained in German children and have been published by Blum and Schweizer (14). Data in results and tables are expressed as mean ± SD.

Statistical analyses were performed using the SSPS software package, version 14 (SSPS Inc., Chicago, IL). Nonparametric tests were used when data were not normally distributed. Relationships between variables were examined by the nonparametric Spearman’s rank correlation. To compare differences between groups, the Kruskal-Wallis nonparametric statistical analysis was used. Nonparametric unpaired samples were compared by the Mann-Whitney U test. For results following a normal distribution, we used the Student’s t test. Significance was defined as a P value < 0.05.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Thirty-two children (41.5%) were homozygous for the full-length allele (fl/fl), 33 (42.9%) were heterozygous (fl/d3), and 12 (15.6%) were homozygous for the genomic deletion of exon 3 (d3/d3). Allele frequencies were in Hardy-Weinberg equilibrium, distributed similarly within both sexes, and comparable with previously reported frequencies in adult control populations (5). There were no statistically significant differences between the genotype groups (fl/fl, fl/d3, and d3/d3) in gestational age, birth weight SDS, birth length SDS, age, sex, and target height SDS (Table 1Go). However, statistically significant differences were seen regarding genotype and catch-up growth.


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  		TABLE 1. Clinical and anthropometric characteristics of the study cohort in relation to the GHR exon 3 genotype

 
From the total of 77 children, 54 (70.1%) had sufficiently caught up (height SDScorrTH ≥ –1 SDS). The highest catch-up rate was seen in the d3/d3 subgroup (12 of 12, 100%), the lowest in the fl/fl subgroup (17 of 32, 53.1%). The differences were highly significant when comparing d3/d3 vs. fl/fl (P = 0.004) and d3/d3 plus fl/d3 vs. fl/fl (P = 0.006). Although not reaching statistical significance, heterozygous individuals showed a trend toward more efficient catch-up growth than homozygous fl/fl children (P = 0.06). A similar trend was even seen between the d3/d3 and fl/d3 subgroup (P = 0.06), suggesting a positive impact of each inherited d3 allele (Fig. 1AGo). Because catch-up growth was defined as height SDS of at least –1 SDS, corrected for target height, these differences were also reflected by higher scores for height SDScorrTH in d3/d3 and fl/d3 individuals (Fig. 1BGo).


Figure 1
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  		FIG. 1. Catch-up growth (A) and height SDScorrTH (B) in relation to the GHR exon 3 genotype (1, fl/fl; 2, fl/d3; 3, d3/d3).

 
From a subgroup of 41 former extremely low birth weight (ELBW) babies with a birth weight of less than 1000 g, serum IGF-I and IGFBP-3 levels were available. Genotype distribution in this subgroup did not differ significantly from the total study cohort (41.5, 41.5, and 17.0% for fl/fl, fl/d3, and d3/d3, respectively). Children with the fl/fl genotype showed lower IGF-I SDS compared with children with d3/d3 or fl/d3 (–0.6 ± 1.2 vs. 0.1 ± 0.5; P < 0.05). In congruence, the IGFBP-3 SDS in fl/fl children was lower compared with the d3/d3 or fl/d3 group (–0.2 ± 1.4 vs. 0.7 ± 1.0; P < 0.05).

Correlation analysis (Table 2Go) revealed significant correlations of the GHR exon 3 genotype with both catch-up growth (P < 0.01) and height SDScorrTH (P < 0.05). Not unexpectedly, both birth length SDS and birth weight SDS also correlated positively with subsequent catch-up and height SDScorrTH, although the correlations with birth weight SDS did not reach significance. No relevant correlations were found between genotype and target height SDS.


