STK4 Deficiency

Mendelian MONDO:0013934 Pathograph 18 Show in embeddings browser Combined immunodeficiency Primary immunodeficiency

STK4 (MST1) deficiency is an autosomal recessive combined immunodeficiency caused by biallelic loss-of-function variants in STK4, the human ortholog of Drosophila Hippo. Loss of the MST1 kinase impairs naive T-cell survival via defective FOXO1 expression, reduced IL-7 receptor and BCL2, and increased FAS-mediated apoptosis, and additionally impairs lymphocyte adhesion and chemotaxis. The disorder is characterized by progressive T- and B-cell lymphopenia (especially CD4 lymphopenia), intermittent neutropenia, hypergammaglobulinemia and elevated IgE, recurrent bacterial and viral infections, cutaneous viral warts (HPV) and molluscum contagiosum, mucocutaneous candidiasis, autoimmunity, EBV-associated (and EBV-negative) lymphoproliferation and lymphoma, and congenital heart defects such as atrial septal defects.

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1
Inheritance
4
Pathophys.
32
Phenotypes
18
Pathograph
1
Genes
4
Medical Actions
2
Differentials
1
Deep Research
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Classifications

Harrison's Part
IMMUNE RHEUMATOLOGIC
IUIS Category
combined immunodeficiency
👪

Inheritance

1
Autosomal recessive HP:0000007
STK4 deficiency is inherited in an autosomal recessive pattern and is caused by biallelic loss-of-function variants in STK4 (MST1).
Autosomal recessive inheritance
Show evidence (2 references)
PMID:34146746 SUPPORT Human Clinical
"Serine/threonine kinase-4 (STK4) deficiency is an autosomal recessive combined immunodeficiency."
Supports autosomal recessive inheritance of STK4 deficiency.
PMID:39110273 SUPPORT Human Clinical
"The patient was born to consanguineous parents living in the United States. Exome sequencing identified a previously unknown biallelic STK4 stop-gain mutation (p.Trp425X)."
Documents the autosomal recessive, biallelic nature of STK4 deficiency in a consanguineous family.
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Pathophysiology

4
Impaired naive T-cell survival
Loss of STK4/MST1 kinase reduces survival of naive T cells. MST1-deficient T cells poorly express the transcription factor FOXO1, the IL-7 receptor, and BCL2, while FAS expression and FAS-mediated apoptosis are up-regulated, causing increased death of naive and proliferating T cells. This is the main mechanism underlying the progressive T-cell lymphopenia.
naive T cell CL:0000898 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves naive T cell (CL:0000898). CL:0000898 is a cell type from the Cell Ontology.
lymphocyte apoptotic process GO:0070227 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased lymphocyte apoptotic process (GO:0070227). GO:0070227 is a biological process from the Gene Ontology. T cell homeostasis GO:0043029 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased T cell homeostasis (GO:0043029). GO:0043029 is a biological process from the Gene Ontology.
Downstream
T-cell lymphopenia Increased death of naive and proliferating T cells produces the progressive T-cell (especially CD4) lymphopenia that is a hallmark of the disorder.
B-cell lymphopenia The combined T- and B-cell lymphopenia seen in patients accompanies the naive-T-cell survival defect, with B-cell lymphopenia developing as part of the same lymphopenic phenotype.
Increased gamma-delta T cell proportion As the conventional alpha-beta CD4+ compartment fails, gamma-delta T cells expand into the space it leaves. The expansion is read as compensatory rather than as a second lesion, but it is incomplete compensation - the expanded cells proliferate poorly on activation - and clinically it is a trap, because it can hold the total CD3+ count in the normal range while CD4+ cells are profoundly depleted.
Show evidence (3 references)
PMID:22174160 SUPPORT Human Clinical
"MST1-deficient T cells poorly expressed the transcription factor FOXO1, the IL-7 receptor, and BCL2. Conversely, FAS expression and the FAS-mediating apoptotic pathway were up-regulated."
Documents the molecular basis of impaired naive T-cell survival: loss of FOXO1/IL-7R/BCL2 and increased FAS-mediated apoptosis.
PMID:22174160 SUPPORT Human Clinical
"These abnormalities suggest that increased cell death of naive and proliferating T cells is the main mechanism underlying this novel immunodeficiency."
Identifies increased T-cell death as the central mechanism of the disorder.
PMID:34427831 SUPPORT Human Clinical
"dysregulated interferon signaling, impaired T cell immunity, and increased T cell apoptosis"
Independent transcriptomic confirmation of impaired T-cell immunity and increased T-cell apoptosis in an STK4-deficient patient.
Increased lymphocyte and neutrophil apoptosis
STK4 is the human ortholog of Drosophila Hippo, the central constituent of a conserved pathway controlling cell growth and apoptosis. STK4-deficient lymphocytes and neutrophils show enhanced loss of mitochondrial membrane potential and increased susceptibility to apoptosis, contributing to lymphopenia and intermittent neutropenia.
neutrophil CL:0000775 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neutrophil (CL:0000775). CL:0000775 is a cell type from the Cell Ontology. 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.
apoptotic process GO:0006915 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology.
Downstream
Intermittent neutropenia Enhanced loss of mitochondrial membrane potential and increased neutrophil apoptosis produce the intermittent neutropenia observed in STK4-deficient patients.
Show evidence (1 reference)
PMID:22294732 SUPPORT Human Clinical
"STK4-deficient lymphocytes and neutrophils exhibit enhanced loss of mitochondrial membrane potential and increased susceptibility to apoptosis."
Supports increased apoptosis of lymphocytes and neutrophils as a mechanism of cytopenias in STK4 deficiency.
Defective lymphocyte adhesion and chemotaxis
MST1 is required for leukocyte trafficking. STK4-deficient leukocytes show deficient chemotaxis after chemokine stimulation despite preserved chemokine receptor expression, and fail to bind effectively to ICAM-1 under flow, indicating a failure to develop high-affinity integrin binding. This trafficking defect impairs thymic egress and immune synapse formation, contributing to immunodeficiency.
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.
leukocyte chemotaxis GO:0030595 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased leukocyte chemotaxis (GO:0030595). GO:0030595 is a biological process from the Gene Ontology. cell adhesion GO:0007155 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cell adhesion (GO:0007155). GO:0007155 is a biological process from the Gene Ontology.
Downstream
Recurrent bacterial infections The profound lymphocyte trafficking defect impairs leukocyte recruitment to sites of infection, contributing to the recurrent bacterial infections seen in STK4 deficiency.
Recurrent pneumonia Defective leukocyte trafficking to the lungs, together with impaired cellular immunity, predisposes to the recurrent pneumonia that is a frequent complication of STK4 deficiency.
Show evidence (3 references)
PMID:26801501 SUPPORT Human Clinical
"Patient leukocytes exhibited deficient chemotaxis after stimulation with CXCL11, despite preserved expression of CXCR3. Patient lymphocytes were also unable to bind effectively to immobilised ICAM-1 under flow conditions, in keeping with a failure to develop high affinity binding."
Documents the adhesion and chemotaxis defect in MST1-deficient leukocytes.
PMID:26801501 SUPPORT Human Clinical
"The observed abnormalities of adhesion and migration imply a profound trafficking defect among human MST1-deficient lymphocytes."
Connects the adhesion/chemotaxis defect to a global lymphocyte trafficking defect contributing to immunodeficiency.
PMID:34427831 SUPPORT Human Clinical
"impaired regulation of cytokine-induced adhesion and leukocyte chemotaxis genes."
Transcriptomic analysis of an STK4-deficient patient shows dysregulation of cytokine-induced adhesion and chemotaxis gene programs, corroborating the trafficking defect.
Impaired innate antiviral interferon signaling
Beyond its role in lymphocyte survival, STK4/MST1 is required for innate antiviral immunity. STK4-deficient cells show significantly impaired type I, II, and III interferon responses and reduced proinflammatory cytokine responses to TLR3, TLR9, and cytosolic nucleic-acid sensor ligands. The interferon defect is attributable to reduced phosphorylation of TBK1 and IRF3, and virus infection induces enhanced apoptotic cell death. This innate antiviral defect contributes to the prominent susceptibility to herpesviruses (EBV, VZV) and papillomaviruses.
plasmacytoid dendritic cell CL:0000784 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves plasmacytoid dendritic cell (CL:0000784). CL:0000784 is a cell type from the Cell Ontology. macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology.
type I interferon-mediated signaling pathway GO:0060337 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased type I interferon-mediated signaling pathway (GO:0060337). GO:0060337 is a biological process from the Gene Ontology. defense response to virus GO:0051607 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased defense response to virus (GO:0051607). GO:0051607 is a biological process from the Gene Ontology.
Downstream
Recurrent viral infections The impaired type I/II/III interferon response and enhanced virus-induced apoptosis impair antiviral defense, producing the prominent susceptibility to viral infections.
Recurrent herpes zoster The innate antiviral interferon defect underlies the severe recurrent herpesvirus infections, including herpes zoster.
Persistent EBV viremia Impaired antiviral immunity contributes to failure to control Epstein-Barr virus, manifesting as persistent EBV viremia.
Persistent human papillomavirus infection Failure of the interferon-dependent antiviral response permits infection by beta-papillomaviruses that are not virulent in immunocompetent hosts, producing epidermodysplasia verruciformis at the severe end of the cutaneous viral spectrum.
Show evidence (3 references)
PMID:33078349 SUPPORT Human Clinical
"We show significantly impaired type I, II, and III interferon (IFN) responses and partly reduced proinflammatory cytokine responses to ligands of Toll-like receptor (TLR)3, TLR9, and the cytosolic RNA and DNA sensors"
Documents the impaired type I, II, and III interferon responses in STK4 deficiency.
PMID:33078349 SUPPORT Human Clinical
"Impaired IFN responses could be attributed to reduced phosphorylation of TBK1 and IRF3. Moreover, virus infection induced enhanced cell death by apoptosis."
Identifies the TBK1-IRF3 axis as the molecular basis of the interferon defect and links viral infection to enhanced apoptosis.
PMID:34427831 SUPPORT Human Clinical
"abnormal fractions of T cell subsets, plasmacytoid dendritic cells, and NK cells"
Documents abnormal plasmacytoid dendritic cell fractions in an STK4-deficient patient, supporting involvement of this type I interferon-producing cell type.
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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 STK4 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

32
Blood 16
T-cell lymphopenia Decreased total T cell count HP:0005403 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased total T cell count (HP:0005403). HP:0005403 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:22294732 SUPPORT Human Clinical
"We describe a novel clinical phenotype associating T- and B-cell lymphopenia, intermittent neutropenia, and atrial septal defects in 3 members of a consanguineous kindred."
Documents T-cell lymphopenia.
PMID:34146746 SUPPORT Human Clinical
"CD4 lymphopenia (9 out 9)"
CD4 lymphopenia was universal in the clinical cohort.
B-cell lymphopenia Decreased total B cell count 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 (1 reference)
PMID:22294732 SUPPORT Human Clinical
"We describe a novel clinical phenotype associating T- and B-cell lymphopenia, intermittent neutropenia, and atrial septal defects in 3 members of a consanguineous kindred."
Documents B-cell lymphopenia.
Intermittent neutropenia Decreased total neutrophil count HP:0001875 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neutropenia, annotated with Decreased total neutrophil count (HP:0001875), qualified as temporality transient. HP:0001875 is a phenotype from the Human Phenotype Ontology.
Temporal: TRANSIENT
Show evidence (1 reference)
PMID:22294732 SUPPORT Human Clinical
"We describe a novel clinical phenotype associating T- and B-cell lymphopenia, intermittent neutropenia, and atrial septal defects in 3 members of a consanguineous kindred."
Documents intermittent neutropenia.
Hypergammaglobulinemia Increased circulating immunoglobulin concentration HP:0010702 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypergammaglobulinemia, annotated with Increased circulating immunoglobulin concentration (HP:0010702). HP:0010702 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30386345 SUPPORT Human Clinical
"elevated DNT cell number, non-malignant lymphadenopathy and hepatosplenomegaly, hematolytic anemia, hypergammaglobulinemia."
Documents hypergammaglobulinemia in an STK4-deficient patient.
Elevated IgE Increased circulating IgE concentration HP:0003212 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating IgE concentration, annotated with Increased circulating IgE concentration (HP:0003212). HP:0003212 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34146746 SUPPORT Human Clinical
"high IgE (4 out 9)"
Elevated IgE was a common laboratory finding in the clinical cohort.
Autoimmune hemolytic anemia HP:0001890 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autoimmune hemolytic anemia (HP:0001890). HP:0001890 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30386345 SUPPORT Human Clinical
"elevated DNT cell number, non-malignant lymphadenopathy and hepatosplenomegaly, hematolytic anemia, hypergammaglobulinemia."
Documents hemolytic (autoimmune) anemia in an STK4-deficient patient with ALPS-like features.
Lymphoproliferative disorder FREQUENT HP:0005523 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphoproliferative disorder (HP:0005523). HP:0005523 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30386345 SUPPORT Human Clinical
"Serine/threonine kinase 4 (STK4) deficiency is an autosomal recessive genetic condition that leads to primary immunodeficiency (PID) typically characterized by lymphopenia, recurrent infections and Epstein Barr Virus (EBV) induced lymphoproliferation and -lymphoma."
Documents EBV-induced lymphoproliferation as a typical feature of STK4 deficiency.
PMID:34146746 SUPPORT Human Clinical
"When 24 patients are analyzed, cutaneous viral infections (n = 20), recurrent pneumonia (n = 18), Epstein Barr virus-associated lymphoproliferation (n = 11), atopic dermatitis (n = 10), autoimmune cytopenia (n = 7), and lymphoma (n = 6) were frequent."
EBV-associated lymphoproliferation in 11 of 24 reviewed patients (46%), supporting the frequent band.
Lymphoma OCCASIONAL HP:0002665 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphoma (HP:0002665). HP:0002665 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:30386345 SUPPORT Human Clinical
"Patient P1 developed a highly malignant B cell lymphoma at the age of 10 years and a second, independent Hodgkin lymphoma 5 years later."
Documents lymphoma development in an STK4-deficient patient.
PMID:30386345 SUPPORT INDIRECT Human Clinical
"Lymphoma development may be due to the lacking tumor suppressive function of STK4 or the perturbed immune surveillance due to the lack of CD4+ T cells."
The proposed mechanism behind the lymphoma predisposition. Indirect because the authors offer it as a hypothesis with two alternatives rather than as a demonstrated mechanism; the description above is worded to match that hedge.
PMID:34146746 SUPPORT Human Clinical
"When 24 patients are analyzed, cutaneous viral infections (n = 20), recurrent pneumonia (n = 18), Epstein Barr virus-associated lymphoproliferation (n = 11), atopic dermatitis (n = 10), autoimmune cytopenia (n = 7), and lymphoma (n = 6) were frequent."
Lymphoma in 6 of 24 reviewed patients (25%), supporting the occasional band.
+ 1 more reference
Eosinophilia FREQUENT Increased total eosinophil count HP:0001880 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intermittent eosinophilia, annotated with Increased total eosinophil count (HP:0001880), qualified as temporality recurrent. HP:0001880 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:34146746 SUPPORT Human Clinical
"intermittent eosinophilia (4 out 9)"
Intermittent eosinophilia in 4 of 9 patients in the clinical cohort (44%), supporting the frequent band.
Decreased circulating IgM concentration FREQUENT Decreased circulating total IgM HP:0002850 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low serum IgM, annotated with Decreased circulating total IgM (HP:0002850). HP:0002850 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34146746 SUPPORT Human Clinical
"low IgM (4 out 9)"
Low IgM in 4 of 9 patients in the clinical cohort (44%), supporting the frequent band.
Decreased naive T cell proportion HP:0031397 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased recent thymic emigrants and naive T cells, annotated with Decreased naive T cell proportion (HP:0031397). HP:0031397 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34146746 SUPPORT Human Clinical
"Decreased recent thymic emigrants, naive and central memory T cells, but increased effector memory T cells were present."
Directly reports the decrease in recent thymic emigrants and naive T cells with a reciprocal effector-memory increase.
Increased plasmablast proportion HP:0032128 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased plasmablast proportion (HP:0032128). HP:0032128 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34146746 SUPPORT Human Clinical
"The increase in plasmablasts (P = .003) and decrease in switched memory B cells (P = .022) were significant."
Quantifies the plasmablast increase against age-matched healthy controls with a reported p value.
Decreased class-switched memory B cell proportion HP:0030388 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased switched memory B cell proportion, annotated with Decreased class-switched memory B cell proportion (HP:0030388). HP:0030388 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34146746 SUPPORT Human Clinical
"The increase in plasmablasts (P = .003) and decrease in switched memory B cells (P = .022) were significant."
Quantifies the switched-memory B-cell decrease with a reported p value.
Increased double-negative T cell number HP:0002851 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated double-negative T cell number, annotated with Increased double-negative T cell number (HP:0002851). HP:0002851 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30386345 SUPPORT Human Clinical
"elevated DNT cell number, non-malignant lymphadenopathy and hepatosplenomegaly, hematolytic anemia, hypergammaglobulinemia."
Documents elevated double-negative T cell number in an STK4-deficient patient.
PMID:30386345 SUPPORT Human Clinical
"None of the patients harbored typically ALPS-associated mutations of the Fas receptor mediated apoptotic pathway and Fas-mediated apoptosis was not affected."
The negative result that separates this ALPS-like presentation from genuine ALPS, and the basis for the differential diagnosis curated below.
Increased gamma-delta T cell proportion HP:0500270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vd2 gamma-delta T cell expansion, annotated with Increased gamma-delta T cell proportion (HP:0500270). HP:0500270 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39110273 SUPPORT Human Clinical
"Despite his low CD4+ T-cell count, the patient had normal counts of CD3+ cells, predominantly double-negative T cells (67.4%), which turned out to be Vδ2+ γδ T cells."
Quantifies the gamma-delta expansion and shows it masking the CD4 deficit behind a normal CD3 count.
PMID:39110273 SUPPORT Human Clinical
"γδ T-cell expansion has frequently been observed in the 33 reported cases with STK4 deficiency."
Establishes that the expansion is a recurring feature across the reported case series, not a one-patient observation.
Decreased regulatory T cell proportion HP:0020113 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced Treg fractions, annotated with Decreased regulatory T cell proportion (HP:0020113). HP:0020113 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33078349 SUPPORT Human Clinical
"the patient displayed some indicators of impaired adaptive immunity in the form of insufficient vaccination responses, T cell lymphopenia, and reduced Treg fractions"
Documents reduced regulatory T-cell fractions in an STK4-deficient patient.
Cardiovascular 2
Hepatosplenomegaly HP:0001433 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatosplenomegaly (HP:0001433). HP:0001433 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30386345 SUPPORT Human Clinical
"elevated DNT cell number, non-malignant lymphadenopathy and hepatosplenomegaly, hematolytic anemia, hypergammaglobulinemia."
Documents hepatosplenomegaly as part of the ALPS-like presentation in an STK4-deficient patient.
Atrial septal defect HP:0001631 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrial septal defect (HP:0001631). HP:0001631 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22294732 SUPPORT Human Clinical
"We describe a novel clinical phenotype associating T- and B-cell lymphopenia, intermittent neutropenia, and atrial septal defects in 3 members of a consanguineous kindred."
Documents atrial septal defects as a congenital cardiac feature.
Endocrine 1
Hypothyroidism HP:0000821 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypothyroidism (HP:0000821). HP:0000821 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33078349 SUPPORT Human Clinical
"as well as a somatic phenotype with hypothyroidism and low stature"
Documents hypothyroidism as part of the somatic phenotype in one patient.
Immune 11
Recurrent bacterial infections HP:0002718 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent bacterial infections (HP:0002718). HP:0002718 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22294732 SUPPORT Human Clinical
"Their clinical histories included recurrent bacterial infections, viral infections, mucocutaneous candidiasis, cutaneous warts, and skin abscesses."
Documents recurrent bacterial infections and skin abscesses.
Recurrent pneumonia FREQUENT HP:0006532 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent pneumonia (HP:0006532). HP:0006532 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34146746 SUPPORT Human Clinical
"recurrent pneumonia (n = 18)"
In a combined cohort of 24 patients, recurrent pneumonia was reported in 18 (75%), supporting frequent occurrence (30-79% band).
Recurrent viral infections HP:0004429 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent viral infections (HP:0004429). HP:0004429 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22294732 SUPPORT Human Clinical
"Their clinical histories included recurrent bacterial infections, viral infections, mucocutaneous candidiasis, cutaneous warts, and skin abscesses."
Documents recurrent viral infections in STK4 deficiency.
Persistent EBV viremia HP:0020072 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Persistent EBV viremia (HP:0020072), qualified as temporality chronic. HP:0020072 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (1 reference)
PMID:34427831 SUPPORT Human Clinical
"recurrent viral and bacterial infections, notably persistent Epstein-Barr virus viremia and pulmonary tuberculosis."
Documents persistent EBV viremia in an STK4-deficient patient.
Recurrent herpes zoster HP:0005353 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent herpes (HP:0005353). HP:0005353 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33078349 SUPPORT Human Clinical
"a clinical presentation consisting of severe recurrent herpes zoster, chronic warts, and recurrent pneumonias"
Documents severe recurrent herpes zoster in an STK4-deficient patient.
Mucocutaneous candidiasis Chronic mucocutaneous candidiasis HP:0002728 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mucocutaneous candidiasis, annotated with Chronic mucocutaneous candidiasis (HP:0002728). HP:0002728 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22294732 SUPPORT Human Clinical
"Their clinical histories included recurrent bacterial infections, viral infections, mucocutaneous candidiasis, cutaneous warts, and skin abscesses."
Documents mucocutaneous candidiasis as a clinical feature.
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 (1 reference)
PMID:34146746 SUPPORT Human Clinical
"autoimmune or inflammatory diseases (7 of 9)"
Autoimmune/inflammatory disease was frequent in the clinical cohort.
Autoimmune cytopenia OCCASIONAL HP:5210419 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autoimmune cytopenia (HP:5210419). HP:5210419 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34146746 SUPPORT Human Clinical
"When 24 patients are analyzed, cutaneous viral infections (n = 20), recurrent pneumonia (n = 18), Epstein Barr virus-associated lymphoproliferation (n = 11), atopic dermatitis (n = 10), autoimmune cytopenia (n = 7), and lymphoma (n = 6) were frequent."
Autoimmune cytopenia in 7 of 24 reviewed patients (29%), supporting the occasional band.
Atopic dermatitis FREQUENT HP:0001047 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atopic dermatitis (HP:0001047). HP:0001047 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34146746 SUPPORT Human Clinical
"When 24 patients are analyzed, cutaneous viral infections (n = 20), recurrent pneumonia (n = 18), Epstein Barr virus-associated lymphoproliferation (n = 11), atopic dermatitis (n = 10), autoimmune cytopenia (n = 7), and lymphoma (n = 6) were frequent."
Atopic dermatitis in 10 of 24 reviewed patients (42%), supporting the frequent band.
Persistent human papillomavirus infection HP:0020114 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epidermodysplasia verruciformis due to HPV38, annotated with Persistent human papillomavirus infection (HP:0020114). HP:0020114 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39110273 SUPPORT Human Clinical
"We describe here a patient in his thirties who presented with epidermodysplasia verruciformis (EV) due to infection with a weakly virulent beta-papillomavirus (HPV38) and CD4+ T-cell lymphopenia."
Documents epidermodysplasia verruciformis from a weakly virulent beta-papillomavirus in a genetically confirmed STK4-deficient patient.
Decreased specific antibody response to vaccination HP:0032140 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Insufficient vaccination responses, annotated with Decreased specific antibody response to vaccination (HP:0032140). HP:0032140 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33078349 SUPPORT Human Clinical
"the patient displayed some indicators of impaired adaptive immunity in the form of insufficient vaccination responses, T cell lymphopenia, and reduced Treg fractions"
Documents insufficient vaccination responses in an STK4-deficient patient.
Integument 1
Cutaneous viral warts Disseminated cutaneous warts HP:0032215 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cutaneous warts, annotated with Disseminated cutaneous warts (HP:0032215). HP:0032215 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:22294732 SUPPORT Human Clinical
"Their clinical histories included recurrent bacterial infections, viral infections, mucocutaneous candidiasis, cutaneous warts, and skin abscesses."
Documents cutaneous warts as a clinical feature.
PMID:34146746 SUPPORT Human Clinical
"cutaneous viral infections (n = 20)"
In a combined cohort of 24 patients, cutaneous viral infections were the most common infection, supporting the prominence of cutaneous viral warts.
Growth 1
Short stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low stature, annotated with Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33078349 SUPPORT Human Clinical
"as well as a somatic phenotype with hypothyroidism and low stature"
Documents low stature as part of the somatic phenotype in one patient.
🧬

