Published online November 1, 2004
PEDIATRICS Vol. 114 No. 5 November 2004, pp. 1281-1286 (doi:10.1542/peds.2004-0417)
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Pediatric Crohn's Disease and Growth Retardation: The Role of Genotype, Phenotype, and Disease Severity

Eytan Wine, MD*,{ddagger}, Shimon S. Reif, MD{ddagger},§, Esther Leshinsky-Silver, PhD||, Batya Weiss, MD, Ron R. Shaoul, MD#, Raanan Shamir, MD**, Dror Wasserman, MD{ddagger},§, Aaron Lerner, MD{ddagger}{ddagger}, Mona Boaz, PhD§§ and Arie Levine, MD*,{ddagger}

* Pediatric Gastroenterology and Nutrition Unit, E. Wolfson Medical Center, Holon, Israel
{ddagger} Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
§ Pediatric Gastroenterology and Nutrition Unit, Dana Children's Hospital, Tel Aviv, Israel
|| Molecular Genetics Laboratory, E. Wolfson Medical Center, Holon, Israel
Pediatric Gastroenterology and Nutrition Unit, Tel-Hashomer Medical Center, Tel Aviv, Israel
# Pediatric Gastroenterology, Bnei Zion Medical Center, Haifa, Israel
** Gastroenterology Division, Rambam Medical Center, Haifa, Israel
{ddagger}{ddagger} Pediatric Gastroenterology, Carmel Medical Center, Haifa, Israel
§§ Epidemiology Unit, E. Wolfson Medical Center, Holon, Israel


   ABSTRACT
TOP
 ABSTRACT
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Background. Delayed growth is a well-established feature of pediatric Crohn's disease. Several factors have been shown to affect growth, including disease location, severity, and treatment. The recently discovered NOD2 gene has been correlated to ileal location of Crohn's disease and subsequently could affect growth through the resulting phenotype or as an independent risk factor. The aim of our study was to determine if growth retardation is affected by genotype independently of disease location or severity.

Methods. Genotyping for 3 NOD2 single-nucleotide polymorphisms was performed in 93 patients with detailed growth records. Parameters including disease location, disease severity, and NOD 2 genotype and their effect on z scores for height and weight at disease onset and during follow-up were analyzed.

Results. NOD2 mutations were correlated with ileal location but not with disease severity or growth retardation. Ileal involvement was significantly associated with height retardation at disease onset and the lowest z score during follow-up. Use of steroids affected weight but not height. Regression models for growth variables revealed that the strongest association with impaired growth is with disease severity (weight- and height-failure odds ratios: 6.17 and 4.52, respectively).

Conclusions. Severity of disease is correlated with growth failure for both height and weight. Location of disease is a weaker predictor of disordered growth and is correlated with growth retardation but not growth failure. The NOD2 genotype was not correlated with growth retardation or growth failure.

Key Words: NOD2 • height failure • weight failure • Crohn's disease • growth • inflammatory bowel disease • genes • pediatric

Abbreviations: CD, Crohn's disease • SNP, single-nucleotide polymorphism • PCR, polymerase chain reaction • OR, odds ratio • CI, 95% confidence interval

Growth retardation is a frequent feature of pediatric Crohn's disease (CD). Up to 30% of patients may suffer from severe growth failure, which may manifest as poor weight gain or short stature1,2 and may be the first presenting symptoms of CD.3 If not treated before puberty, this impairment may become irreversible.4–6

Several mechanisms have been implicated in the pathogenesis of growth retardation in CD. Nutritional factors have been shown to have a major contribution.7–10 Cytokine production induced by chronic inflammation may cause anorexia.11–13 Reduced intake caused by anorexia and postprandial pain,14 together with increased requirements caused by chronic inflammation, create an ongoing caloric and protein deficit.1,9 Malabsorption in CD is caused by a combination of diseased intestinal absorptive surface,15 fistulas, bacterial overgrowth,16 and resection.1 Endocrine factors have been hypothesized, but conflicting data exist.17 Steroids have a well-documented effect on growth, causing growth suppression (although weight gain may be obtained),18–20 but there are conflicting reports regarding their effect.9,21

Genetic susceptibility for CD is suggested by several observations: ethnic differences,22 familial clustering, twin concordance,23,24 and association with genetic disorders.25 The first disease-associated mutations for CD were found on the NOD2/CARD15 gene, located on the pericentromeric region of chromosome 16.26–28 The intracellular product of this gene, expressed in macrophages, monocytes, Paneth cells, and intestinal epithelium, serves as a pattern-recognition receptor for bacterial signals, leading to activation of nuclear factor {kappa}B.29 Three loci on the NOD2 gene have been identified as independent risk factors for the development of CD.26–28

