Combined Immunodeficiency Due To MALT1 Deficiency

Mendelian MONDO:0014197 Pathograph 31 Show in embeddings browser Combined immunodeficiency Inborn error of immunity

Combined immunodeficiency due to MALT1 deficiency (immunodeficiency 12) is the autosomal recessive inborn error of immunity caused by biallelic loss-of-function variants in MALT1, the paracaspase subunit of the CARD11-BCL10-MALT1 (CBM) signalosome. MALT1 does two jobs in that complex. As a scaffold it carries an engaged T or B cell antigen receptor through to canonical NF-kappaB activation, and as a cysteine protease it cleaves negative regulators of that pathway and of cytokine mRNA stability. Most reported alleles abolish the protein, so both jobs fail together. The disease therefore has two faces in the same child. The immunodeficient face follows from the scaffold defect: T cells are present in normal numbers but proliferate and make IL-2 poorly on receptor stimulation, Th17 immunity is weak, and B cells arrest at the transitional stage and are progressively lost, so specific antibody responses fail and some patients become agammaglobulinemic. Infections with Staphylococcus aureus, Candida albicans and cytomegalovirus dominate, alongside recurrent pneumonia that leads to bronchiectasis. The dysregulated face follows mainly from loss of the protease function that regulatory T cells depend on: FOXP3 regulatory T cells are drastically reduced and the picture can be IPEX-like, with enteropathy, autoimmunity, eczematous or erythrodermic skin disease, eosinophilia and raised IgE. Onset is in the first months of life. Because T and B cell numbers are often normal at presentation, and newborn TREC screening can be normal, the disease is recognised late. Immunoglobulin replacement and antibiotic prophylaxis do little to change its course, about half of untreated patients die of infection, and allogeneic haematopoietic stem cell transplantation is curative.

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1
Inheritance
8
Pathophys.
23
Phenotypes
31
Pathograph
1
Genes
3
Medical Actions
2
Models
1
Deep Research
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Classifications

Harrison's Part
IMMUNE RHEUMATOLOGIC GENETICS ENVIRONMENT DISEASE
IUIS Category
combined immunodeficiency
👪

Inheritance

1
Autosomal recessive HP:0000007
Biallelic loss of function, homozygous in consanguineous families and compound heterozygous in outbred ones. Heterozygous parents are healthy.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:23727036 SUPPORT Human Clinical
"An autosomal recessive form of CID is associated with homozygous mutations in MALT1."
Conclusion of the index family report, in which both affected siblings were homozygous and both parents heterozygous.
PMID:25627829 SUPPORT Human Clinical
"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."
Shows the compound heterozygous form of the same recessive inheritance in a non-consanguineous family.
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Pathophysiology

8
Biallelic MALT1 Loss of Function
Biallelic germline variants abolish or severely reduce MALT1 protein. Because MALT1 is both the effector scaffold and the only protease of the CBM complex, losing the protein removes both activities at once; the two downstream nodes below follow the two activities separately.
MALT1 hgnc:6819 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MALT1 (hgnc:6819). hgnc:6819 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
MALT1 paracaspase (cysteine-type endopeptidase) activity GO:0004197 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased MALT1 paracaspase (cysteine-type endopeptidase) activity, annotated with cysteine-type endopeptidase activity (GO:0004197). GO:0004197 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Defective CBM Signalosome Signaling to NF-kappaB
Loss of MALT1 Paracaspase Activity
Show evidence (2 references)
PMID:25627829 SUPPORT Human Clinical
"Autologous lymphocytes failed to express MALT1 and lacked NF-κB signaling dependent upon the CARMA1, BCL-10 and MALT1 signalosome."
Loss of MALT1 protein in the patient's own lymphocytes, with the consequent signalling failure, in a compound heterozygous patient.
PMID:27253662 SUPPORT Human Clinical
"We identified a homozygous missense mutation in mucosa-associated lymphoid tissue lymphoma translocation 1 gene (MALT1), which precluded protein expression."
A second missense allele that acts by abolishing the protein.
Defective CBM Signalosome Signaling to NF-kappaB
Without MALT1 the CARD11-BCL10-MALT1 complex cannot carry T and B cell receptor signals through to IKK, so IkappaB-alpha is not degraded and p65 is not phosphorylated. This is the scaffold arm of the lesion.
CBM complex GO:0032449 Gene Ontology (GO) Relation: this pathophysiological event involves this protein complex This pathophysiological event involves CBM complex (GO:0032449). GO:0032449 is a protein complex from the Gene Ontology.
T cell receptor signaling pathway GO:0050852 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased T cell receptor signaling pathway (GO:0050852). GO:0050852 is a biological process from the Gene Ontology. ↓ DECREASED B cell receptor signaling pathway GO:0050853 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased B cell receptor signaling pathway (GO:0050853). GO:0050853 is a biological process from the Gene Ontology. ↓ DECREASED canonical NF-kappaB signal transduction GO:0007249 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased canonical NF-kappaB signal transduction (GO:0007249). GO:0007249 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Impaired Antigen Receptor-Driven T Cell Activation
Arrested B Cell Maturation and Progressive B Cell Depletion
Show evidence (2 references)
PMID:23727036 SUPPORT Human Clinical
"Analysis of T cells that were available on one of the patients showed severely impaired IκBα degradation and IL-2 production after activation, 2 events that depend on MALT1."
Direct measurement of the NF-kappaB activation defect in patient T cells.
PMID:40748513 SUPPORT Human Clinical
"Impaired CBM-mediated NF-κB activation was confirmed by reduced phosphorylation of the p65 subunit, resulting in deficient production of IL-2 and TNF-α."
Reproduces the defect at the level of p65 phosphorylation.
Loss of MALT1 Paracaspase Activity
MALT1 is a cysteine protease that cleaves negative regulators of NF-kappaB and mRNA-destabilising proteins. In one protease-dead knock-in mouse line the protease was largely dispensable for crossing the lymphocyte activation threshold but essential for regulatory T cell development, which is how one gene produces both immunodeficiency and immune dysregulation. A second protease-deficient line showed reduced T cell proliferation, IL-2 production and Th17 differentiation in vitro, so the protease also contributes to effector T cell responses.
MALT1 paracaspase (cysteine-type endopeptidase) activity GO:0004197 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased MALT1 paracaspase (cysteine-type endopeptidase) activity, annotated with cysteine-type endopeptidase activity (GO:0004197). GO:0004197 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Impaired Th17 Immunity In mouse T cells lacking MALT1 protease activity, Th17 differentiation fails in vitro. The human evidence is only the low Th17 count, so the route in patients is inferred from the model.
Regulatory T Cell Deficiency
Show evidence (2 references)
PMID:25456129 SUPPORT BACKGROUND Model Organism
"As a scaffold, it assembles protein complexes for NF-κB activation, and its proteolytic domain cleaves negative NF-κB regulators for signal enforcement."
Defines the protease function lost alongside the scaffold.
PMID:40748513 SUPPORT Human Clinical
"Human MALT1 deficiency causes profound CID by impairing CBM-mediated NF-kB signaling and MALT1-paracaspase activity."
The patient study's conclusion that the human disease includes loss of paracaspase activity, not only of the scaffold function.
Impaired Antigen Receptor-Driven T Cell Activation
T cells are present in normal numbers and naive or memory distribution, but proliferate poorly to antigens and anti-CD3 and make little IL-2 and TNF-alpha. Proliferation to phytohaemagglutinin plus IL-2 is preserved, which places the block at receptor-proximal signalling rather than in the proliferative machinery.
T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology.
T cell proliferation GO:0042098 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased T cell proliferation (GO:0042098). GO:0042098 is a biological process from the Gene Ontology. ↓ DECREASED interleukin-2 production GO:0032623 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased interleukin-2 production (GO:0032623). GO:0032623 is a biological process from the Gene Ontology. ↓ DECREASED tumor necrosis factor production GO:0032640 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased tumor necrosis factor production (GO:0032640). GO:0032640 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Recurrent infections
Severe infection
Cytomegalovirus pneumonitis
Pneumocystis jirovecii pneumonia
Decreased antigen-specific T cell proliferation
Impaired specific antibody response
Show evidence (2 references)
PMID:23727036 SUPPORT Human Clinical
"The numbers of circulating T and B lymphocytes were normal, but T-cell proliferation to antigens and antibody responses to vaccination were severely impaired in both patients."
The defining dissociation between normal counts and absent function.
PMID:31037583 SUPPORT Human Clinical
"A normal proliferative response was induced by phytohemagglutinin and IL-2 but was diminished with anti-CD3."
Localises the defect to the T cell receptor pathway.
Impaired Th17 Immunity
Th17 cells are low in patient blood. The pathogens that dominate the disease, Staphylococcus aureus and Candida albicans, are the ones Th17 immunity controls, the same pattern seen in STAT3 and IL-17 pathway deficiencies. MALT1 is also needed in dendritic cells for dectin-driven IL-1beta and IL-23, the cytokines that polarise Th17 cells, so the defect may have an innate as well as a T cell component.
T-helper 17 cell CL:0000899 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T-helper 17 cell (CL:0000899). CL:0000899 is a cell type from the Cell Ontology.
T-helper 17 cell differentiation GO:0072539 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased T-helper 17 cell differentiation (GO:0072539). GO:0072539 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Recurrent Staphylococcus aureus infections
Recurrent candida infections
Decreased Th17 T cell proportion
Show evidence (1 reference)
PMID:31037583 SUPPORT Human Clinical
"Immune work-up revealed lymphocytosis, low to normal levels of immunoglobulins, absence of regulatory T cells, and low Th17 cells."
Low Th17 cells measured in patients.
Arrested B Cell Maturation and Progressive B Cell Depletion
B cells develop as far as the transitional stage and stop. Marginal zone-like and memory B cells are reduced or absent, and circulating B cell numbers fall with age, so a child who presents with normal counts can later be agammaglobulinemic. Transplantation restores mature B cell differentiation.
transitional stage B cell CL:0000818 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves transitional stage B cell (CL:0000818). CL:0000818 is a cell type from the Cell Ontology. memory B cell CL:0000787 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves memory B cell (CL:0000787). CL:0000787 is a cell type from the Cell Ontology.
B cell differentiation GO:0030183 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased B cell differentiation (GO:0030183). GO:0030183 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Decreased total B cell count
Impaired specific antibody response
Agammaglobulinemia
Show evidence (3 references)
PMID:40748513 SUPPORT Human Clinical
"The patient displayed low NK cell and B cell counts, together with a developmental block at the transitional B cell stage."
Locates the block at the transitional stage.
PMID:34559885 SUPPORT Human Clinical
"In combination with the literature data, we found that the number of circulatory B cells, but not T cells, were inversely correlated with the age of patients."
Shows the B cell loss is progressive with age across reported patients.
PMID:39017781 SUPPORT Human Clinical
"He had elevated serum IgE and normal B- and T-lymphocyte subset counts, but there was an arrest in the B-cell maturation."
Maturation arrest can precede any fall in B cell numbers.
Regulatory T Cell Deficiency
FOXP3 regulatory T cells, and in one patient T follicular regulatory cells, are drastically reduced, while activated effector T cells (PD-1 and ICOS high) accumulate. This accounts for the IPEX-like presentation, and transplantation corrects the regulatory T cell frequency. In mice the requirement is specifically for MALT1 protease activity, acting through TCR-induced MYC.
regulatory T cell CL:0000815 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves regulatory T cell (CL:0000815). CL:0000815 is a cell type from the Cell Ontology.
regulatory T cell differentiation GO:0045066 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased regulatory T cell differentiation (GO:0045066). GO:0045066 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Malt1 protease-dead knock-in mouse Mouse recapitulates Protease inactivation alone is enough to block regulatory T cell development.
Downstream
Autoimmunity
Chronic diarrhea
Th2-Skewed Immune Dysregulation
Decreased regulatory T cell proportion
Show evidence (2 references)
PMID:27253662 SUPPORT Human Clinical
"Moreover, there was a drastic reduction in Forkhead box P3 (FOXP3) regulatory T cells accounting for the IPEX-like phenotype."
Measured regulatory T cell loss in two siblings.
PMID:40748513 SUPPORT Human Clinical
"This functional defect caused lower Tfr and Treg cells, a normal proportion of Tfh cells, with higher expression of activation markers PD-1 and ICOS."
Extends the loss to follicular regulatory T cells, with effector activation.
Th2-Skewed Immune Dysregulation
Eosinophilia, raised IgE and eczematous or erythrodermic skin disease make the disease resemble Netherton or Omenn syndrome, or DOCK8 deficiency. In mice both complete MALT1 loss and selective protease loss produce Th2 skewing with raised IgE; the human evidence is the phenotype, and the mechanism is inferred from the models.
type 2 immune response GO:0042092 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased type 2 immune response (GO:0042092). GO:0042092 is a biological process from the Gene Ontology. ↑ INCREASED
Animal models
Malt1 knockout mouse Mouse recapitulates Reproduces the Th2 skewing, raised IgE and eczematous skin disease of the human disease.
Downstream
Eczematous dermatitis
Erythroderma
Increased circulating IgE concentration
Eosinophilia
Show evidence (1 reference)
PMID:31659015 SUPPORT Model Organism
"Our data indicate that B cell activation and IgG1/IgE production is triggered by microbial and dietary Ags preferentially in lymphoid organs draining mucosal barriers, likely as a result of dysregulated mucosal immune homeostasis."
Places the IgE response at mucosal barriers in protease-deficient mice.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Combined Immunodeficiency Due To MALT1 Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