Genetic Associations

1
STK4 (CAUSATIVE)
Gene: STK4 hgnc:11408 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is STK4 (hgnc:11408). hgnc:11408 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (3 references)
PMID:22294732 SUPPORT Human Clinical
"Homozygosity mapping and candidate gene sequencing revealed a homozygous premature termination mutation in the gene STK4 (serine threonine kinase 4, formerly having the symbol MST1)."
Establishes STK4 (MST1) as the causative gene with a homozygous loss-of-function mutation.
PMID:22174160 SUPPORT Human Clinical
"we report a primary immunodeficiency phenotype associated with MST1 deficiency and primarily characterized by a progressive loss of naive T cells."
Independent identification of MST1 (STK4) deficiency as the cause of this primary immunodeficiency.
PMID:34427831 SUPPORT Human Clinical
"a novel, homozygous nonsense STK4 mutation (NM_006282.2:c.871C > T, p.Arg291*) identified in a pediatric patient"
Documents allelic heterogeneity with a homozygous nonsense STK4 variant causing loss of function.
💊

Medical Actions

4
Immunoglobulin replacement therapy
Action: immunoglobulin infusion therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunoglobulin infusion therapy, annotated with Immunoglobulin Therapy (NCIT:C62710). NCIT:C62710 is a clinical intervention from the NCI Thesaurus. Ontology label: Immunoglobulin Therapy NCIT:C62710
Immunoglobulin substitution (IVIG/SCIG) is a mainstay of treatment to manage humoral immune deficiency.
Mechanism Target:
MODULATES Impaired naive T-cell survival — Immunoglobulin substitution does not correct the T-cell survival defect itself but compensates for the downstream humoral immune deficiency that results from impaired lymphocyte function.
Show evidence (1 reference)
PMID:34146746 SUPPORT Human Clinical
"Immunoglobulins, antibacterial, and antiviral prophylaxis are the mainstays of treatment."
Immunoglobulin replacement is a mainstay that compensates for the humoral consequences of the underlying lymphocyte defect.
Show evidence (1 reference)
PMID:34146746 SUPPORT Human Clinical
"Immunoglobulins, antibacterial, and antiviral prophylaxis are the mainstays of treatment."
Identifies immunoglobulin substitution as a mainstay of treatment.
Antimicrobial prophylaxis
Action: antimicrobial agent therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is antimicrobial agent therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Antibacterial and antiviral prophylaxis are mainstays of treatment to prevent recurrent infections.
Show evidence (1 reference)
PMID:34146746 SUPPORT Human Clinical
"Immunoglobulins, antibacterial, and antiviral prophylaxis are the mainstays of treatment."
Identifies antibacterial/antiviral prophylaxis as a mainstay of treatment.
Hematopoietic stem cell transplantation
Action: hematopoietic stem cell transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hematopoietic stem cell transplantation, annotated with Hematopoietic Cell Transplantation (NCIT:C15431). NCIT:C15431 is a clinical intervention from the NCI Thesaurus. Ontology label: Hematopoietic Cell Transplantation NCIT:C15431
Platform: Cell therapy
Allogeneic HSCT is the potential definitive therapy aiming to restore the immune system, though more data are needed to recommend it as a uniformly safe therapy.
Mechanism Target:
RESTORES Impaired naive T-cell survival — Allogeneic HSCT replaces the STK4-deficient hematopoietic system with donor cells, restoring normal naive T-cell survival and broader immune function.
Show evidence (1 reference)
PMID:30386345 SUPPORT Human Clinical
"State-of-the-art treatment regimens consist of prevention or treatment of infections, immunoglobulin substitution (IVIG) and restoration of the immune system by hematopoietic stem cell transplantation."
HSCT restores the immune system by replacing the defective hematopoietic compartment, correcting the underlying mechanisms.
Show evidence (2 references)
PMID:30386345 SUPPORT Human Clinical
"State-of-the-art treatment regimens consist of prevention or treatment of infections, immunoglobulin substitution (IVIG) and restoration of the immune system by hematopoietic stem cell transplantation."
Identifies HSCT as the immune-restorative treatment for STK4 deficiency.
PMID:34146746 SUPPORT Human Clinical
"However, more data are needed to recommend hematopoietic stem cell transplantation as a safe therapy."
Notes the uncertainty around HSCT safety, qualifying its role as definitive therapy.
Immunomodulatory therapy
Action: immunomodulatory therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunomodulatory therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Used for the inflammatory and autoimmune complications rather than for the immunodeficiency itself. The cohort review presents this as a permissive option ("clinicians may use") rather than a recommendation, and no specific agent or regimen is named in the cited source, so none is curated here.
Target Phenotypes: Autoimmunity HP:0002960 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Autoimmunity (HP:0002960). HP:0002960 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34146746 SUPPORT INDIRECT Human Clinical
"Clinicians may use immunomodulatory therapies during inflammatory or autoimmune complications."
Indirect: the source states this as a permissible option without naming an agent, a regimen, or an outcome.
📈

Progression

2
Symptom onset and diagnostic delay
Age: Median 6 years 8 months at onset; median 7 years 5 months at diagnosis
STK4 deficiency is not typically a neonatal SCID presentation. In the nine-patient clinical cohort the median age at symptom onset was 6 years 8 months and the median age at diagnosis 7 years 5 months, with both ranges extending past 20 years. The gap between the two medians is short, so the delay in this disease is mostly in when it starts declaring itself rather than in how long recognition then takes - but the upper end of the range is what matters for ascertainment, since an adult presenting with CD4 lymphopenia, warts and lymphoma is a recognised route to the diagnosis.
Show evidence (2 references)
PMID:34146746 SUPPORT Human Clinical
"In the cohort, median age at symptom onset and age at diagnosis were 6 years 8 months (range, 6-248 months) and 7 years 5 months (range, 6-260 months), respectively."
Reports both medians and their ranges in the nine-patient cohort.
PMID:39110273 SUPPORT Human Clinical
"The patient had no relevant history of infectious disease during childhood other than mild wart-like lesion on the skin, but he developed diffuse large B-cell lymphoma (DLBCL) and EBV viremia with a low viral load in his thirties."
A worked example of the late end of the range: an essentially unremarkable childhood followed by lymphoma in the fourth decade.
Variable clinical penetrance
Recorded because it constrains how the rest of this entry should be read. Infectious-disease penetrance varies substantially between patients with the same genetic defect, so the phenotype frequencies curated here describe a reported case series rather than the expected course of any individual patient.
Show evidence (1 reference)
PMID:39110273 SUPPORT Human Clinical
"The clinical penetrance of infectious diseases varies considerably among patients with inborn errors of immunity (IEI), even for identical genetic defects."
States the variable-penetrance principle, offered by the authors as the frame for their own STK4 case.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from STK4 Deficiency:

Autosomal recessive hyper-IgE syndrome Not Yet Curated MONDO:0018037
Overlapping Features The cohort review names this as the crucial differential, because the two diseases share the two features that most readily prompt the diagnosis: atopy and CD4 lymphopenia. Elevated IgE is common in STK4 deficiency, so the immunoglobulin pattern does not separate them either.
Distinguishing Features
  • Progressive T- and B-cell lymphopenia with intermittent neutropenia favours STK4 deficiency.
  • Congenital heart defects such as atrial septal defect are reported in STK4 deficiency.
  • EBV-driven lymphoproliferation and lymphoma are characteristic of STK4 deficiency.
  • Identification of a biallelic loss-of-function STK4 variant is confirmatory.
Show evidence (1 reference)
PMID:34146746 SUPPORT Human Clinical
"The differential diagnosis with autosomal recessive hyper-IgE syndrome is crucial. Because, atopy and CD4 lymphopenia are common in both diseases."
The authors' own identification of the differential and of the two features that make it difficult.
Autoimmune lymphoproliferative syndrome MONDO:0017979
Overlapping Features STK4-deficient patients can present with a full ALPS-like picture - elevated double-negative T cells, non-malignant lymphadenopathy, hepatosplenomegaly, haemolytic anaemia and hypergammaglobulinaemia - and both patients in one report were initially given a clinical ALPS diagnosis.
Distinguishing Features
  • ALPS-associated FAS-pathway mutations were absent in the STK4-deficient patients.
  • FAS-mediated apoptosis was intact, unlike in genuine ALPS.
  • Recurrent infections and CD4 lymphopenia point away from ALPS toward a combined immunodeficiency.
Show evidence (2 references)
PMID:30386345 SUPPORT Human Clinical
"Also patient P1 presented with ALPS-like features (lymphadenopathy, elevated DNT cell number and increased Vitamin B12 levels) and both were initially clinically diagnosed as ALPS-like."
Documents the ALPS-like misdirection in two STK4-deficient patients.
PMID:30386345 SUPPORT Human Clinical
"None of the patients harbored typically ALPS-associated mutations of the Fas receptor mediated apoptotic pathway and Fas-mediated apoptosis was not affected."
The genetic and functional findings that exclude genuine ALPS.
{ }