NOD2 variants have been shown to correlate with ileal involvement and a fibrostenosing course of CD.30–32 Involvement of the small intestine can lead to malabsorption and decreased intake,15 which are considered to be leading causes for growth failure in CD patients.1,4 A recent study has found an association between NOD2 mutations and lower weight at diagnosis,33 but an interaction of genotype, independent of phenotype, has not been preformed previously. It is unclear at present if the association between NOD2 mutations and lower weight at diagnosis is a true effect of genotype or is caused by the associated phenotype, which includes ileal involvement. Most of the previous studies investigating growth in CD have regarded height and weight at diagnosis. A drawback of this approach is that growth failure occurring after onset has not been evaluated longitudinally.

The aim of our study is to determine the role of NOD2 mutations on growth retardation in CD at onset and during follow-up and to evaluate if this association is related to genotype, phenotype, or severity of disease.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Study Population
Patients were consecutively recruited from 6 pediatric gastroenterology programs throughout central and northern Israel. The recruitment protocol was approved by an institutional review board, and a ministry of health-approved genetic research review board. Signed informed consent was obtained from parents. Inclusion criteria included age <18 years, diagnosis of CD confirmed by clinical, radiologic, endoscopic and histopathologic findings, and presence of disease for at least 1 year with follow-up. All patients were evaluated endoscopically.

End points for this study were z scores for weight and height at onset and at the lowest point after diagnosis (z score nadirs), through the age of 16 years for height, and through the age of 18 years for weight. Presence of growth retardation was defined as a z score less than –1, and growth failure was defined as a z score less than –2. To define an independent association between genotype and growth, we carefully recorded location of disease and measures of severity that may have impacted on growth retardation at those points in time. In choosing parameters that reflect disease severity over prolonged time periods, we steered away from single-point measurements and chose measures that were well documented during the 12 months before the lowest recorded z scores for height and weight. Measures of severity included cumulative duration of hospitalization over 14 days, use of steroids, second line therapy, immunosuppressive therapy, and other medication use. Second-line therapy was defined as the need for corticosteroids or infliximab for active disease during the year before measured nadirs for height and weight. All data (analyzed retrospectively) were recorded from patient files by a single investigator (E.W.). The z score was calculated for each measurement by using ANTHRO 1.02 software (based on World Health Organization standard growth charts).

Genetic Analysis
Three loci on the NOD2 gene were examined: the single-nucleotide polymorphisms (SNPs) G908R, 1007fs, and R702W.

Genomic DNA was extracted from whole peripheral venous blood by using a commercially available kit (Gentra, Minneapolis, MN) in accordance with manufacturer instructions.

Mutations of the NOD2 gene were analyzed by pyrosequencing technology.34 The primer sequences for polymerase chain reaction (PCR) as well as for the pyrosequencing are summarized in Table 1. PCR was performed in a 50-µL volume containing 10 mM Tris · HCl (pH 8.3), 50 mM KCl, 1.5 mM MgCl2, 250 µM dNTPs, 1 µM of each primer, 200 ng of genomic DNA, and 1.25 U of AmpliTaq Gold DNA polymerase (Perkin-Elmer Applied Biosystems, Norwalk, CT) with an initial denaturation step of 10 minutes at 95°C to activate the polymerase followed by 35 cycles of 94°C for 15 seconds, 60°C for 45 seconds, 72°C for 45 seconds, and final elongation of 10 minutes at 72°C. Predicted sizes were confirmed by agarose gel electrophoresis. PCR products were prepared for pyrosequencing analysis by using the PSQ sample-preparation kit according to the standard protocol from Pyrosequencing AB (Uppsala, Sweden) and analyzed for the various SNPs on a PSQ 96MA Pyrosequencer using 0.2 µM sequencing primers and the SNP reagent kit according to standard protocols. The order of nucleotide dispensation was decided based on suggestions provided by PSQ HS 96 SNP 1.0 software (Pyrosequencing AB), which also was used for automatic assay evaluation and genotype scoring.


