MALT1 deficiency is a rare disorder causing combined immunodeficiency due to impaired CBM-complex assembly in response to receptor stimulation, and secondary impaired downstream signaling with reduced NFkB activation. We describe a 5-monbth-old male who presented at 1-month of age with severe steroid-dependent erythroderma, FTT, recurrent bacterial infections and low IgG.
PIDD gene panel revealed two novel MALT1 mutations (c.6571C>T, p.R191X; c.1666-1668delGAG, p.Glu556del) with both parents carrying only the wild type alleles, suggesting either cis or trans two de-novo mutations. While the clinical presentation supported HSCT, functional evaluation was required to establish pathogenicity of the two mutations.
Flow-based IkBa degradation and P65 phosphorylation assays were performed pre and post-transplant, together with evaluation of cytokine production and lymphocyte immunophenotyping.
Patient's PBMCs showed impaired IkBa degradation and significantly reduced P65 phosphorylation (Fig 1a,b). Immunophenotyping showed low regulatory T-cells (Fig 1c). However, and in contrast to previous reports, intracellular cytokine staining showed normal percent of IL17+CD4+ T-cells and increased percent of IL2+CD4+ T-cells, suggesting possible residual CBM-complex activity (Fig 1d,e). Repeated evaluation 4 months post alemtuzumab-based matched-sibling-donor transplant showed reconstitution of IkBa degradation and P65 phosphorylation (Fig 1f,g), and recovery of Treg immunophenotyping. Clinically, the patient is now 5 months post-transplant with stable mix donor chimerism, off immunosuppressants and IVIg and with complete resolution of his symptoms.
The normal IL17 and increased IL2 production suggest that different mutations could result in residual MALT1 activity and therefore clinical variability. In addition, mixed donor chimerism in the range of 45% is sufficient for complete clinical resolution.