Source YAML

click to show 
name: STK4 Deficiency
creation_date: '2026-06-04T00:00:00Z'
category: Mendelian
synonyms:
- MST1 deficiency
- Combined immunodeficiency due to STK4 deficiency
- T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations
- TIIAC
description: >-
  STK4 (MST1) deficiency is an autosomal recessive combined immunodeficiency
  caused by biallelic loss-of-function variants in STK4, the human ortholog of
  Drosophila Hippo. Loss of the MST1 kinase impairs naive T-cell survival via
  defective FOXO1 expression, reduced IL-7 receptor and BCL2, and increased
  FAS-mediated apoptosis, and additionally impairs lymphocyte adhesion and
  chemotaxis. The disorder is characterized by progressive T- and B-cell
  lymphopenia (especially CD4 lymphopenia), intermittent neutropenia,
  hypergammaglobulinemia and elevated IgE, recurrent bacterial and viral
  infections, cutaneous viral warts (HPV) and molluscum contagiosum,
  mucocutaneous candidiasis, autoimmunity, EBV-associated (and EBV-negative)
  lymphoproliferation and lymphoma, and congenital heart defects such as atrial
  septal defects.
disease_term:
  preferred_term: STK4 deficiency
  term:
    id: MONDO:0013934
    label: combined immunodeficiency due to STK4 deficiency
parents:
- Combined immunodeficiency
- Primary immunodeficiency
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
    notes: >-
      STK4 deficiency is an inborn error of immunity (primary immunodeficiency),
      best classified under disorders of the immune system.
    evidence:
    - reference: PMID:30386345
      reference_title: "EBV Negative Lymphoma and Autoimmune Lymphoproliferative Syndrome Like Phenotype Extend the Clinical Spectrum of Primary Immunodeficiency Caused by STK4 Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Serine/threonine kinase 4 (STK4) deficiency is an autosomal recessive
        genetic condition that leads to primary immunodeficiency (PID)
      explanation: >-
        Establishes STK4 deficiency as a primary immunodeficiency, an immune
        system disorder under the immunology/rheumatology grouping.
  iuis_category:
    classification_value: combined immunodeficiency
    notes: >-
      STK4 (MST1) deficiency is classified by IUIS as a combined immunodeficiency
      affecting cellular and humoral immunity (Table 1). The quoted IUIS table
      row comes from the classification tables in the cached full text rather
      than from the abstract.
    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
      snippet: "STK4 deficiency STK4 AR 614868"
      explanation: >-
        Table 1 disease-row text listing STK4 deficiency (autosomal recessive)
        among the immunodeficiencies affecting cellular and humoral immunity.
    - reference: PMID:34146746
      reference_title: "Diversity in Serine/Threonine Protein Kinase-4 Deficiency and Review of the Literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Serine/threonine kinase-4 (STK4) deficiency is an autosomal
        recessive combined immunodeficiency.
      explanation: >-
        Establishes STK4 deficiency as a combined immunodeficiency, consistent
        with the IUIS combined-immunodeficiency category.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    STK4 deficiency is inherited in an autosomal recessive pattern and is caused
    by biallelic loss-of-function variants in STK4 (MST1).
  evidence:
  - reference: PMID:34146746
    reference_title: "Diversity in Serine/Threonine Protein Kinase-4 Deficiency and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Serine/threonine kinase-4 (STK4) deficiency is an autosomal
      recessive combined immunodeficiency.
    explanation: Supports autosomal recessive inheritance of STK4 deficiency.
  - reference: PMID:39110273
    reference_title: "Epidermodysplasia Verruciformis and Vδ2 γδ T-cell Expansion in STK4 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient was born to consanguineous parents living in the United States.
      Exome sequencing identified a previously unknown biallelic STK4 stop-gain
      mutation (p.Trp425X).
    explanation: >-
      Documents the autosomal recessive, biallelic nature of STK4 deficiency in a
      consanguineous family.
pathophysiology:
- name: Impaired naive T-cell survival
  description: >-
    Loss of STK4/MST1 kinase reduces survival of naive T cells. MST1-deficient
    T cells poorly express the transcription factor FOXO1, the IL-7 receptor,
    and BCL2, while FAS expression and FAS-mediated apoptosis are up-regulated,
    causing increased death of naive and proliferating T cells. This is the main
    mechanism underlying the progressive T-cell lymphopenia.
  cell_types:
  - preferred_term: naive T cell
    term:
      id: CL:0000898
      label: naive T cell
  biological_processes:
  - preferred_term: lymphocyte apoptotic process
    term:
      id: GO:0070227
      label: lymphocyte apoptotic process
    modifier: INCREASED
  - preferred_term: T cell homeostasis
    term:
      id: GO:0043029
      label: T cell homeostasis
    modifier: DECREASED
  evidence:
  - reference: PMID:22174160
    reference_title: "MST1 mutations in autosomal recessive primary immunodeficiency characterized by defective naive T-cell survival."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MST1-deficient T cells poorly expressed the transcription factor FOXO1,
      the IL-7 receptor, and BCL2. Conversely, FAS expression and the
      FAS-mediating apoptotic pathway were up-regulated.
    explanation: >-
      Documents the molecular basis of impaired naive T-cell survival: loss of
      FOXO1/IL-7R/BCL2 and increased FAS-mediated apoptosis.
  - reference: PMID:22174160
    reference_title: "MST1 mutations in autosomal recessive primary immunodeficiency characterized by defective naive T-cell survival."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These abnormalities suggest that increased cell death of naive and
      proliferating T cells is the main mechanism underlying this novel
      immunodeficiency.
    explanation: >-
      Identifies increased T-cell death as the central mechanism of the disorder.
  - reference: PMID:34427831
    reference_title: "A Novel STK4 Mutation Impairs T Cell Immunity Through Dysregulation of Cytokine-Induced Adhesion and Chemotaxis Genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      dysregulated interferon signaling, impaired T cell immunity, and increased
      T cell apoptosis
    explanation: >-
      Independent transcriptomic confirmation of impaired T-cell immunity and
      increased T-cell apoptosis in an STK4-deficient patient.
  downstream:
  - target: T-cell lymphopenia
    causal_link_type: DIRECT
    description: >-
      Increased death of naive and proliferating T cells produces the
      progressive T-cell (especially CD4) lymphopenia that is a hallmark of the
      disorder.
    evidence:
    - reference: PMID:22174160
      reference_title: "MST1 mutations in autosomal recessive primary immunodeficiency characterized by defective naive T-cell survival."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These abnormalities suggest that increased cell death of naive and
        proliferating T cells is the main mechanism underlying this novel
        immunodeficiency.
      explanation: >-
        Links increased T-cell death to the progressive T-cell lymphopenia
        characteristic of STK4 deficiency.
  - target: B-cell lymphopenia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The combined T- and B-cell lymphopenia seen in patients accompanies the
      naive-T-cell survival defect, with B-cell lymphopenia developing as part
      of the same lymphopenic phenotype.
    evidence:
    - reference: PMID:22294732
      reference_title: "The phenotype of human STK4 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We describe a novel clinical phenotype associating T- and B-cell
        lymphopenia, intermittent neutropenia, and atrial septal defects in 3
        members of a consanguineous kindred.
      explanation: >-
        Documents B-cell lymphopenia co-occurring with the T-cell defect in
        STK4 deficiency.
  - target: Increased gamma-delta T cell proportion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      As the conventional alpha-beta CD4+ compartment fails, gamma-delta T cells expand into the
      space it leaves. The expansion is read as compensatory rather than as a second lesion, but
      it is incomplete compensation - the expanded cells proliferate poorly on activation - and
      clinically it is a trap, because it can hold the total CD3+ count in the normal range while
      CD4+ cells are profoundly depleted.
    evidence:
    - reference: PMID:39110273
      reference_title: "Epidermodysplasia Verruciformis and Vδ2 γδ T-cell Expansion in STK4 Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In conclusion, γδ T-cell expansion may act as a compensatory mechanism to combat viral infection, providing immune protection in immunocompromised individuals.
      explanation: >-
        The authors' interpretation of the expansion as compensatory, which is the claim this edge
        records.
    - reference: PMID:39110273
      reference_title: "Epidermodysplasia Verruciformis and Vδ2 γδ T-cell Expansion in STK4 Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        their ability to proliferate in response to T-cell activation was impaired, as was that of CD4+ T cells.
      explanation: >-
        Qualifies the compensation: the expanded gamma-delta cells share the proliferative defect
        of the CD4+ cells they are standing in for.
- name: Increased lymphocyte and neutrophil apoptosis
  description: >-
    STK4 is the human ortholog of Drosophila Hippo, the central constituent of a
    conserved pathway controlling cell growth and apoptosis. STK4-deficient
    lymphocytes and neutrophils show enhanced loss of mitochondrial membrane
    potential and increased susceptibility to apoptosis, contributing to
    lymphopenia and intermittent neutropenia.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:22294732
    reference_title: "The phenotype of human STK4 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      STK4-deficient lymphocytes and neutrophils exhibit enhanced loss of
      mitochondrial membrane potential and increased susceptibility to
      apoptosis.
    explanation: >-
      Supports increased apoptosis of lymphocytes and neutrophils as a
      mechanism of cytopenias in STK4 deficiency.
  downstream:
  - target: Intermittent neutropenia
    causal_link_type: DIRECT
    description: >-
      Enhanced loss of mitochondrial membrane potential and increased
      neutrophil apoptosis produce the intermittent neutropenia observed in
      STK4-deficient patients.
    evidence:
    - reference: PMID:22294732
      reference_title: "The phenotype of human STK4 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        STK4-deficient lymphocytes and neutrophils exhibit enhanced loss of
        mitochondrial membrane potential and increased susceptibility to
        apoptosis.
      explanation: >-
        Connects increased neutrophil apoptosis to the intermittent neutropenia
        phenotype.
- name: Defective lymphocyte adhesion and chemotaxis
  description: >-
    MST1 is required for leukocyte trafficking. STK4-deficient leukocytes show
    deficient chemotaxis after chemokine stimulation despite preserved chemokine
    receptor expression, and fail to bind effectively to ICAM-1 under flow,
    indicating a failure to develop high-affinity integrin binding. This
    trafficking defect impairs thymic egress and immune synapse formation,
    contributing to immunodeficiency.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: leukocyte chemotaxis
    term:
      id: GO:0030595
      label: leukocyte chemotaxis
    modifier: DECREASED
  - preferred_term: cell adhesion
    term:
      id: GO:0007155
      label: cell adhesion
    modifier: DECREASED
  evidence:
  - reference: PMID:26801501
    reference_title: "Defective Leukocyte Adhesion and Chemotaxis Contributes to Combined Immunodeficiency in Humans with Autosomal Recessive MST1 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient leukocytes exhibited deficient chemotaxis after stimulation with
      CXCL11, despite preserved expression of CXCR3. Patient lymphocytes were
      also unable to bind effectively to immobilised ICAM-1 under flow
      conditions, in keeping with a failure to develop high affinity binding.
    explanation: >-
      Documents the adhesion and chemotaxis defect in MST1-deficient leukocytes.
  - reference: PMID:26801501
    reference_title: "Defective Leukocyte Adhesion and Chemotaxis Contributes to Combined Immunodeficiency in Humans with Autosomal Recessive MST1 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The observed abnormalities of adhesion and migration imply a profound
      trafficking defect among human MST1-deficient lymphocytes.
    explanation: >-
      Connects the adhesion/chemotaxis defect to a global lymphocyte trafficking
      defect contributing to immunodeficiency.
  - reference: PMID:34427831
    reference_title: "A Novel STK4 Mutation Impairs T Cell Immunity Through Dysregulation of Cytokine-Induced Adhesion and Chemotaxis Genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      impaired regulation of cytokine-induced adhesion and leukocyte chemotaxis
      genes.
    explanation: >-
      Transcriptomic analysis of an STK4-deficient patient shows dysregulation of
      cytokine-induced adhesion and chemotaxis gene programs, corroborating the
      trafficking defect.
  downstream:
  - target: Recurrent bacterial infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The profound lymphocyte trafficking defect impairs leukocyte recruitment
      to sites of infection, contributing to the recurrent bacterial infections
      seen in STK4 deficiency.
    evidence:
    - reference: PMID:26801501
      reference_title: "Defective Leukocyte Adhesion and Chemotaxis Contributes to Combined Immunodeficiency in Humans with Autosomal Recessive MST1 Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The observed abnormalities of adhesion and migration imply a profound
        trafficking defect among human MST1-deficient lymphocytes.
      explanation: >-
        Links the leukocyte trafficking defect to the combined immunodeficiency
        underlying recurrent bacterial infections.
  - target: Recurrent pneumonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Defective leukocyte trafficking to the lungs, together with impaired
      cellular immunity, predisposes to the recurrent pneumonia that is a
      frequent complication of STK4 deficiency.
    evidence:
    - reference: PMID:26801501
      reference_title: "Defective Leukocyte Adhesion and Chemotaxis Contributes to Combined Immunodeficiency in Humans with Autosomal Recessive MST1 Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The observed abnormalities of adhesion and migration imply a profound
        trafficking defect among human MST1-deficient lymphocytes.
      explanation: >-
        Links the lymphocyte trafficking defect to impaired pulmonary host
        defense and recurrent pneumonia.
- name: Impaired innate antiviral interferon signaling
  description: >-
    Beyond its role in lymphocyte survival, STK4/MST1 is required for innate
    antiviral immunity. STK4-deficient cells show significantly impaired type I,
    II, and III interferon responses and reduced proinflammatory cytokine
    responses to TLR3, TLR9, and cytosolic nucleic-acid sensor ligands. The
    interferon defect is attributable to reduced phosphorylation of TBK1 and
    IRF3, and virus infection induces enhanced apoptotic cell death. This innate
    antiviral defect contributes to the prominent susceptibility to herpesviruses
    (EBV, VZV) and papillomaviruses.
  cell_types:
  - preferred_term: plasmacytoid dendritic cell
    term:
      id: CL:0000784
      label: plasmacytoid dendritic cell
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: type I interferon-mediated signaling pathway
    term:
      id: GO:0060337
      label: type I interferon-mediated signaling pathway
    modifier: DECREASED
  - preferred_term: defense response to virus
    term:
      id: GO:0051607
      label: defense response to virus
    modifier: DECREASED
  evidence:
  - reference: PMID:33078349
    reference_title: "STK4 Deficiency Impairs Innate Immunity and Interferon Production Through Negative Regulation of TBK1-IRF3 Signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We show significantly impaired type I, II, and III interferon (IFN)
      responses and partly reduced proinflammatory cytokine responses to ligands
      of Toll-like receptor (TLR)3, TLR9, and the cytosolic RNA and DNA sensors
    explanation: >-
      Documents the impaired type I, II, and III interferon responses in STK4
      deficiency.
  - reference: PMID:33078349
    reference_title: "STK4 Deficiency Impairs Innate Immunity and Interferon Production Through Negative Regulation of TBK1-IRF3 Signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Impaired IFN responses could be attributed to reduced phosphorylation of
      TBK1 and IRF3. Moreover, virus infection induced enhanced cell death by
      apoptosis.
    explanation: >-
      Identifies the TBK1-IRF3 axis as the molecular basis of the interferon
      defect and links viral infection to enhanced apoptosis.
  - reference: PMID:34427831
    reference_title: "A Novel STK4 Mutation Impairs T Cell Immunity Through Dysregulation of Cytokine-Induced Adhesion and Chemotaxis Genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      abnormal fractions of T cell subsets, plasmacytoid dendritic cells, and
      NK cells
    explanation: >-
      Documents abnormal plasmacytoid dendritic cell fractions in an
      STK4-deficient patient, supporting involvement of this type I
      interferon-producing cell type.
  downstream:
  - target: Recurrent viral infections
    causal_link_type: DIRECT
    description: >-
      The impaired type I/II/III interferon response and enhanced
      virus-induced apoptosis impair antiviral defense, producing the prominent
      susceptibility to viral infections.
    evidence:
    - reference: PMID:33078349
      reference_title: "STK4 Deficiency Impairs Innate Immunity and Interferon Production Through Negative Regulation of TBK1-IRF3 Signaling."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Impaired IFN responses could be attributed to reduced phosphorylation of
        TBK1 and IRF3. Moreover, virus infection induced enhanced cell death by
        apoptosis.
      explanation: >-
        Links the interferon defect and virus-induced apoptosis to impaired
        antiviral defense underlying recurrent viral infections.
  - target: Recurrent herpes zoster
    causal_link_type: DIRECT
    description: >-
      The innate antiviral interferon defect underlies the severe recurrent
      herpesvirus infections, including herpes zoster.
    evidence:
    - reference: PMID:33078349
      reference_title: "STK4 Deficiency Impairs Innate Immunity and Interferon Production Through Negative Regulation of TBK1-IRF3 Signaling."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        a clinical presentation consisting of severe recurrent herpes zoster,
        chronic warts, and recurrent pneumonias
      explanation: >-
        Connects the interferon-signaling defect to the severe recurrent herpes
        zoster phenotype.
  - target: Persistent EBV viremia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired antiviral immunity contributes to failure to control
      Epstein-Barr virus, manifesting as persistent EBV viremia.
    evidence:
    - reference: PMID:34427831
      reference_title: "A Novel STK4 Mutation Impairs T Cell Immunity Through Dysregulation of Cytokine-Induced Adhesion and Chemotaxis Genes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        recurrent viral and bacterial infections, notably persistent Epstein-Barr
        virus viremia and pulmonary tuberculosis.
      explanation: >-
        Documents persistent EBV viremia as a consequence of impaired antiviral
        immunity in an STK4-deficient patient.
  - target: Persistent human papillomavirus infection
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Failure of the interferon-dependent antiviral response permits infection by
      beta-papillomaviruses that are not virulent in immunocompetent hosts, producing
      epidermodysplasia verruciformis at the severe end of the cutaneous viral spectrum.
    evidence:
    - reference: PMID:39110273
      reference_title: "Epidermodysplasia Verruciformis and Vδ2 γδ T-cell Expansion in STK4 Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We describe here a patient in his thirties who presented with epidermodysplasia verruciformis (EV) due to infection with a weakly virulent beta-papillomavirus (HPV38) and CD4+ T-cell lymphopenia.
      explanation: >-
        Links the STK4-deficient immune defect to disease from a papillomavirus that is
        specifically noted as weakly virulent.
phenotypes:
