Combined Immunodeficiency Due to MALT1 Mutations, Treated by Hematopoietic Cell Transplantation

Abstract

PurposeA male infant developed generalized rash, intestinal inflammation and severe infections including persistent cytomegalovirus. Family history was negative, T cell receptor excision circles were normal, and engraftment of maternal cells was absent. No defects were found in multiple genes associated with severe combined immunodeficiency. A 9/10 HLA matched unrelated hematopoietic cell transplant (HCT) led to mixed chimerism with clinical resolution. We sought an underlying cause for this patient’s immune deficiency and dysregulation.MethodsClinical and laboratory features were reviewed. Whole exome sequencing and analysis of genomic DNA from the patient, parents and 2 unaffected siblings was performed, revealing 2 MALT1 variants. With a host-specific HLA-C antibody, we assessed MALT1 expression and function in the patient’s post-HCT autologous and donor lymphocytes. Wild type MALT1 cDNA was added to transformed autologous patient B cells to assess functional correction.ResultsThe patient had compound heterozygous DNA variants affecting exon 10 of MALT1 (isoform a, NM_006785.3), a maternally inherited splice acceptor c.1019-2A > G, and a de novo deletion of c.1059C leading to a frameshift and premature termination. Autologous lymphocytes failed to express MALT1 and lacked NF-κB signaling dependent upon the CARMA1, BCL-10 and MALT1 signalosome. Transduction with wild type MALT1 cDNA corrected the observed defects.ConclusionsOur nonconsanguineous patient with early onset profound combined immunodeficiency and immune dysregulation due to compound heterozygous MALT1 mutations extends the clinical and immunologic phenotype reported in 2 prior families. Clinical cure was achieved with mixed chimerism after nonmyeloablative conditioning and HCT.Electronic supplementary materialThe online version of this article (doi:10.1007/s10875-014-0125-1) contains supplementary material, which is available to authorized users.

Hematopoietic stem cell transplantations for primary immune deficiencies associated with NFκB mutations: A review of the literature

“…Although mutations in all 3 CBM signalosome proteins have been described, HSCT has only been reported between 2013 and 2016 in 6 patients with MALT1 and CARD11 mutations (Greil et al 2013;Stepensky et al 2013;Punwani et al 2015;Charbit-Henrion et al 2016;Rozmus et al 2016). A summary of patient characteristics can be found in Table 7.…”

The Paracaspase MALT1

“…In addition, mutations in MALT1 have recently been described in several patients with combined immunodeficiency (CID) [95–97]. CID is characterized by severely impaired T and B cell functions, while total cell numbers remain unchanged.…”

“…No functional protein was detectable. At the age of 18 months the patient received a curative hematopoietic stem cell transplant followed later by an additional donor T cell infusion [97]. …”

Omenn syndrome associated with a functional reversion due to a somatic second-site mutation in CARD11 deficiency

“…Eczematous dermatitis has been observed in 1 additional patient with CARD11 deficiency 37 and in 2 of 4 patients with mutations in the gene encoding MALT1, 44,45 another member of the CARMA1-BCL10-MALT1 (CBM) signalosome complex. T-cell lymphocytic infiltrations have been reported in the skin biopsies of 2 MALT1-deficient patients, but the clonality of the infiltrates was not further investigated.…”