Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.

CARD15/NOD2 encodes a protein involved in bacterial recognition by monocytes. Mutations in CARD15 have recently been found in patients with Crohn disease (CD), a chronic inflammatory condition of the digestive tract. Here, we report the mutational analyses of CARD15 in 453 patients with CD, including 166 sporadic and 287 familial cases, 159 patients with ulcerative colitis (UC), and 103 healthy control subjects. Of 67 sequence variations identified, 9 had an allele frequency >5% in patients with CD. Six of them were considered to be polymorphisms, and three (R702W, G908R, and 1007fs) were confirmed to be independently associated with susceptibility to CD. Also considered as potential disease-causing mutations (DCMs) were 27 rare additional mutations. The three main variants (R702W, G908R, and 1007fs) represented 32%, 18%, and 31%, respectively, of the total CD mutations, whereas the total of the 27 rare mutations represented 19% of DCMs. Altogether, 93% of the mutations were located in the distal third of the gene. No mutations were found to be associated with UC. In contrast, 50% of patients with CD carried at least one DCM, including 17% who had a double mutation. This observation confirmed the gene-dosage effect in CD. The patients with double-dose mutations were characterized by a younger age at onset (16.9 years vs. 19.8 years; P=.01), a more frequent stricturing phenotype (53% vs. 28%; P=.00003; odds ratio 2.92), and a less frequent colonic involvement (43% vs. 62%; P=.003; odds ratio 0.44) than were seen in those patients who had no mutation. The severity of the disease and extraintestinal manifestations were not different for any of the CARD15 genotypes. The proportion of familial and sporadic cases and the proportion of patients with smoking habits were similar in the groups of patients with CD with or without mutation. These findings provide tools for a DNA-based test of susceptibility and for genetic counseling in inflammatory bowel disease.

Infliximab produces spectacular results for children with severe CD and is well tolerated. However, its effect is transitory for many (90%), with frequent relapses despite continued immunosuppressors. Long-term management with infliximab should be tested despite its worrying side effects.

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Hoyeraal-Hreidarsson syndrome represents a severe variant of dyskeratosis congenita (Zinsser-Cole-Engman syndrome). This X-linked recessive, progressive, multisystemic disorder reported so far in 12 pedigrees is characterised by intrauterine growth retardation, microcephaly, cerebellar hypoplasia, mental retardation, progressive combined immune deficiency and aplastic anaemia. Mutations in the DKC1gene on Xq28 have been identified in the X-linked form of dyskeratosis congenita and in some Hoyeraal-Hreidarsson syndrome patients. We report on two sibs and two other unrelated patients with the striking clinical features of Hoyeraal-Hreidarsson syndrome. Noticeably, all four had early digestive problems, with chronic, bloody diarrhoea and feeding problems causing one of the most difficult problems in the supportive treatment of this uniformly lethal condition. Pathological changes in the proliferative compartment of the digestive mucosa included alterations of the glandular architecture and focal rarefaction of the glands. This aspect seems consistent with altered telomerase function associated with a dyskerin mutation which may decrease the proliferative capacity of digestive epithelial cells. A missense mutation 146 C-->T (Thr49Met) in the DKC1gene was found in two unrelated patients, whereas mutation screening was negative for one single case. The absence of mutations of the DKC1gene in patients with Hoyeraal-Hreidarsson syndrome emphasises the probable implication of one or more other loci.

IFX is well tolerated and safe as maintenance therapy for pediatric CD, with a clear advantage when used on a scheduled 2-month basis compared to an "on demand" basis.

MTX improved the clinical course in most pediatric CD patients who escaped or did not tolerate AZA. Short-time toxicity of MTX resulted in drug discontinuation in <10%. These data point to a beneficial and safe use of MTX in the treatment of pediatric CD.