- name: Recurrent bacterial infections
  description: >-
    Patients have a history of recurrent bacterial infections including
    respiratory infections, skin abscesses, and septicemia.
  phenotype_term:
    preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
  evidence:
  - reference: PMID:22294732
    reference_title: "The phenotype of human STK4 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Their clinical histories included recurrent bacterial infections, viral
      infections, mucocutaneous candidiasis, cutaneous warts, and skin
      abscesses.
    explanation: Documents recurrent bacterial infections and skin abscesses.
- name: Recurrent pneumonia
  description: >-
    Recurrent pneumonia is a frequent complication, reported in 18 of 24
    reviewed patients, reflecting impaired cellular immunity and defective
    leukocyte trafficking to the lungs.
  phenotype_term:
    preferred_term: Recurrent pneumonia
    term:
      id: HP:0006532
      label: Recurrent pneumonia
  frequency: FREQUENT
  evidence:
  - reference: PMID:34146746
    reference_title: "Diversity in Serine/Threonine Protein Kinase-4 Deficiency and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recurrent pneumonia (n = 18)"
    explanation: >-
      In a combined cohort of 24 patients, recurrent pneumonia was reported in
      18 (75%), supporting frequent occurrence (30-79% band).
- name: Recurrent viral infections
  description: >-
    Patients experience recurrent viral infections, particularly cutaneous viral
    infections (HPV warts, molluscum contagiosum) and EBV.
  phenotype_term:
    preferred_term: Recurrent viral infections
    term:
      id: HP:0004429
      label: Recurrent viral infections
  evidence:
  - reference: PMID:22294732
    reference_title: "The phenotype of human STK4 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Their clinical histories included recurrent bacterial infections, viral
      infections, mucocutaneous candidiasis, cutaneous warts, and skin
      abscesses.
    explanation: Documents recurrent viral infections in STK4 deficiency.
- name: Persistent EBV viremia
  description: >-
    Persistent Epstein-Barr virus viremia is a characteristic feature reflecting
    impaired antiviral T-cell immunity and predisposes to EBV-associated
    lymphoproliferation and lymphoma.
  phenotype_term:
    preferred_term: Persistent EBV viremia
    term:
      id: HP:0020072
      label: Persistent EBV viremia
    temporality: CHRONIC
  evidence:
  - reference: PMID:34427831
    reference_title: "A Novel STK4 Mutation Impairs T Cell Immunity Through Dysregulation of Cytokine-Induced Adhesion and Chemotaxis Genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      recurrent viral and bacterial infections, notably persistent Epstein-Barr
      virus viremia and pulmonary tuberculosis.
    explanation: Documents persistent EBV viremia in an STK4-deficient patient.
- name: Recurrent herpes zoster
  description: >-
    Severe recurrent herpesvirus infections, including herpes zoster, occur and
    reflect the impaired innate antiviral interferon response and defective
    T-cell immunity.
  phenotype_term:
    preferred_term: Recurrent herpes
    term:
      id: HP:0005353
      label: Recurrent herpes
  evidence:
  - reference: PMID:33078349
    reference_title: "STK4 Deficiency Impairs Innate Immunity and Interferon Production Through Negative Regulation of TBK1-IRF3 Signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a clinical presentation consisting of severe recurrent herpes zoster,
      chronic warts, and recurrent pneumonias
    explanation: >-
      Documents severe recurrent herpes zoster in an STK4-deficient patient.
- name: Cutaneous viral warts
  description: >-
    Cutaneous viral (HPV) warts are a characteristic feature; cutaneous viral
    infections were present in the large majority of reviewed patients.
  phenotype_term:
    preferred_term: Cutaneous warts
    term:
      id: HP:0032215
      label: Disseminated cutaneous warts
  evidence:
  - reference: PMID:22294732
    reference_title: "The phenotype of human STK4 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Their clinical histories included recurrent bacterial infections, viral
      infections, mucocutaneous candidiasis, cutaneous warts, and skin
      abscesses.
    explanation: Documents cutaneous warts as a clinical feature.
  - reference: PMID:34146746
    reference_title: "Diversity in Serine/Threonine Protein Kinase-4 Deficiency and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cutaneous viral infections (n = 20)"
    explanation: >-
      In a combined cohort of 24 patients, cutaneous viral infections were the
      most common infection, supporting the prominence of cutaneous viral warts.
- name: Mucocutaneous candidiasis
  description: >-
    Chronic mucocutaneous candidiasis reflects impaired antifungal T-cell
    immunity.
  phenotype_term:
    preferred_term: Mucocutaneous candidiasis
    term:
      id: HP:0002728
      label: Chronic mucocutaneous candidiasis
  evidence:
  - reference: PMID:22294732
    reference_title: "The phenotype of human STK4 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Their clinical histories included recurrent bacterial infections, viral
      infections, mucocutaneous candidiasis, cutaneous warts, and skin
      abscesses.
    explanation: Documents mucocutaneous candidiasis as a clinical feature.
- name: T-cell lymphopenia
  description: >-
    Progressive loss of naive T cells with CD4 lymphopenia is a hallmark of STK4
    deficiency; CD4 lymphopenia was present in all patients in a clinical cohort.
  phenotype_term:
    preferred_term: Decreased total T cell count
    term:
      id: HP:0005403
      label: Decreased total T cell count
  evidence:
  - reference: PMID:22294732
    reference_title: "The phenotype of human STK4 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a novel clinical phenotype associating T- and B-cell
      lymphopenia, intermittent neutropenia, and atrial septal defects in 3
      members of a consanguineous kindred.
    explanation: Documents T-cell lymphopenia.
  - reference: PMID:34146746
    reference_title: "Diversity in Serine/Threonine Protein Kinase-4 Deficiency and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CD4 lymphopenia (9 out 9)"
    explanation: CD4 lymphopenia was universal in the clinical cohort.
- name: B-cell lymphopenia
  description: >-
    B-cell lymphopenia accompanies the T-cell defect, with abnormal B-cell
    subsets (increased plasmablasts, decreased switched memory B cells).
  phenotype_term:
    preferred_term: Decreased total B cell count
    term:
      id: HP:0010976
      label: Decreased total B cell count
  evidence:
  - reference: PMID:22294732
    reference_title: "The phenotype of human STK4 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a novel clinical phenotype associating T- and B-cell
      lymphopenia, intermittent neutropenia, and atrial septal defects in 3
      members of a consanguineous kindred.
    explanation: Documents B-cell lymphopenia.
- name: Intermittent neutropenia
  description: >-
    Intermittent (transient) neutropenia occurs and reflects increased
    neutrophil apoptosis.
  phenotype_term:
    preferred_term: Neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
    temporality: TRANSIENT
  evidence:
  - reference: PMID:22294732
    reference_title: "The phenotype of human STK4 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a novel clinical phenotype associating T- and B-cell
      lymphopenia, intermittent neutropenia, and atrial septal defects in 3
      members of a consanguineous kindred.
    explanation: Documents intermittent neutropenia.
- name: Hypergammaglobulinemia
  description: >-
    Dysregulated immunoglobulin levels are common, including
    hypergammaglobulinemia and elevated IgE, alongside low IgM in some patients.
  phenotype_term:
    preferred_term: Hypergammaglobulinemia
    term:
      id: HP:0010702
      label: Increased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:30386345
    reference_title: "EBV Negative Lymphoma and Autoimmune Lymphoproliferative Syndrome Like Phenotype Extend the Clinical Spectrum of Primary Immunodeficiency Caused by STK4 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      elevated DNT cell number, non-malignant lymphadenopathy and
      hepatosplenomegaly, hematolytic anemia, hypergammaglobulinemia.
    explanation: Documents hypergammaglobulinemia in an STK4-deficient patient.
- name: Elevated IgE
  description: >-
    Elevated serum IgE is common and contributes to the differential diagnosis
    with autosomal recessive hyper-IgE syndrome.
  phenotype_term:
    preferred_term: Elevated circulating IgE concentration
    term:
      id: HP:0003212
      label: Increased circulating IgE concentration
  evidence:
  - reference: PMID:34146746
    reference_title: "Diversity in Serine/Threonine Protein Kinase-4 Deficiency and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "high IgE (4 out 9)"
    explanation: Elevated IgE was a common laboratory finding in the clinical cohort.
- name: Autoimmunity
  description: >-
    Autoimmune and inflammatory manifestations are common, including autoimmune
    hemolytic anemia and other autoimmune phenomena.
  phenotype_term:
    preferred_term: Autoimmunity
    term:
      id: HP:0002960
      label: Autoimmunity
  evidence:
  - reference: PMID:34146746
    reference_title: "Diversity in Serine/Threonine Protein Kinase-4 Deficiency and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "autoimmune or inflammatory diseases (7 of 9)"
    explanation: Autoimmune/inflammatory disease was frequent in the clinical cohort.
  frequency: FREQUENT
- name: Autoimmune cytopenia
  description: >-
    Immune-mediated destruction of blood cells - most often haemolytic anaemia - is the commonest
    single autoimmune manifestation, and is distinct from the intermittent neutropenia that arises
    from increased neutrophil apoptosis.
  phenotype_term:
    preferred_term: Autoimmune cytopenia
    term:
      id: HP:5210419
      label: Autoimmune cytopenia
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:34146746
    reference_title: "Diversity in Serine/Threonine Protein Kinase-4 Deficiency and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      When 24 patients are analyzed, cutaneous viral infections (n = 20), recurrent pneumonia (n = 18), Epstein Barr virus-associated lymphoproliferation (n = 11), atopic dermatitis (n = 10), autoimmune cytopenia (n = 7), and lymphoma (n = 6) were frequent.
    explanation: Autoimmune cytopenia in 7 of 24 reviewed patients (29%), supporting the occasional band.
- name: Autoimmune hemolytic anemia
  description: >-
    Autoimmune hemolytic anemia is reported among the autoimmune manifestations
    of STK4 deficiency.
  phenotype_term:
    preferred_term: Autoimmune hemolytic anemia
    term:
      id: HP:0001890
      label: Autoimmune hemolytic anemia
  evidence:
  - reference: PMID:30386345
    reference_title: "EBV Negative Lymphoma and Autoimmune Lymphoproliferative Syndrome Like Phenotype Extend the Clinical Spectrum of Primary Immunodeficiency Caused by STK4 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      elevated DNT cell number, non-malignant lymphadenopathy and
      hepatosplenomegaly, hematolytic anemia, hypergammaglobulinemia.
    explanation: >-
      Documents hemolytic (autoimmune) anemia in an STK4-deficient patient with
      ALPS-like features.
- name: Lymphoproliferative disorder
  description: >-
    EBV-associated lymphoproliferation is characteristic; patients can present
    with non-malignant lymphadenopathy, hepatosplenomegaly, and ALPS-like
    features.
  phenotype_term:
    preferred_term: Lymphoproliferative disorder
    term:
      id: HP:0005523
      label: Lymphoproliferative disorder
  evidence:
  - reference: PMID:30386345
    reference_title: "EBV Negative Lymphoma and Autoimmune Lymphoproliferative Syndrome Like Phenotype Extend the Clinical Spectrum of Primary Immunodeficiency Caused by STK4 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Serine/threonine kinase 4 (STK4) deficiency is an autosomal recessive
      genetic condition that leads to primary immunodeficiency (PID) typically
      characterized by lymphopenia, recurrent infections and Epstein Barr Virus
      (EBV) induced lymphoproliferation and -lymphoma.
    explanation: >-
      Documents EBV-induced lymphoproliferation as a typical feature of STK4
      deficiency.
  - reference: PMID:34146746
    reference_title: "Diversity in Serine/Threonine Protein Kinase-4 Deficiency and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      When 24 patients are analyzed, cutaneous viral infections (n = 20), recurrent pneumonia (n = 18), Epstein Barr virus-associated lymphoproliferation (n = 11), atopic dermatitis (n = 10), autoimmune cytopenia (n = 7), and lymphoma (n = 6) were frequent.
    explanation: >-
      EBV-associated lymphoproliferation in 11 of 24 reviewed patients (46%), supporting the
      frequent band.
  frequency: FREQUENT
- name: Hepatosplenomegaly
  description: >-
    Hepatosplenomegaly occurs as part of the ALPS-like lymphoproliferative
    presentation alongside non-malignant lymphadenopathy.
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  evidence:
  - reference: PMID:30386345
    reference_title: "EBV Negative Lymphoma and Autoimmune Lymphoproliferative Syndrome Like Phenotype Extend the Clinical Spectrum of Primary Immunodeficiency Caused by STK4 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      elevated DNT cell number, non-malignant lymphadenopathy and
      hepatosplenomegaly, hematolytic anemia, hypergammaglobulinemia.
    explanation: >-
      Documents hepatosplenomegaly as part of the ALPS-like presentation in an
      STK4-deficient patient.
- name: Lymphoma
  description: >-
    Patients are prone to lymphoma, including EBV-associated and EBV-negative
    B-cell lymphoma, diffuse large B-cell lymphoma, and Hodgkin lymphoma. The
    authors who reported the first EBV-negative case proposed either loss of the
    tumour-suppressive function of STK4 or perturbed immune surveillance from the
    CD4+ T-cell deficit as the explanation; neither has been established over the
    other, so both are recorded as candidate mechanisms rather than as the cause.
  phenotype_term:
    preferred_term: Lymphoma
    term:
      id: HP:0002665
      label: Lymphoma
  evidence:
  - reference: PMID:30386345
    reference_title: "EBV Negative Lymphoma and Autoimmune Lymphoproliferative Syndrome Like Phenotype Extend the Clinical Spectrum of Primary Immunodeficiency Caused by STK4 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient P1 developed a highly malignant B cell lymphoma at the age of 10
      years and a second, independent Hodgkin lymphoma 5 years later.
    explanation: Documents lymphoma development in an STK4-deficient patient.
  - reference: PMID:30386345
    reference_title: "EBV Negative Lymphoma and Autoimmune Lymphoproliferative Syndrome Like Phenotype Extend the Clinical Spectrum of Primary Immunodeficiency Caused by STK4 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lymphoma development may be due to the lacking tumor suppressive function of STK4 or the perturbed immune surveillance due to the lack of CD4+ T cells.
    directness: INDIRECT
    explanation: >-
      The proposed mechanism behind the lymphoma predisposition. Indirect because the
      authors offer it as a hypothesis with two alternatives rather than as a demonstrated
      mechanism; the description above is worded to match that hedge.
  - reference: PMID:34146746
    reference_title: "Diversity in Serine/Threonine Protein Kinase-4 Deficiency and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      When 24 patients are analyzed, cutaneous viral infections (n = 20), recurrent pneumonia (n = 18), Epstein Barr virus-associated lymphoproliferation (n = 11), atopic dermatitis (n = 10), autoimmune cytopenia (n = 7), and lymphoma (n = 6) were frequent.
    explanation: Lymphoma in 6 of 24 reviewed patients (25%), supporting the occasional band.
  - reference: PMID:39110273
    reference_title: "Epidermodysplasia Verruciformis and Vδ2 γδ T-cell Expansion in STK4 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      he developed diffuse large B-cell lymphoma (DLBCL) and EBV viremia with a low viral load in his thirties.
    explanation: >-
      Documents DLBCL arising in adulthood, showing the lymphoma risk is not confined to
      childhood.
  frequency: OCCASIONAL
- name: Atrial septal defect
  description: >-
    Congenital heart defects, particularly atrial septal defects, occur in STK4
    deficiency.
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  evidence:
  - reference: PMID:22294732
    reference_title: "The phenotype of human STK4 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a novel clinical phenotype associating T- and B-cell
      lymphopenia, intermittent neutropenia, and atrial septal defects in 3
      members of a consanguineous kindred.
    explanation: Documents atrial septal defects as a congenital cardiac feature.
- name: Atopic dermatitis
  description: >-
    Atopy is common enough to be a diagnostic trap: it is one of the two features (with CD4
    lymphopenia) that STK4 deficiency shares with autosomal recessive hyper-IgE syndrome, and it
    is why the differential between them matters.
  phenotype_term:
    preferred_term: Atopic dermatitis
    term:
      id: HP:0001047
      label: Atopic dermatitis
  frequency: FREQUENT
  evidence:
  - reference: PMID:34146746
    reference_title: "Diversity in Serine/Threonine Protein Kinase-4 Deficiency and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      When 24 patients are analyzed, cutaneous viral infections (n = 20), recurrent pneumonia (n = 18), Epstein Barr virus-associated lymphoproliferation (n = 11), atopic dermatitis (n = 10), autoimmune cytopenia (n = 7), and lymphoma (n = 6) were frequent.
    explanation: >-
      Atopic dermatitis in 10 of 24 reviewed patients (42%), supporting the frequent band.
- name: Eosinophilia
  description: Intermittent eosinophilia accompanies the atopic phenotype.
  phenotype_term:
    preferred_term: Intermittent eosinophilia
    term:
      id: HP:0001880
      label: Increased total eosinophil count
    temporality: RECURRENT
  frequency: FREQUENT
  evidence:
  - reference: PMID:34146746
    reference_title: "Diversity in Serine/Threonine Protein Kinase-4 Deficiency and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "intermittent eosinophilia (4 out 9)"
    explanation: >-
      Intermittent eosinophilia in 4 of 9 patients in the clinical cohort (44%), supporting the
      frequent band.
- name: Decreased circulating IgM concentration
  description: >-
    Immunoglobulin levels in STK4 deficiency are dysregulated rather than uniformly low or high:
    IgG, IgA and IgE are commonly raised while IgM is often reduced. An entry that recorded only
    the hypergammaglobulinaemia would mislead a reader into expecting all classes to move
    together.
  phenotype_term:
    preferred_term: Low serum IgM
    term:
      id: HP:0002850
      label: Decreased circulating total IgM
  frequency: FREQUENT
  evidence:
  - reference: PMID:34146746
    reference_title: "Diversity in Serine/Threonine Protein Kinase-4 Deficiency and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "low IgM (4 out 9)"
    explanation: Low IgM in 4 of 9 patients in the clinical cohort (44%), supporting the frequent band.
- name: Decreased naive T cell proportion
  description: >-
    The T-cell compartment is skewed as well as depleted: recent thymic emigrants, naive T cells
    and central memory T cells all fall while effector memory T cells rise. This is the cellular
    signature of the naive-T-cell survival defect, and it is measurable before total counts drop.
  phenotype_term:
    preferred_term: Decreased recent thymic emigrants and naive T cells
    term:
      id: HP:0031397
      label: Decreased naive T cell proportion
  evidence:
  - reference: PMID:34146746
    reference_title: "Diversity in Serine/Threonine Protein Kinase-4 Deficiency and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Decreased recent thymic emigrants, naive and central memory T cells, but increased effector memory T cells were present.
    explanation: >-
      Directly reports the decrease in recent thymic emigrants and naive T cells with a reciprocal
      effector-memory increase.
- name: Increased plasmablast proportion
  description: >-
    The B-cell compartment is abnormal in composition, not only in number. Plasmablasts are
    increased and class-switched memory B cells decreased, both statistically significant against
    age-matched controls.
  phenotype_term:
    preferred_term: Increased plasmablast proportion
    term:
      id: HP:0032128
      label: Increased plasmablast proportion
  evidence:
  - reference: PMID:34146746
    reference_title: "Diversity in Serine/Threonine Protein Kinase-4 Deficiency and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The increase in plasmablasts (P = .003) and decrease in switched memory B cells (P = .022) were significant.