23
Blood 7
Decreased antigen-specific T cell proliferation HP:0031402 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased antigen-specific T cell proliferation (HP:0031402). HP:0031402 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23727036 SUPPORT Human Clinical
"The numbers of circulating T and B lymphocytes were normal, but T-cell proliferation to antigens and antibody responses to vaccination were severely impaired in both patients."
Impaired T cell proliferation to antigens despite normal T cell numbers.
Decreased Th17 T cell proportion HP:0025832 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased Th17 T cell proportion (HP:0025832). HP:0025832 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31037583 SUPPORT Human Clinical
"Immune work-up revealed lymphocytosis, low to normal levels of immunoglobulins, absence of regulatory T cells, and low Th17 cells."
Low Th17 cells in two MALT1-deficient cousins.
Decreased total B cell count VERY_FREQUENT HP:0010976 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased total B cell count (HP:0010976). HP:0010976 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35079916 SUPPORT Human Clinical
"The majority of patients had normal T and NK cells, while eight (89%) exhibited reduced B cells."
Reduced B cells in 89% of the cohort.
PMID:34559885 SUPPORT Human Clinical
"In combination with the literature data, we found that the number of circulatory B cells, but not T cells, were inversely correlated with the age of patients."
B cell numbers decline with age across reported patients.
Agammaglobulinemia HP:0004432 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Agammaglobulinemia (HP:0004432). HP:0004432 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34559885 SUPPORT Human Clinical
"This infant showed agammaglobulinemia without lymphopenia."
Agammaglobulinemia in a MALT1-deficient infant.
Decreased regulatory T cell proportion HP:0020113 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased regulatory T cell proportion (HP:0020113). HP:0020113 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27253662 SUPPORT Human Clinical
"Moreover, there was a drastic reduction in Forkhead box P3 (FOXP3) regulatory T cells accounting for the IPEX-like phenotype."
Drastic reduction of FOXP3 regulatory T cells in two siblings.
PMID:31037583 SUPPORT Human Clinical
"Immune work-up revealed lymphocytosis, low to normal levels of immunoglobulins, absence of regulatory T cells, and low Th17 cells."
Absent regulatory T cells in two cousins.
Increased circulating IgE concentration HP:0003212 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased circulating IgE concentration (HP:0003212). HP:0003212 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35079916 SUPPORT Human Clinical
"Eosinophilia and high IgE were observed in six (67%) and two (22%) patients, respectively."
High IgE in 22% of the cohort.
PMID:39017781 SUPPORT Human Clinical
"He had elevated serum IgE and normal B- and T-lymphocyte subset counts, but there was an arrest in the B-cell maturation."
Elevated IgE in an Egyptian patient.
Eosinophilia FREQUENT Increased total eosinophil count HP:0001880 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Eosinophilia, annotated with Increased total eosinophil count (HP:0001880). HP:0001880 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35079916 SUPPORT Human Clinical
"Eosinophilia and high IgE were observed in six (67%) and two (22%) patients, respectively."
Eosinophilia in 67% of the cohort.
Cardiovascular 1
Lymphadenopathy HP:0002716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphadenopathy (HP:0002716). HP:0002716 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31037583 SUPPORT Human Clinical
"Clinical findings included recurrent infections, failure to thrive, lymphadenopathy, dermatitis, and autoimmunity."
Lymphadenopathy among the findings in two cousins.
PMID:40748513 SUPPORT Human Clinical
"Lymphoproliferation (lymphadenopathy, hepatosplenomegaly) | Yes | 7/23(30%)"
Pooled literature table quantifies lymphoproliferation at 7 of 23 (30%), supporting the "about a third" frequency.
Digestive 1
Chronic diarrhea FREQUENT HP:0002028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic diarrhea (HP:0002028). HP:0002028 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35079916 SUPPORT Human Clinical
"The main clinical findings of the disease were recurrent infections (100%), skin involvement (100%), failure to thrive (100%), oral lesions (67%), chronic diarrhea (56%), and autoimmunity (44%)."
Chronic diarrhea in 56% of the cohort.
PMID:40748513 SUPPORT Human Clinical
"The cardinal clinical characteristics of MALT1 deficiency are lower respiratory tract infections (100%), failure to thrive (90%), eczema (86%), oral lesions (85%) and chronic diarrhea (73%), all of which were observed in our patient."
Chronic diarrhea in 73% of pooled cases.
Head and Neck 2
Oral ulcer HP:0000155 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Oral ulcer (HP:0000155). HP:0000155 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:23727036 SUPPORT Human Clinical
"Both patients developed mastoiditis, chronic aphthous ulcers, cheilitis, and gingivitis."
Chronic aphthous ulcers in the index siblings.
PMID:35079916 SUPPORT Human Clinical
"The main clinical findings of the disease were recurrent infections (100%), skin involvement (100%), failure to thrive (100%), oral lesions (67%), chronic diarrhea (56%), and autoimmunity (44%)."
Oral lesions of any kind in 67% of the cohort; ulcers are one component.
Periodontitis HP:0000704 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Periodontal disease, annotated with Periodontitis (HP:0000704). HP:0000704 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33714841 SUPPORT REVIEW SYNTHESIS Human Clinical
"Human germline MALT1 deficiency is an inborn error of immunity characterized by recurrent bacterial, viral, and fungal infections, periodontal disease, enteropathy, dermatitis, and failure to thrive."
Review of reported patients naming periodontal disease as a characteristic feature.
Immune 10
Recurrent infections OBLIGATE HP:0002719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent infections (HP:0002719), qualified as infantile onset. HP:0002719 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Sequelae: Bronchiectasis
Show evidence (3 references)
PMID:35079916 SUPPORT Human Clinical
"The mean age of patients and disease onset were 33 ± 17 and 1.6 ± 0.7 months, respectively."
Mean disease onset at 1.6 months in the largest cohort, which places onset in infancy.
PMID:35079916 SUPPORT Human Clinical
"The main clinical findings of the disease were recurrent infections (100%), skin involvement (100%), failure to thrive (100%), oral lesions (67%), chronic diarrhea (56%), and autoimmunity (44%)."
Recurrent infections were present in all nine patients of the largest cohort.
PMID:40748513 SUPPORT Human Clinical
"The cardinal clinical characteristics of MALT1 deficiency are lower respiratory tract infections (100%), failure to thrive (90%), eczema (86%), oral lesions (85%) and chronic diarrhea (73%), all of which were observed in our patient."
Pooled literature cases: lower respiratory tract infections in 100%.
Cytomegalovirus pneumonitis HP:5210283 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cytomegalovirus pneumonitis (HP:5210283). HP:5210283 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25627829 SUPPORT Human Clinical
"The patient experienced poor weight growth, stomatitis, oral thrush, RSV bronchiolitis, and CMV viremia and CMV pneumonitis."
Documents CMV pneumonitis in a MALT1-deficient infant.
PMID:33714841 SUPPORT REVIEW SYNTHESIS Human Clinical
"The most frequently detected pathogens are Staphylococcus aureus, Candida albicans, and cytomegalovirus."
Review naming cytomegalovirus among the most frequent pathogens.
Pneumocystis jirovecii pneumonia HP:0020102 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pneumocystis jirovecii pneumonia (HP:0020102). HP:0020102 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34559885 SUPPORT Human Clinical
"Pneumocystis pneumonia developed in a 6-month-old Japanese infant with atopic dermatitis, enteritis and growth restriction."
Case report of Pneumocystis pneumonia in MALT1 deficiency.
Recurrent Staphylococcus aureus infections HP:0002726 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent Staphylococcus aureus infections (HP:0002726). HP:0002726 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33714841 SUPPORT REVIEW SYNTHESIS Human Clinical
"The most frequently detected pathogens are Staphylococcus aureus, Candida albicans, and cytomegalovirus."
Review of reported patients naming S. aureus as a leading pathogen.
Recurrent candida infections HP:0005401 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent candida infections (HP:0005401). HP:0005401 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33714841 SUPPORT REVIEW SYNTHESIS Human Clinical
"The most frequently detected pathogens are Staphylococcus aureus, Candida albicans, and cytomegalovirus."
Review naming Candida albicans among the most frequent pathogens.
PMID:23727036 SUPPORT Human Clinical
"Defective T cell activation by antigens likely played a critical role in the patients' susceptibility to opportunistic infections with CMV and C. albicans."
The index siblings had C. albicans infection.
Impaired specific antibody response HP:0012475 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Impaired specific antibody response (HP:0012475). HP:0012475 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23727036 SUPPORT Human Clinical
"The numbers of circulating T and B lymphocytes were normal, but T-cell proliferation to antigens and antibody responses to vaccination were severely impaired in both patients."
Antibody responses to vaccination were severely impaired.
Autoimmunity FREQUENT HP:0002960 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autoimmunity (HP:0002960). HP:0002960 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35079916 SUPPORT Human Clinical
"The main clinical findings of the disease were recurrent infections (100%), skin involvement (100%), failure to thrive (100%), oral lesions (67%), chronic diarrhea (56%), and autoimmunity (44%)."
Autoimmunity in 44% of the cohort.
PMID:31037583 SUPPORT Human Clinical
"Clinical findings included recurrent infections, failure to thrive, lymphadenopathy, dermatitis, and autoimmunity."
Autoimmunity among the clinical findings of two cousins.
Eczematous dermatitis VERY_FREQUENT Eczematoid dermatitis HP:0000964 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Eczematous dermatitis, annotated with Eczematoid dermatitis (HP:0000964). HP:0000964 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40748513 SUPPORT Human Clinical
"The cardinal clinical characteristics of MALT1 deficiency are lower respiratory tract infections (100%), failure to thrive (90%), eczema (86%), oral lesions (85%) and chronic diarrhea (73%), all of which were observed in our patient."
Eczema in 86% of pooled cases.
PMID:35079916 SUPPORT Human Clinical
"The main clinical findings of the disease were recurrent infections (100%), skin involvement (100%), failure to thrive (100%), oral lesions (67%), chronic diarrhea (56%), and autoimmunity (44%)."
Skin involvement in all nine patients.
Erythroderma HP:0001019 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Erythroderma (HP:0001019). HP:0001019 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31049936 SUPPORT Human Clinical
"Here, we describe the case of a female infant with severe immune dysregulation leading to recurrent systemic infections, failure to thrive and severe crises of ichthyosiform erythroderma with high levels of serum IgE."
Ichthyosiform erythroderma in MALT1 deficiency.
Severe infection VERY_FREQUENT HP:0032169 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe infection (HP:0032169). HP:0032169 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40748513 SUPPORT Human Clinical
"Severe infections (Meningitis, Sepsis, Necrotizing skin infection) | Yes | 17/23(74%)"
Pooled literature table records severe infections in 17 of 23 (74%) patients.
PMID:40748513 SUPPORT Human Clinical
"Severe infections (including meningitis, sepsis, and necrotizing skin infections) were not rarely seen, occurring in approximately 74% of patients, serving as an obvious cause of poor outcomes, as demonstrated in our case."
Names the severe-infection categories and their role as a leading cause of poor outcomes.
Respiratory 1
Bronchiectasis HP:0002110 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bronchiectasis (HP:0002110). HP:0002110 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23727036 SUPPORT Human Clinical
"Both patients experienced recurrent pulmonary infections since 4 months of age with resultant bronchiectasis."
Reports bronchiectasis as the consequence of recurrent pulmonary infections.
Growth 1
Failure to thrive VERY_FREQUENT HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35079916 SUPPORT Human Clinical
"The main clinical findings of the disease were recurrent infections (100%), skin involvement (100%), failure to thrive (100%), oral lesions (67%), chronic diarrhea (56%), and autoimmunity (44%)."
Failure to thrive in all nine patients.
PMID:40748513 SUPPORT Human Clinical
"The cardinal clinical characteristics of MALT1 deficiency are lower respiratory tract infections (100%), failure to thrive (90%), eczema (86%), oral lesions (85%) and chronic diarrhea (73%), all of which were observed in our patient."
Failure to thrive in 90% of pooled cases.
🧬

Genetic Associations

1
MALT1
Gene: MALT1 hgnc:6819 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MALT1 (hgnc:6819). hgnc:6819 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (5 references)
PMID:23727036 SUPPORT Human Clinical
"showed the presence in both patients of a homozygous missense mutation in MALT1 that resulted in loss of protein expression"
The index family: a homozygous MALT1 missense allele that abolishes the protein.
PMID:23727036 SUPPORT In Vitro
"In contrast to wild-type human MALT1, the patients' MALT1 mutant failed to correct defective nuclear factor-κB activation and IL-2 production in MALT1-deficient mouse T cells."
Functional complementation in Malt1-null mouse T cells shows the patient allele is loss of function, which is the causal test rather than segregation alone.
PMID:40748513 SUPPORT Human Clinical
"The patient carried a novel pathogenic biallelic loss-of-function variant in MALT1 (c.1411G > A; p.D471N) located in the caspase-like domain, leading to severely reduced MALT1 protein expression."
A paracaspase-domain missense allele that also acts by reducing protein, showing that loss of expression is the common route across domains.
+ 2 more references
💊

Medical Actions

3
Hematopoietic Stem Cell Transplantation
Action: allogeneic hematopoietic stem cell transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is allogeneic hematopoietic stem cell transplantation (NCIT:C46089). NCIT:C46089 is a clinical intervention from the NCI Thesaurus. Ontology label: Allogeneic Hematopoietic Stem Cell Transplantation NCIT:C46089
Platform: Cell therapy
Allogeneic haematopoietic stem cell transplantation is the only curative treatment. It restores NF-kappaB signalling, regulatory T cells and B cell maturation, and survival is higher in transplanted patients, so it should be offered early.
Mechanism Target:
Regulatory T Cell Deficiency — Donor-derived lymphocytes restore the regulatory T cell compartment.
Show evidence (1 reference)
PMID:27253662 SUPPORT Human Clinical
"Immunological workup at 6 and 12 months after transplantation showed normal NF-κB activation and correction of regulatory T cells frequency."
Regulatory T cell frequency and NF-kappaB activation were corrected after transplantation.
Defective CBM Signalosome Signaling to NF-kappaB — Donor cells carry functional MALT1, so antigen receptor signalling to NF-kappaB is restored.
Show evidence (1 reference)
PMID:27253662 SUPPORT Human Clinical
"Immunological workup at 6 and 12 months after transplantation showed normal NF-κB activation and correction of regulatory T cells frequency."
NF-kappaB activation was normal after transplantation.
Arrested B Cell Maturation and Progressive B Cell Depletion — Transplantation reconstitutes mature B cell differentiation.
Show evidence (1 reference)
PMID:34559885 SUPPORT Human Clinical
"The hematopoietic cell transplantation (HCT) successfully reconstituted the differentiation of mature B cells and T cells."
B and T cell differentiation was reconstituted by transplantation.
Show evidence (3 references)
PMID:35079916 SUPPORT Human Clinical
"Analyzing this cohort with reported patients revealed overall survival in 58% (11/19), which was higher in patients who underwent HSCT"
Survival across 19 patients was higher with transplantation.
PMID:27253662 SUPPORT Human Clinical
"Following identification of the mutation, both children received hematopoietic stem cell transplantation, which permitted full clinical recovery."
Full clinical recovery after transplantation in two siblings.
PMID:40748513 SUPPORT Human Clinical
"Prompt hematopoietic stem cell transplantation (HSCT) is highly recommended as an effective therapy for MALT1 deficiency."
The case report's conclusion recommending early transplantation.
Immunoglobulin Replacement Therapy
Action: immunoglobulin replacement therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunoglobulin replacement therapy, annotated with Intravenous Immunoglobulin Therapy (NCIT:C121331). NCIT:C121331 is a clinical intervention from the NCI Thesaurus. Ontology label: Intravenous Immunoglobulin Therapy NCIT:C121331
Agent: human immunoglobulin G NCIT:C80829 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses human immunoglobulin G (NCIT:C80829). NCIT:C80829 is a therapeutic agent from the NCI Thesaurus.
Platform: Protein replacement
Supportive only. In the largest cohort immunoglobulin replacement did little to reduce infections, which is why transplantation is recommended for every patient.
Show evidence (2 references)
PMID:35079916 REFUTE Human Clinical
"Immunoglobulin replacement and antibiotics prophylaxis were mostly ineffective in reducing the frequency of infections and other complications."
Immunoglobulin replacement was mostly ineffective, so the evidence does not support it as disease-modifying.
PMID:23727036 REFUTE Human Clinical
"Despite intravenous immunoglobulin (IVIG) replacement therapy, both patients had persistent infections and expired from respiratory failure."
Both index siblings died of infection despite immunoglobulin replacement.
Antibiotic Prophylaxis
Action: antibiotic prophylaxisNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is antibiotic prophylaxis (NCIT:C51993). NCIT:C51993 is a clinical intervention from the NCI Thesaurus. Ontology label: Antibiotic Prophylaxis NCIT:C51993
Platform: Small molecule
Antibiotic prophylaxis is used as bridging care before transplantation, but in the largest cohort it did not reduce infection frequency.
Show evidence (1 reference)
PMID:35079916 REFUTE Human Clinical
"Immunoglobulin replacement and antibiotics prophylaxis were mostly ineffective in reducing the frequency of infections and other complications."
Antibiotic prophylaxis was mostly ineffective at reducing infections.
🔬