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  		TABLE 1. Entry Data for Cohort

 
Data Analysis
Analysis of data was conducted by using SPSS statistical analysis software (SPSS Inc, Chicago, IL). For continuous variables such as age and z scores, descriptive statistics were calculated and reported as mean ± SD. Normalcy of distribution of continuous variables was assessed by using the Kolmogorov-Smirnov test. All continuous variables were normally distributed and were compared by mutation using the t test for independent samples. Categorical variables such as gender, disease location, and markers of disease severity were described by using frequency distributions. The {chi}2 test with 99% Monte Carlo confidence intervals was used to detect differences in categorical variables by mutation, disease location, or disease severity. Logistic regression analysis was used to model growth failure. All tests were 2-sided and considered significant at P < .05.


   RESULTS
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Study Population
Records of both NOD2 variants and detailed growth charts were available for 93 patients. Eighteen additional patients were excluded because of insufficient follow-up or data. The average age of diagnosis was 12.1 years (range: 0.9–18 years). Males accounted for 60% of the cohort, which is characteristic of all pediatric CD cohorts in Israel. Entry data are presented in Table 1. NOD2 mutations were found in 33 (35%) patients. The most common SNP was G908R, occurring in 20 patients (22%). 1007fs and R702W were found in 9 (10%) and 8 (9%) patients, respectively. Thirty patients had evidence of a severe course during the year before their lowest growth percentiles. The nadir for z scores appeared at diagnosis in 50 patients (54%) and during follow-up for the remaining 43 patients (46%). Among the 43 patients with lowest z scores during follow-up, 9 (21%) received sustained nasogastric nutritional therapy adjacent to their nadir, and 3 (7%) of them required total parenteral nutrition as well. Eight patients (9%) underwent bowel resection, in most cases subsequent to the period of their lowest recorded z scores. Sixty-two patients (66.6%) suffered from growth retardation (defined as z score < –1); weight retardation was more frequent than height retardation. Growth failure (z score < –2) occurred in 29 patients (31%), 25 (27%) for weight and 17 (18.3%) for height.

Genotype-Phenotype Correlation
NOD2 mutations were found to be correlated with ileal involvement. Of subjects with ileal disease location, 43.7% had a mutation, compared with 9.1% of subjects with disease located elsewhere. Alternatively, 91% of NOD2-positive patients had ileal involvement, compared with 67% in NOD2-negative patients (P = .004). Of the 21 patients with Crohn's colitis, only 2 had NOD2 mutations, compared with 11 of 28 with only ileal disease and 20 of 43 with ileocolic involvement (P = .03).

There was no correlation between disease severity and the presence of NOD2 mutations. Of the patients receiving steroids or immunosuppressive therapy, 46% were NOD2-positive and 54% were NOD2-negative (not significant).

The correlation between NOD2 and growth is presented in Tables 2 and 3. There was no correlation for height or weight with z scores at onset or for the lowest z score during childhood.


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  		TABLE 2. Distribution of z Scores According to the Presence of NOD2 Mutations

 

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  		TABLE 3. Effect of NOD2 Mutations on Prevalence of Growth Retardation and Failure

 
Disease Location and Growth
Table 4 demonstrates the effect of disease location on growth. Ileal involvement was significantly correlated with growth retardation for height at both disease onset and during height and weight nadirs (P = .02 and .01 respectively). Similar trends were shown for weight but did not reach statistical significance. Growth failure was not correlated with ileal location of disease.


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  		TABLE 4. Prevalence of Growth Retardation and Failure According to Disease Location

 
No significant correlation was demonstrated between growth and disease involvement of colon or ileocolonic disease or the proximal intestine.

Disease Severity and Growth
A clear connection was found between disease-severity measures and growth failure. Use of both steroids and immunosuppressive therapies were correlated to weight and growth failure during z score nadirs (P = .01 and .002, respectively). Immunosuppression was connected to height failure as well (P = .008). Hospitalization for ≥2 weeks in the year before the lowest growth measure was significantly correlated with height retardation (P = .04) and weight failure (P = .02). Overall severity, defined as the presence of ≥1 measures of severity, was correlated with growth failure for both height and weight (P = .01 and P < .0001, respectively), compared with subjects without any of the mentioned features of severity.

Growth-Failure Variables
Logistic regression was used to model each of the growth-variable models (Table 5). Age and gender were forced into all models. Immunosuppression increased the risk for both height and weight failure. Steroid therapy and hospitalization for ≥2 weeks in the year before the lowest growth measure increased the risk for weight failure. The presence of >1 marker of severity added an additional risk of 60% for growth failure to the previous risk (odds ratio [OR]: 1.64; 95% confidence interval [CI]: 1.2-2.3; P = .001).


