Thompson & Thompson Genetics in Medicine, 8th Edition

Case 11. Crohn Disease (Increased Risk from NOD2 Mutations)

Multifactorial Inheritance


• Multifactorial inheritance

• Autoimmune disease

• Ethnic predilection

Major Phenotypic Features

• Episodic abdominal pain, cramping, and diarrhea

• Occasional hematochezia (blood in the stool)

• May involve any segment of the intestinal tract

• Transmural ulceration and granulomas of the gastrointestinal tract

• Fistulas

• Patchy involvement usually of the terminal ileum and ascending colon

• Extraintestinal manifestations including inflammation of the joints, eyes, and skin

History and Physical Findings

P.L. is a 14-year-old white male brought to the emergency department by his mother for severe right lower quadrant pain and nausea without vomiting or fever. His history revealed intermittent nonbloody diarrhea for 1 year, no significant constipation, 1-hour postprandial lower quadrant abdominal pain relieved by defecation, and nocturnal abdominal pain that awakens him from sleep. The patient's developmental history was normal except that his growth was noted to have dropped from the 50th-75th percentile to the 25th percentile during the past 2 years. Family history was significant in that a first cousin on the paternal side had Crohn disease. Physical examination revealed peritoneal signs, hyperactive bowel sounds, and diffuse lower abdominal pain to palpation without palpable masses or organomegaly. A stool guaiac test was trace positive. Peripheral blood count revealed only a slightly elevated white blood cell count and a slight microcytic hypochromic anemia. Urinalysis and abdominal plain films were unremarkable. A computed tomographic scan showed mucosal inflammation extending from the distal ileum into the ascending colon. Upper endoscopy and colonoscopy with biopsy were performed, revealing transmural ulceration of the distal ileum with moderate to severe ulceration of the ileocecal junction, consistent with Crohn disease.

Subsequent genetic testing identified a Gly908Arg mutation on one allele of the NOD2 (CARD15) gene, confirming the diagnosis of Crohn disease.


Disease Etiology and Incidence

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract that primarily affects adolescents and young adults. The disease is divided into two major categories, Crohn disease (CD) and ulcerative colitis, each of which occurs with approximately equal frequency in the population. IBD affects 1 in 500 to 1 in 1000 individuals, with a twofold to fourfold increased prevalence in individuals of Ashkenazi Jewish backgrounds compared with non–Ashkenazi Jewish whites. Both disorders show substantial familial clustering and increased concordance rates in monozygotic twins, but they do not follow a mendelian inheritance pattern and are therefore classified as multifactorial. Three different common variants in the NOD2 gene (also known as CARD15) have been found to significantly increase the risk for development of CD (but not of ulcerative colitis) with an additive effect; heterozygotes have a 1.5-fold to fourfold increased risk, whereas homozygotes or compound heterozygotes have a 15- to 40-fold increased risk. The absolute risk among homozygotes or compound heterozygotes therefore approaches 1% to 2%.


Because of inflammation in the intestinal tract, IBD was long thought to be an autoimmune disease. Case-control studies in whites revealed three single nucleotide polymorphisms (SNPs) with strong evidence for association with the disease; all three were found to be in the coding exons of the NOD2 gene and to cause either amino acid substitutions (Gly908Arg and Arg702Trp) or premature termination of the protein (3020insC), an intracellular pattern recognition receptor named for its nucleotide-binding oligomerization domain. Additional studies in several independent cohorts of CD patients have confirmed that these variants are strongly associated with CD.

The NOD2 protein binds to gram-negative bacterial cell walls and participates in the inflammatory response to bacteria by activating the nuclear factor κB (NF-κB) transcription factor in mononuclear leukocytes. The three variants all reduce the ability of the NOD2 protein to activate NF-κB, suggesting that the variants in this gene alter the ability of monocytes in the intestinal wall to respond to resident bacteria, thereby predisposing to an abnormal, inflammatory response. Thus NOD2 variants are likely to be the alleles actually responsible for increased susceptibility to CD at this IBD locus, which is designated IBD1.