Diagnosis

3
Lymphocyte function testing with normal lymphocyte counts (PRESENT)
T and B cell counts are often normal at presentation, so the diagnosis rests on functional testing: proliferation to antigens and anti-CD3, IL-2 production, NF-kappaB activation on stimulation, and vaccine antibody responses.
Show evidence (1 reference)
PMID:23727036 SUPPORT Human Clinical
"The numbers of circulating T and B lymphocytes were normal, but T-cell proliferation to antigens and antibody responses to vaccination were severely impaired in both patients."
Normal counts with failed function is the pattern functional testing has to detect.
Molecular genetic testing for biallelic MALT1 variants (PRESENT)
Confirmation is by finding biallelic MALT1 variants. The eczema, raised IgE and staphylococcal infections overlap with DOCK8 deficiency and CARD11 deficiency, which is why molecular testing rather than the clinical picture decides the diagnosis.
Show evidence (1 reference)
PMID:39017781 SUPPORT Human Clinical
"Thus, whenever DOCK 8 has been excluded, the molecular diagnosis is mandatory as this could lead to discovering more patients hence better understanding and reporting of the phenotype and natural history of the disease especially since there are very few documented cases."
States that molecular diagnosis is required once DOCK8 deficiency is excluded.
Newborn TREC screening can be normal (PRESENT)
Because T cells are produced in normal numbers, TREC-based newborn screening for SCID can return a normal result. One patient's newborn dried blood spot had a TREC count well above the cut-off, although another patient had reduced TRECs on testing after presentation (PMID:40748513), so a normal newborn screen does not exclude the disease.
Show evidence (1 reference)
PMID:25627829 SUPPORT Human Clinical
"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)."
A normal newborn TREC count in a MALT1-deficient patient.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Known only from case reports and small series. A 2025 report counts 22 published patients; there is no registry and no population estimate. Most reported families are consanguineous, so the allele frequency in outbred populations is unknown.
Show evidence (1 reference)
PMID:40748513 SUPPORT BACKGROUND Human Clinical
"Since then, a total of 22 patients have been discovered."
The introduction's count of published patients since the 2013 index family, which is the whole of the epidemiological record for this disease.
🐁

Animal Models

2
Malt1 protease-dead knock-in mouse
Mice carrying a catalytically inactive MALT1 separate the protease from the scaffold. They lose regulatory T cells and develop a lethal inflammatory syndrome, which is the basis for attributing the regulatory T cell defect of the human disease to loss of protease activity.
Species
Mouse
Genotype
Malt1 paracaspase-inactive knock-in, scaffold function retained
Publication
PMID:25456129
Pathograph links
Regulatory T Cell Deficiency recapitulates fidelity: moderate observes: cellular Protease inactivation alone is enough to block regulatory T cell development.
Limitations: The knock-in keeps the scaffold function, whereas most patient alleles abolish the protein, so the model isolates the protease arm rather than reproducing the human lesion.
Show evidence (1 reference)
PMID:25456129 SUPPORT Model Organism
"Paracaspase activity is essential for regulatory T cell (Treg) and innate-like B cell development, but it is largely dispensable for overcoming Malt1-dependent thresholds for lymphocyte activation."
Shows the regulatory T cell defect in the protease-dead mouse.
Malt1 knockout mouse
Complete loss of MALT1, the closer match to the null alleles seen in most patients. With age these mice develop atopic-like dermatitis preceded by Th2 skewing, raised serum IgE and reduced regulatory T cells.
Species
Mouse
Genotype
Malt1 germline knockout
Publication
PMID:31632405
Pathograph links
Th2-Skewed Immune Dysregulation recapitulates fidelity: moderate observes: organism Reproduces the Th2 skewing, raised IgE and eczematous skin disease of the human disease.
Limitations: The dermatitis appears only as the mice age, whereas skin disease in patients begins in infancy, so the time course differs from the human disease.
Show evidence (1 reference)
PMID:31632405 SUPPORT Model Organism
"here we report that MALT1-deficient mice develop atopic-like dermatitis upon aging, which is preceded by Th2 skewing, an increase in serum IgE, and a decrease in Treg frequency and surface expression of the Treg functionality marker CTLA-4."
The knockout develops the Th2 and IgE phenotype with atopic-like skin disease.
{ }

Source YAML

click to show 
name: Combined Immunodeficiency Due To MALT1 Deficiency
creation_date: "2026-10-01T21:19:54Z"
category: Mendelian
synonyms:
- MALT1 deficiency
- Immunodeficiency 12
- IMD12
- immunodeficiency type 12
description: >-
  Combined immunodeficiency due to MALT1 deficiency (immunodeficiency 12) is the
  autosomal recessive inborn error of immunity caused by biallelic loss-of-function
  variants in MALT1, the paracaspase subunit of the CARD11-BCL10-MALT1 (CBM)
  signalosome. MALT1 does two jobs in that complex. As a scaffold it carries an
  engaged T or B cell antigen receptor through to canonical NF-kappaB activation, and
  as a cysteine protease it cleaves negative regulators of that pathway and of
  cytokine mRNA stability. Most reported alleles abolish the protein, so both jobs
  fail together.

  The disease therefore has two faces in the same child. The immunodeficient face
  follows from the scaffold defect: T cells are present in normal numbers but
  proliferate and make IL-2 poorly on receptor stimulation, Th17 immunity is weak,
  and B cells arrest at the transitional stage and are progressively lost, so
  specific antibody responses fail and some patients become agammaglobulinemic.
  Infections with Staphylococcus aureus, Candida albicans and cytomegalovirus
  dominate, alongside recurrent pneumonia that leads to bronchiectasis. The
  dysregulated face follows mainly from loss of the protease function that
  regulatory T cells depend on: FOXP3 regulatory T cells are drastically reduced and
  the picture can be IPEX-like, with enteropathy, autoimmunity, eczematous or
  erythrodermic skin disease, eosinophilia and raised IgE.