    explanation: >-
      Quantifies the plasmablast increase against age-matched healthy controls with a reported p
      value.
- name: Decreased class-switched memory B cell proportion
  description: >-
    Reduced class-switched memory B cells accompany the plasmablast expansion and are the B-cell
    correlate of impaired humoral memory.
  phenotype_term:
    preferred_term: Decreased switched memory B cell proportion
    term:
      id: HP:0030388
      label: Decreased class-switched memory B cell proportion
  evidence:
  - reference: PMID:34146746
    reference_title: "Diversity in Serine/Threonine Protein Kinase-4 Deficiency and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The increase in plasmablasts (P = .003) and decrease in switched memory B cells (P = .022) were significant.
    explanation: Quantifies the switched-memory B-cell decrease with a reported p value.
- name: Increased double-negative T cell number
  description: >-
    Elevated CD4-CD8- double-negative T cells are the finding that makes STK4 deficiency
    mimic ALPS. Critically, the resemblance is superficial: in the reported patients neither an
    ALPS-associated FAS-pathway mutation nor a FAS-mediated apoptosis defect was present.
  phenotype_term:
    preferred_term: Elevated double-negative T cell number
    term:
      id: HP:0002851
      label: Increased double-negative T cell number
  evidence:
  - reference: PMID:30386345
    reference_title: "EBV Negative Lymphoma and Autoimmune Lymphoproliferative Syndrome Like Phenotype Extend the Clinical Spectrum of Primary Immunodeficiency Caused by STK4 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      elevated DNT cell number, non-malignant lymphadenopathy and
      hepatosplenomegaly, hematolytic anemia, hypergammaglobulinemia.
    explanation: Documents elevated double-negative T cell number in an STK4-deficient patient.
  - reference: PMID:30386345
    reference_title: "EBV Negative Lymphoma and Autoimmune Lymphoproliferative Syndrome Like Phenotype Extend the Clinical Spectrum of Primary Immunodeficiency Caused by STK4 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      None of the patients harbored typically ALPS-associated mutations of the Fas receptor mediated apoptotic pathway and Fas-mediated apoptosis was not affected.
    explanation: >-
      The negative result that separates this ALPS-like presentation from genuine ALPS, and the
      basis for the differential diagnosis curated below.
- name: Increased gamma-delta T cell proportion
  description: >-
    Gamma-delta T cells expand, and in one adult patient the expanded population accounted for
    most circulating CD3+ cells despite a low CD4+ count - so a normal total CD3 count can conceal
    the CD4 deficit. The proposed reading is compensatory rather than pathological, though the
    expanded cells were themselves functionally impaired.
  phenotype_term:
    preferred_term: Vd2 gamma-delta T cell expansion
    term:
      id: HP:0500270
      label: Increased gamma-delta T cell proportion
  evidence:
  - reference: PMID:39110273
    reference_title: "Epidermodysplasia Verruciformis and Vδ2 γδ T-cell Expansion in STK4 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Despite his low CD4+ T-cell count, the patient had normal counts of CD3+ cells, predominantly double-negative T cells (67.4%), which turned out to be Vδ2+ γδ T cells.
    explanation: >-
      Quantifies the gamma-delta expansion and shows it masking the CD4 deficit behind a normal
      CD3 count.
  - reference: PMID:39110273
    reference_title: "Epidermodysplasia Verruciformis and Vδ2 γδ T-cell Expansion in STK4 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      γδ T-cell expansion has frequently been observed in the 33 reported cases with STK4 deficiency.
    explanation: >-
      Establishes that the expansion is a recurring feature across the reported case series, not a
      one-patient observation.
- name: Persistent human papillomavirus infection
  description: >-
    Beyond ordinary cutaneous warts, STK4 deficiency can produce epidermodysplasia verruciformis -
    disseminated infection with a beta-papillomavirus that is not virulent in immunocompetent
    hosts. The reported patient's HPV38 disease is the clearest demonstration that the
    papillomavirus susceptibility here is qualitative and not just a matter of wart burden.
  phenotype_term:
    preferred_term: Epidermodysplasia verruciformis due to HPV38
    term:
      id: HP:0020114
      label: Persistent human papillomavirus infection
  evidence:
  - reference: PMID:39110273
    reference_title: "Epidermodysplasia Verruciformis and Vδ2 γδ T-cell Expansion in STK4 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe here a patient in his thirties who presented with epidermodysplasia verruciformis (EV) due to infection with a weakly virulent beta-papillomavirus (HPV38) and CD4+ T-cell lymphopenia.
    explanation: >-
      Documents epidermodysplasia verruciformis from a weakly virulent beta-papillomavirus in a
      genetically confirmed STK4-deficient patient.
- name: Decreased specific antibody response to vaccination
  description: >-
    Insufficient vaccine responses were documented alongside the T-cell abnormalities, which
    matters practically: it is part of the case for immunoglobulin replacement rather than relying
    on active immunisation.
  phenotype_term:
    preferred_term: Insufficient vaccination responses
    term:
      id: HP:0032140
      label: Decreased specific antibody response to vaccination
  evidence:
  - reference: PMID:33078349
    reference_title: "STK4 Deficiency Impairs Innate Immunity and Interferon Production Through Negative Regulation of TBK1-IRF3 Signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the patient displayed some indicators of impaired adaptive immunity in the form of insufficient vaccination responses, T cell lymphopenia, and reduced Treg fractions
    explanation: Documents insufficient vaccination responses in an STK4-deficient patient.
- name: Decreased regulatory T cell proportion
  description: >-
    Reduced regulatory T-cell fractions offer a plausible link between the same lesion and the
    autoimmune half of the phenotype, which the T-cell survival defect alone does not explain.
  phenotype_term:
    preferred_term: Reduced Treg fractions
    term:
      id: HP:0020113
      label: Decreased regulatory T cell proportion
  evidence:
  - reference: PMID:33078349
    reference_title: "STK4 Deficiency Impairs Innate Immunity and Interferon Production Through Negative Regulation of TBK1-IRF3 Signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the patient displayed some indicators of impaired adaptive immunity in the form of insufficient vaccination responses, T cell lymphopenia, and reduced Treg fractions
    explanation: Documents reduced regulatory T-cell fractions in an STK4-deficient patient.
- name: Hypothyroidism
  description: >-
    A non-immunological feature reported in one patient. Recorded because the entry otherwise
    reads as a purely immune disorder, and STK4/MST1 is a Hippo-pathway kinase with roles beyond
    lymphocytes; a single case does not establish it as a disease feature.
  phenotype_term:
    preferred_term: Hypothyroidism
    term:
      id: HP:0000821
      label: Hypothyroidism
  evidence:
  - reference: PMID:33078349
    reference_title: "STK4 Deficiency Impairs Innate Immunity and Interferon Production Through Negative Regulation of TBK1-IRF3 Signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      as well as a somatic phenotype with hypothyroidism and low stature
    explanation: Documents hypothyroidism as part of the somatic phenotype in one patient.
- name: Short stature
  description: Reported with hypothyroidism as part of the somatic phenotype in one patient.
  phenotype_term:
    preferred_term: Low stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:33078349
    reference_title: "STK4 Deficiency Impairs Innate Immunity and Interferon Production Through Negative Regulation of TBK1-IRF3 Signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      as well as a somatic phenotype with hypothyroidism and low stature
    explanation: Documents low stature as part of the somatic phenotype in one patient.
genetic:
- name: STK4
  gene_term:
    preferred_term: STK4
    term:
      id: hgnc:11408
      label: STK4
  association: CAUSATIVE
  notes: >-
    STK4 deficiency is caused by biallelic loss-of-function variants in STK4
    (formerly MST1), typically homozygous premature-termination, frameshift,
    nonsense, or splice-site mutations that abolish MST1 protein expression.
  evidence:
  - reference: PMID:22294732
    reference_title: "The phenotype of human STK4 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Homozygosity mapping and candidate gene sequencing revealed a homozygous
      premature termination mutation in the gene STK4 (serine threonine kinase
      4, formerly having the symbol MST1).
    explanation: >-
      Establishes STK4 (MST1) as the causative gene with a homozygous
      loss-of-function mutation.
  - reference: PMID:22174160
    reference_title: "MST1 mutations in autosomal recessive primary immunodeficiency characterized by defective naive T-cell survival."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we report a primary immunodeficiency phenotype associated with MST1
      deficiency and primarily characterized by a progressive loss of naive T
      cells.
    explanation: >-
      Independent identification of MST1 (STK4) deficiency as the cause of this
      primary immunodeficiency.
  - reference: PMID:34427831
    reference_title: "A Novel STK4 Mutation Impairs T Cell Immunity Through Dysregulation of Cytokine-Induced Adhesion and Chemotaxis Genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a novel, homozygous nonsense STK4 mutation (NM_006282.2:c.871C > T,
      p.Arg291*) identified in a pediatric patient
    explanation: >-
      Documents allelic heterogeneity with a homozygous nonsense STK4 variant
      causing loss of function.
treatments:
- name: Immunoglobulin replacement therapy
  description: >-
    Immunoglobulin substitution (IVIG/SCIG) is a mainstay of treatment to manage
    humoral immune deficiency.
  treatment_term:
    preferred_term: immunoglobulin infusion therapy
    term:
      id: NCIT:C62710
      label: Immunoglobulin Therapy
  target_mechanisms:
  - target: Impaired naive T-cell survival
    treatment_effect: MODULATES
    description: >-
      Immunoglobulin substitution does not correct the T-cell survival defect
      itself but compensates for the downstream humoral immune deficiency that
      results from impaired lymphocyte function.
    evidence:
    - reference: PMID:34146746
      reference_title: "Diversity in Serine/Threonine Protein Kinase-4 Deficiency and Review of the Literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Immunoglobulins, antibacterial, and antiviral prophylaxis are the
        mainstays of treatment.
      explanation: >-
        Immunoglobulin replacement is a mainstay that compensates for the
        humoral consequences of the underlying lymphocyte defect.
  evidence:
  - reference: PMID:34146746
    reference_title: "Diversity in Serine/Threonine Protein Kinase-4 Deficiency and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunoglobulins, antibacterial, and antiviral prophylaxis are the
      mainstays of treatment.
    explanation: Identifies immunoglobulin substitution as a mainstay of treatment.
- name: Antimicrobial prophylaxis
  description: >-
    Antibacterial and antiviral prophylaxis are mainstays of treatment to
    prevent recurrent infections.
  treatment_term:
    preferred_term: antimicrobial agent therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:34146746
    reference_title: "Diversity in Serine/Threonine Protein Kinase-4 Deficiency and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunoglobulins, antibacterial, and antiviral prophylaxis are the
      mainstays of treatment.
    explanation: Identifies antibacterial/antiviral prophylaxis as a mainstay of treatment.
- name: Hematopoietic stem cell transplantation
  description: >-
    Allogeneic HSCT is the potential definitive therapy aiming to restore the
    immune system, though more data are needed to recommend it as a uniformly
    safe therapy.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Impaired naive T-cell survival
    treatment_effect: RESTORES
    description: >-
      Allogeneic HSCT replaces the STK4-deficient hematopoietic system with
      donor cells, restoring normal naive T-cell survival and broader immune
      function.
    evidence:
    - reference: PMID:30386345
      reference_title: "EBV Negative Lymphoma and Autoimmune Lymphoproliferative Syndrome Like Phenotype Extend the Clinical Spectrum of Primary Immunodeficiency Caused by STK4 Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        State-of-the-art treatment regimens consist of prevention or treatment of
        infections, immunoglobulin substitution (IVIG) and restoration of the
        immune system by hematopoietic stem cell transplantation.
      explanation: >-
        HSCT restores the immune system by replacing the defective
        hematopoietic compartment, correcting the underlying mechanisms.
  evidence:
  - reference: PMID:30386345
    reference_title: "EBV Negative Lymphoma and Autoimmune Lymphoproliferative Syndrome Like Phenotype Extend the Clinical Spectrum of Primary Immunodeficiency Caused by STK4 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      State-of-the-art treatment regimens consist of prevention or treatment of
      infections, immunoglobulin substitution (IVIG) and restoration of the
      immune system by hematopoietic stem cell transplantation.
    explanation: Identifies HSCT as the immune-restorative treatment for STK4 deficiency.
  - reference: PMID:34146746
    reference_title: "Diversity in Serine/Threonine Protein Kinase-4 Deficiency and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, more data are needed to recommend hematopoietic stem cell
      transplantation as a safe therapy.
    explanation: >-
      Notes the uncertainty around HSCT safety, qualifying its role as definitive
      therapy.
- name: Immunomodulatory therapy
  description: >-
    Used for the inflammatory and autoimmune complications rather than for the immunodeficiency
    itself. The cohort review presents this as a permissive option ("clinicians may use") rather
    than a recommendation, and no specific agent or regimen is named in the cited source, so none
    is curated here.
  treatment_term:
    preferred_term: immunomodulatory therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Autoimmunity
    term:
      id: HP:0002960
      label: Autoimmunity
  evidence:
  - reference: PMID:34146746
    reference_title: "Diversity in Serine/Threonine Protein Kinase-4 Deficiency and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinicians may use immunomodulatory therapies during inflammatory or autoimmune complications.
    directness: INDIRECT
    explanation: >-
      Indirect: the source states this as a permissible option without naming an
      agent, a regimen, or an outcome.
progression:
- phase: Symptom onset and diagnostic delay
  age_range: Median 6 years 8 months at onset; median 7 years 5 months at diagnosis
  notes: >-
    STK4 deficiency is not typically a neonatal SCID presentation. In the nine-patient clinical
    cohort the median age at symptom onset was 6 years 8 months and the median age at diagnosis 7
    years 5 months, with both ranges extending past 20 years. The gap between the two medians is
    short, so the delay in this disease is mostly in when it starts declaring itself rather than
    in how long recognition then takes - but the upper end of the range is what matters for
    ascertainment, since an adult presenting with CD4 lymphopenia, warts and lymphoma is a
    recognised route to the diagnosis.
  evidence:
  - reference: PMID:34146746
    reference_title: "Diversity in Serine/Threonine Protein Kinase-4 Deficiency and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the cohort, median age at symptom onset and age at diagnosis were 6 years 8 months (range, 6-248 months) and 7 years 5 months (range, 6-260 months), respectively.
    explanation: Reports both medians and their ranges in the nine-patient cohort.
  - reference: PMID:39110273
    reference_title: "Epidermodysplasia Verruciformis and Vδ2 γδ T-cell Expansion in STK4 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient had no relevant history of infectious disease during childhood other than mild wart-like lesion on the skin, but he developed diffuse large B-cell lymphoma (DLBCL) and EBV viremia with a low viral load in his thirties.
    explanation: >-
      A worked example of the late end of the range: an essentially unremarkable childhood
      followed by lymphoma in the fourth decade.
- phase: Variable clinical penetrance
  notes: >-
    Recorded because it constrains how the rest of this entry should be read. Infectious-disease
    penetrance varies substantially between patients with the same genetic defect, so the
    phenotype frequencies curated here describe a reported case series rather than the expected
    course of any individual patient.
  evidence:
  - reference: PMID:39110273
    reference_title: "Epidermodysplasia Verruciformis and Vδ2 γδ T-cell Expansion in STK4 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical penetrance of infectious diseases varies considerably among patients with inborn errors of immunity (IEI), even for identical genetic defects.
    explanation: >-
      States the variable-penetrance principle, offered by the authors as the frame for their own
      STK4 case.
differential_diagnoses:
- name: Autosomal recessive hyper-IgE syndrome
  description: >-
    The cohort review names this as the crucial differential, because the two diseases share the
    two features that most readily prompt the diagnosis: atopy and CD4 lymphopenia. Elevated IgE
    is common in STK4 deficiency, so the immunoglobulin pattern does not separate them either.
  distinguishing_features:
  - Progressive T- and B-cell lymphopenia with intermittent neutropenia favours STK4 deficiency.
  - Congenital heart defects such as atrial septal defect are reported in STK4 deficiency.
  - EBV-driven lymphoproliferation and lymphoma are characteristic of STK4 deficiency.
  - Identification of a biallelic loss-of-function STK4 variant is confirmatory.
  disease_term:
    preferred_term: autosomal recessive hyper-IgE syndrome
    term:
      id: MONDO:0018037
      label: hyper-IgE syndrome
  evidence:
  - reference: PMID:34146746
    reference_title: "Diversity in Serine/Threonine Protein Kinase-4 Deficiency and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The differential diagnosis with autosomal recessive hyper-IgE syndrome is crucial. Because, atopy and CD4 lymphopenia are common in both diseases.
    explanation: >-
      The authors' own identification of the differential and of the two features that make it
      difficult.
- name: Autoimmune lymphoproliferative syndrome
  description: >-
    STK4-deficient patients can present with a full ALPS-like picture - elevated double-negative T
    cells, non-malignant lymphadenopathy, hepatosplenomegaly, haemolytic anaemia and
    hypergammaglobulinaemia - and both patients in one report were initially given a clinical ALPS
    diagnosis.
  distinguishing_features:
  - ALPS-associated FAS-pathway mutations were absent in the STK4-deficient patients.
  - FAS-mediated apoptosis was intact, unlike in genuine ALPS.
  - Recurrent infections and CD4 lymphopenia point away from ALPS toward a combined immunodeficiency.
  disease_term:
    preferred_term: autoimmune lymphoproliferative syndrome
    term:
      id: MONDO:0017979
      label: autoimmune lymphoproliferative syndrome
  evidence:
  - reference: PMID:30386345
    reference_title: "EBV Negative Lymphoma and Autoimmune Lymphoproliferative Syndrome Like Phenotype Extend the Clinical Spectrum of Primary Immunodeficiency Caused by STK4 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Also patient P1 presented with ALPS-like features (lymphadenopathy, elevated DNT cell number and increased Vitamin B12 levels) and both were initially clinically diagnosed as ALPS-like.
    explanation: Documents the ALPS-like misdirection in two STK4-deficient patients.
  - reference: PMID:30386345
    reference_title: "EBV Negative Lymphoma and Autoimmune Lymphoproliferative Syndrome Like Phenotype Extend the Clinical Spectrum of Primary Immunodeficiency Caused by STK4 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      None of the patients harbored typically ALPS-associated mutations of the Fas receptor mediated apoptotic pathway and Fas-mediated apoptosis was not affected.
    explanation: The genetic and functional findings that exclude genuine ALPS.
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 29 citations 2026-06-04T01:07:14.603364

