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Combined immunodeficiency due to MALT1 mutations, treated by hematopoietic cell transplantation.

Punwani D, Wang H, Chan AY, Cowan MJ, Mallott J, Sunderam U, Mollenauer M, Srinivasan R, Brenner SE, Mulder A, Claas FH, Weiss A, Puck JM - J. Clin. Immunol. (2015)

Bottom Line: No defects were found in multiple genes associated with severe combined immunodeficiency.Our 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of California San Francisco School of Medicine, and UCSF Benioff Children's Hospital, Box 0519, 513 Parnassus Avenue, HSE-301A, San Francisco, CA, 94143-0519, USA.

ABSTRACT

Purpose: A 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.

Methods: Clinical 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.

Results: The 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.

Conclusions: Our 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.

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a, Skin lesions, showing (i) facial erythroderma (ii) dorsal trunk and (iii) close-up with linear distribution of lesions corresponding to excoriations. b, Schematic representation of MALT1 protein (isoform a, NP_006776.1), illustrating death domain, 3 immunoglobulin (Ig)-like domains, and paracaspase domain [30]. Mutations are shown for our patient (black) and prior homozygous cases (blue) [22, 23]. c, Browser view of patient stacked DNA sequence tracks, demonstrating >30X coverage with individual reads homozygous for either the splice disrupting variant c.1019-2A > G or the single nucleotide deletion cDNA c.1060delC (the former also present in maternal DNA, not shown) (ClinVar number SCV000196510). Colored blocks, non-reference nucleotides; black blocks, deleted nucleotides. Below, genomic sequence of MALT1 exon 10 (isoform a, NM_006785.3) and protein translation with reference sequence (black) and de novo deleted sequence (red)
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Fig1: a, Skin lesions, showing (i) facial erythroderma (ii) dorsal trunk and (iii) close-up with linear distribution of lesions corresponding to excoriations. b, Schematic representation of MALT1 protein (isoform a, NP_006776.1), illustrating death domain, 3 immunoglobulin (Ig)-like domains, and paracaspase domain [30]. Mutations are shown for our patient (black) and prior homozygous cases (blue) [22, 23]. c, Browser view of patient stacked DNA sequence tracks, demonstrating >30X coverage with individual reads homozygous for either the splice disrupting variant c.1019-2A > G or the single nucleotide deletion cDNA c.1060delC (the former also present in maternal DNA, not shown) (ClinVar number SCV000196510). Colored blocks, non-reference nucleotides; black blocks, deleted nucleotides. Below, genomic sequence of MALT1 exon 10 (isoform a, NM_006785.3) and protein translation with reference sequence (black) and de novo deleted sequence (red)

Mentions: The infant, born at term to non-consanguineous parents with negative family history, developed blood-streaked diarrhea and a desquamating, erythematous pruritic rash, the latter evolving into firm erythematous papules affecting trunk, palms and soles (Fig. 1a, Table 1). There were no indications of environmental atopy; IgE was undetectable, and steroids were ineffective. Skin biopsies showed perivascular lymphocytic infiltration in the dermis. Following monthly otitis media infections, an immune workup showed expansion of CD4 and CD8 T cell populations with high proportions of naïve CD45RA T cells, but impaired in vitro proliferative responses (Tables 1 and 2). Maternal T cell engraftment was absent, and the newborn dried blood spot, retrieved from the time of the patient’s birth, had 627 T cell receptor excision circles (TRECs)/μL (normal >40). B and NK cells were present, but low immunoglobulin levels and absent antibody responses to vaccines necessitated immunoglobulin infusions. The patient experienced poor weight growth, stomatitis, oral thrush, RSV bronchiolitis, and CMV viremia and CMV pneumonitis.Fig. 1


Combined immunodeficiency due to MALT1 mutations, treated by hematopoietic cell transplantation.

Punwani D, Wang H, Chan AY, Cowan MJ, Mallott J, Sunderam U, Mollenauer M, Srinivasan R, Brenner SE, Mulder A, Claas FH, Weiss A, Puck JM - J. Clin. Immunol. (2015)

a, Skin lesions, showing (i) facial erythroderma (ii) dorsal trunk and (iii) close-up with linear distribution of lesions corresponding to excoriations. b, Schematic representation of MALT1 protein (isoform a, NP_006776.1), illustrating death domain, 3 immunoglobulin (Ig)-like domains, and paracaspase domain [30]. Mutations are shown for our patient (black) and prior homozygous cases (blue) [22, 23]. c, Browser view of patient stacked DNA sequence tracks, demonstrating >30X coverage with individual reads homozygous for either the splice disrupting variant c.1019-2A > G or the single nucleotide deletion cDNA c.1060delC (the former also present in maternal DNA, not shown) (ClinVar number SCV000196510). Colored blocks, non-reference nucleotides; black blocks, deleted nucleotides. Below, genomic sequence of MALT1 exon 10 (isoform a, NM_006785.3) and protein translation with reference sequence (black) and de novo deleted sequence (red)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4352191&req=5

Fig1: a, Skin lesions, showing (i) facial erythroderma (ii) dorsal trunk and (iii) close-up with linear distribution of lesions corresponding to excoriations. b, Schematic representation of MALT1 protein (isoform a, NP_006776.1), illustrating death domain, 3 immunoglobulin (Ig)-like domains, and paracaspase domain [30]. Mutations are shown for our patient (black) and prior homozygous cases (blue) [22, 23]. c, Browser view of patient stacked DNA sequence tracks, demonstrating >30X coverage with individual reads homozygous for either the splice disrupting variant c.1019-2A > G or the single nucleotide deletion cDNA c.1060delC (the former also present in maternal DNA, not shown) (ClinVar number SCV000196510). Colored blocks, non-reference nucleotides; black blocks, deleted nucleotides. Below, genomic sequence of MALT1 exon 10 (isoform a, NM_006785.3) and protein translation with reference sequence (black) and de novo deleted sequence (red)
Mentions: The infant, born at term to non-consanguineous parents with negative family history, developed blood-streaked diarrhea and a desquamating, erythematous pruritic rash, the latter evolving into firm erythematous papules affecting trunk, palms and soles (Fig. 1a, Table 1). There were no indications of environmental atopy; IgE was undetectable, and steroids were ineffective. Skin biopsies showed perivascular lymphocytic infiltration in the dermis. Following monthly otitis media infections, an immune workup showed expansion of CD4 and CD8 T cell populations with high proportions of naïve CD45RA T cells, but impaired in vitro proliferative responses (Tables 1 and 2). Maternal T cell engraftment was absent, and the newborn dried blood spot, retrieved from the time of the patient’s birth, had 627 T cell receptor excision circles (TRECs)/μL (normal >40). B and NK cells were present, but low immunoglobulin levels and absent antibody responses to vaccines necessitated immunoglobulin infusions. The patient experienced poor weight growth, stomatitis, oral thrush, RSV bronchiolitis, and CMV viremia and CMV pneumonitis.Fig. 1

Bottom Line: No defects were found in multiple genes associated with severe combined immunodeficiency.Our 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of California San Francisco School of Medicine, and UCSF Benioff Children's Hospital, Box 0519, 513 Parnassus Avenue, HSE-301A, San Francisco, CA, 94143-0519, USA.

ABSTRACT

Purpose: A 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.

Methods: Clinical 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.

Results: The 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.

Conclusions: Our 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.

Show MeSH
Related in: MedlinePlus