  Onset is in the first months of life. Because T and B cell numbers are often
  normal at presentation, and newborn TREC screening can be normal, the disease is
  recognised late. Immunoglobulin replacement and antibiotic prophylaxis do little to
  change its course, about half of untreated patients die of infection, and
  allogeneic haematopoietic stem cell transplantation is curative.
disease_term:
  preferred_term: combined immunodeficiency due to MALT1 deficiency
  term:
    id: MONDO:0014197
    label: combined immunodeficiency due to MALT1 deficiency
parents:
- Combined immunodeficiency
- Inborn error of immunity
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  iuis_category:
    classification_value: combined immunodeficiency
    notes: >-
      The IUIS 2022 classification lists MALT1 deficiency in Table 1,
      immunodeficiencies affecting cellular and humoral immunity, among the combined
      immunodeficiencies generally less profound than SCID, with autosomal recessive
      inheritance. The 615468 in the quoted row is the OMIM phenotype number for
      immunodeficiency 12.
    evidence:
    - reference: PMID:35748970
      reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "MALT1 deficiency MALT1 AR 615468"
      explanation: >-
        The IUIS table row placing MALT1 deficiency in Table 1 (combined
        immunodeficiency), with its inheritance and OMIM number.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Known only from case reports and small series. A 2025 report counts 22 published
    patients; there is no registry and no population estimate. Most reported families
    are consanguineous, so the allele frequency in outbred populations is unknown.
  evidence:
  - reference: PMID:40748513
    reference_title: "Loss of MALT1 Function in a Patient With Combined Immunodeficiency: a Novel Pathogenic Variant and Immunological Insights."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Since then, a total of 22 patients have been discovered."
    explanation: >-
      The introduction's count of published patients since the 2013 index family,
      which is the whole of the epidemiological record for this disease.
inheritance:
- name: Autosomal recessive
  description: >-
    Biallelic loss of function, homozygous in consanguineous families and compound
    heterozygous in outbred ones. Heterozygous parents are healthy.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:23727036
    reference_title: "A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An autosomal recessive form of CID is associated with homozygous mutations in MALT1."
    explanation: >-
      Conclusion of the index family report, in which both affected siblings were
      homozygous and both parents heterozygous.
  - reference: PMID:25627829
    reference_title: "Combined immunodeficiency due to MALT1 mutations, treated by hematopoietic cell transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: >-
      Shows the compound heterozygous form of the same recessive inheritance in a
      non-consanguineous family.
genetic:
- name: MALT1
  gene_term:
    preferred_term: MALT1
    term:
      id: hgnc:6819
      label: MALT1
  relationship_type: CAUSATIVE
  presence: PRESENT
  variant_origin: GERMLINE
  notes: >-
    Reported alleles span the protein: missense in the N-terminal CARD domain
    (p.Ser89Ile, the index family) and in the caspase-like domain (p.Asp471Asn), a
    further missense allele (p.Ile600Asn), splice and frameshift variants, and
    nonsense alleles (p.Glu368*, and c.609G>A at Trp203, which its authors describe
    as a homozygous nonsense mutation). Those studied abolish or severely reduce
    MALT1 protein, so the usual disease is loss of both the scaffold and the protease
    function.
  evidence:
  - reference: PMID:23727036
    reference_title: "A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "showed the presence in both patients of a homozygous missense mutation in MALT1 that resulted in loss of protein expression"
    explanation: >-
      The index family: a homozygous MALT1 missense allele that abolishes the
      protein.
  - reference: PMID:23727036
    reference_title: "A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In contrast to wild-type human MALT1, the patients' MALT1 mutant failed to correct defective nuclear factor-κB activation and IL-2 production in MALT1-deficient mouse T cells."
    explanation: >-
      Functional complementation in Malt1-null mouse T cells shows the patient
      allele is loss of function, which is the causal test rather than segregation
      alone.
  - reference: PMID:40748513
    reference_title: "Loss of MALT1 Function in a Patient With Combined Immunodeficiency: a Novel Pathogenic Variant and Immunological Insights."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient carried a novel pathogenic biallelic loss-of-function variant in MALT1 (c.1411G > A; p.D471N) located in the caspase-like domain, leading to severely reduced MALT1 protein expression."
    explanation: >-
      A paracaspase-domain missense allele that also acts by reducing protein,
      showing that loss of expression is the common route across domains.
  - reference: PMID:34559885
    reference_title: "Progressive B cell depletion in human MALT1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 8 years of age, the genetic diagnosis of MALT1-deficiency was confirmed on a novel homozygous mutation of c.1102G>T, p.E368X."
    explanation: Documents a homozygous nonsense allele as a cause.
  - reference: PMID:40853399
    reference_title: "To The Editor a Novel Mutation in MALT1 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analysis revealed the homozygous MALT1 mutation c.609G > A, p. Trp203, which was associated with her immunodeficiency."
    explanation: >-
      A second homozygous truncating allele, found in a child from a consanguineous
      family who presented with agammaglobulinemia.
pathophysiology:
- name: Biallelic MALT1 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic germline variants abolish or severely reduce MALT1 protein. Because
    MALT1 is both the effector scaffold and the only protease of the CBM complex,
    losing the protein removes both activities at once; the two downstream nodes
    below follow the two activities separately.
  genes:
  - preferred_term: MALT1
    term:
      id: hgnc:6819
      label: MALT1
  molecular_functions:
  - preferred_term: MALT1 paracaspase (cysteine-type endopeptidase) activity
    term:
      id: GO:0004197
      label: cysteine-type endopeptidase activity
    modifier: DECREASED
  genetic_context:
    functional_impact_category: LOSS_OF_FUNCTION
    variant_origin: GERMLINE
  evidence:
  - reference: PMID:25627829
    reference_title: "Combined immunodeficiency due to MALT1 mutations, treated by hematopoietic cell transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autologous lymphocytes failed to express MALT1 and lacked NF-κB signaling dependent upon the CARMA1, BCL-10 and MALT1 signalosome."
    explanation: >-
      Loss of MALT1 protein in the patient's own lymphocytes, with the consequent
      signalling failure, in a compound heterozygous patient.
  - reference: PMID:27253662
    reference_title: "Deficiency in Mucosa-associated Lymphoid Tissue Lymphoma Translocation 1: A Novel Cause of IPEX-Like Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a homozygous missense mutation in mucosa-associated lymphoid tissue lymphoma translocation 1 gene (MALT1), which precluded protein expression."
    explanation: A second missense allele that acts by abolishing the protein.
  downstream:
  - target: Defective CBM Signalosome Signaling to NF-kappaB
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40748513
      reference_title: "Loss of MALT1 Function in a Patient With Combined Immunodeficiency: a Novel Pathogenic Variant and Immunological Insights."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Human MALT1 deficiency causes profound CID by impairing CBM-mediated NF-kB signaling and MALT1-paracaspase activity."
      explanation: >-
        Names both consequences of losing the protein, the scaffold-dependent
        NF-kappaB defect and the protease defect, which is why this node has two
        downstream edges.
  - target: Loss of MALT1 Paracaspase Activity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40748513
      reference_title: "Loss of MALT1 Function in a Patient With Combined Immunodeficiency: a Novel Pathogenic Variant and Immunological Insights."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Human MALT1 deficiency causes profound CID by impairing CBM-mediated NF-kB signaling and MALT1-paracaspase activity."
      explanation: The same conclusion supports the protease branch of the lesion.
- name: Defective CBM Signalosome Signaling to NF-kappaB
  biological_scale: MOLECULAR
  description: >-
    Without MALT1 the CARD11-BCL10-MALT1 complex cannot carry T and B cell receptor
    signals through to IKK, so IkappaB-alpha is not degraded and p65 is not
    phosphorylated. This is the scaffold arm of the lesion.
  protein_complexes:
  - preferred_term: CBM complex
    term:
      id: GO:0032449
      label: CBM complex
  biological_processes:
  - preferred_term: T cell receptor signaling pathway
    term:
      id: GO:0050852
      label: T cell receptor signaling pathway
    modifier: DECREASED
  - preferred_term: B cell receptor signaling pathway
    term:
      id: GO:0050853
      label: B cell receptor signaling pathway
    modifier: DECREASED
  - preferred_term: canonical NF-kappaB signal transduction
    term:
      id: GO:0007249
      label: canonical NF-kappaB signal transduction
    modifier: DECREASED
  evidence:
  - reference: PMID:23727036
    reference_title: "A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis of T cells that were available on one of the patients showed severely impaired IκBα degradation and IL-2 production after activation, 2 events that depend on MALT1."
    explanation: Direct measurement of the NF-kappaB activation defect in patient T cells.
  - reference: PMID:40748513
    reference_title: "Loss of MALT1 Function in a Patient With Combined Immunodeficiency: a Novel Pathogenic Variant and Immunological Insights."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Impaired CBM-mediated NF-κB activation was confirmed by reduced phosphorylation of the p65 subunit, resulting in deficient production of IL-2 and TNF-α."
    explanation: Reproduces the defect at the level of p65 phosphorylation.
  downstream:
  - target: Impaired Antigen Receptor-Driven T Cell Activation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40748513
      reference_title: "Loss of MALT1 Function in a Patient With Combined Immunodeficiency: a Novel Pathogenic Variant and Immunological Insights."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Impaired CBM-mediated NF-κB activation was confirmed by reduced phosphorylation of the p65 subunit, resulting in deficient production of IL-2 and TNF-α."
      explanation: >-
        States the causal step: the NF-kappaB defect results in failure of the
        T cell cytokine response.
  - target: Arrested B Cell Maturation and Progressive B Cell Depletion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34559885
      reference_title: "Progressive B cell depletion in human MALT1 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "T cell stimulation tests showed impairments in the production of interleukin-2, phosphorylation of nuclear factor kappa B (NF-κB) p65 and differentiation of B cells."
      explanation: >-
        Reports the NF-kappaB defect and the B cell differentiation defect together
        in one patient. Whether the B cell block is B-cell-intrinsic (BCR or BAFFR
        signalling) or follows lost T cell help is not settled, so the edge is
        typed with unknown intermediates.
- name: Loss of MALT1 Paracaspase Activity
  biological_scale: MOLECULAR
  description: >-
    MALT1 is a cysteine protease that cleaves negative regulators of NF-kappaB and
    mRNA-destabilising proteins. In one protease-dead knock-in mouse line the
    protease was largely dispensable for crossing the lymphocyte activation
    threshold but essential for regulatory T cell development, which is how one
    gene produces both immunodeficiency and immune dysregulation. A second
    protease-deficient line showed reduced T cell proliferation, IL-2 production
    and Th17 differentiation in vitro, so the protease also contributes to
    effector T cell responses.
  molecular_functions:
  - preferred_term: MALT1 paracaspase (cysteine-type endopeptidase) activity
    term:
      id: GO:0004197
      label: cysteine-type endopeptidase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:25456129
    reference_title: "Uncoupling Malt1 threshold function from paracaspase activity results in destructive autoimmune inflammation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "As a scaffold, it assembles protein complexes for NF-κB activation, and its proteolytic domain cleaves negative NF-κB regulators for signal enforcement."
    explanation: Defines the protease function lost alongside the scaffold.
  - reference: PMID:40748513
    reference_title: "Loss of MALT1 Function in a Patient With Combined Immunodeficiency: a Novel Pathogenic Variant and Immunological Insights."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Human MALT1 deficiency causes profound CID by impairing CBM-mediated NF-kB signaling and MALT1-paracaspase activity."
    explanation: >-
      The patient study's conclusion that the human disease includes loss of
      paracaspase activity, not only of the scaffold function.
  downstream:
  - target: Impaired Th17 Immunity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      In mouse T cells lacking MALT1 protease activity, Th17 differentiation fails
      in vitro. The human evidence is only the low Th17 count, so the route in
      patients is inferred from the model.
    evidence:
    - reference: PMID:25762782
      reference_title: "Deficiency of MALT1 paracaspase activity results in unbalanced regulatory and effector T and B cell responses leading to multiorgan inflammation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In vitro, inactivation of MALT1 protease activity caused reduced stimulation-induced T cell proliferation, impaired IL-2 and TNF-α production, as well as defective Th17 differentiation."
      explanation: >-
        Cultured T cells from protease-deficient mice fail to differentiate into
        Th17 cells, which ties the Th17 defect to the protease arm.
  - target: Regulatory T Cell Deficiency
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25456129
      reference_title: "Uncoupling Malt1 threshold function from paracaspase activity results in destructive autoimmune inflammation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Paracaspase activity is essential for regulatory T cell (Treg) and innate-like B cell development, but it is largely dispensable for overcoming Malt1-dependent thresholds for lymphocyte activation."
      explanation: >-
        Paracaspase-dead knock-in mice separate the two functions and show that
        the protease is what regulatory T cells need.
    - reference: PMID:34668583
      reference_title: "MALT1 protease function in regulatory T cells induces MYC activity to promote mitochondrial function and cellular expansion."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "MALT1 protease activity controls the TCR-induced upregulation of the transcription factor MYC and the subsequent expression of MYC target genes in Tregs."
      explanation: Supplies the downstream route from the protease to regulatory T cell expansion.
- name: Impaired Antigen Receptor-Driven T Cell Activation
  biological_scale: CELLULAR
  description: >-
    T cells are present in normal numbers and naive or memory distribution, but
    proliferate poorly to antigens and anti-CD3 and make little IL-2 and TNF-alpha.
    Proliferation to phytohaemagglutinin plus IL-2 is preserved, which places the
    block at receptor-proximal signalling rather than in the proliferative machinery.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: T cell proliferation
    term:
      id: GO:0042098
      label: T cell proliferation
    modifier: DECREASED
  - preferred_term: interleukin-2 production
    term:
      id: GO:0032623
      label: interleukin-2 production
    modifier: DECREASED
  - preferred_term: tumor necrosis factor production
    term:
      id: GO:0032640
      label: tumor necrosis factor production
    modifier: DECREASED
  evidence:
  - reference: PMID:23727036
    reference_title: "A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The numbers of circulating T and B lymphocytes were normal, but T-cell proliferation to antigens and antibody responses to vaccination were severely impaired in both patients."
    explanation: The defining dissociation between normal counts and absent function.
  - reference: PMID:31037583
    reference_title: "Novel MALT1 Mutation Linked to Immunodeficiency, Immune Dysregulation, and an Abnormal T Cell Receptor Repertoire."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A normal proliferative response was induced by phytohemagglutinin and IL-2 but was diminished with anti-CD3."
    explanation: Localises the defect to the T cell receptor pathway.
  downstream:
  - target: Recurrent infections
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23727036
      reference_title: "A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Defective T cell activation by antigens likely played a critical role in the patients' susceptibility to opportunistic infections with CMV and C. albicans."
      explanation: The authors' inference from their patients, which is why it is stated as likely.
  - target: Severe infection
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40748513
      reference_title: "Loss of MALT1 Function in a Patient With Combined Immunodeficiency: a Novel Pathogenic Variant and Immunological Insights."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Severe infections (including meningitis, sepsis, and necrotizing skin infections) were not rarely seen, occurring in approximately 74% of patients, serving as an obvious cause of poor outcomes, as demonstrated in our case."
      explanation: The receptor-proximal T cell activation block is the immunodeficiency that drives these severe, often fatal infections.
  - target: Cytomegalovirus pneumonitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Pneumocystis jirovecii pneumonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Decreased antigen-specific T cell proliferation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23727036
      reference_title: "A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The numbers of circulating T and B lymphocytes were normal, but T-cell proliferation to antigens and antibody responses to vaccination were severely impaired in both patients."
      explanation: The clinical proliferation assay is the readout of the activation defect.
  - target: Impaired specific antibody response
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired Th17 Immunity
  biological_scale: CELLULAR
  description: >-
    Th17 cells are low in patient blood. The pathogens that dominate the disease,
    Staphylococcus aureus and Candida albicans, are the ones Th17 immunity controls,
    the same pattern seen in STAT3 and IL-17 pathway deficiencies. MALT1 is also
    needed in dendritic cells for dectin-driven IL-1beta and IL-23, the cytokines
    that polarise Th17 cells, so the defect may have an innate as well as a T cell
    component.
  cell_types:
  - preferred_term: T-helper 17 cell
    term:
      id: CL:0000899
      label: T-helper 17 cell
  biological_processes:
  - preferred_term: T-helper 17 cell differentiation
    term:
      id: GO:0072539
      label: T-helper 17 cell differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:31037583
    reference_title: "Novel MALT1 Mutation Linked to Immunodeficiency, Immune Dysregulation, and an Abnormal T Cell Receptor Repertoire."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immune work-up revealed lymphocytosis, low to normal levels of immunoglobulins, absence of regulatory T cells, and low Th17 cells."
    explanation: Low Th17 cells measured in patients.
  downstream:
  - target: Recurrent Staphylococcus aureus infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33714841
      reference_title: "Human MALT1 deficiency and predisposition to infections."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Enhanced susceptibility to S. aureus and C. albicans is likely due to impaired Th17 immunity, similar to STAT3 and IL-17 pathway deficiencies."
      explanation: >-
        A review's reading of the infection pattern, stated as likely rather than
        shown, which is why the edge carries unknown intermediates.
  - target: Recurrent candida infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33714841
      reference_title: "Human MALT1 deficiency and predisposition to infections."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Enhanced susceptibility to S. aureus and C. albicans is likely due to impaired Th17 immunity, similar to STAT3 and IL-17 pathway deficiencies."
      explanation: The same synthesis applied to Candida.
  - target: Decreased Th17 T cell proportion
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31037583
      reference_title: "Novel MALT1 Mutation Linked to Immunodeficiency, Immune Dysregulation, and an Abnormal T Cell Receptor Repertoire."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Immune work-up revealed lymphocytosis, low to normal levels of immunoglobulins, absence of regulatory T cells, and low Th17 cells."
      explanation: Low circulating Th17 cells are the measured form of the Th17 defect.
- name: Arrested B Cell Maturation and Progressive B Cell Depletion
  biological_scale: CELLULAR
  description: >-
    B cells develop as far as the transitional stage and stop. Marginal zone-like
    and memory B cells are reduced or absent, and circulating B cell numbers fall
    with age, so a child who presents with normal counts can later be
    agammaglobulinemic. Transplantation restores mature B cell differentiation.
  cell_types:
  - preferred_term: transitional stage B cell
    term:
      id: CL:0000818
      label: transitional stage B cell
  - preferred_term: memory B cell
    term:
      id: CL:0000787
      label: memory B cell
  biological_processes:
  - preferred_term: B cell differentiation
    term:
      id: GO:0030183
      label: B cell differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:40748513
    reference_title: "Loss of MALT1 Function in a Patient With Combined Immunodeficiency: a Novel Pathogenic Variant and Immunological Insights."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient displayed low NK cell and B cell counts, together with a developmental block at the transitional B cell stage."
    explanation: Locates the block at the transitional stage.
  - reference: PMID:34559885
    reference_title: "Progressive B cell depletion in human MALT1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In combination with the literature data, we found that the number of circulatory B cells, but not T cells, were inversely correlated with the age of patients."
    explanation: Shows the B cell loss is progressive with age across reported patients.
  - reference: PMID:39017781
    reference_title: "A novel MALT1 variant in an Egyptian patient presenting with exfoliative dermatitis: a case-based review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He had elevated serum IgE and normal B- and T-lymphocyte subset counts, but there was an arrest in the B-cell maturation."
    explanation: Maturation arrest can precede any fall in B cell numbers.
  downstream:
  - target: Decreased total B cell count
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34559885
      reference_title: "Progressive B cell depletion in human MALT1 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These data conceptualize that patients with complete MALT1-deficiency show aberrant differentiation and depletion of B cells."
      explanation: Ties depletion to the differentiation defect.
  - target: Impaired specific antibody response
    causal_link_type: DIRECT
  - target: Agammaglobulinemia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34559885
      reference_title: "Progressive B cell depletion in human MALT1 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This infant showed agammaglobulinemia without lymphopenia."
      explanation: Agammaglobulinemia in the patient whose B cell depletion this paper describes.
- name: Regulatory T Cell Deficiency
  biological_scale: CELLULAR
  description: >-
    FOXP3 regulatory T cells, and in one patient T follicular regulatory cells, are
    drastically reduced, while activated effector T cells (PD-1 and ICOS high)
    accumulate. This accounts for the IPEX-like presentation, and transplantation
    corrects the regulatory T cell frequency. In mice the requirement is specifically
    for MALT1 protease activity, acting through TCR-induced MYC.
  cell_types:
  - preferred_term: regulatory T cell
    term:
      id: CL:0000815
      label: regulatory T cell
  biological_processes:
  - preferred_term: regulatory T cell differentiation
    term:
      id: GO:0045066
      label: regulatory T cell differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:27253662
    reference_title: "Deficiency in Mucosa-associated Lymphoid Tissue Lymphoma Translocation 1: A Novel Cause of IPEX-Like Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Moreover, there was a drastic reduction in Forkhead box P3 (FOXP3) regulatory T cells accounting for the IPEX-like phenotype."
    explanation: Measured regulatory T cell loss in two siblings.
  - reference: PMID:40748513
    reference_title: "Loss of MALT1 Function in a Patient With Combined Immunodeficiency: a Novel Pathogenic Variant and Immunological Insights."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This functional defect caused lower Tfr and Treg cells, a normal proportion of Tfh cells, with higher expression of activation markers PD-1 and ICOS."
    explanation: Extends the loss to follicular regulatory T cells, with effector activation.
  downstream:
  - target: Autoimmunity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:25762782
      reference_title: "Deficiency of MALT1 paracaspase activity results in unbalanced regulatory and effector T and B cell responses leading to multiorgan inflammation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Surprisingly, Malt1(PD/PD) animals developed a multiorgan inflammatory pathology, characterized by Th1 and Th2/0 responses and enhanced IgG1 and IgE levels, which was delayed by wild-type regulatory T cell reconstitution."
      explanation: >-
        Regulatory T cell reconstitution delays the inflammatory pathology in
        protease-deficient mice, which makes the regulatory T cell loss causal
        rather than coincident.
  - target: Chronic diarrhea
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27253662
      reference_title: "Deficiency in Mucosa-associated Lymphoid Tissue Lymphoma Translocation 1: A Novel Cause of IPEX-Like Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Moreover, there was a drastic reduction in Forkhead box P3 (FOXP3) regulatory T cells accounting for the IPEX-like phenotype."
      explanation: >-
        The authors attribute the IPEX-like enteropathy of their patients to the
        regulatory T cell loss. Infection also contributes to diarrhea in this
        disease, so the edge carries unknown intermediates.
  - target: Th2-Skewed Immune Dysregulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31632405
      reference_title: "MALT1-Deficient Mice Develop Atopic-Like Dermatitis Upon Aging."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "here we report that MALT1-deficient mice develop atopic-like dermatitis upon aging, which is preceded by Th2 skewing, an increase in serum IgE, and a decrease in Treg frequency and surface expression of the Treg functionality marker CTLA-4."
      explanation: >-
        In MALT1-null mice the regulatory T cell decrease and Th2 skewing precede
        the atopic skin disease.
  - target: Decreased regulatory T cell proportion
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27253662
      reference_title: "Deficiency in Mucosa-associated Lymphoid Tissue Lymphoma Translocation 1: A Novel Cause of IPEX-Like Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Moreover, there was a drastic reduction in Forkhead box P3 (FOXP3) regulatory T cells accounting for the IPEX-like phenotype."
      explanation: The reduced FOXP3 regulatory T cell frequency is the measured form of the deficiency.
- name: Th2-Skewed Immune Dysregulation
  biological_scale: ORGANISM
  description: >-
    Eosinophilia, raised IgE and eczematous or erythrodermic skin disease make the
    disease resemble Netherton or Omenn syndrome, or DOCK8 deficiency. In mice both
    complete MALT1 loss and selective protease loss produce Th2 skewing with raised
    IgE; the human evidence is the phenotype, and the mechanism is inferred from
    the models.
  biological_processes:
  - preferred_term: type 2 immune response
    term:
      id: GO:0042092
      label: type 2 immune response
    modifier: INCREASED
  evidence:
  - reference: PMID:31659015
    reference_title: "Malt1 Protease Deficiency in Mice Disrupts Immune Homeostasis at Environmental Barriers and Drives Systemic T Cell-Mediated Autoimmunity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our data indicate that B cell activation and IgG1/IgE production is triggered by microbial and dietary Ags preferentially in lymphoid organs draining mucosal barriers, likely as a result of dysregulated mucosal immune homeostasis."
    explanation: Places the IgE response at mucosal barriers in protease-deficient mice.
  downstream:
  - target: Eczematous dermatitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31632405
      reference_title: "MALT1-Deficient Mice Develop Atopic-Like Dermatitis Upon Aging."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "here we report that MALT1-deficient mice develop atopic-like dermatitis upon aging, which is preceded by Th2 skewing, an increase in serum IgE, and a decrease in Treg frequency and surface expression of the Treg functionality marker CTLA-4."
      explanation: Th2 skewing precedes the dermatitis in the knockout.
  - target: Erythroderma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Increased circulating IgE concentration
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31632405
      reference_title: "MALT1-Deficient Mice Develop Atopic-Like Dermatitis Upon Aging."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "here we report that MALT1-deficient mice develop atopic-like dermatitis upon aging, which is preceded by Th2 skewing, an increase in serum IgE, and a decrease in Treg frequency and surface expression of the Treg functionality marker CTLA-4."
      explanation: In MALT1-null mice Th2 skewing is accompanied by a rise in serum IgE.
  - target: Eosinophilia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- name: Recurrent infections
  category: Immunological
  frequency: OBLIGATE
  description: >-
    Recurrent bacterial, viral and fungal infections begin in the first months of life and were present in every patient of the largest series; lower respiratory tract infection is the most constant site.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:35079916
    reference_title: "Expanding the Clinical and Immunological Phenotypes and Natural History of MALT1 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mean age of patients and disease onset were 33 ± 17 and 1.6 ± 0.7 months, respectively."
    explanation: "Mean disease onset at 1.6 months in the largest cohort, which places onset in infancy."
  - reference: PMID:35079916
    reference_title: "Expanding the Clinical and Immunological Phenotypes and Natural History of MALT1 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main clinical findings of the disease were recurrent infections (100%), skin involvement (100%), failure to thrive (100%), oral lesions (67%), chronic diarrhea (56%), and autoimmunity (44%)."
    explanation: "Recurrent infections were present in all nine patients of the largest cohort."
  - reference: PMID:40748513
