Early-onset inflammatory bowel diseases can result from a wide spectrum of rare mendelian disorders. Early molecular diagnosis is crucial in defining treatment and in improving life expectancy. Herein we aimed at defining the mechanism of an immunodeficiency-polyendrocrinopathy and enteropathy-X-linked (IPEX)–like disease combined with a severe immunodeficiency in 2 siblings born from distantly related parents.
Whole exome sequencing was performed on blood-extracted genomic DNA from the 2 affected children and their parents on the genomic platform of Institut IMAGINE. Candidate gene mutation was identified using the in-house software PolyWeb and confirmed by Sanger sequencing. Protein expression was determined by western blot. Flow cytometry was used to assess consequences of the mutation on lymphocyte phenotype and nuclear factor-kappa B (NF-κB) activation at diagnosis and after treatment by hematopoietic stem cell transplantation.
We identified a homozygous missense mutation in mucosa-associated lymphoid tissue lymphoma translocation 1 gene (MALT1), which precluded protein expression. In keeping with the known function of MALT1, NF-κB–dependent lymphocyte activation was severely impaired. Moreover, there was a drastic reduction in Forkhead box P3 (FOXP3) regulatory T cells accounting for the IPEX-like phenotype. Following identification of the mutation, both children received hematopoietic stem cell transplantation, which permitted full clinical recovery. Immunological workup at 6 and 12 months after transplantation showed normal NF-κB activation and correction of regulatory T cells frequency.
Along with FOXP3, interleukin 2 receptor alpha chain (IL2RA), and cytotoxic T-lymphocyte protein 4 precursor (CTLA-4) mutations, MALT1 deficiency should now be considered as a possible cause of IPEX-like syndrome associated with immunodeficiency that can be cured by hematopoietic stem cell transplantation.
Supplemental Digital Content is available in the text
*INSERM, UMR1163, Laboratory of Intestinal Immunity
†Université Paris Descartes-Sorbonne Paris Cité and Institut IMAGINE
‡Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Department of Pediatric Gastroenterology, Paris
§GENIUS Group (GENetically and/or ImmUne mediated enteropathieS) From ESPGHAN (European Society for Paediatric Gastroenterology, Hepatology and Nutrition)
||Department of Allergology, Rheumatology and Clinical Immunology
¶Department of Haemato-oncology, University Children's Hospital, University Medical Center, Ljubljana, Slovenia
#Institut de Minéralogie, de Physique des Matériaux, et de Cosmochimie, Sorbonne Universités—UMR CNRS 7590, UPMC Université Paris 6, Muséum National d’Histoire Naturelle, IRD UMR 206, IUC
**Bioinformatics Platform, Université Paris-Descartes-Paris Sorbonne Centre and Institut IMAGINE
††Genomic platform, Institut IMAGINE, Paris, France
‡‡Department of Gastroenterology, Hepatology and Nutrition, University Children's Hospital
§§Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
||||INSERM, UMR1163, Immunogenetics of Pediatric Autoimmunity, Paris, France.
Address correspondence and reprint requests to Nadine Cerf-Bensussan, Laboratory of Intestinal Immunity, Institut IMAGINE-INSERM UMR 1163, Université Paris Descartes-Sorbonne Paris Cité. 24, boulevard du Montparnasse, 75015 Paris, France (e-mail: email@example.com).
Received 19 February, 2016
Accepted 4 May, 2016
Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal's Web site (www.jpgn.org).
This work was supported by Institutional grants from INSERM, by the European grant ERC-2013-AdG-339407-IMMUNOBIOTA, by the Investissement d’Avenir grant ANR-10-IAHU-01, by the Fondation Princesse Grace and by University Medical Centre Ljubljana Research Grant 20140208. FCH was supported by fellowships from Institut IMAGINE and from INSERM. NCB benefits from an Interface-Assistance Publique-Hôpitaux de Paris.
Drs Fabienne Charbit-Henrion and Anja Koren Jeverica shared first authorship.
Drs Frank M. Ruemmele, Tadej Avčin, and Nadine Cerf-Bensussan shared senior authorship.
For more information: http://www.institutimagine.org/en/research/23-research-labs/119-laboratory-of-intestinal-immunity.html; www.genius-group.org
The authors report no conflicts of interest.