PATHOGENESIS

Although the cause is unclear, IBD is believed to result from an interaction of

genetics, host immunity, and environmental factors. One of the most important risk
factors for developing IBD is a positive family history of the disorder. Other possible
factors include a child's living conditions,
maternal smoking, and older maternal age
during pregnancy.'" Controversial factors include the protective role of breast-
feeding and whether certain vaccines, in particular measles vaccines, are risk factors
for devel-oping IBD. The most recent evidence does not suggest this latter
association.2
Despite extensive effort, a gene defect responsible for pediatric onset IBD has not
been identified. However, genetics seem to play a significant role in patients who
present earlier in life. Monozygotic twins have a 50% concordance risk for Crohn
disease and children of parents with Crohn disease have a 33% risk of developing the
disease.3.14 A single gene for IBD has yet to be identimied but the number of sus-
ceptibility loci associated with IBD has grown exponentially. The gene for NOD2/
CAHDI5 (caspase activation recruitment domain, an important protein In innate im-
munity, was
1 of the first associated risk alleles for Crohn disease, with a 20-fold to
40-fold increased risk of developing disease if a person has 2 risk alleles." More
recentdy, genome-wide association studies (GWAS) have identified more than 100
in-dependent gene loci associated with the disease. GWAS in children and young
adults have reproduced loci implicated in the GWAS of adult-onset Crohn disease."
There is extensive crossover of genes between Crohn dise ase and ulcerative colitis,
demonstrating the common link between these chronic inflammatory conditions and
the spectrum of the disease. o
The genetic loci identified in patents with Crohn dis-
ease and ulcerative colitis implicate many biologically relevant immune pathways, such as
interleukin (IL)-23 and IL-10. For the most part, although overlap exists, Crohn disease gene
variations seem to be in pathways involved in microbe recognition and immune system
responses such as autophagy, whereas ulcerative colitis genes seem to be invoved in
intestinal barrier integrity and function.5 In infants,
1 genetic muta-
tion of significant interest is found in the IL-10 pathway. This rare autosomal reces-
sive mutation leads to an infantle form of severe IBD, which sometimes requires bone
marrow transplantation.