    reference_title: "Loss of MALT1 Function in a Patient With Combined Immunodeficiency: a Novel Pathogenic Variant and Immunological Insights."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cardinal clinical characteristics of MALT1 deficiency are lower respiratory tract infections (100%), failure to thrive (90%), eczema (86%), oral lesions (85%) and chronic diarrhea (73%), all of which were observed in our patient."
    explanation: "Pooled literature cases: lower respiratory tract infections in 100%."
  sequelae:
  - target: Bronchiectasis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23727036
      reference_title: "A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Both patients experienced recurrent pulmonary infections since 4 months of age with resultant bronchiectasis."
      explanation: "The index family's recurrent pulmonary infections led to bronchiectasis."
- name: Bronchiectasis
  category: Respiratory
  description: >-
    Structural airway damage left by repeated pneumonia in the index siblings.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:23727036
    reference_title: "A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients experienced recurrent pulmonary infections since 4 months of age with resultant bronchiectasis."
    explanation: "Reports bronchiectasis as the consequence of recurrent pulmonary infections."
- name: Cytomegalovirus pneumonitis
  category: Infectious
  description: >-
    CMV is one of the three most frequent pathogens. In one patient CMV viremia and pneumonitis persisted despite ganciclovir and foscarnet and cleared only after transplantation and donor CMV-specific T cell infusion.
  phenotype_term:
    preferred_term: Cytomegalovirus pneumonitis
    term:
      id: HP:5210283
      label: Cytomegalovirus pneumonitis
  evidence:
  - reference: PMID:25627829
    reference_title: "Combined immunodeficiency due to MALT1 mutations, treated by hematopoietic cell transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient experienced poor weight growth, stomatitis, oral thrush, RSV bronchiolitis, and CMV viremia and CMV pneumonitis."
    explanation: "Documents CMV pneumonitis in a MALT1-deficient infant."
  - reference: PMID:33714841
    reference_title: "Human MALT1 deficiency and predisposition to infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The most frequently detected pathogens are Staphylococcus aureus, Candida albicans, and cytomegalovirus."
    explanation: "Review naming cytomegalovirus among the most frequent pathogens."
- name: Pneumocystis jirovecii pneumonia
  category: Infectious
  description: >-
    Opportunistic Pneumocystis pneumonia was the presenting infection in a Japanese infant with complete MALT1 deficiency.
  phenotype_term:
    preferred_term: Pneumocystis jirovecii pneumonia
    term:
      id: HP:0020102
      label: Pneumocystis jirovecii pneumonia
  evidence:
  - reference: PMID:34559885
    reference_title: "Progressive B cell depletion in human MALT1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pneumocystis pneumonia developed in a 6-month-old Japanese infant with atopic dermatitis, enteritis and growth restriction."
    explanation: "Case report of Pneumocystis pneumonia in MALT1 deficiency."
- name: Recurrent Staphylococcus aureus infections
  category: Infectious
  description: >-
    Staphylococcus aureus is the most frequently isolated bacterium, including skin superinfection of the dermatitis.
  phenotype_term:
    preferred_term: Recurrent Staphylococcus aureus infections
    term:
      id: HP:0002726
      label: Recurrent Staphylococcus aureus infections
  evidence:
  - reference: PMID:33714841
    reference_title: "Human MALT1 deficiency and predisposition to infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The most frequently detected pathogens are Staphylococcus aureus, Candida albicans, and cytomegalovirus."
    explanation: "Review of reported patients naming S. aureus as a leading pathogen."
- name: Recurrent candida infections
  category: Infectious
  description: >-
    Mucocutaneous and invasive Candida albicans infection, including oral thrush and candida esophagitis.
  phenotype_term:
    preferred_term: Recurrent candida infections
    term:
      id: HP:0005401
      label: Recurrent candida infections
  evidence:
  - reference: PMID:33714841
    reference_title: "Human MALT1 deficiency and predisposition to infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The most frequently detected pathogens are Staphylococcus aureus, Candida albicans, and cytomegalovirus."
    explanation: "Review naming Candida albicans among the most frequent pathogens."
  - reference: PMID:23727036
    reference_title: "A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Defective T cell activation by antigens likely played a critical role in the patients' susceptibility to opportunistic infections with CMV and C. albicans."
    explanation: "The index siblings had C. albicans infection."
- name: Decreased antigen-specific T cell proliferation
  category: Immunological
  description: >-
    T cells are present in normal numbers but proliferate poorly to recall antigens and to anti-CD3.
  phenotype_term:
    preferred_term: Decreased antigen-specific T cell proliferation
    term:
      id: HP:0031402
      label: Decreased antigen-specific T cell proliferation
  evidence:
  - reference: PMID:23727036
    reference_title: "A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The numbers of circulating T and B lymphocytes were normal, but T-cell proliferation to antigens and antibody responses to vaccination were severely impaired in both patients."
    explanation: "Impaired T cell proliferation to antigens despite normal T cell numbers."
- name: Impaired specific antibody response
  category: Immunological
  description: >-
    Vaccine and polysaccharide antibody responses fail even when total immunoglobulin levels are normal.
  phenotype_term:
    preferred_term: Impaired specific antibody response
    term:
      id: HP:0012475
      label: Impaired specific antibody response
  evidence:
  - reference: PMID:23727036
    reference_title: "A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The numbers of circulating T and B lymphocytes were normal, but T-cell proliferation to antigens and antibody responses to vaccination were severely impaired in both patients."
    explanation: "Antibody responses to vaccination were severely impaired."
- name: Decreased Th17 T cell proportion
  category: Immunological
  description: >-
    Circulating Th17 cells are low, matching the S. aureus and Candida susceptibility.
  phenotype_term:
    preferred_term: Decreased Th17 T cell proportion
    term:
      id: HP:0025832
      label: Decreased Th17 T cell proportion
  evidence:
  - reference: PMID:31037583
    reference_title: "Novel MALT1 Mutation Linked to Immunodeficiency, Immune Dysregulation, and an Abnormal T Cell Receptor Repertoire."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immune work-up revealed lymphocytosis, low to normal levels of immunoglobulins, absence of regulatory T cells, and low Th17 cells."
    explanation: "Low Th17 cells in two MALT1-deficient cousins."
- name: Decreased total B cell count
  category: Immunological
  frequency: VERY_FREQUENT
  description: >-
    B cells are reduced in most patients and fall further with age, a progressive depletion that follows the transitional-stage block.
  phenotype_term:
    preferred_term: Decreased total B cell count
    term:
      id: HP:0010976
      label: Decreased total B cell count
  evidence:
  - reference: PMID:35079916
    reference_title: "Expanding the Clinical and Immunological Phenotypes and Natural History of MALT1 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The majority of patients had normal T and NK cells, while eight (89%) exhibited reduced B cells."
    explanation: "Reduced B cells in 89% of the cohort."
  - reference: PMID:34559885
    reference_title: "Progressive B cell depletion in human MALT1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In combination with the literature data, we found that the number of circulatory B cells, but not T cells, were inversely correlated with the age of patients."
    explanation: "B cell numbers decline with age across reported patients."
- name: Agammaglobulinemia
  category: Immunological
  description: >-
    Immunoglobulin levels range from normal to low; complete agammaglobulinemia has been reported with progressive B cell loss.
  phenotype_term:
    preferred_term: Agammaglobulinemia
    term:
      id: HP:0004432
      label: Agammaglobulinemia
  evidence:
  - reference: PMID:34559885
    reference_title: "Progressive B cell depletion in human MALT1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This infant showed agammaglobulinemia without lymphopenia."
    explanation: "Agammaglobulinemia in a MALT1-deficient infant."
- name: Decreased regulatory T cell proportion
  category: Immunological
  description: >-
    FOXP3 regulatory T cells are drastically reduced or absent and are restored by transplantation.
  phenotype_term:
    preferred_term: Decreased regulatory T cell proportion
    term:
      id: HP:0020113
      label: Decreased regulatory T cell proportion
  evidence:
  - reference: PMID:27253662
    reference_title: "Deficiency in Mucosa-associated Lymphoid Tissue Lymphoma Translocation 1: A Novel Cause of IPEX-Like Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Moreover, there was a drastic reduction in Forkhead box P3 (FOXP3) regulatory T cells accounting for the IPEX-like phenotype."
    explanation: "Drastic reduction of FOXP3 regulatory T cells in two siblings."
  - reference: PMID:31037583
    reference_title: "Novel MALT1 Mutation Linked to Immunodeficiency, Immune Dysregulation, and an Abnormal T Cell Receptor Repertoire."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immune work-up revealed lymphocytosis, low to normal levels of immunoglobulins, absence of regulatory T cells, and low Th17 cells."
    explanation: "Absent regulatory T cells in two cousins."
- name: Autoimmunity
  category: Immunological
  frequency: FREQUENT
  description: >-
    Autoimmune manifestations occur in about 40% of patients; the picture can be IPEX-like.
  phenotype_term:
    preferred_term: Autoimmunity
    term:
      id: HP:0002960
      label: Autoimmunity
  evidence:
  - reference: PMID:35079916
    reference_title: "Expanding the Clinical and Immunological Phenotypes and Natural History of MALT1 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main clinical findings of the disease were recurrent infections (100%), skin involvement (100%), failure to thrive (100%), oral lesions (67%), chronic diarrhea (56%), and autoimmunity (44%)."
    explanation: "Autoimmunity in 44% of the cohort."
  - reference: PMID:31037583
    reference_title: "Novel MALT1 Mutation Linked to Immunodeficiency, Immune Dysregulation, and an Abnormal T Cell Receptor Repertoire."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical findings included recurrent infections, failure to thrive, lymphadenopathy, dermatitis, and autoimmunity."
    explanation: "Autoimmunity among the clinical findings of two cousins."
- name: Chronic diarrhea
  category: Digestive
  frequency: FREQUENT
  description: >-
    Enteropathy with chronic diarrhea; in the IPEX-like presentation it reflects immune dysregulation, and intestinal infection contributes in others.
  phenotype_term:
    preferred_term: Chronic diarrhea
    term:
      id: HP:0002028
      label: Chronic diarrhea
  evidence:
  - reference: PMID:35079916
    reference_title: "Expanding the Clinical and Immunological Phenotypes and Natural History of MALT1 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main clinical findings of the disease were recurrent infections (100%), skin involvement (100%), failure to thrive (100%), oral lesions (67%), chronic diarrhea (56%), and autoimmunity (44%)."
    explanation: "Chronic diarrhea in 56% of the cohort."
  - reference: PMID:40748513
    reference_title: "Loss of MALT1 Function in a Patient With Combined Immunodeficiency: a Novel Pathogenic Variant and Immunological Insights."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cardinal clinical characteristics of MALT1 deficiency are lower respiratory tract infections (100%), failure to thrive (90%), eczema (86%), oral lesions (85%) and chronic diarrhea (73%), all of which were observed in our patient."
    explanation: "Chronic diarrhea in 73% of pooled cases."
- name: Eczematous dermatitis
  category: Integumentary
  frequency: VERY_FREQUENT
  description: >-
    Skin involvement is near universal, usually eczema.
  phenotype_term:
    preferred_term: Eczematous dermatitis
    term:
      id: HP:0000964
      label: Eczematoid dermatitis
  evidence:
  - reference: PMID:40748513
    reference_title: "Loss of MALT1 Function in a Patient With Combined Immunodeficiency: a Novel Pathogenic Variant and Immunological Insights."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cardinal clinical characteristics of MALT1 deficiency are lower respiratory tract infections (100%), failure to thrive (90%), eczema (86%), oral lesions (85%) and chronic diarrhea (73%), all of which were observed in our patient."
    explanation: "Eczema in 86% of pooled cases."
  - reference: PMID:35079916
    reference_title: "Expanding the Clinical and Immunological Phenotypes and Natural History of MALT1 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main clinical findings of the disease were recurrent infections (100%), skin involvement (100%), failure to thrive (100%), oral lesions (67%), chronic diarrhea (56%), and autoimmunity (44%)."
    explanation: "Skin involvement in all nine patients."
- name: Erythroderma
  category: Integumentary
  description: >-
    Severe ichthyosiform erythroderma or exfoliative dermatitis can mimic Netherton or Omenn syndrome.
  phenotype_term:
    preferred_term: Erythroderma
    term:
      id: HP:0001019
      label: Erythroderma
  evidence:
  - reference: PMID:31049936
    reference_title: "Refining the dermatological spectrum in primary immunodeficiency: mucosa-associated lymphoid tissue lymphoma translocation protein 1 deficiency mimicking Netherton/Omenn syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we describe the case of a female infant with severe immune dysregulation leading to recurrent systemic infections, failure to thrive and severe crises of ichthyosiform erythroderma with high levels of serum IgE."
    explanation: "Ichthyosiform erythroderma in MALT1 deficiency."
- name: Increased circulating IgE concentration
  category: Immunological
  description: >-
    Raised IgE is reported in a minority of the largest cohort and in several case reports.
  phenotype_term:
    preferred_term: Increased circulating IgE concentration
    term:
      id: HP:0003212
      label: Increased circulating IgE concentration
  evidence:
  - reference: PMID:35079916
    reference_title: "Expanding the Clinical and Immunological Phenotypes and Natural History of MALT1 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eosinophilia and high IgE were observed in six (67%) and two (22%) patients, respectively."
    explanation: "High IgE in 22% of the cohort."
  - reference: PMID:39017781
    reference_title: "A novel MALT1 variant in an Egyptian patient presenting with exfoliative dermatitis: a case-based review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He had elevated serum IgE and normal B- and T-lymphocyte subset counts, but there was an arrest in the B-cell maturation."
    explanation: "Elevated IgE in an Egyptian patient."
- name: Eosinophilia
  category: Hematological
  frequency: FREQUENT
  description: >-
    Blood eosinophilia was present in two thirds of the largest cohort.
  phenotype_term:
    preferred_term: Eosinophilia
    term:
      id: HP:0001880
      label: Increased total eosinophil count
  evidence:
  - reference: PMID:35079916
    reference_title: "Expanding the Clinical and Immunological Phenotypes and Natural History of MALT1 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eosinophilia and high IgE were observed in six (67%) and two (22%) patients, respectively."
    explanation: "Eosinophilia in 67% of the cohort."
- name: Failure to thrive
  category: Growth
  frequency: VERY_FREQUENT
  description: >-
    Growth failure from infancy, present in nearly all patients.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:35079916
    reference_title: "Expanding the Clinical and Immunological Phenotypes and Natural History of MALT1 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main clinical findings of the disease were recurrent infections (100%), skin involvement (100%), failure to thrive (100%), oral lesions (67%), chronic diarrhea (56%), and autoimmunity (44%)."
    explanation: "Failure to thrive in all nine patients."
  - reference: PMID:40748513
    reference_title: "Loss of MALT1 Function in a Patient With Combined Immunodeficiency: a Novel Pathogenic Variant and Immunological Insights."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cardinal clinical characteristics of MALT1 deficiency are lower respiratory tract infections (100%), failure to thrive (90%), eczema (86%), oral lesions (85%) and chronic diarrhea (73%), all of which were observed in our patient."
    explanation: "Failure to thrive in 90% of pooled cases."
- name: Oral ulcer
  category: Digestive
  description: >-
    Oral lesions (aphthous ulcers, cheilitis, gingivitis, thrush) are common. The
    published frequencies (67% in the largest cohort, 85% across pooled cases) are
    for oral lesions of any kind, so no frequency is recorded for ulcers alone.
  phenotype_term:
    preferred_term: Oral ulcer
    term:
      id: HP:0000155
      label: Oral ulcer
  evidence:
  - reference: PMID:23727036
    reference_title: "A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients developed mastoiditis, chronic aphthous ulcers, cheilitis, and gingivitis."
    explanation: "Chronic aphthous ulcers in the index siblings."
  - reference: PMID:35079916
    reference_title: "Expanding the Clinical and Immunological Phenotypes and Natural History of MALT1 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main clinical findings of the disease were recurrent infections (100%), skin involvement (100%), failure to thrive (100%), oral lesions (67%), chronic diarrhea (56%), and autoimmunity (44%)."
    explanation: "Oral lesions of any kind in 67% of the cohort; ulcers are one component."
- name: Periodontitis
  category: Digestive
  description: >-
    Periodontal disease is listed among the defining features of MALT1 deficiency,
    alongside the gingivitis and oral ulceration of the index siblings.
  phenotype_term:
    preferred_term: Periodontal disease
    term:
      id: HP:0000704
      label: Periodontitis
  evidence:
  - reference: PMID:33714841
    reference_title: "Human MALT1 deficiency and predisposition to infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Human germline MALT1 deficiency is an inborn error of immunity characterized by recurrent bacterial, viral, and fungal infections, periodontal disease, enteropathy, dermatitis, and failure to thrive."
    explanation: "Review of reported patients naming periodontal disease as a characteristic feature."
- name: Severe infection
  category: Immunological
  frequency: VERY_FREQUENT
  description: >-
    Beyond the near-universal recurrent respiratory infections, severe
    life-threatening infections (meningitis, sepsis, necrotizing skin infection)
    occur in roughly three-quarters of patients and are a leading cause of death.
  phenotype_term:
    preferred_term: Severe infection
    term:
      id: HP:0032169
      label: Severe infection
  evidence:
  - reference: PMID:40748513
    reference_title: "Loss of MALT1 Function in a Patient With Combined Immunodeficiency: a Novel Pathogenic Variant and Immunological Insights."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severe infections (Meningitis, Sepsis, Necrotizing skin infection) | Yes | 17/23(74%)"
    explanation: Pooled literature table records severe infections in 17 of 23 (74%) patients.
  - reference: PMID:40748513
    reference_title: "Loss of MALT1 Function in a Patient With Combined Immunodeficiency: a Novel Pathogenic Variant and Immunological Insights."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severe infections (including meningitis, sepsis, and necrotizing skin infections) were not rarely seen, occurring in approximately 74% of patients, serving as an obvious cause of poor outcomes, as demonstrated in our case."
    explanation: Names the severe-infection categories and their role as a leading cause of poor outcomes.
- name: Lymphadenopathy
  category: Immunological
  description: >-
    Lymphoproliferation (lymphadenopathy, hepatosplenomegaly) is reported in about a third of patients.
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  evidence:
  - reference: PMID:31037583
    reference_title: "Novel MALT1 Mutation Linked to Immunodeficiency, Immune Dysregulation, and an Abnormal T Cell Receptor Repertoire."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical findings included recurrent infections, failure to thrive, lymphadenopathy, dermatitis, and autoimmunity."
    explanation: "Lymphadenopathy among the findings in two cousins."
  - reference: PMID:40748513
    reference_title: "Loss of MALT1 Function in a Patient With Combined Immunodeficiency: a Novel Pathogenic Variant and Immunological Insights."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lymphoproliferation (lymphadenopathy, hepatosplenomegaly) | Yes | 7/23(30%)"
    explanation: Pooled literature table quantifies lymphoproliferation at 7 of 23 (30%), supporting the "about a third" frequency.
treatments:
- name: Hematopoietic Stem Cell Transplantation
  description: >-
    Allogeneic haematopoietic stem cell transplantation is the only curative treatment.
    It restores NF-kappaB signalling, regulatory T cells and B cell maturation, and
    survival is higher in transplanted patients, so it should be offered early.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: allogeneic hematopoietic stem cell transplantation
    term:
      id: NCIT:C46089
      label: Allogeneic Hematopoietic Stem Cell Transplantation
  target_mechanisms:
  - target: Regulatory T Cell Deficiency
    description: Donor-derived lymphocytes restore the regulatory T cell compartment.
    evidence:
    - reference: PMID:27253662
      reference_title: "Deficiency in Mucosa-associated Lymphoid Tissue Lymphoma Translocation 1: A Novel Cause of IPEX-Like Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Immunological workup at 6 and 12 months after transplantation showed normal NF-κB activation and correction of regulatory T cells frequency."
      explanation: "Regulatory T cell frequency and NF-kappaB activation were corrected after transplantation."
  - target: Defective CBM Signalosome Signaling to NF-kappaB
    description: Donor cells carry functional MALT1, so antigen receptor signalling to NF-kappaB is restored.
    evidence:
    - reference: PMID:27253662
      reference_title: "Deficiency in Mucosa-associated Lymphoid Tissue Lymphoma Translocation 1: A Novel Cause of IPEX-Like Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Immunological workup at 6 and 12 months after transplantation showed normal NF-κB activation and correction of regulatory T cells frequency."
      explanation: "NF-kappaB activation was normal after transplantation."
  - target: Arrested B Cell Maturation and Progressive B Cell Depletion
    description: Transplantation reconstitutes mature B cell differentiation.
    evidence:
    - reference: PMID:34559885
      reference_title: "Progressive B cell depletion in human MALT1 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The hematopoietic cell transplantation (HCT) successfully reconstituted the differentiation of mature B cells and T cells."
      explanation: "B and T cell differentiation was reconstituted by transplantation."
  evidence:
  - reference: PMID:35079916
    reference_title: "Expanding the Clinical and Immunological Phenotypes and Natural History of MALT1 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analyzing this cohort with reported patients revealed overall survival in 58% (11/19), which was higher in patients who underwent HSCT"
    explanation: "Survival across 19 patients was higher with transplantation."
  - reference: PMID:27253662
    reference_title: "Deficiency in Mucosa-associated Lymphoid Tissue Lymphoma Translocation 1: A Novel Cause of IPEX-Like Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Following identification of the mutation, both children received hematopoietic stem cell transplantation, which permitted full clinical recovery."
    explanation: "Full clinical recovery after transplantation in two siblings."
  - reference: PMID:40748513
    reference_title: "Loss of MALT1 Function in a Patient With Combined Immunodeficiency: a Novel Pathogenic Variant and Immunological Insights."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prompt hematopoietic stem cell transplantation (HSCT) is highly recommended as an effective therapy for MALT1 deficiency."
    explanation: "The case report's conclusion recommending early transplantation."
- name: Immunoglobulin Replacement Therapy
  description: >-
    Supportive only. In the largest cohort immunoglobulin replacement did little to
    reduce infections, which is why transplantation is recommended for every patient.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: immunoglobulin replacement therapy
    term:
      id: NCIT:C121331
      label: Intravenous Immunoglobulin Therapy
    therapeutic_agent:
    - preferred_term: human immunoglobulin G
      term:
        id: NCIT:C80829
        label: Human Immunoglobulin G
  evidence:
  - reference: PMID:35079916
    reference_title: "Expanding the Clinical and Immunological Phenotypes and Natural History of MALT1 Deficiency."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunoglobulin replacement and antibiotics prophylaxis were mostly ineffective in reducing the frequency of infections and other complications."
    explanation: "Immunoglobulin replacement was mostly ineffective, so the evidence does not support it as disease-modifying."
  - reference: PMID:23727036
    reference_title: "A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite intravenous immunoglobulin (IVIG) replacement therapy, both patients had persistent infections and expired from respiratory failure."
    explanation: "Both index siblings died of infection despite immunoglobulin replacement."
- name: Antibiotic Prophylaxis
  description: >-
    Antibiotic prophylaxis is used as bridging care before transplantation, but in
    the largest cohort it did not reduce infection frequency.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: antibiotic prophylaxis
    term:
      id: NCIT:C51993
      label: Antibiotic Prophylaxis
  evidence:
  - reference: PMID:35079916
    reference_title: "Expanding the Clinical and Immunological Phenotypes and Natural History of MALT1 Deficiency."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunoglobulin replacement and antibiotics prophylaxis were mostly ineffective in reducing the frequency of infections and other complications."
    explanation: "Antibiotic prophylaxis was mostly ineffective at reducing infections."
diagnosis:
- name: Lymphocyte function testing with normal lymphocyte counts
  description: >-
    T and B cell counts are often normal at presentation, so the diagnosis rests on
    functional testing: proliferation to antigens and anti-CD3, IL-2 production,
    NF-kappaB activation on stimulation, and vaccine antibody responses.
  presence: PRESENT
  evidence:
  - reference: PMID:23727036
    reference_title: "A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The numbers of circulating T and B lymphocytes were normal, but T-cell proliferation to antigens and antibody responses to vaccination were severely impaired in both patients."
    explanation: Normal counts with failed function is the pattern functional testing has to detect.
- name: Molecular genetic testing for biallelic MALT1 variants
  description: >-
    Confirmation is by finding biallelic MALT1 variants. The eczema, raised IgE and
    staphylococcal infections overlap with DOCK8 deficiency and CARD11 deficiency,
    which is why molecular testing rather than the clinical picture decides the
    diagnosis.
  presence: PRESENT
  evidence:
  - reference: PMID:39017781
    reference_title: "A novel MALT1 variant in an Egyptian patient presenting with exfoliative dermatitis: a case-based review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thus, whenever DOCK 8 has been excluded, the molecular diagnosis is mandatory as this could lead to discovering more patients hence better understanding and reporting of the phenotype and natural history of the disease especially since there are very few documented cases."
    explanation: States that molecular diagnosis is required once DOCK8 deficiency is excluded.
- name: Newborn TREC screening can be normal
  description: >-
    Because T cells are produced in normal numbers, TREC-based newborn screening for
    SCID can return a normal result. One patient's newborn dried blood spot had a
    TREC count well above the cut-off, although another patient had reduced TRECs
    on testing after presentation (PMID:40748513), so a normal newborn screen does
    not exclude the disease.
  presence: PRESENT
  evidence:
  - reference: PMID:25627829
    reference_title: "Combined immunodeficiency due to MALT1 mutations, treated by hematopoietic cell transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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)."
    explanation: A normal newborn TREC count in a MALT1-deficient patient.
animal_models:
- name: Malt1 protease-dead knock-in mouse
  species: Mouse
  genotype: Malt1 paracaspase-inactive knock-in, scaffold function retained
  publication: PMID:25456129
  description: >-
    Mice carrying a catalytically inactive MALT1 separate the protease from the
    scaffold. They lose regulatory T cells and develop a lethal inflammatory
    syndrome, which is the basis for attributing the regulatory T cell defect of the
    human disease to loss of protease activity.
  modeled_mechanisms:
  - target: Regulatory T Cell Deficiency
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Protease inactivation alone is enough to block regulatory T cell development.
    limitations: >-
      The knock-in keeps the scaffold function, whereas most patient alleles abolish
      the protein, so the model isolates the protease arm rather than reproducing
      the human lesion.
    evidence:
    - reference: PMID:25456129
      reference_title: "Uncoupling Malt1 threshold function from paracaspase activity results in destructive autoimmune inflammation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Paracaspase activity is essential for regulatory T cell (Treg) and innate-like B cell development, but it is largely dispensable for overcoming Malt1-dependent thresholds for lymphocyte activation."
      explanation: Shows the regulatory T cell defect in the protease-dead mouse.
- name: Malt1 knockout mouse
  species: Mouse
  genotype: Malt1 germline knockout
  publication: PMID:31632405
  description: >-
    Complete loss of MALT1, the closer match to the null alleles seen in most
    patients. With age these mice develop atopic-like dermatitis preceded by Th2
    skewing, raised serum IgE and reduced regulatory T cells.
  modeled_mechanisms:
  - target: Th2-Skewed Immune Dysregulation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Reproduces the Th2 skewing, raised IgE and eczematous skin disease of the human disease.
    limitations: >-
      The dermatitis appears only as the mice age, whereas skin disease in patients
      begins in infancy, so the time course differs from the human disease.
    evidence:
    - reference: PMID:31632405
      reference_title: "MALT1-Deficient Mice Develop Atopic-Like Dermatitis Upon Aging."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "here we report that MALT1-deficient mice develop atopic-like dermatitis upon aging, which is preceded by Th2 skewing, an increase in serum IgE, and a decrease in Treg frequency and surface expression of the Treg functionality marker CTLA-4."
      explanation: The knockout develops the Th2 and IgE phenotype with atopic-like skin disease.
📚

