[Diagnosis of a rare and severe inflammatory bowel disease in an infant with peri-orificial ulcerations]. / Diagnostic d'une maladie inflammatoire rare et sévère de l'intestin chez un nourrisson présentant des ulcérations péri-orificielles.

We report the case of an infant aged 8 and a half months, who had an apparent life-threatening event and died despite optimal resuscitation management. The medical history was marked by mild symptoms, mainly feeding difficulties and progressively settling skin lesions. Parents were related (first cousins) and the patient had two healthy older sisters. Autopsy showed growth delay, symmetrical erythematous and ulcerated periorificial lesions associated with punctiform erythematous lesions of the face and alopecia. Microscopic examination revealed deep bronchial inhalation with the onset of infectious pneumopathy, major inflammatory ulceration of the gastrointestinal tract, hepatic steatosis, brain stem and pancreas abnormalities. We conclude that the cause of death was a multi-visceral failure with inhalation pneumopathy, in a context of very early onset inflammatory bowel disease (VEO-IBD). Genetic consultation, into a rare disease reference center, allowed to orient the analysis, to identify a homozygous pathogenic variant in the IL10RA gene, confirming the diagnostic of an autosomal recessive very early onset inflammatory bowel disease (inflammatory bowel disease 28, early-onset, autosomal recessive, #613148).

Resistance of B-Cell Lymphomas to CAR T-Cell Therapy Is Associated With Genomic Tumor Changes Which Can Result in Transdifferentiation.

Despite the impressive efficacy of chimeric antigen receptor (CAR) T-cell therapy (CART) in B-cell non-Hodgkin lymphomas, durable responses are uncommon. The histopathologic and molecular features associated with treatment failure are still largely unknown. Therefore, we have analyzed 19 sequential tumor samples from 9 patients, prior anti-CD19 CART (pre-CART) and at relapse (post-CART), using immunohistochemistry, fluorescence in situ hybridization, array comparative genomic hybridization, next-generation DNA and RNA sequencing, and genome-scale DNA methylation. The initial diagnosis was diffuse large B-cell lymphoma (n=6), double-hit high-grade B-cell lymphoma (n=1), and Burkitt lymphoma (n=2). Histopathologic features were mostly retained at relapse in 7/9 patients, except the frequent loss of 1 or several B-cell markers. The remaining 2 cases (1 diffuse large B-cell lymphoma and 1 Burkitt lymphoma) displayed a dramatic phenotypic shift in post-CART tumors, with the drastic downfall of B-cell markers and emergence of T-cell or histiocytic markers, despite the persistence of identical clonal immunoglobulin gene rearrangements. The post-CART tumor with aberrant T-cell phenotype showed reduced mRNA expression of most B-cell genes with increased methylation of their promoter. Fluorescence in situ hybridization and comparative genomic hybridization showed global stability of chromosomal alterations in all paired samples, including 17p/TP53 deletions. New pathogenic variants acquired in post-CART samples included mutations triggering the PI3K pathway (PIK3R1, PIK3R2, PIK3C2G) or associated with tumor aggressiveness (KRAS, INPP4B, SF3B1, SYNE1, TBL1XR1). These results indicate that CART-resistant B-cell non-Hodgkin lymphomas display genetic remodeling, which may result in profound dysregulation of B-cell differentiation. Acquired mutations in the PI3K and KRAS pathways suggest that some targeted therapies could be useful to overcome CART resistance.