The NOD2 variants are clearly neither necessary nor sufficient to cause CD. They are not necessary because, although half of all white patients with CD have one or two copies of a NOD2 variant, half do not. Estimates are that the NOD2 variants account, at most, for 20% of the genetic contribution to IBD in whites. Furthermore, the particular variants associated with disease risk in Europe are not found in Asian or African populations, and CD in these populations shows no association with NOD2. The variants are also not sufficient to cause the disease. The NOD2 variants are common in Europe; 20% of the population are heterozygous for these alleles yet show no signs of IBD. Even in the highest-risk genotype, those who are homozygotes or compound heterozygotes for the NOD2 variants, penetrance is less than 10%. The low penetrance points strongly to other genetic or environmental factors that act on genotypic susceptibility at the NOD2 locus. The obvious connection between an IBD and structural protein variants in the NOD2 protein, a modulator of the innate antibacterial inflammatory response, is a strong clue that the intestinal microenvironment may be an important environmental factor contributing to pathogenesis.

Phenotype and Natural History

Presenting in adolescence or young adulthood, CD most often affects segments of the gastrointestinal tract, such as the terminal small intestine (ileum) and portions of the ascending colon, but it can occur anywhere within the digestive tract, with granulomatous inflammation (Fig. C-11) that penetrates the wall of the intestine and produces narrowing and scarring. Onset is usually insidious with a history of nocturnal abdominal pain, diarrhea, and gradual weight loss.


FIGURE C-11 A, Endoscopic appearance of ileitis in a patient with Crohn disease. B, Multiple granulomas in the wall of the small intestine in a patient with Crohn disease. See Sources & Acknowledgments.

Fistulous tracks and intraabdominal abscesses can occur and may be life-threatening. Hospitalization is frequent, and surgery for abscesses may be necessary in CD. Symptoms outside the gastrointestinal tract in CD may include arthritis of the spine and joints, inflammation of the eyes (uveitis), skin involvement (erythema nodosum and pyoderma gangrenosum), primary sclerosing cholangitis, and hypercoagulability. There is also an increased risk for adenocarcinoma of the intestine in long-standing CD, although the risk is not as great as the substantial risk in ulcerative colitis.


Currently there is no cure for IBD. The goals of treatment include induction of remission, maintenance of remission, minimization of side effects of treatment, and improvement of the quality of life. Five main categories of drugs are used alone or in combination to treat CD flare-ups: antiinflammatory medications, corticosteroids, antibiotics, immune modulators, and mixed inflammatory-immune modulators. All of the antiinflammatory medications are derivatives of mesalamine, and the choice of which antiinflammatory medication to use is based on side effect profile and location of disease within the intestine. During the acute phase of the disease, corticosteroids are the mainstay of therapy. These medications, combined with dietary modification, are used to decrease the severity of the disease and to prevent flare-ups. Because fiber is poorly digested, its intake should be reduced in patients with CD. As a result of chronic inflammation and scarring, malnutrition is common. Folate, iron, calcium, and vitamin B12 commonly need to be supplemented. Surgery to remove diseased bowel, to drain abscesses, and to close fistulous tracks is often necessary.

Inheritance Risk

The empirical risk for development of IBD is approximately 1% to 8% in a sibling of an IBD patient and falls to 0.1% to 0.2% in second-degree relatives, findings not compatible with classic autosomal recessive or dominant inheritance. However, this sibling recurrence is still high compared with the risk in the general population (the relative risk ratio, λs, for siblings is between 10 and 30) (see Chapter 8). In one large twin registry, monozygotic twins showed a concordance rate for CD of 44%; dizygotic twins were concordant only 4% of the time. Concordance in ulcerative colitis was only 6% in monozygotic twins but still much higher than in dizygotic twins, in whom no concordant twins were observed. Thus the genetic epidemiological data all strongly support classification of IBD as a disorder with a strong genetic contribution but with complex inheritance.

Questions for Small Group Discussion

1. Discuss possible environmental factors that play a role in CD.

2. How could variation in innate immunity interact with these environmental factors?

3. How should a family member of a patient with CD who is found to have one of the NOD2 variants be counseled? Should the testing be done? Why or why not?


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Van Limbergen J, Wilson DC, Satsangi J. The genetics of Crohn's disease. Ann Rev Genomics Hum Genet. 2009;10:89–116.