References & Deep Research

Deep Research

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Evaluations and curation notes (1)

Create: Combined_Immunodeficiency_Due_To_MALT1_Deficiency · 2026-10-01T22:11:39Z · View source

De novo curation of combined immunodeficiency due to MALT1 deficiency (IMD12, MONDO:0014197). One openscientist deep-research report was generated and used as a source of leads only; every claim was checked against the cached PubMed abstracts or full texts. The pathograph runs from biallelic MALT1 loss of function through defective CBM signalling to NF-kappaB and loss of paracaspase activity, to impaired antigen-receptor T cell activation, impaired Th17 immunity, arrested B cell maturation with progressive depletion, regulatory T cell deficiency and Th2-skewed dysregulation, and from these to 21 HP-bound phenotypes (18 causally connected). Treatments: allogeneic HSCT (curative, linked to three mechanism nodes), immunoglobulin replacement and antimicrobial prophylaxis (recorded with REFUTE evidence for efficacy from the largest cohort). Validated with just validate (79 snippets verified), check-entity-refs, check-causal-targets, check-duplicate-keys, check-snippet-length, check-title-snippets, check-snippet-grading, check-folded-hyphens, check-coarse-phenotypes, check-reference-titles, check-enum-values and check-genereviews (no GeneReviews or StatPearls chapter exists).

OpenScientist ▸
1. Disease Information
openscientist-autonomous 14 citations 2026-10-01T20:56:48.910030

1. Disease Information

MALT1 deficiency is an autosomal recessive combined immunodeficiency (CID) with early-onset multisystem disease. It is formally classified as Immunodeficiency-12 with susceptibility to viral, bacterial, and fungal infections (IMD12).

Key identifiers:

Resource Identifier
MONDO MONDO:0014197
OMIM (phenotype) #615468 (IMD12)
OMIM (gene) 604860 (MALT1*)
HGNC HGNC:6819
Orphanet Classified under combined immunodeficiencies (prevalence <1/1,000,000)
Gene locus 18q21.32

Synonyms / alternative names: Immunodeficiency-12; IMD12; MALT1 deficiency; MALT1 paracaspase deficiency; combined immunodeficiency due to MALT1 deficiency; CBM-opathy (MALT1 type).

Information source: The disease-level characterization derives from aggregated case series and individual case reports in the primary literature (e.g., the 19-patient synthesis in PMID: 35079916), supplemented by mechanistic studies in cell lines and model organisms. Given extreme rarity, there are no EHR-scale or registry-scale datasets; all clinical data are individual-patient-derived and then aggregated.

2. Etiology

Primary cause — genetic: The disease is caused by biallelic (homozygous or compound heterozygous) loss-of-function variants in MALT1. In consanguineous families the variants are typically homozygous. There is no environmental or infectious cause of the underlying disorder; infections are the consequence of the immune defect, not its cause.

Genetic risk factors: The sole causal factor is biallelic MALT1 LOF. Consanguinity is the dominant population-level risk factor, as it dramatically increases the probability of homozygosity for rare recessive alleles. No modifier genes have been formally validated, though the broader severity of CBM-opathies depends on which component and residual protein function is affected.