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: STK4 Deficiency
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on STK4 Deficiency covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

STK4 Deficiency (MST1 deficiency): Comprehensive Disease Characteristics Report

Executive summary

STK4 deficiency (also called MST1 deficiency) is a rare autosomal recessive combined immunodeficiency (CID) caused by biallelic loss-of-function variants in STK4 (encoding MST1, a Hippo-pathway kinase). It is characterized by profound CD4+ T-cell lymphopenia, impaired naïve T-cell homeostasis with increased apoptosis, intermittent neutropenia, variable dysgammaglobulinemia, recurrent bacterial/viral/fungal infections (notably EBV viremia and viral skin disease including HPV warts/epidermodysplasia verruciformis), and increased risk of lymphoproliferation/lymphoma, sometimes even EBV-negative. Recent 2024 case reports broaden the spectrum to adult-onset recognition with γδ T-cell expansion and atypically mild courses with residual/truncated STK4 protein. (abdollahpour2012thephenotypeof pages 1-2, schipp2018ebvnegativelymphoma pages 1-2, alsaud2024auniquestk4 pages 2-3, ying2024epidermodysplasiaverruciformisand pages 8-8)

Target Disease

  • Disease Name: STK4 Deficiency
  • Category: Mendelian / Inborn error of immunity (combined immunodeficiency)
  • MONDO ID: MONDO:0013934 (“combined immunodeficiency due to STK4 deficiency”) (OpenTargets Search: STK4 deficiency,immunodeficiency due to STK4 deficiency,primary immunodeficiency STK4)

1. Disease information

Definition/overview

Human STK4 (MST1) deficiency is an autosomal recessive inborn error of immunity presenting as combined immunodeficiency with prominent CD4+ T-cell lymphopenia, susceptibility to infections (bacterial/viral/fungal), and complications including EBV-associated lymphoproliferation and lymphoma. (schipp2018ebvnegativelymphoma pages 1-2, radwan2020acaseof pages 1-2, guennoun2021anovelstk4 pages 1-3)

Key identifiers (retrieved)

A structured identifier summary is provided here: | Identifier/resource | Value | Supported name/synonym(s) | Evidence / URL | |---|---|---|---| | MONDO | MONDO:0013934 | combined immunodeficiency due to STK4 deficiency | OpenTargets disease-target association lists disease as “combined immunodeficiency due to STK4 deficiency” with MONDO_0013934 (OpenTargets Search: STK4 deficiency,immunodeficiency due to STK4 deficiency,primary immunodeficiency STK4) | | OMIM / MIM (gene) | STK4; MIM:604965 | STK4, serine threonine kinase 4; MST1 (protein/literature synonym) | Abdollahpour et al. explicitly give “STK4; MIM: 604965” (Blood 2012, DOI: https://doi.org/10.1182/blood-2011-09-378158) (abdollahpour2012thephenotypeof pages 1-2) | | Literature disease label | not a separate registry identifier in current evidence | STK4 deficiency | Used as article/disease label in “The phenotype of human STK4 deficiency” (Blood 2012, DOI: https://doi.org/10.1182/blood-2011-09-378158) and “STK4 deficiency impairs innate immunity and interferon production…” (J Clin Immunol 2021, DOI: https://doi.org/10.1007/s10875-020-00891-7) (abdollahpour2012thephenotypeof pages 1-2, jørgensen2021stk4deficiencyimpairs pages 1-2) | | Literature disease label | not a separate registry identifier in current evidence | MST1 deficiency | Used in literature as synonym, e.g., “autosomal recessive MST1 deficiency” / “MST1 (STK4) deficiency” (J Clin Immunol 2016, DOI: https://doi.org/10.1007/s10875-016-0232-2) (dang2016defectiveleukocyteadhesion pages 1-2) | | Literature disease label | aligns with MONDO label above | combined immunodeficiency due to STK4 deficiency | Supported by OpenTargets MONDO label and by multiple papers describing STK4 deficiency as an autosomal recessive combined immunodeficiency (OpenTargets Search: STK4 deficiency,immunodeficiency due to STK4 deficiency,primary immunodeficiency STK4, guennoun2021anovelstk4 pages 1-3, alsaud2024auniquestk4 pages 1-2) | | Key 2024 literature naming | case-report terminology | STK4 deficiency; STK4 (MST1) deficiency | Al-Saud 2024: Front Immunol, DOI: https://doi.org/10.3389/fimmu.2024.1329610; Ying 2024: J Clin Immunol, DOI: https://doi.org/10.1007/s10875-024-01780-z (alsaud2024auniquestk4 pages 1-2, ying2024epidermodysplasiaverruciformisand pages 8-8) | | ICD-10 | not retrieved in current evidence | — | not retrieved in current evidence | | ICD-11 | not retrieved in current evidence | — | not retrieved in current evidence | | MeSH | not retrieved in current evidence | — | not retrieved in current evidence | | Orphanet | not retrieved in current evidence | — | not retrieved in current evidence |

Table: This table compiles the disease identifiers and literature-supported names/synonyms for STK4 deficiency available in the currently gathered evidence. It distinguishes registry-backed identifiers from labels used in the clinical literature and flags vocabularies not yet retrieved.

Notes on missing identifiers: ICD-10/ICD-11, MeSH, and Orphanet identifiers were not present in the retrieved full texts used for evidence extraction, and are therefore not reported here (rather than inferred). (artifact-00)

Synonyms / alternative names

  • STK4 deficiency (most common in clinical case literature) (abdollahpour2012thephenotypeof pages 1-2)
  • MST1 deficiency / MST1 (STK4) deficiency (dang2016defectiveleukocyteadhesion pages 1-2)
  • “Combined immunodeficiency due to STK4 deficiency” (MONDO label) (OpenTargets Search: STK4 deficiency,immunodeficiency due to STK4 deficiency,primary immunodeficiency STK4)

Evidence origin

The current knowledge summarized here is derived primarily from: - Aggregated peer-reviewed primary literature (case reports/series and mechanistic studies) (abdollahpour2012thephenotypeof pages 1-2, schipp2018ebvnegativelymphoma pages 1-2, radwan2020acaseof pages 1-2, dang2016defectiveleukocyteadhesion pages 1-2) - Disease-level aggregation in OpenTargets/MONDO mappings (OpenTargets Search: STK4 deficiency,immunodeficiency due to STK4 deficiency,primary immunodeficiency STK4)

2. Etiology

Disease causal factors

  • Genetic: Biallelic (homozygous) loss-of-function variants in STK4 (MST1) cause autosomal recessive CID. Examples include nonsense, frameshift, splice, and large deletions. (abdollahpour2012thephenotypeof pages 1-2, schipp2018ebvnegativelymphoma pages 1-2, jørgensen2021stk4deficiencyimpairs pages 2-4, radwan2020acaseof pages 1-2)
  • Mechanistic: Loss of MST1 disrupts immune cell survival, trafficking/adhesion, and antiviral interferon signaling, producing combined immunodeficiency and immune dysregulation. (dang2016defectiveleukocyteadhesion pages 1-2, jørgensen2021stk4deficiencyimpairs pages 1-2)

Risk factors

  • Consanguinity is repeatedly noted in reported families and is consistent with autosomal recessive inheritance. (abdollahpour2012thephenotypeof pages 3-4, dang2016defectiveleukocyteadhesion pages 1-2, ying2024epidermodysplasiaverruciformisand pages 1-2)

Protective factors

No genetic/environmental protective factors were identified in the retrieved evidence.

Gene–environment interactions

A 2024 STK4-deficient EV case explicitly frames clinical variability as influenced by “pathogen exposure, healthcare access and host-environment interactions,” indicating penetrance is modulated by exposure context even for identical genetic defects. (ying2024epidermodysplasiaverruciformisand pages 1-2)

3. Phenotypes

A phenotype scaffold with suggested HPO mappings is provided here: | Phenotype category | Description | Typical onset/course in retrieved evidence | Suggested HPO term(s) | Key supporting citations | |---|---|---|---|---| | Recurrent infections | Recurrent bacterial and viral infections are a core feature of STK4 deficiency/combined immunodeficiency. Reported examples include recurrent otitis, chest infections, skin abscesses, urinary infections, severe gastroenteritis, pneumonias, VZV/herpes zoster, and cryptosporidiosis. Frequency: not quantified in retrieved sources. | Usually childhood onset; can persist chronically into adolescence/adulthood. | HP:0002719 Recurrent infections; HP:0011106 Recurrent respiratory infections; HP:0002027 Recurrent skin infections | (abdollahpour2012thephenotypeof pages 1-2, schipp2018ebvnegativelymphoma pages 1-2, schipp2018ebvnegativelymphoma pages 7-8, alsaud2024auniquestk4 pages 2-3, radwan2020acaseof pages 1-2, dang2016defectiveleukocyteadhesion pages 1-2, jørgensen2021stk4deficiencyimpairs pages 1-2) | | EBV viremia / EBV-associated disease | Persistent EBV viremia and EBV-associated lymphoproliferative disease are repeatedly reported; one 2024 paper notes nearly half of reported patients had EBV viremia. Frequency in the full literature is incompletely quantified in retrieved primary sources. | Often appears in childhood to adolescence; may be persistent/chronic. | HP:0031864 Epstein-Barr virus infection; HP:0012315 Viremia; HP:0002841 Recurrent viral infections | (schipp2018ebvnegativelymphoma pages 1-2, radwan2020acaseof pages 1-2, guennoun2021anovelstk4 pages 1-3, alsaud2024auniquestk4 pages 1-2) | | Lymphoma / lymphoproliferation | B-cell lymphoma, Hodgkin lymphoma, Burkitt lymphoma, and EBV-associated lymphoproliferation have been reported; lymphoma may occur even without detectable EBV. Frequency: not quantified in retrieved sources. | Childhood or adolescence in reported cases; severe, progressive complication. | HP:0002664 Neoplasm; HP:0100753 B-cell lymphoma; HP:0002830 Recurrent lymphoma | (schipp2018ebvnegativelymphoma pages 1-2, schipp2018ebvnegativelymphoma pages 7-8, radwan2020acaseof pages 1-2) | | Warts / HPV disease | Cutaneous warts are common in case reports; HPV types 57 and 84 were documented in an early family, and EV/HPV susceptibility is part of the phenotype spectrum. One 2024 case specifically reported epidermodysplasia verruciformis due to HPV38. Frequency: not quantified in retrieved sources. | Often begins in childhood; can be chronic/persistent. | HP:0001923 Cutaneous warts; HP:0200058 Epidermodysplasia verruciformis; HP:0012372 Viral skin infection | (abdollahpour2012thephenotypeof pages 3-4, alsaud2024auniquestk4 pages 2-3, ying2024epidermodysplasiaverruciformisand pages 8-8) | | Mucocutaneous candidiasis / oral thrush | Recurrent mucocutaneous candidiasis, oral thrush, and related fungal mucosal infections are recurrently described. Frequency: not quantified in retrieved sources. | Childhood onset; often recurrent. | HP:0002721 Chronic mucocutaneous candidiasis; HP:0000175 Oral candidiasis | (abdollahpour2012thephenotypeof pages 1-2, abdollahpour2012thephenotypeof pages 3-4, alsaud2024auniquestk4 pages 2-3, radwan2020acaseof pages 1-2) | | Tuberculosis / mycobacterial-like infection | Pulmonary tuberculosis, granulomatous lymphadenopathy evoking mycobacterial infection, and prolonged anti-TB therapy have been reported in individual patients. Frequency: not quantified in retrieved sources. | Childhood to adolescence; may be prolonged/relapsing. | HP:0032264 Tuberculosis; HP:0002840 Increased susceptibility to mycobacterial infection; HP:0002716 Lymphadenopathy | (guennoun2021stk4deficiencyunderlies pages 15-19, radwan2020acaseof pages 1-2, guennoun2021anovelstk4 pages 1-3) | | Autoimmunity / ALPS-like phenotype | Autoimmune hemolytic anemia, thrombocytopenia, polyarthritis, lymphadenopathy, hepatosplenomegaly, elevated double-negative T cells, and ALPS-like presentations extend the phenotype. Fas-mediated apoptosis was reportedly intact. Frequency: not quantified in retrieved sources. | Childhood to adolescence; variable, relapsing or persistent immune dysregulation. | HP:0001890 Autoimmune hemolytic anemia; HP:0001744 Splenomegaly; HP:0002716 Lymphadenopathy; HP:0001945 Fever; HP:0012649 Autoimmunity | (schipp2018ebvnegativelymphoma pages 1-2, schipp2018ebvnegativelymphoma pages 7-8) | | Cardiac defects | Structural cardiac anomalies are reported, including atrial septal defect, patent foramen ovale, valvular insufficiency, and pulmonary valve stenosis. Frequency: not quantified in retrieved sources. | Congenital/childhood-recognized; generally non-progressive structural findings. | HP:0001631 Atrial septal defect; HP:0001653 Patent foramen ovale; HP:0001642 Pulmonary valve stenosis | (abdollahpour2012thephenotypeof pages 1-2, abdollahpour2012thephenotypeof pages 3-4, schipp2018ebvnegativelymphoma pages 7-8, alsaud2024auniquestk4 pages 1-2) | | Hypothyroidism / short stature | One STK4-deficient child had hypothyroidism and short stature as part of the broader syndromic presentation. Frequency: not quantified in retrieved sources. | Childhood; chronic. | HP:0000821 Hypothyroidism; HP:0004322 Short stature | (jørgensen2021stk4deficiencyimpairs pages 1-2) | | CD4 lymphopenia | Profound CD4+ T-cell lymphopenia is among the most consistent laboratory hallmarks; values in retrieved reports include very low absolute CD4 counts and reduced naive CD4 subsets. | Usually detected in childhood; chronic/persistent. | HP:0005403 CD4 lymphocytopenia; HP:0011839 Abnormality of T cell count | (abdollahpour2012thephenotypeof pages 1-2, schipp2018ebvnegativelymphoma pages 1-2, schipp2018ebvnegativelymphoma pages 7-8, radwan2020acaseof pages 1-2, guennoun2021stk4deficiencyunderlies pages 15-19, dang2016defectiveleukocyteadhesion pages 1-2) | | T- and B-cell lymphopenia | Combined T- and B-cell lymphopenia is frequently described, though severity is variable and some cases retain a near-normal CD19+ fraction. Frequency: not quantified in retrieved sources. | Childhood onset; chronic. | HP:0001888 Lymphopenia; HP:0005404 B lymphocytopenia; HP:0011839 Abnormality of T cell count | (abdollahpour2012thephenotypeof pages 1-2, abdollahpour2012thephenotypeof pages 3-4, alsaud2024auniquestk4 pages 2-3, guennoun2021stk4deficiencyunderlies pages 15-19, guennoun2021anovelstk4 pages 1-3) | | Dysgammaglobulinemia | Immunoglobulin abnormalities are variable, including hypergammaglobulinemia, low IgG2/poor vaccine responses, elevated IgM, hypogammaglobulinemia, or dysregulated immunoglobulin levels. Frequency: not quantified in retrieved sources. | Variable across childhood/adolescence; chronic. | HP:0004313 Decreased circulating IgG level; HP:0010783 Elevated circulating IgM level; HP:0010701 Abnormality of immune system physiology | (schipp2018ebvnegativelymphoma pages 1-2, schipp2018ebvnegativelymphoma pages 7-8, alsaud2024auniquestk4 pages 2-3, dang2016defectiveleukocyteadhesion pages 1-2, jørgensen2021stk4deficiencyimpairs pages 1-2) | | Neutropenia | Intermittent or persistent neutropenia is repeatedly reported; sometimes accompanied by apparently normal marrow maturation. Frequency: not quantified in retrieved sources. | Usually childhood onset; intermittent/fluctuating in several reports. | HP:0001875 Neutropenia; HP:0001889 Frequent infections | (abdollahpour2012thephenotypeof pages 1-2, abdollahpour2012thephenotypeof pages 3-4, alsaud2024auniquestk4 pages 2-3, radwan2020acaseof pages 1-2) | | Double-negative T-cell expansion / ALPS-like immunophenotype | Elevated TCRαβ+ CD4-CD8- double-negative T cells were reported in ALPS-like patients. Frequency: not quantified in retrieved sources. | Childhood/adolescent presentation; persistent in reported cases. | HP:0033079 Increased double negative T cells; HP:0012649 Autoimmunity | (schipp2018ebvnegativelymphoma pages 1-2, schipp2018ebvnegativelymphoma pages 7-8) | | γδ T-cell expansion | Expanded γδ T-cell populations, including Vδ2+ γδ T-cell predominance, have been described and may represent a compensatory antiviral response. One 2024 report states γδ T-cell expansion has frequently been observed among 33 reported cases. | Can be recognized in adulthood as well as earlier disease; chronic. | HP:0011832 Abnormal lymphocyte physiology; HP:0011839 Abnormality of T cell count | (ying2024epidermodysplasiaverruciformisand pages 8-8) | | Naive T-cell depletion / increased apoptosis | Beyond numeric lymphopenia, patients show marked loss of naïve T cells with increased apoptosis and defective T-cell survival. Frequency: not quantified in retrieved sources. | Chronic immunologic abnormality from childhood onward. | HP:0011839 Abnormality of T cell count; HP:0030783 Increased lymphocyte apoptosis | (guennoun2021stk4deficiencyunderlies pages 15-19, dang2016defectiveleukocyteadhesion pages 1-2, guennoun2021anovelstk4 pages 1-3) | | Defective leukocyte adhesion / chemotaxis | Functional phenotype includes impaired chemotaxis and adhesion (e.g., deficient CXCL11 responses, impaired ICAM-1/LFA-1 binding), relevant to host defense and trafficking. Frequency: not quantified in retrieved sources. | Chronic cellular defect; detected on functional testing rather than routine clinical exam. | HP:0012640 Abnormal leukocyte chemotaxis; HP:0011893 Abnormal leukocyte function | (dang2016defectiveleukocyteadhesion pages 1-2, guennoun2021anovelstk4 pages 1-3) |

Table: This table summarizes the major clinical and laboratory phenotypes reported for STK4 deficiency, along with likely HPO mappings and supporting citations from the retrieved evidence. It is useful as a KB-ready phenotype scaffold when frequencies are incompletely quantified in the available primary reports.