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  		TABLE 2. Correlation coefficients for genotype, anthropometric data, and catch-up growth

 
In accordance with previous follow-up reports (2, 15), we found a higher rate of catch-up in children born AGA (47 of 64, 83%) compared with those born SGA (seven of 13, 54%). Impaired intrauterine growth (referred to as SGA in Table 2Go) correlated negatively with postnatal catch-up growth and height SDScorrTH, although not reaching significance in our cohort. To examine further whether the impact of the GHRd3 variant becomes stronger with decreasing birth weight, we repeated the statistical analyses for the subgroup of ELBW preterm infants (n = 53). Allele frequencies were comparable to those obtained for the entire cohort. Despite smaller sample size, significance levels for the differences regarding the three genotypes and catch-up hardly varied (P = 0.006 for fl/fl vs. d3/d3; P = 0.004 for fl/fl vs. fl/d3 + d3/d3), with the exception of a now statistically significant difference (P < 0.05) when comparing fl/fl homozygotes against fl/d3 heterozygotes. Moreover, the positive correlation coefficient for genotype and catch-up growth increased from 0.357 to 0.434 (P = 0.001), suggesting a higher impact of the GHR genotype in ELBW children.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Our data revealed a highly significant influence of the GHR exon 3 genotype on the postnatal growth pattern of VLBW and ELBW preterm infants. Those who carry at least one GHRd3 allele are more likely to exhibit catch-up growth during the first years of life. To our knowledge, this is the first report on a common genomic variant that predicts postnatal catch-up but does not affect birth weight itself.

The outcome of VLBW infants and preterm babies improved dramatically over the past two decades, followed by an increasing number of huge follow-up programs. Knops et al. (2) recently reported a follow-up study on 1338 children born with gestational age less than 32 wk and/or birth weight less than 1500 g. Nearly all children who were born AGA had attained normal height at 10 yr, but many SGA children still showed stunting. Intrauterine growth retardation had more predictive value than gestational age. Furthermore, the authors underlined the predictive value of early weight gain during the first year of life, and little to no catch-up was detected once children had reached the age of 5 yr (2). In our series, children were examined at a mean age of 6 yr. We also observed a more efficient catch-up growth in children born AGA compared with those born SGA. However, the negative correlation between intrauterine growth failure leading to birth SGA and catch-up growth did not reach significance, whereas the positive correlation regarding the birth length SDS did, which is probably due to our relatively small sample size. On the other hand, the GHR exon 3 genotype revealed a highly significant impact on postnatal growth, and in congruence with this, higher serum levels of IGF-I and IGFBP-3 were detected in children heterozygous or homozygous for GHRd3. Moreover, we did not find any correlation between genotype and body length or weight at birth, which further underlines the impact of the GHRd3 isoform in supporting postnatal catch-up growth.

During the past 3 yr, the GHR exon 3 genotype has been studied extensively in the context of growth delay, and several studies reported the association of the d3-isoform with increased responsiveness to GH therapy (3, 4, 5). However, no significant influence on spontaneous growth was found so far. Audi et al. (13) recently reported on an increased frequency of the fl/fl genotype found in a cohort of Spanish short SGA children. In addition, they noticed that the parental height scores of these children were not equally distributed, with the lowest target heights in homozygous d3/d3 children and the highest scores for fl/fl children. They speculated whether the latter children therefore were unable to recover growth delay more efficiently (13). Considering that no significant differences between genotype and final adult height in healthy controls could be detected so far (13, 16), a bias due to the selection of short SGA children seems not unlikely. Most recent work on the impact of the GHR genotype in GH-treated children investigated cohorts that were mainly selected by growth failure (4, 5, 7) and did not find significant influence of the genotype onto spontaneous growth before start of therapy. Similarly, Mericq et al. (17) analyzed the GHR genotype in 38 prepubertal children who were born at term but SGA and failed to detect any association between catch-up growth and the GHR exon 3 variant. It is noteworthy that an unknown fraction in the study of Mericq et al. was recruited from a pediatric endocrinology clinic and thus most likely was selected for short stature. This is further underlined by the mean height of their study cohort of –1.99 SDS, as opposed to –0.8 SDS in our study. Furthermore, in contrast to Mericq et al. (17), we analyzed children who were born with a birth weight of less than 1500 g, but the majority of our subjects were born AGA, and not SGA. Thus, the results of these two studies are derived from children with a different medical background, and consequently, they are not comparable.