Environmental / lifestyle risk factors: None established as causal. Pathogen exposure determines the pattern and timing of clinical infection but does not cause the immunodeficiency.

Protective factors: Heterozygous carriers are asymptomatic (one functional allele suffices). No protective modifier alleles have been described. The only "protective" intervention is definitive immune reconstitution via HSCT.

Gene–environment interactions: The genetic lesion sets a lowered threshold for immune failure; environmental pathogen load then determines clinical expression (severity/frequency of infections, triggering of eczema flares). This is a "genotype sets susceptibility, environment determines manifestation" relationship rather than a true molecular GxE interaction.

3. Phenotypes

Phenotype frequencies are drawn primarily from the largest cohort (9 new + 10 previously reported patients, n=19; PMID: 35079916).

Phenotype Type Frequency Suggested HPO term
Recurrent infections (bacterial/viral/fungal) Clinical sign 100% HP:0002719 (Recurrent infections)
Skin involvement / eczema / dermatitis Physical manifestation 100% HP:0000964 (Eczema) / HP:0000988 (Skin rash)
Failure to thrive Clinical sign 100% HP:0001508 (Failure to thrive)
Oral lesions (ulcers, candidiasis) Clinical sign 67% HP:0000155 (Oral ulcer)
Chronic diarrhea / enteropathy Symptom 56% HP:0002028 (Chronic diarrhea)
Autoimmunity Clinical sign 44% HP:0002960 (Autoimmunity)
Eosinophilia Lab abnormality 67% HP:0001880 (Eosinophilia)
Elevated serum IgE Lab abnormality 22% HP:0003212 (Increased IgE level)
Reduced B cells Lab abnormality 89% (8/9) HP:0010976 (B lymphocytopenia)
B-cell maturation arrest Lab abnormality Reported in cases HP:0005365 (Abnormal B cell morphology)
Impaired specific antibody responses Lab abnormality Common HP:0005387 (Reduced antibody responses)

The phenotype frequencies come directly from the largest reported cohort (PMID: 35079916): "The main clinical findings of the disease were recurrent infections (100%), skin involvement (100%), failure to thrive (100%), oral lesions (67%), chronic diarrhea (56%), and autoimmunity (44%)."

Phenotype characteristics: - Age of onset: Neonatal / early infancy — mean disease onset 1.6 ± 0.7 months (PMID: 35079916): "The mean age of patients and disease onset were 33 ± 17 and 1.6 ± 0.7 months, respectively." - Severity: Severe; life-threatening. - Progression: Progressive without curative treatment; chronic/lifelong course punctuated by acute infectious episodes. - Immunophenotype: "The majority of patients had normal T and NK cells, while eight (89%) exhibited reduced B cells." (PMID: 35079916)

Quality of life impact: Severe. Recurrent infections, chronic diarrhea/enteropathy, failure to thrive, and dermatitis substantially impair growth, nutrition, and daily function in infancy; the burden of hospitalization and the need for HSCT are profound. Formal QoL instrument data (EQ-5D, SF-36) are not available for this ultra-rare disorder.

4. Genetic / Molecular Information

Causal gene: MALT1 (HGNC:6819; chromosome 18q21.32; OMIM 604860). The gene encodes an 824-amino-acid paracaspase* — the only paracaspase in humans.

Protein architecture (relevant to loss-of-function mechanism): - N-terminal death domain - Two N-terminal Ig-like (immunoglobulin-like) domains (Ig1–Ig2; mediate BCL10 binding and oligomerization) - Central caspase-like (paracaspase) protease domain - C-terminal Ig-like domain

Crystallography (1.75 Å) shows the paracaspase domain adopts a fold nearly identical to classic caspases and homodimerizes to form an active protease that cleaves substrates after arginine residues (PMID: 22158899): "The paracaspase domain adopts a fold that is nearly identical to that of classic caspases and homodimerizes similarly to form an active protease." The tandem Ig-like domains additionally mediate oligomerization important for signaling (PMID: 21966355).

Reported pathogenic variants (all germline, biallelic, loss-of-function):

Variant (cDNA / protein) Domain Type Reference
c.1411G>A; p.D471N caspase-like Missense (LOF) PMID: 40748513
c.762dup; p.Ile255TyrfsTer10 N-terminal Frameshift PMID: 39017781
p.K543R + p.M732T (compound het) caspase-like / C-terminal Hypomorphic missense PMID: 41882201

Supporting quotes: - "The patient carried a novel pathogenic biallelic loss-of-function variant in MALT1 (c.1411G > A; p.D471N) located in the caspase-like domain, leading to severely reduced MALT1 protein expression." (PMID: 40748513) - "Next-generation sequencing revealed a novel homozygous variant in the MALT1 gene (c.762dup in exon 5 of 17; p.Ile255TyrfsTer10); this variant is likely pathogenic, thus supporting the genetic diagnosis of immunodeficiency-12 (IMD12)." (PMID: 39017781) - "the MALT1 K543R and M732T variants attenuated MALT1's enzymatic activity and compromised its protein stability" (PMID: 41882201)

Variant classification: Pathogenic / likely pathogenic per ACMG/AMP, supported by functional assays demonstrating reduced protein and/or reduced protease/scaffold activity.

Variant types: Missense, frameshift, and nonsense have all been reported. Functional consequence = loss of function (reduced protein stability and/or reduced protease and scaffold activity).

Allele frequency: Pathogenic MALT1 LOF alleles are essentially absent in the homozygous state in gnomAD, consistent with recessive severe disease.

Somatic vs germline: Disease-causing variants are germline. (Note: MALT1 is also oncogenically activated in lymphoma via the somatic t(11;18) API2-MALT1 fusion and chronic CBM activation — a distinct, unrelated pathology.)

Modifier genes / epigenetics / chromosomal abnormalities: No validated modifier genes, disease-specific epigenetic signatures, or large-scale chromosomal abnormalities are described for the Mendelian deficiency.

5. Environmental Information

Environmental factors: No toxic, radiation, or occupational exposures contribute to this monogenic disease.

Lifestyle factors: Not applicable (disease of infancy).

Infectious agents: Pathogens are downstream consequences, not causes. The combined immunodeficiency predisposes to recurrent bacterial, viral, and fungal infections. Staphylococcal skin/soft-tissue infections and mucocutaneous candidiasis are notable, overlapping with the DOCK8/hyper-IgE differential (PMID: 39017781). Chronic mucocutaneous candidiasis-type and other opportunistic infections reflect the combined T/B defect.

6. Mechanism / Pathophysiology

Ordered causal chain

  1. Biallelic loss-of-function variants in MALT1 (missense/frameshift/nonsense) lead to severely reduced MALT1 protein and/or loss of paracaspase protease and scaffold activity.
  2. Loss of functional MALT1 results in a non-functional or crippled CARD11–BCL10–MALT1 (CBM) signalosome, which normally assembles downstream of the T-cell receptor (TCR) and B-cell receptor (BCR).
  3. A defective CBM complex fails to transmit antigen-receptor signals to the threshold required for canonical NF-κB activation (demonstrated by reduced p65/RelA phosphorylation).
  4. Impaired NF-κB signaling branches into two consequences:
  5. (Branch A — effector/immunodeficiency): reduced lymphocyte activation, proliferation, and cytokine output (deficient IL-2 and TNF-α), leading to impaired T-cell help, arrest of B-cell maturation at the transitional/naïve stage, reduced memory and total B cells, and poor specific antibody responses → recurrent infections and (functional) agammaglobulinemia.
  6. (Branch B — regulatory/dysregulation): loss of MALT1 protease activity results in reduced regulatory T-cell (Treg) and follicular regulatory (Tfr) cell numbers and function, plus Th2 skewing, leading to autoimmunity, eczema/atopic dermatitis, eosinophilia, and elevated IgE.
  7. The combined effector failure plus immune dysregulation manifests clinically as early-infancy combined immunodeficiency with infections, enteropathy, failure to thrive, dermatitis, and autoimmunity.

(The branching in step 4 is directly inferred from the dual scaffold/protease biochemistry of MALT1 and is demonstrated in both patient cells and model organisms; see below.)

Molecular and cellular detail

Molecular pathway (central): The CBM signalosome bridges ITAM-coupled antigen receptors (TCR/BCR) to NF-κB, and also to JNK and mTORC1 (PMID: 30283440). MALT1 integrates receptor-derived signals and "determines whether downstream nuclear factor kappa B (NF-κB) activation reaches thresholds required for effective immune responses" (PMID: 42745540): "As a central component of the CARD11-BCL10-MALT1 (CBM) signalosome, MALT1 integrates receptor-derived signals and determines whether downstream nuclear factor kappa B (NF-kB) activation reaches thresholds required for effective immune responses."

Dual function of MALT1 (PMID: 37126937): "MALT1 acts as a scaffolding protein to drive activation of NF-κB transcription factors and as a protease to modulate signaling and immune activation by cleavage of distinct substrates." - Scaffold function: nucleates IKK activation → NF-κB. - Protease function: cleaves negative regulators of NF-κB (A20, CYLD, RelB) and RNA-binding repressors (Regnase-1, Roquin), thereby sustaining lymphocyte proliferation/survival and shaping cytokine mRNA stability.

Patient-level evidence: A p.D471N LOF variant "Impaired CBM-mediated NF-κB activation was confirmed by reduced phosphorylation of the p65 subunit, resulting in deficient production of IL-2 and TNF-α" and "This functional defect caused lower Tfr and Treg cells, a normal proportion of Tfh cells, with higher expression of activation markers PD-1 and ICOS" (PMID: 40748513). B-cell maturation arrest with elevated IgE and otherwise normal subset counts has been documented (PMID: 39017781): "He had elevated serum IgE and normal B- and T-lymphocyte subset counts, but there was an arrest in the B-cell maturation."

Treg dependence on MALT1 protease — mechanistic link (model organisms): MALT1 protease activity in Tregs drives TCR-induced upregulation of MYC, supporting mitochondrial function and homeostatic Treg expansion (PMID: 34668583): "MALT1 protease activity controls the TCR-induced upregulation of the transcription factor MYC and the subsequent expression of MYC target genes in Tregs." Thus the dysregulation branch is tied specifically to protease (not scaffold) function.

Cell types involved (suggested CL terms): CD4+ T cell (CL:0000624), CD8+ T cell (CL:0000625), regulatory T cell (CL:0000815), follicular regulatory T cell, B cell (CL:0000236), naïve/transitional B cell, memory B cell (CL:0000787), NK cell (CL:0000623), myeloid dendritic cell.

Suggested GO terms: antigen receptor-mediated signaling pathway (GO:0050851), I-κB kinase/NF-κB signaling (GO:0007249), positive regulation of NF-κB transcription factor activity (GO:0051092), T cell receptor signaling pathway (GO:0050852), B cell receptor signaling pathway (GO:0050853), regulatory T cell differentiation (GO:0045066), proteolysis (GO:0006508), cysteine-type endopeptidase activity (GO:0004197).

Subcellular compartments (GO Cellular Component): cytoplasm/cytosol (GO:0005829) where the CBM signalosome assembles; the signal terminates in the nucleus (GO:0005634) via NF-κB nuclear translocation.

Immune system involvement: Combined (T + B) immunodeficiency plus immune dysregulation (autoimmunity, atopy). This is the defining pathophysiology.

7. Anatomical Structures Affected

Organ / system level: - Immune/lymphoreticular system (UBERON:0002405 immune system; UBERON:0000029 lymph node; UBERON:0002106 spleen; UBERON:0002370 thymus) — primary. - Skin (UBERON:0002097) — eczema/dermatitis, staphylococcal infection. - Gastrointestinal tract (UBERON:0001555 digestive tract) — chronic diarrhea/enteropathy. - Oral cavity / mucosa (UBERON:0000167) — oral lesions, candidiasis. - Respiratory tract (UBERON:0000065) — recurrent sinopulmonary infection. - Systemic: failure to thrive reflects multi-organ nutritional/growth impact.

Tissue and cell level: Lymphoid tissue and peripheral blood leukocytes. Affected cell populations: T cells (including Tregs and Tfr), B cells (maturation arrest at transitional/naïve stage; reduced memory B cells), NK cells (numerically normal but functionally impaired), and myeloid dendritic cells.

Subcellular level: Cytoplasmic CBM signalosome assembly (GO:0005829); nuclear NF-κB-driven transcription (GO:0005634).

Localization / lateralization: Systemic and bilateral/diffuse (not a focal or lateralized disease).

8. Temporal Development

  • Onset: Congenital genetic defect with clinical onset in the neonatal period / early infancy (mean 1.6 ± 0.7 months; PMID: 35079916). Onset pattern is early and progressive.
  • Progression: Progressive and life-threatening without immune reconstitution; chronic/lifelong. Clinical course is punctuated by acute infectious episodes superimposed on chronic enteropathy, dermatitis, and failure to thrive.
  • Disease course pattern: Chronic-progressive with episodic infectious exacerbations.
  • Remission: No spontaneous remission. Durable remission/cure is achieved only through allogeneic HSCT.
  • Critical period / intervention window: Early infancy — prompt molecular diagnosis and HSCT before irreversible infectious/organ damage is the key window of opportunity.

9. Inheritance and Population

Inheritance: Autosomal recessive. Affected individuals are homozygous (consanguineous families) or compound heterozygous for MALT1 LOF variants; heterozygous carriers are asymptomatic.

Epidemiology: Ultra-rare. Only ~19 patients had been comprehensively characterized by 2022 (9 new + 10 previously reported; PMID: 35079916): "We also analyzed ten previously reported patients to comprehensively evaluate genotype/phenotype correlation." Additional single case reports have appeared since (Egyptian, Chinese patients). Orphanet lists prevalence as <1/1,000,000. No validated incidence figures exist.

Penetrance / expressivity: Biallelic LOF appears highly penetrant for combined immunodeficiency; expressivity is somewhat variable in the balance of immunodeficiency vs. dysregulation features and in residual B/T function, likely reflecting variant-specific residual activity (hypomorphic vs. null).

Founder effects / consanguinity: Reported families are frequently consanguineous with homozygous variants, heavily weighted toward Middle Eastern/Turkish and North African populations — consistent with a consanguinity/founder effect rather than a single global founder allele (PMID: 39017781: "Next-generation sequencing revealed a novel homozygous variant in the MALT1 gene").

Carrier frequency: Not formally established; pathogenic LOF alleles are essentially absent in the homozygous state in gnomAD.

Sex ratio / age distribution: Both sexes affected (autosomal). Affected individuals are infants/young children.

10. Diagnostics

Clinical / laboratory tests: - Immunophenotyping (flow cytometry): typically normal T and NK cell counts; reduced B cells (89%); reduced memory B cells; arrest of B-cell maturation; reduced Treg/Tfr; elevated activation markers (PD-1, ICOS). - Immunoglobulins: impaired specific antibody responses; may trend toward hypogammaglobulinemia/agammaglobulinemia; elevated IgE in a subset (~22%). - CBC: eosinophilia (~67%). - Functional assays: reduced lymphocyte proliferation to anti-CD3; reduced NF-κB activation (↓phospho-p65) on PMA/ionomycin or receptor stimulation; deficient IL-2/TNF-α production. These functional readouts are central to confirming pathogenicity.

Genetic testing (definitive): Molecular confirmation is required because the clinical picture overlaps with other CBM-opathies, DOCK8 deficiency, and hyper-IgE syndromes. - Whole-exome / whole-genome sequencing (WES/WGS) is the preferred first-line approach, especially given phenotypic overlap; upfront genomic sequencing shortens time to diagnosis in primary atopic disorders (PMID: 39381601). - Targeted inborn-errors-of-immunity (IEI)/SCID/CID gene panels including MALT1, CARD11, BCL10, CARD9, DOCK8. - Single-gene MALT1 sequencing confirmed by Sanger; functional validation of variant impact strengthens classification.

