Project Summary/Abstract
Growth impairment is a common complication of pediatric Crohn’s disease. Normalization of
growth is a marker of disease control and successful Crohn’s disease therapy. Treatment
strategies for improving growth impairment and final adult height are currently suboptimal. The
impact of Crohn’s disease on growth is potentially mediated by many factors, including
inflammation, genetics, microbiome, nutrition, and medications. The continued presence of
growth impairment primarily reflects continued suboptimal treatment of the underlying
inflammation characteristic of Crohn’s disease. We hypothesize that the inflammation
characteristic of Crohn’s disease has greater negative effects on endocrine growth regulators
(IGF-1 levels, sex hormone levels, and gonadotropin levels) in males and that these greater
negative inflammatory effects help to explain the increased susceptibility to growth impairment
in males. This hypothesis is based on our analyses of data collected from our completed
prospective multicenter longitudinal study of sex differences in growth impairment (Growth
Study Part 1). Our Part 1 data show that as bone age progresses, standardized height gain is
lower in males. Our Part 1 findings suggest inflammation exerts a greater negative effect on
hormone levels and growth in males, and indicate that sex-specific molecular pathways lead to
growth impairment in children with Crohn’s disease. The primary pathway to growth impairment
appears be the growth hormone/IGF-1 axis in males and the hypothalamic/pituitary/gonadal axis
in females. Developing a sex-specific risk-based treatment approach for children with Crohn’s
disease is essential. However, the specific molecular mechanisms causing sex differences in
growth impairment remain poorly characterized. Here, we propose to expand and continue to
follow our cohort to harvest information on the proteome (Aim 1) and genome (Aim 2) to provide
new insights into growth impairment. These data will enhance our ability to determine the
underlying mechanisms of sex differences in growth impairment (Aims 1 and 2) and develop
robust sex-specific predictive models to identify high-risk patients (Aim 3). Part 2 of the Growth
Study will generate essential data that will enable us to develop a highly needed sex-specific
risk- based pediatric Crohn’s disease treatment approach, which will represent a major
paradigm shift in clinical practice. Institution of appropriate personalized sex-specific risk-based
medical therapies targeting the underlying inflammation (since improved growth results from
improved disease control) is essential since only a very narrow therapeutic interval is available
to intervene to improve growth before growth plates close.