The association reported here of a common genomic GHR variant with postnatal catch-up growth might have further consequences. Similar to SGA children, preterm babies with VLBW are considered to be at increased risk to develop metabolic diseases, in particular type 2 diabetes mellitus. Recent work revealed evidence for early-onset reduction of insulin sensitivity both in children born SGA and in prematurely born AGA children, and more rapid postnatal catch-up growth seems to be associated with greater impairment of insulin sensitivity in both groups (18, 19, 20). Considering that both preterm babies and term SGA infants suffer from adverse environment during similar stages of development (preterm after birth, SGA in utero), impaired perinatal programming, as initially suggested in the concept of Barker and co-workers (21, 22) and modified by others (23, 24, 25), may have occurred in both (19). However, there are certain endocrine differences. Of particular interest, low plasma IGF-I and IGFBP-3 levels during childhood have been observed in former very preterm babies, whereas elevated IGF-I levels were demonstrated in term SGA children (26, 27), albeit individual concentrations of circulating IGF-I correlate with short-term postnatal growth velocity within both groups (26, 28, 29). Conversely, low serum IGF-I in an adult random cohort has been associated with increased risk of type 2 diabetes mellitus (30). Another adult cohort, although revealing IGF-I to be positively associated with fasting glucose, failed to give evidence that IGF-I concentrations in elderly people are programmed by reduced fetal growth (31). Indeed, it has been demonstrated that low birth weight itself and postnatal growth represent two independent determinants of subsequent insulin sensitivity and secretion (20). During the early postnatal period after preterm birth, high GH levels in conjunction with relatively low IGF-I are likely to reflect an immature fetal state of the GH/IGF-I axis, with relatively low GHR expression and lesser although not negligible effects of GH. IGF-I, on the other hand, exerts major growth-promoting effects in both pre- and postnatal life, and also in the early postnatal period of VLBW infants, short-term growth is IGF-I dependent (29). In the fetus, IGF-I is directly regulated by the glucose/insulin axis, presumably to ensure a close linkage between maternal nutritional status and fetal growth (32). Later, once the mature GH/IGF-I axis is established, IGF-I expression is mainly regulated by GH action. Nonetheless, in addition to various paracrine and endocrine effects of IGF-I on somatic growth and tissue maintenance (33), there is a considerable cross-talk between GH/IGF-I and insulin signaling, and both GH signaling itself as well as circulating IGF-I are vulnerable players in maintaining physiological insulin sensitivity (34). Thus, future studies using life-long modifiers of the GH/GHR interaction may be useful to further pinpoint the origin of altered metabolism in former VLBW babies. Data that focus on the GHR exon 3 isoform in the context of metabolism and insulin sensitivity are very limited so far. A recent study in 38 prepubertal SGA children failed to find any modulating effect (17). On the other hand, Kratzsch and colleagues (35, 36), who previously investigated distribution patterns of the GH-binding protein either containing or lacking the GHR exon 3 in adult control individuals, reported on correlations of the exon 3-lacking variant with metabolic risk factors such as increased fasting insulin and higher body fat mass.

To conclude, our data define the d3-variant of the GHR as an important predictor of catch-up growth in VLBW preterm infants. Future research will be necessary to clarify the entire impact of the GHR exon 3 isoforms on the cross-talk of growth and metabolism in childhood.


   Acknowledgments
 
We thank Mrs. R. Maslak for her excellent laboratory contributions to this work.


   Footnotes
 
This work was supported by a grant from Pfizer, Germany.

Disclosure Statement: F.S., S.S., and P.B. have nothing to declare. B.G. has been paid lecture fees by Lilly and Pfizer. J.W. has received lecture fees from Lilly and Novo Nordisk.

First Published Online August 21, 2007

Abbreviations: AGA, Appropriate for gestational age; ELBW, extremely low birth weight; fl, full-length; GHR, GH receptor; IGFBP-3, IGF-binding protein 3; SDS, SD score; SDScorrTH, SDS corrected for target height; SGA, small for gestational age; VLBW, very low birth weight.

Received April 27, 2007.

Accepted August 13, 2007.


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 Introduction
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 Results
 Discussion
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The exon 3-deleted/full-length Growth Hormone Receptor Polymorphism Does Not Influence the Effect of Puberty or Growth Hormone Therapy on Glucose Homeostasis in Short Non-Growth Hormone-Deficient Small-for-Gestational-Age Children: Results from a Two-Year Controlled Prospective Study
J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2709 - 2715.
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