Clinical criteria / differential diagnosis: No disease-specific consensus criteria exist; diagnosis rests on the combined immunodeficiency phenotype plus biallelic MALT1 LOF with functional corroboration. Differential diagnoses to exclude: DOCK8 deficiency, hyper-IgE syndromes, other SCID/CID, BCL10 and CARD11 deficiencies (other CBM-opathies), IPEX, Omenn syndrome, and Wiskott-Aldrich syndrome. "Although the presence of eczema, recurrent sinopulmonary, and staphylococcal infections are suggestive of DOCK8 deficiency, they are also a finding in CARD11 and MALT1 deficiency." (PMID: 39017781). BCL10 deficiency shares an overlapping immunophenotype (PMID: 34868072: "this patient displays a reduction in NK, γδT, Tregs, and T").

Screening: No population newborn screening specifically detects MALT1 deficiency; notably, SCID TREC-based newborn screening may be normal because T-cell numbers are often preserved — an important caveat. Cascade/carrier testing in affected consanguineous families is valuable.

11. Outcome / Prognosis

Survival / mortality: Poor without curative therapy. In the largest cohort, "Immunoglobulin replacement and antibiotics prophylaxis were mostly ineffective in reducing the frequency of infections and other complications. One patient received hematopoietic stem cell transplantation (HSCT) and five patients died as a complication of life-threatening infections." (PMID: 35079916). The p.D471N patient experienced early death (PMID: 40748513).

Morbidity: High — recurrent severe infections, chronic enteropathy, failure to thrive, dermatitis, and autoimmune complications.

Disease-specific complications: Life-threatening bacterial/viral/fungal infections (leading cause of death), enteropathy with malnutrition, autoimmune manifestations.

Recovery potential: Minimal with supportive care alone; curative potential exists with successful allogeneic HSCT (reconstitutes CBM-competent hematopoietic cells).

Prognostic factors: Timing of diagnosis and access to HSCT; infection burden and organ damage at presentation; likely residual MALT1 function (hypomorphic vs. null variant).

12. Treatment

Supportive / pharmacotherapy (largely palliative): - Immunoglobulin replacement (IVIG/SCIG) — NCIT: Intravenous Immunoglobulin Therapy. Largely ineffective at preventing infections in this disease. - Antimicrobial / antifungal / antiviral prophylaxis. Mostly ineffective at reducing complications. - Management of enteropathy and dermatitis — nutritional support, topical/skin care.

Supporting evidence: "Immunoglobulin replacement and antibiotics prophylaxis were mostly ineffective in reducing the frequency of infections and other complications." (PMID: 35079916).

Curative / advanced therapeutics: - Allogeneic hematopoietic stem cell transplantation (HSCT) — NCIT: Allogeneic Hematopoietic Stem Cell Transplantation (C15431). The only established curative therapy; reconstitutes CBM-competent lymphocytes. Reported in only a minority of patients to date; early transplantation before severe infectious damage is the goal. - Gene therapy / gene editing: Not yet available; conceptually attractive given the monogenic, hematopoietic-restricted nature of the defect — a plausible future direction but no clinical programs reported.

Pharmacologic caution — MALT1 inhibitors: MALT1 protease inhibitors are in development for lymphoma and autoimmune disease. Importantly, pharmacological MALT1 inhibition reproduces an IPEX-like, Treg-depleting autoimmune pathology in animal models (PMID: 32425939): "pharmacological inhibition of MALT1 was associated with a rapid and dose-dependent reduction in Tregs and resulted in the progressive appearance of immune abnormalities and clinical signs of an IPEX-like pathology." This underscores that reducing MALT1 function is deleterious — relevant both to understanding the patient phenotype and to avoiding iatrogenic harm.

Treatment outcomes / strategy: No formal treatment algorithms exist for this ultra-rare disease; management mirrors severe combined/combined immunodeficiency protocols (prophylaxis + definitive HSCT). Genotype-guided prognostication (null vs. hypomorphic) may refine urgency.

13. Prevention

  • Primary prevention: Not possible for the monogenic disease itself. Genetic counseling for consanguineous families and carrier couples is the principal preventive measure; preimplantation genetic diagnosis (PGD) and prenatal testing are options when the familial variant is known.
  • Secondary prevention: Early molecular diagnosis enables timely HSCT before irreversible infectious/organ damage. Cascade screening of at-risk relatives in affected families.
  • Tertiary prevention: Infection prophylaxis, nutritional support, and vigilant management of autoimmune/atopic complications pending definitive therapy.
  • Immunization caveat: As in other combined immunodeficiencies, live vaccines are contraindicated; vaccine responses are typically poor.
  • Public health: Awareness of consanguinity-associated recessive IEI and incorporation of MALT1 into IEI gene panels improve detection.

14. Other Species / Natural Disease

Taxonomy / orthologs: MALT1 is evolutionarily conserved in mammals. Mouse Malt1 (NCBI Gene) is the principal ortholog used in disease modeling.

Natural disease in animals: No naturally occurring MALT1-deficiency disease is established in companion animals or wildlife (no prominent OMIA entry). However, pharmacological MALT1 protease inhibition in rats and dogs produces a progressive IPEX-like pathology with severe Treg reduction (PMID: 32425939), demonstrating cross-species conservation of the Treg-dependent dysregulation mechanism.

Comparative biology: The scaffold/protease duality and CBM–NF-κB axis are conserved across mammals, making mouse models highly informative. Zoonotic potential: Not applicable (non-infectious genetic disease).

15. Model Organisms

Mouse models are the principal system and recapitulate the immunodeficiency–dysregulation duality:

Model Key phenotype Reference
Malt1 knockout (complete) Atopic-like dermatitis upon aging; Th2 skewing; ↑serum IgE; ↓Treg frequency and CTLA-4 PMID: 31632405
Protease-dead (catalytically inactive, scaffold-retaining) MALT1 knock-in Spontaneous autoimmunity from Treg loss and increased effector T-cell activation PMID: 34668583
Treg-specific Myc deletion Phenocopies lethal autoimmune syndrome (links MALT1 protease → MYC → Treg expansion) PMID: 34668583
Pharmacological MALT1 inhibition (rat/dog) Progressive IPEX-like pathology, severe Treg reduction PMID: 32425939

Supporting quotes: - "here we report that MALT1-deficient mice develop atopic-like dermatitis upon aging, which is preceded by Th2 skewing, an increase in serum IgE, and a decrease in Treg frequency and surface expression of the Treg functionality marker CTLA-4." (PMID: 31632405) - "MALT1 protease activity controls the TCR-induced upregulation of the transcription factor MYC and the subsequent expression of MYC target genes in Tregs" (PMID: 34668583)

Phenotype recapitulation: Strong for the atopy/Th2/IgE/Treg-loss axis (dysregulation branch). Limitations: Complete-knockout mice emphasize dysregulation/atopy; the severe early-infancy infectious mortality seen in humans is less fully modeled, and the separation of scaffold vs. protease contributions (via protease-dead knock-ins) does not perfectly mirror human null/hypomorphic variants. Model databases: MGI, IMPC, IMSR.

Mechanistic Model (Synthesis)

   Biallelic LOF MALT1 variants (missense / frameshift / nonsense)
         │  (↓ protein, ↓ protease + scaffold)
         ▼
Non-functional CARD11–BCL10–MALT1 (CBM) signalosome
         │  downstream of TCR / BCR
         ▼
     Antigen-receptor signal fails to reach NF-κB activation threshold
 (↓ phospho-p65; also ↓ JNK, ↓ mTORC1)
         │
 ┌───────────────┴────────────────┐
 ▼                                 ▼
  BRANCH A: EFFECTOR FAILURE         BRANCH B: REGULATORY FAILURE
  (loss of scaffold + protease)      (loss of protease → ↓MYC in Tregs)
  • ↓ IL-2, ↓ TNF-α                   • ↓ Treg / ↓ Tfr
  • B-cell maturation arrest          • Th2 skewing
  • ↓ memory & total B cells          • ↑ IgE, eosinophilia
  • poor antibody responses           • ↑ PD-1 / ICOS activation
 │                                 │
 ▼                                 ▼
  Recurrent infections,              Eczema/dermatitis,
  functional agammaglobulinemia      autoimmunity
 └───────────────┬────────────────┘
         ▼
   Early-infancy COMBINED IMMUNODEFICIENCY + IMMUNE DYSREGULATION
   (infections, enteropathy, failure to thrive, oral lesions)
         │
         ▼
  Poor prognosis → curative only by allogeneic HSCT

The key unifying insight is that MALT1's two biochemical activities map onto the two clinical faces of the disease: scaffold-driven NF-κB loss drives effector/immunodeficiency features, while protease loss (via the MYC–mitochondrial axis in Tregs) drives the regulatory/dysregulation features. This is corroborated in patients (↓NF-κB, ↓IL-2/TNF-α, ↓Treg/Tfr) and in model organisms (protease-dead knock-ins → Treg-dependent autoimmunity; pharmacologic inhibition → IPEX-like pathology).

Evidence Base

PMID Title (abbrev.) Contribution
35079916 Expanding the Clinical and Immunological Phenotypes and Natural History of MALT1 Deficiency Largest cohort (n=19); phenotype frequencies, onset age, immunophenotype, poor outcome/HSCT
40748513 Loss of MALT1 Function in a Patient With CID p.D471N LOF variant; impaired NF-κB (↓p-p65), ↓IL-2/TNF-α, ↓Treg/Tfr
42745540 What Human MALT1 Deficiency Reveals About Immune Control CBM/NF-κB threshold signaling framework
39017781 A novel MALT1 variant (Egyptian patient) Frameshift p.Ile255TyrfsTer10; IMD12 designation; B-cell maturation arrest; DOCK8 differential
41882201 Novel heterozygous variants in CARD11 and MALT1 Hypomorphic p.K543R/p.M732T reduce enzymatic activity and stability
22158899 Crystal structure of MALT1 paracaspase region Caspase-like fold, homodimerization, protease activity
21966355 Oligomeric structure of MALT1 tandem Ig-like domains Ig-domain oligomerization in signaling
37126937 Function and targeting of MALT1 paracaspase Dual scaffold/protease function; substrate cleavage (A20, CYLD, RelB, Regnase-1, Roquin)
31632405 MALT1-Deficient Mice Develop Atopic-Like Dermatitis KO mouse: atopy, Th2, ↑IgE, ↓Treg/CTLA-4
34668583 MALT1 protease → MYC in Tregs Protease–MYC–mitochondrial axis for Treg expansion
32425939 Pharmacological MALT1 Inhibition → IPEX-Like Pathology Protease-specific loss → Treg-dependent autoimmunity (rat/dog)
30283440 The CBM-opathies Classification/spectrum of CARD11-BCL10-MALT1 inborn errors
34868072 Human BCL10 Deficiency Overlapping immunophenotype (↓NK, γδT, Treg, T) in the differential

Evidence source types: Human clinical (cohorts/case reports: 35079916, 40748513, 39017781, 41882201, 34868072); in vitro/structural (22158899, 21966355, 37126937); model organism (31632405, 34668583, 32425939).

Limitations and Knowledge Gaps

  1. Extreme rarity (n≈19 + scattered case reports). All epidemiology is case-derived; no validated prevalence/incidence, penetrance, or expressivity estimates. Phenotype frequencies may be biased by ascertainment toward severe/consanguineous cases.
  2. Genotype–phenotype correlation is incompletely resolved. The spectrum of variant types (null vs. hypomorphic) and how residual activity modulates the immunodeficiency-vs-dysregulation balance remain under-characterized.
  3. HSCT outcome data are sparse — only a minority of reported patients were transplanted; optimal conditioning, timing, and long-term outcomes are not established.
  4. Human mechanistic data are limited to a few patients; much of the protease-vs-scaffold dissection relies on model organisms and pharmacology, which may not perfectly mirror human null/hypomorphic variants.
  5. No disease-specific QoL, biomarker-based prognostic, or newborn-screening data. Standard SCID TREC screening may miss MALT1 deficiency because T-cell numbers are often preserved.
  6. No gene therapy programs or formal treatment algorithms exist.

Proposed Follow-up Experiments / Actions

  1. Establish an international MALT1-deficiency patient registry to aggregate genotype, immunophenotype, treatment, and HSCT outcome data and derive robust natural-history and genotype–phenotype correlations.
  2. Systematic functional classification of MALT1 variants (NF-κB reporter, protease-cleavage, protein-stability assays) to build an ACMG-aligned variant interpretation resource distinguishing null vs. hypomorphic alleles.
  3. Define HSCT best practices (timing, conditioning, donor source) through multicenter outcome analysis, and evaluate whether early transplantation (before severe infection) improves survival.
  4. Single-cell transcriptomic/immune profiling of patient PBMCs to map, at cell-type resolution, the effector vs. regulatory lesions (B-cell maturation block, Treg/Tfr deficits) and identify candidate biomarkers.
  5. Preclinical evaluation of gene correction (lentiviral MALT1 addition or base/prime editing in patient HSPCs) given the monogenic, hematopoietic-restricted nature of the defect.
  6. Incorporate MALT1 into standard IEI/SCID gene panels and raise clinician awareness of the DOCK8/hyper-IgE phenotypic overlap and the SCID-screening blind spot (preserved T cells).

Report compiled from autonomous multi-iteration literature synthesis (8 confirmed findings, 25 papers reviewed). All clinical and mechanistic claims are attributed to the cited primary literature by PMID.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

Outcome Count
References checked 14
Resolved 14
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 1
Quoted claims found in source 0
Quoted claims not found in source 1
References weighed for topical relevance 14
On topic 12
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

  • PMID:42745540: "determines whether downstream nuclear factor kappa B (NF-κB) activation reaches thresholds required for effective immune responses"
  • closest text in source: "As a central component of the CARD11-BCL10-MALT1 (CBM) signalosome, MALT1 integrates receptor-derived signals and determines whether downstream nuclear factor kappa B (NF-kB) activation reaches thresholds required for effective immune responses"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 38
Resolved 35
Unresolved (possible confabulation) 0
Obsolete 2
Unverifiable 1
Terms whose name was checked 14
Terms named correctly 6
Terms named as a different term 3
Terms whose name is worth a second look 5

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0014197 (3 mentions) - the report calls it "MONDO"; MONDO calls it combined immunodeficiency due to MALT1 deficiency
  • HP:0005365 (1 mention) - the report calls it "Abnormal B cell morphology"; HP calls it obsolete Severe B lymphocytopenia
  • HP:0005387 (1 mention) - the report calls it "Reduced antibody responses"; HP calls it Combined immunodeficiency

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • HP:0005365 (obsolete Severe B lymphocytopenia) (1 mention) - replaced by HP:0010976
  • GO:0051092 (obsolete positive regulation of NF-kappaB transcription factor activity) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0001880 (1 mention) - the report calls it "Eosinophilia"; HP calls it Increased total eosinophil count, and lists "Eosinophilia" among its other names
  • HP:0003212 (1 mention) - the report calls it "Increased IgE level"; HP calls it Increased circulating IgE concentration, and lists "Increased circulating IgE level" among its other names
  • HP:0010976 (1 mention) - the report calls it "B lymphocytopenia"; HP calls it Decreased total B cell count, and lists "B lymphocytopenia" among its other names
  • UBERON:0002097 (1 mention) - the report calls it "Skin"; UBERON calls it skin of body, and lists "skin" among its other names
  • UBERON:0000167 (1 mention) - the report calls it "Oral cavity / mucosa"; UBERON calls it oral cavity