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  		TABLE 5. Regression Modals for Growth According to Different Parameters

 
On the other hand, ileal disease, which was found to cause height retardation, did not predict growth failure for either weight or height. Mutations also did not predict growth failure in any of the models (weight: 0.54 [OR], 0.14-2.11 [CI], P = not significant; height: 1.03 [OR], 0.3-3.1 [CI], P = not significant).


   DISCUSSION
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Growth retardation is a common, often problematic feature of CD.9,10,17,21 Although the underlying pathogenesis is unclear, impaired nutritional status and use of steroids have been implicated. The reasons underlying nutritional impairment and need for steroids could be caused by genetic predisposition to severity of attacks or to specific phenotypes of the disease. The recent discovery of NOD2 disease-associated mutations as well as recent studies involving phenotype have implicated all these factors in causing growth retardation.33,35–37 Most recent studies have evaluated growth retardation at disease onset or during a therapeutic trial. As a result, subsequent growth failure may not have been recorded. What has been lacking to date is an analysis that combines all these parameters and evaluates their independent effect on growth retardation and growth failure beyond the age of disease onset.

Measures of disease severity were found in our study to be the best predictors of growth failure, demonstrating ORs of 4.5 for weight and 6.2 for height. Because influence of disease activity or severity on growth can occur over a period of time leading up to the growth nadir, we evaluated measures that we felt were adequately documented over a period of 1 year before the lowest documented growth period after disease diagnosis. Although steroid use could directly affect growth independent of disease severity, the presence of all disease-severity parameters were significantly and independently associated with growth failure. In fact, all other parameters chosen showed a higher risk for weight failure, although this result may be temporarily masked by fluid accumulation that can occur with steroid therapy. Although severity measures such as use of immune suppression were highly correlated with height failure, steroid use before height failure did not achieve statistical significance, which might indicate that the effect of steroids on growth may be limited and reflect growth loss occurring primarily during treatment periods. This finding is supported by a previous study.10

Disease severity, marked by intense inflammation and extent of disease, may act through malabsorption and secretion of anorexigenic cytokines. Cytokines such as tumor necrosis factor {alpha} and IL-1 have been correlated with growth failure.11–13 Tumor necrosis factor {alpha} has been shown to induce cachexia, which can contribute to poor nutrition and growth failure.

Disease location can affect growth mainly by disrupting normal nutrient absorption or increasing losses through diarrhea. This connection has been demonstrated mainly for jejunal and ileal involvement.1,15 Reduced stature was recently correlated to jejunal involvement in a large prospective study.35 Our study found a significant connection between ileal involvement and height retardation (but not failure) at both disease onset and lowest point (P = .02 and 0.01, respectively). Although intestinal involvement may independently serve as a risk factor for decreased linear growth, regression analysis did not find that location was a reason for linear growth failure, indicating that location has less of an affect on growth than disease severity.

Carriage of the NOD2 variants was not correlated with either growth retardation or failure for height or weight in our cohort. A previous study found NOD2 to be associated with low weight at diagnosis.33 Limitations of that study include reference only to growth measurements at diagnosis and no correction for phenotype in analysis. NOD2 has a well-established association to ileal involvement,30–32 which may affect growth, as demonstrated in several previous studies.1,15,35 Our study confirmed a significant correlation between ileal involvement and linear growth retardation. Another possible connection between NOD2 and growth could be through genotype effect on severity.36,37 Such an effect was not demonstrated in our study.

Evaluation of polymorphisms that affect inflammation, cytokine production, anorexia, and metabolism may cast some light on the interaction between inflammation, growth, and nutrition. Understanding the mechanisms involved in compromising growth in CD may enable us to optimize therapy by improving appetite, supplying adequate nutrition, and reducing the adverse effects of the resulting inflammatory response, which could alter present therapeutic strategies and lead to therapeutic options that are not available today.


   CONCLUSIONS
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Severity of disease is correlated with growth failure for both height and weight. Location of disease is a weaker predictor of disordered growth and is correlated with growth retardation but not growth failure. The NOD2 genotype was not correlated with growth retardation or growth failure.


   FOOTNOTES
 
Accepted Apr 29, 2004.

Address correspondence to Arie Levine MD, Pediatric Gastroenterology Service, E. Wolfson Medical Center, POB 5, Holon 58100, Israel. E-mail: alevine{at}wolfson.health.gov.il or a-levine{at}inter.net.il


   REFERENCES
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics

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