Hallmark phenotypes (high-confidence)

  • CD4+ T-cell lymphopenia (often profound) with reduction of naïve subsets (abdollahpour2012thephenotypeof pages 4-6, dang2016defectiveleukocyteadhesion pages 1-2)
  • Recurrent infections: bacterial/viral/fungal; respiratory infections and skin infections common (abdollahpour2012thephenotypeof pages 1-2, alsaud2024auniquestk4 pages 2-3)
  • Viral susceptibility, including EBV viremia/LPD and viral skin disease (warts/EV) (schipp2018ebvnegativelymphoma pages 1-2, ying2024epidermodysplasiaverruciformisand pages 1-2)
  • Intermittent neutropenia in multiple reports (abdollahpour2012thephenotypeof pages 3-4, radwan2020acaseof pages 1-2)
  • Lymphoma predisposition including EBV-negative lymphoma (schipp2018ebvnegativelymphoma pages 1-2, schipp2018ebvnegativelymphoma pages 2-3)

Quantitative examples / statistics from recent studies

  • Double-negative T-cell predominance: A 2024 adult case had predominantly double-negative T cells (67.4%), identified as Vδ2+ γδ T cells. (ying2024epidermodysplasiaverruciformisand pages 1-2)
  • Case count note: The same 2024 report states “γδ T-cell expansion has frequently been observed in the 33 reported cases with STK4 deficiency.” (ying2024epidermodysplasiaverruciformisand pages 1-2)
  • EBV proportion estimate (secondary within a primary paper): A 2024 case report states “nearly half of the patients” exhibit EBV viremia, reflecting the authors’ synthesis of published cases (not a de novo cohort analysis). (alsaud2024auniquestk4 pages 1-2)

Quality of life impact

Direct QoL instrument data (e.g., SF-36/EQ-5D) were not identified in the retrieved sources. Clinically, recurrent infections, chronic viral skin disease, and malignancy risk imply significant morbidity and healthcare utilization. (radwan2020acaseof pages 1-2, ying2024epidermodysplasiaverruciformisand pages 1-2)

4. Genetic / molecular information

Causal gene

  • STK4 (MST1), OMIM/MIM 604965 (gene identifier explicitly present in Blood 2012) (abdollahpour2012thephenotypeof pages 1-2)

Pathogenic variants (examples from retrieved primary literature)

Representative variants reported: - c.G750A, p.W250X (homozygous stop) in a consanguineous family (Blood 2012) (abdollahpour2012thephenotypeof pages 4-6) - c.442C>T, p.Arg148Stop (homozygous nonsense) (Dang 2016) (dang2016defectiveleukocyteadhesion pages 1-2) - c.1103delT, p.M368RfsX2 (frameshift) and c.525+2T>G (splice donor) (Schipp 2018) (schipp2018ebvnegativelymphoma pages 1-2) - Large deletion involving exons 4–8 (Radwan 2020) (radwan2020acaseof pages 1-2) - c.871C>T, p.Arg291 (homozygous nonsense) (Guennoun 2021) (guennoun2021anovelstk4 pages 1-3) - c.523dupA, p.(L174fsTer45) (homozygous frameshift) (Jørgensen 2021) (jørgensen2021stk4deficiencyimpairs pages 1-2) - p.Trp425X* (biallelic stop-gain; adult EV/γδ T-cell expansion case) (Ying 2024) (ying2024epidermodysplasiaverruciformisand pages 1-2)

A KB-ready tabular summary of genetics/diagnostics/treatments across key reports is provided here: | Study (year) | Patient Count | Variant(s) (cDNA/protein) | Diagnostic Method(s) | Key Labs (CD4/T/B/NK, Ig) | Key Infections/Complications | Treatments (IVIG, prophylaxis, HSCT, chemo/rituximab) | Outcomes | |---|---|---|---|---|---|---|---| | Abdollahpour et al. (2012) (abdollahpour2012thephenotypeof pages 1-2, abdollahpour2012thephenotypeof pages 3-4) | 3 | c.G750A, p.W250X | Gene sequencing, SNP homozygosity mapping, Western blot | Profound CD4+, T, and B lymphopenia; high IgE, IgG, IgA; low IgM; neutropenia | Recurrent bacterial/viral infections, skin abscesses, mucocutaneous candidiasis, cutaneous warts (HPV57/84), EBV lymphadenopathy, ASD | NR | NR | | Dang et al. (2016) (dang2016defectiveleukocyteadhesion pages 1-2) | 3 | c.442C>T, p.Arg148Stop | WES, linkage analysis, Sanger sequencing, Western blot | Profound CD4 lymphopenia, absent naive T cells, hypergammaglobulinemia, low IgG2 | Recurrent infections, cryptosporidiosis, EBV-LPD | Rituximab, steroids, HSCT | 1 died from HSCT complications, 1 fatal CMV immune dysregulation, 1 good HSCT outcome | | Schipp et al. (2018) (schipp2018ebvnegativelymphoma pages 1-2) | 2 | c.1103delT (p.M368RfsX2); c.525+2T>G | Targeted exome enrichment, WES, Sanger, qRT-PCR, Western blot | Profound CD4 lymphopenia, elevated DNT cells, variable Ig (low IgG, high IgM/IgA) | Recurrent infections, EBV-negative B-cell and Hodgkin lymphoma, ALPS-like phenotype, active EBV, pulmonary valve stenosis | NHL-BFM 04 chemo, IVIG, steroids, rituximab, HSCT | P1 achieved complete lymphoma remission | | Radwan et al. (2020) (radwan2020acaseof pages 1-2) | 1 | Large deletion (exons 4-8) | Targeted NGS panel | Profound CD4 lymphopenia (0.26x10^9/L), high IgE (800 IU/L) | Recurrent chest infections, persistent EBV viremia, mycobacterial-like caseous granuloma, Burkitt's lymphoma | Anti-TB therapy, monthly IVIG, LMB chemotherapy | Died (chemo failed to control lymphoma) | | Guennoun et al. (2021) (guennoun2021stk4deficiencyunderlies pages 15-19) | 1 | c.871C>T, p.Arg291* | WGS, Sanger, qRT-PCR, Western blot, PhIP-Seq, flow cytometry | Selective CD4+ lymphopenia, reduced naive T cells, normal B and NK counts, expanded CD56bright NK | Recurrent skin/chest infections, bronchiectasis, pulmonary TB, persistent EBV viremia, intermittent neutropenia | Prolonged anti-TB drugs, asthma therapy | Persistent EBV viremia, recurrent hospitalizations | | Jørgensen et al. (2021) (jørgensen2021stk4deficiencyimpairs pages 1-2, jørgensen2021stk4deficiencyimpairs pages 2-4) | 1 | c.523dupA, p.(L174fsTer45) | Targeted NGS panel, Sanger, Western blot, RT-qPCR | Profound CD4 lymphopenia, reduced switched B cells, hyperglobulinemia, intermittent neutropenia | Severe herpes zoster, chronic warts, recurrent pneumonias, hypothyroidism, short stature | Ig substitution (IVIG) | Surviving (HSCT not planned) | | Al-Saud et al. (2024) (alsaud2024auniquestk4 pages 2-3, alsaud2024auniquestk4 pages 1-2) | 1 | Novel truncation of C-terminal SARAH domain | NGS, flow cytometry | Severe T cell lymphopenia (<500/mm3), low B cells, normal NK cells, high IgM, normal IgG/IgA | Recurrent infections (otitis, UTI, oral thrush), severe gastroenteritis | IVIG (0.4 g/kg/4 weeks), prophylactic antibiotics and antifungals | Surviving well (mild clinical phenotype) | | Ying et al. (2024) (ying2024epidermodysplasiaverruciformisand pages 8-8, ying2024epidermodysplasiaverruciformisand pages 1-2) | 1 | p.Trp425X | Exome sequencing, Sanger, flow cytometry | CD4+ T-cell lymphopenia, 67.4% DNT cells (Vδ2+ γδ T cells) | Epidermodysplasia verruciformis (HPV38), DLBCL, EBV viremia | NR | NR |

Table: A summary of STK4 deficiency patient cases from the retrieved literature, outlining key genetic variants, diagnostic methods, immunologic lab results, clinical complications, and treatments.

Functional consequence (current understanding)

Most reported variants are predicted/observed to cause loss of MST1 protein (e.g., nonsense variants with absent protein on Western blot) or truncation that disrupts key domains. (dang2016defectiveleukocyteadhesion pages 1-2, abdollahpour2012thephenotypeof pages 4-6)

Modifier genes / epigenetics / chromosomal abnormalities

No modifier genes, disease-specific epigenetic signatures, or recurrent chromosomal abnormalities were identified in retrieved evidence.

5. Environmental information

Infectious exposures as key non-genetic determinants

The phenotype is heavily shaped by infectious exposures, including: - EBV viremia/LPD and lymphoma (schipp2018ebvnegativelymphoma pages 1-2, radwan2020acaseof pages 1-2) - HPV-associated warts and EV (abdollahpour2012thephenotypeof pages 3-4, ying2024epidermodysplasiaverruciformisand pages 1-2) - Tuberculosis/mycobacterial-like pathology in some cases (radwan2020acaseof pages 1-2, guennoun2021anovelstk4 pages 1-3)

No toxin, radiation, or lifestyle risk factors were identified in retrieved evidence.

6. Mechanism / pathophysiology

Core causal chain (integrated)

1) Biallelic STK4 loss-of-function → reduced/absent MST1 kinase activity (dang2016defectiveleukocyteadhesion pages 1-2) 2) Impaired lymphocyte survival and homeostasis (loss of naïve T cells; apoptosis susceptibility; FOXO/IL-7R/BCL2 axis disruption) → CD4-predominant lymphopenia (abdollahpour2012thephenotypeof pages 4-6, jørgensen2021stk4deficiencyimpairs pages 1-2) 3) Defective leukocyte trafficking and immune synapse/adhesion (LFA-1 affinity/ICAM-1 binding; chemotaxis) → ineffective immune surveillance and responses (dang2016defectiveleukocyteadhesion pages 1-2) 4) Impaired innate antiviral signaling, including reduced TBK1/IRF3 phosphorylation → deficient type I/II/III interferon responses → viral susceptibility (including herpesviruses) (jørgensen2021stk4deficiencyimpairs pages 1-2) 5) Downstream clinical outcomes: recurrent infections, chronic viral skin disease, EBV-associated lymphoproliferation and lymphoma; variable immune dysregulation/autoimmunity. (schipp2018ebvnegativelymphoma pages 1-2, radwan2020acaseof pages 1-2)

Key pathways and molecular processes (with ontology suggestions)

1) Hippo signaling (canonical vs non-canonical) - Canonical Hippo axis: MST1/2 → LATS1/2 → YAP/TAZ; however, immune phenotypes often reflect non-canonical Hippo signaling in immune cells. (ueda2020mst12balanceimmune pages 1-2, louis2024thehippokinases pages 1-2) - GO suggestions: - GO:0035329 hippo signaling - GO:0008285 negative regulation of cell proliferation

2) T-cell survival/apoptosis and FOXO axis - STK4 deficiency is associated with impaired T-cell immunity and increased apoptosis; one mechanistic paper lists reduced expression of Foxo1, IL-7R, and BCL2 with increased apoptosis susceptibility. (jørgensen2021stk4deficiencyimpairs pages 1-2) - Blood 2012 provides functional evidence of increased apoptosis susceptibility and mitochondrial membrane potential loss in patient T cells and neutrophils, and decreased FOXO3 expression in PBMCs. (abdollahpour2012thephenotypeof pages 4-6) - GO suggestions: GO:0006915 apoptotic process; GO:0042981 regulation of apoptotic process

3) Leukocyte adhesion/migration (integrins; chemotaxis) - Human MST1 deficiency shows impaired ICAM-1 adhesion under flow and reduced chemotaxis to CXCL11 despite preserved CXCR3, supporting a trafficking defect. (dang2016defectiveleukocyteadhesion pages 1-2) - GO suggestions: GO:0050900 leukocyte migration; GO:0030595 leukocyte chemotaxis

4) Interferon signaling (TBK1–IRF3) - STK4 deficiency can cause “significantly impaired type I, II, and III interferon responses” tied to reduced TBK1/IRF3 phosphorylation. (jørgensen2021stk4deficiencyimpairs pages 1-2) - GO suggestions: GO:0035455 response to interferon-alpha; GO:0060337 type I interferon signaling pathway

5) Innate immunity / macrophage antibacterial restriction (2024 development) - A 2024 mBio study generated Mst1/2 knockout macrophages and reports cytokine changes (TNFα, CXCL10, IL-1ra), non-canonical inflammatory Hippo signaling independent of LATS1/2 inhibition, and restriction of infection by Legionella, E. coli, and Pseudomonas. (louis2024thehippokinases pages 1-2) - GO suggestions: GO:0006955 immune response; GO:0009615 response to virus; GO:0042742 defense response to bacterium

Cell types involved (CL suggestions)

  • T cells: CL:0000084 (T cell), CL:0000624 (CD4-positive, alpha-beta T cell)
  • γδ T cells noted in 2024 adult case: CL:0000798 (gamma-delta T cell) (ying2024epidermodysplasiaverruciformisand pages 1-2)
  • Macrophages: CL:0000235 (macrophage) (louis2024thehippokinases pages 1-2)

7. Anatomical structures affected

Based on clinical reports: - Immune system / hematolymphoid tissues: lymph nodes, blood immune compartments (lymphopenia, lymphadenopathy/LPD) (abdollahpour2012thephenotypeof pages 4-6) - Skin: warts/EV lesions (ying2024epidermodysplasiaverruciformisand pages 1-2) - Lung/respiratory tract: recurrent pneumonias/bronchiectasis (guennoun2021stk4deficiencyunderlies pages 15-19) - Heart: atrial septal defect / pulmonary valve stenosis reported in some patients (abdollahpour2012thephenotypeof pages 4-6, schipp2018ebvnegativelymphoma pages 2-3)

UBERON suggestions: - UBERON:0002405 immune system - UBERON:0002048 lung - UBERON:0002097 skin - UBERON:0000948 heart

8. Temporal development

  • Onset: commonly in childhood with recurrent infections and lymphopenia (abdollahpour2012thephenotypeof pages 1-2, radwan2020acaseof pages 1-2); however, 2024 data show adult recognition with relatively mild childhood infection history but later lymphoma/EV (ying2024epidermodysplasiaverruciformisand pages 1-2).
  • Course: chronic immunodeficiency with episodic infections; risk of progressive complications (EBV viremia, lymphoma). (schipp2018ebvnegativelymphoma pages 1-2, radwan2020acaseof pages 1-2)

9. Inheritance and population

Inheritance

  • Autosomal recessive inheritance is repeatedly documented, commonly in consanguineous families. (abdollahpour2012thephenotypeof pages 3-4, dang2016defectiveleukocyteadhesion pages 1-2, ying2024epidermodysplasiaverruciformisand pages 1-2)

Epidemiology

Prevalence/incidence and carrier frequency were not quantified in the retrieved evidence and should be populated from Orphanet/registry sources in a subsequent pass (not inferred here).

10. Diagnostics

Clinical tests / immune phenotyping

Common diagnostic findings include: - Profound CD4 lymphopenia and reduced naïve T-cell subsets; variable B-cell defects and dysgammaglobulinemia; intermittent neutropenia. (abdollahpour2012thephenotypeof pages 4-6, jørgensen2021stk4deficiencyimpairs pages 2-4) - Functional immunology (chemotaxis/adhesion assays) can reveal trafficking defects (ICAM-1 adhesion under flow; CXCL11 chemotaxis). (dang2016defectiveleukocyteadhesion pages 1-2)

Genetic testing approaches in primary reports

  • WES: used in Dang 2016 and Ying 2024. (dang2016defectiveleukocyteadhesion pages 1-2, ying2024epidermodysplasiaverruciformisand pages 1-2)
  • WGS with Sanger confirmation: Guennoun 2021. (guennoun2021stk4deficiencyunderlies pages 15-19)
  • Targeted NGS PID gene panels: Jørgensen 2021; Radwan 2020. (jørgensen2021stk4deficiencyimpairs pages 2-4, radwan2020acaseof pages 1-2)
  • Protein expression by Western blot/immunoblotting to confirm loss of MST1 protein in null variants. (dang2016defectiveleukocyteadhesion pages 1-2, guennoun2021stk4deficiencyunderlies pages 15-19)

Differential diagnosis (examples explicitly mentioned)

  • DOCK8 deficiency (phenotypic overlap, including high IgE features; STK4 considered in this context) (radwan2020acaseof pages 1-2)
  • WHIM/CXCR4, G6PC3 deficiency, ELANE/HAX1 congenital neutropenia were genetically excluded in a Blood 2012 workup. (abdollahpour2012thephenotypeof pages 4-6)
  • ALPS-like presentations and other EBV/LPD-associated IEIs (e.g., ITK, MAGT1, SAP/XIAP, CD27) discussed in Schipp 2018. (schipp2018ebvnegativelymphoma pages 2-3)

11. Outcome / prognosis

  • Prognosis is heterogeneous: some patients survive with supportive therapy; others develop severe malignancy or infection-related complications.
  • HSCT outcomes are variable, including transplant-related mortality and post-transplant immune dysregulation in the Dang 2016 cohort. (dang2016defectiveleukocyteadhesion pages 1-2)
  • Fatal lymphoma outcome occurred in an Egyptian child despite chemotherapy, in whom HSCT was postponed due to donor unavailability and transient clinical improvement on IVIG. (radwan2020acaseof pages 1-2)

Quantitative survival rates were not available in retrieved evidence.

12. Treatment

Current applications / real-world implementations (from case literature)

Supportive and definitive treatments reported include: - Immunoglobulin replacement (IVIG): commonly used; one 2024 case specifies 0.4 g/kg every 4 weeks plus antibacterial prophylaxis with good clinical status. (alsaud2024auniquestk4 pages 2-3) - Antimicrobial therapy / prophylaxis: prolonged anti-tuberculosis regimens and prophylactic antibacterial treatment are reported. (guennoun2021stk4deficiencyunderlies pages 15-19, alsaud2024auniquestk4 pages 2-3) - Rituximab and steroids for EBV-associated lymphoproliferation (Dang 2016). (dang2016defectiveleukocyteadhesion pages 1-2) - Chemotherapy for lymphoma (e.g., NHL-BFM 04 protocol; LMB chemotherapy listed in one fatal Burkitt lymphoma case). (schipp2018ebvnegativelymphoma pages 2-3, radwan2020acaseof pages 1-2) - HSCT: used as immune reconstitution in some cases, with variable outcomes. (dang2016defectiveleukocyteadhesion pages 1-2)

MAXO suggestions (non-exhaustive)

  • MAXO:0000761 Immunoglobulin replacement therapy
  • MAXO:0000061 Antibiotic therapy
  • MAXO:0000062 Antifungal therapy
  • MAXO:0001020 Hematopoietic stem cell transplantation
  • MAXO:0000647 Chemotherapy
  • MAXO:0000102 Anti-CD20 monoclonal antibody therapy (rituximab)

Clinical trials

A targeted clinical trial program specific to STK4 deficiency was not identified in the retrieved ClinicalTrials search results in this run.

13. Prevention

No disease-specific primary prevention exists for a Mendelian CID. Preventive practice is largely tertiary prevention: - infection prophylaxis and early treatment - immunoglobulin replacement - vaccination strategy individualized to immune competence (not detailed in retrieved sources) - malignancy vigilance (EBV monitoring; lymphoma surveillance) (schipp2018ebvnegativelymphoma pages 1-2, radwan2020acaseof pages 1-2)

14. Other species / natural disease

No naturally occurring veterinary STK4 deficiency syndrome was identified in retrieved evidence.

15. Model organisms

Multiple sources note that mouse Mst1/Mst1/2 deficiency models recapitulate immune phenotypes (lymphopenia, trafficking defects, altered apoptosis), and 2024 data extend MST1/2 function to macrophage antibacterial defense and conserved roles in amoebae. (ueda2020mst12balanceimmune pages 1-2, louis2024thehippokinases pages 1-2, bouchard2020hipposignaltransduction pages 4-6)

Recent developments (2023–2024 prioritized)

1) Adult presentation and EV with HPV38 + γδ T-cell compensation: A 2024 J Clin Immunol report describes EV due to HPV38, adult-onset lymphoma/EBV viremia, and a striking Vδ2+ γδ T-cell expansion (67.4% DNT cells), proposing γδ expansion as compensatory antiviral protection. (ying2024epidermodysplasiaverruciformisand pages 1-2) 2) Milder phenotype from SARAH-domain truncation escaping NMD: A 2024 Frontiers in Immunology case emphasizes that some downstream truncations evade nonsense-mediated decay, producing a truncated protein and a relatively mild clinical course despite severe lymphopenia. (alsaud2024auniquestk4 pages 1-2) 3) Innate immunity and non-canonical Hippo signaling in macrophages (2024 mBio): Knockout studies show MST1/2 regulate macrophage gene programs and cytokine release independently of canonical LATS1/2 effects, and restrict multiple bacterial infections, supporting broader innate immune roles relevant to STK4 deficiency susceptibility. (louis2024thehippokinases pages 1-2)

Evidence quality and limitations

  • The clinical evidence base is dominated by case reports and small case series, limiting robust frequency estimates for phenotypes, genotype–phenotype correlations, and survival statistics.
  • Several key registry identifiers (Orphanet, ICD, MeSH) and PubMed PMIDs were not available directly in the retrieved text evidence used in this run; therefore they are not asserted here.

Visual evidence

  • Table/Figure evidence of immunologic parameters and clinical features (warts and cardiac defects) was retrieved from the Blood 2012 report (Table 1 and Figure 1) (abdollahpour2012thephenotypeof media f08af791, abdollahpour2012thephenotypeof media cada1af7).

References

  1. (abdollahpour2012thephenotypeof pages 1-2): Hengameh Abdollahpour, Giridharan Appaswamy, Daniel Kotlarz, Jana Diestelhorst, Rita Beier, Alejandro A. Schäffer, E. Michael Gertz, Axel Schambach, Hans H. Kreipe, Dietmar Pfeifer, Karin R. Engelhardt, Nima Rezaei, Bodo Grimbacher, Sabine Lohrmann, Roya Sherkat, and Christoph Klein. The phenotype of human stk4 deficiency. Blood, 119:3450-3457, Apr 2012. URL: https://doi.org/10.1182/blood-2011-09-378158, doi:10.1182/blood-2011-09-378158. This article has 388 citations and is from a highest quality peer-reviewed journal.

  2. (schipp2018ebvnegativelymphoma pages 1-2): Cyrill Schipp, David Schlütermann, Andrea Hönscheid, Schafiq Nabhani, Jessica Höll, Prasad T. Oommen, Sebastian Ginzel, Bernhard Fleckenstein, Björn Stork, Arndt Borkhardt, Polina Stepensky, and Ute Fischer. Ebv negative lymphoma and autoimmune lymphoproliferative syndrome like phenotype extend the clinical spectrum of primary immunodeficiency caused by stk4 deficiency. Frontiers in Immunology, Oct 2018. URL: https://doi.org/10.3389/fimmu.2018.02400, doi:10.3389/fimmu.2018.02400. This article has 59 citations and is from a peer-reviewed journal.

  3. (alsaud2024auniquestk4 pages 2-3): Bandar Al-Saud, Huda Alajlan, Hibah Alruwaili, Latifa Almoaibed, Amer Al-Mazrou, Hazem Ghebeh, Monther Al-Alwan, and Anas M. Alazami. A unique stk4 mutation truncating only the c-terminal sarah domain results in a mild clinical phenotype despite severe t cell lymphopenia: case report. Frontiers in Immunology, Feb 2024. URL: https://doi.org/10.3389/fimmu.2024.1329610, doi:10.3389/fimmu.2024.1329610. This article has 5 citations and is from a peer-reviewed journal.

  4. (ying2024epidermodysplasiaverruciformisand pages 8-8): Wenjing Ying, Xin Long, Travis Vandergriff, Hemanth Karnati, Meghan Heberton, Mingyi Chen, Xiaochuan Wang, Christian Wysocki, and Xiao-Fei Kong. Epidermodysplasia verruciformis and vδ2 γδ t-cell expansion in stk4 deficiency. Journal of Clinical Immunology, Aug 2024. URL: https://doi.org/10.1007/s10875-024-01780-z, doi:10.1007/s10875-024-01780-z. This article has 4 citations and is from a domain leading peer-reviewed journal.

  5. (OpenTargets Search: STK4 deficiency,immunodeficiency due to STK4 deficiency,primary immunodeficiency STK4): Open Targets Query (STK4 deficiency,immunodeficiency due to STK4 deficiency,primary immunodeficiency STK4, 17 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  6. (radwan2020acaseof pages 1-2): Nesrine Radwan, Rasha El-Owaidy, Zeinab A. El-Sayed, Ashraf Abdel-Baky, Alaa El-Haddad, Hanaa Rashad, Eman Naguib Khorshed, Craig D. Platt, Jacqueline G. Wallace, Janet Chou, Elham Hossny, and Shereen Medhat Reda. A case of stk4 deficiency with complications evoking mycobacterial infection. Journal of Clinical Immunology, 40:665-669, May 2020. URL: https://doi.org/10.1007/s10875-020-00783-w, doi:10.1007/s10875-020-00783-w. This article has 13 citations and is from a domain leading peer-reviewed journal.

  7. (guennoun2021anovelstk4 pages 1-3): Andrea Guennoun, Salim Bougarn, Taushif Khan, Rafah Mackeh, Mahbuba Rahman, Fatima Al-Ali, Manar Ata, Waleed Aamer, Debra Prosser, Tanwir Habib, Evonne Chin-Smith, Khawla Al-Darwish, Qian Zhang, Alya Al-Shakaki, Amal Robay, Ronald G. Crystal, Khalid Fakhro, Amal Al-Naimi, Eman Al Maslamani, Amjad Tuffaha, Ibrahim Janahi, Mohammad Janahi, Donald R. Love, Mohammed Yousuf Karim, Bernice Lo, Amel Hassan, Mehdi Adeli, and Nico Marr. A novel stk4 mutation impairs t cell immunity through dysregulation of cytokine-induced adhesion and chemotaxis genes. Journal of Clinical Immunology, 41:1839-1852, Aug 2021. URL: https://doi.org/10.1007/s10875-021-01115-2, doi:10.1007/s10875-021-01115-2. This article has 14 citations and is from a domain leading peer-reviewed journal.

  8. (jørgensen2021stk4deficiencyimpairs pages 1-2): Sofie E. Jørgensen, Ali Al-Mousawi, Kristian Assing, Ulla Hartling, Dorthe Grosen, Niels Fisker, Christian Nielsen, Marianne A. Jakobsen, and Trine H. Mogensen. Stk4 deficiency impairs innate immunity and interferon production through negative regulation of tbk1-irf3 signaling. Journal of Clinical Immunology, 41:109-124, Oct 2021. URL: https://doi.org/10.1007/s10875-020-00891-7, doi:10.1007/s10875-020-00891-7. This article has 25 citations and is from a domain leading peer-reviewed journal.

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  10. (alsaud2024auniquestk4 pages 1-2): Bandar Al-Saud, Huda Alajlan, Hibah Alruwaili, Latifa Almoaibed, Amer Al-Mazrou, Hazem Ghebeh, Monther Al-Alwan, and Anas M. Alazami. A unique stk4 mutation truncating only the c-terminal sarah domain results in a mild clinical phenotype despite severe t cell lymphopenia: case report. Frontiers in Immunology, Feb 2024. URL: https://doi.org/10.3389/fimmu.2024.1329610, doi:10.3389/fimmu.2024.1329610. This article has 5 citations and is from a peer-reviewed journal.

  11. (jørgensen2021stk4deficiencyimpairs pages 2-4): Sofie E. Jørgensen, Ali Al-Mousawi, Kristian Assing, Ulla Hartling, Dorthe Grosen, Niels Fisker, Christian Nielsen, Marianne A. Jakobsen, and Trine H. Mogensen. Stk4 deficiency impairs innate immunity and interferon production through negative regulation of tbk1-irf3 signaling. Journal of Clinical Immunology, 41:109-124, Oct 2021. URL: https://doi.org/10.1007/s10875-020-00891-7, doi:10.1007/s10875-020-00891-7. This article has 25 citations and is from a domain leading peer-reviewed journal.

  12. (abdollahpour2012thephenotypeof pages 3-4): Hengameh Abdollahpour, Giridharan Appaswamy, Daniel Kotlarz, Jana Diestelhorst, Rita Beier, Alejandro A. Schäffer, E. Michael Gertz, Axel Schambach, Hans H. Kreipe, Dietmar Pfeifer, Karin R. Engelhardt, Nima Rezaei, Bodo Grimbacher, Sabine Lohrmann, Roya Sherkat, and Christoph Klein. The phenotype of human stk4 deficiency. Blood, 119:3450-3457, Apr 2012. URL: https://doi.org/10.1182/blood-2011-09-378158, doi:10.1182/blood-2011-09-378158. This article has 388 citations and is from a highest quality peer-reviewed journal.

  13. (ying2024epidermodysplasiaverruciformisand pages 1-2): Wenjing Ying, Xin Long, Travis Vandergriff, Hemanth Karnati, Meghan Heberton, Mingyi Chen, Xiaochuan Wang, Christian Wysocki, and Xiao-Fei Kong. Epidermodysplasia verruciformis and vδ2 γδ t-cell expansion in stk4 deficiency. Journal of Clinical Immunology, Aug 2024. URL: https://doi.org/10.1007/s10875-024-01780-z, doi:10.1007/s10875-024-01780-z. This article has 4 citations and is from a domain leading peer-reviewed journal.

  14. (schipp2018ebvnegativelymphoma pages 7-8): Cyrill Schipp, David Schlütermann, Andrea Hönscheid, Schafiq Nabhani, Jessica Höll, Prasad T. Oommen, Sebastian Ginzel, Bernhard Fleckenstein, Björn Stork, Arndt Borkhardt, Polina Stepensky, and Ute Fischer. Ebv negative lymphoma and autoimmune lymphoproliferative syndrome like phenotype extend the clinical spectrum of primary immunodeficiency caused by stk4 deficiency. Frontiers in Immunology, Oct 2018. URL: https://doi.org/10.3389/fimmu.2018.02400, doi:10.3389/fimmu.2018.02400. This article has 59 citations and is from a peer-reviewed journal.

  15. (guennoun2021stk4deficiencyunderlies pages 15-19): Andrea Guennoun, Salim Bougarn, Taushif Khan, Rafah Mackeh, Mahbuba Rahman, Fatima Al Ali, Manar Ata, Waleed Aamer, Debra Prosser, Tanwir Habib, Evonne Chin-Smith, Khawla Al-Darwish, Qian Zhang, Alya Al-Shakaki, Amal Robay, Ronald Crystal, Khalid Fakhro, Amal Al-Naimi, Eman Al Maslamani, Amjad Tuffaha, Ibrahim Janahi, Mohammad Janahi, Donald Love, Mohammed Yousuf Karim, Bernice Lo, Amel Hassan, Mehdi Adeli, and Nico Marr. Stk4 deficiency underlies impaired interferon signaling and t cell immunity. ArXiv, Mar 2021. URL: https://doi.org/10.21203/rs.3.rs-328827/v1, doi:10.21203/rs.3.rs-328827/v1. This article has 0 citations.

  16. (abdollahpour2012thephenotypeof pages 4-6): Hengameh Abdollahpour, Giridharan Appaswamy, Daniel Kotlarz, Jana Diestelhorst, Rita Beier, Alejandro A. Schäffer, E. Michael Gertz, Axel Schambach, Hans H. Kreipe, Dietmar Pfeifer, Karin R. Engelhardt, Nima Rezaei, Bodo Grimbacher, Sabine Lohrmann, Roya Sherkat, and Christoph Klein. The phenotype of human stk4 deficiency. Blood, 119:3450-3457, Apr 2012. URL: https://doi.org/10.1182/blood-2011-09-378158, doi:10.1182/blood-2011-09-378158. This article has 388 citations and is from a highest quality peer-reviewed journal.

  17. (schipp2018ebvnegativelymphoma pages 2-3): Cyrill Schipp, David Schlütermann, Andrea Hönscheid, Schafiq Nabhani, Jessica Höll, Prasad T. Oommen, Sebastian Ginzel, Bernhard Fleckenstein, Björn Stork, Arndt Borkhardt, Polina Stepensky, and Ute Fischer. Ebv negative lymphoma and autoimmune lymphoproliferative syndrome like phenotype extend the clinical spectrum of primary immunodeficiency caused by stk4 deficiency. Frontiers in Immunology, Oct 2018. URL: https://doi.org/10.3389/fimmu.2018.02400, doi:10.3389/fimmu.2018.02400. This article has 59 citations and is from a peer-reviewed journal.

  18. (ueda2020mst12balanceimmune pages 1-2): Yoshihiro Ueda, Naoyuki Kondo, and Tatsuo Kinashi. Mst1/2 balance immune activation and tolerance by orchestrating adhesion, transcription, and organelle dynamics in lymphocytes. Frontiers in Immunology, May 2020. URL: https://doi.org/10.3389/fimmu.2020.00733, doi:10.3389/fimmu.2020.00733. This article has 28 citations and is from a peer-reviewed journal.

  19. (louis2024thehippokinases pages 1-2): Brendyn M. St. Louis, Sydney M. Quagliato, Yu-Ting Su, Gregory Dyson, and Pei-Chung Lee. The hippo kinases control inflammatory hippo signaling and restrict bacterial infection in phagocytes. May 2024. URL: https://doi.org/10.1128/mbio.03429-23, doi:10.1128/mbio.03429-23. This article has 8 citations and is from a domain leading peer-reviewed journal.

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  21. (abdollahpour2012thephenotypeof media f08af791): Hengameh Abdollahpour, Giridharan Appaswamy, Daniel Kotlarz, Jana Diestelhorst, Rita Beier, Alejandro A. Schäffer, E. Michael Gertz, Axel Schambach, Hans H. Kreipe, Dietmar Pfeifer, Karin R. Engelhardt, Nima Rezaei, Bodo Grimbacher, Sabine Lohrmann, Roya Sherkat, and Christoph Klein. The phenotype of human stk4 deficiency. Blood, 119:3450-3457, Apr 2012. URL: https://doi.org/10.1182/blood-2011-09-378158, doi:10.1182/blood-2011-09-378158. This article has 388 citations and is from a highest quality peer-reviewed journal.

  22. (abdollahpour2012thephenotypeof media cada1af7): Hengameh Abdollahpour, Giridharan Appaswamy, Daniel Kotlarz, Jana Diestelhorst, Rita Beier, Alejandro A. Schäffer, E. Michael Gertz, Axel Schambach, Hans H. Kreipe, Dietmar Pfeifer, Karin R. Engelhardt, Nima Rezaei, Bodo Grimbacher, Sabine Lohrmann, Roya Sherkat, and Christoph Klein. The phenotype of human stk4 deficiency. Blood, 119:3450-3457, Apr 2012. URL: https://doi.org/10.1182/blood-2011-09-378158, doi:10.1182/blood-2011-09-378158. This article has 388 citations and is from a highest quality peer-reviewed journal.

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