Immunodeficiency 14B, Autosomal Recessive

Mendelian MONDO:0023655 Pathograph 14 Show in embeddings browser

Immunodeficiency 14B (IMD14B, OMIM 619281) is an ultra-rare autosomal recessive inborn error of immunity caused by biallelic loss-of-function variants in PIK3CD, which encodes p110-delta, the leukocyte-restricted catalytic subunit of class IA phosphoinositide 3-kinase delta. It is the mirror image of a disease the knowledge base already holds. Heterozygous activating variants in the same gene cause activated PI3K-delta syndrome (APDS1 / IMD14A), a lymphoproliferative combined immunodeficiency; biallelic null variants cause this one, a predominantly humoral immunodeficiency with autoimmunity and enterocolitis. One gene, two directions, two diseases - which is why IMD14B is curated separately rather than as a subtype of the APDS entry. Roughly ten patients have been reported, and the literature carries its own health warning: three of them had a second, concurrent immune-gene mutation, so their phenotypes cannot be attributed to PIK3CD alone. The entry marks that confounding explicitly rather than pooling all reported features into one clean picture. The mechanism has an unusual external check. Idelalisib, a p110-delta-specific inhibitor used in haematological malignancy, causes severe colitis in treated patients - pharmacological loss of the same activity, in adults, producing the same gut disease. That is curated as a distinct line of supporting evidence.

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1
Inheritance
11
Pathophys.
6
Phenotypes
2
Gaps
14
Pathograph
1
Genes
3
Medical Actions
3
Differentials
1
Models
2
References
1
Deep Research
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Inheritance

1
Autosomal recessive HP:0000007
Disease requires biallelic loss-of-function variants. Reported genotypes are predominantly homozygous, reflecting consanguinity in the ascertained families. Heterozygous carriers are unaffected, which is what separates this from the dominant gain-of-function disease at the same locus.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:41026257 SUPPORT Human Clinical
"Mutations in PIK3CD, which encodes an immune-specific catalytic subunit of PI3K, cause both dominant (activating) and recessive (loss of function) immune deficiencies in humans."
States the two-mode architecture of PIK3CD disease and places IMD14B on the recessive loss-of-function side.
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Discussions and Knowledge Gaps

2
Why do human PIK3CD-deficient B cells fail to class-switch even when supplied with CD40L and IL-21, when mouse B cells lacking p110-delta can still class-switch given external T-cell help?
HUMAN MODEL MISMATCH mismatch_human_b_cell_class_switching_versus_mouse
Attached to
pathophysiology#Defective B-Cell Proliferation and Class-Switch Recombination
Most of what is known about PI3K-delta in immunity comes from mice, and the mouse predicts that T-cell help should rescue class-switch recombination. Human patient B cells do not behave that way: proliferation and switching remain impaired under CD40L and IL-21 stimulation, which is precisely the help that should have rescued them. The authors of the sibling study raise this themselves. If the human B-cell requirement for PI3K-delta is genuinely broader than the mouse's, then mouse models will systematically understate the humoral severity of this disease, and a therapy validated on murine class-switching would not translate. The alternative is that the in vitro stimulation conditions do not reproduce germinal-centre help faithfully enough, in which case the discrepancy is methodological rather than biological.
Proposed experiments
Matched-protocol class-switch recombination in human and murine p110-delta-null B cells
exp_side_by_side_human_mouse_csr
Run identical stimulation protocols on patient-derived and p110-delta-null murine B cells in the same laboratory, varying CD40L and IL-21 dose and timing. A species difference that survives protocol matching is biological; one that disappears is an artefact of how the two literatures were generated.
Class-switching in a germinal-centre organoid supplied with autologous T-cell help
exp_germinal_centre_organoid_switching
Test patient B cells in a three-dimensional germinal-centre system with autologous T cells rather than recombinant CD40L, to establish whether physiological help rescues switching where soluble stimulation does not.
Which features of the reported IMD14B phenotype are attributable to PIK3CD loss alone, given that a third of published patients carry a second immune-gene defect and the index case was immunophenotyped after rituximab?
KNOWLEDGE GAP gap_confounded_phenotype_attribution
Attached to
pathophysiology#Loss of Immune Tolerance
This is a small-numbers problem with a specific and unusually well-documented shape. Of roughly ten reported patients, three also carry a concurrent mutation in another immune gene, so their phenotypes cannot be assigned to PIK3CD. Separately, the index case's B-cell findings - low B cells, absent class-switched memory, low immunoglobulins - were measured after treatment with the B-cell-depleting antibody rituximab, and the reporting authors say explicitly that these are consistent with either the drug or a primary B-cell abnormality. The unconfounded evidence for the humoral phenotype therefore rests on a smaller set of patients than the headline count suggests, and the 2025 sibship is valuable precisely because it is untreated and unconfounded. Until more such families are reported, any frequency estimate for this disease would be assembled from a denominator that does not really exist.
Proposed experiments
Registry of biallelic PIK3CD patients stratified by confounder status
exp_unconfounded_imd14b_registry
Collect reported and unreported biallelic PIK3CD patients into a single registry that records, per patient, whether a second immune-gene variant is present and whether immunophenotyping preceded or followed B-cell-depleting or immunosuppressive therapy. Only the untreated, single-locus subset can support statements about the disease's intrinsic phenotype.
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Pathophysiology

11
Biallelic PIK3CD Loss of Function
Homozygous or compound heterozygous null or severely hypomorphic PIK3CD alleles. Reported classes include nonsense, frameshift and in-frame deletion variants; the index case carried a homozygous 21 bp deletion with a 2 bp insertion in exon 5 producing p.Q170Vfs*41 and no detectable full-length protein.
Downstream
Loss of p110-delta Protein with Secondary p85-alpha Reduction
Show evidence (1 reference)
PMID:41026257 SUPPORT Human Clinical
"Here we report a family with three affected children carrying a novel bi-allelic, truncating mutation in PIK3CD."
Documents a biallelic truncating genotype in three affected siblings.
Loss of p110-delta Protein with Secondary p85-alpha Reduction
Truncating alleles abolish p110-delta protein. The consequence is not confined to the catalytic subunit: because p110-delta and the p85-alpha regulatory subunit associate constitutively, loss of p110-delta also reduces p85-alpha expression. The lesion therefore removes the holoenzyme rather than just half of it.
1-phosphatidylinositol-3-kinase activity GO:0016303 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves 1-phosphatidylinositol-3-kinase activity (GO:0016303), qualified as loss of function. GO:0016303 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
Downstream
Failure of PIP3 Generation on Antigen and Cytokine Receptor Engagement
Show evidence (1 reference)
PMID:41026257 SUPPORT Human Clinical
"Immunoblot confirmed loss of protein along with reduced expression of the associated p85α regulatory subunit."
Demonstrates both the loss of p110-delta and the secondary reduction of its obligate regulatory partner.
Failure of PIP3 Generation on Antigen and Cytokine Receptor Engagement
PI3K-delta phosphorylates PIP2 to PIP3 at the leukocyte plasma membrane downstream of antigen and cytokine receptors. Patient T lymphoblasts fail to generate PIP3 on T-cell receptor engagement, which is the proximal signalling failure from which the rest of the disease follows.
Downstream
Impaired AKT-mTOR Signalling and Lymphocyte Metabolic Reprogramming
Show evidence (1 reference)
PMID:31073077 SUPPORT Human Clinical
"patient-derived T lymphoblasts were profoundly impaired in their ability to generate PIP3 upon T cell receptor (TCR) engagement"
Direct measurement of the proximal signalling defect in patient cells.
Impaired AKT-mTOR Signalling and Lymphocyte Metabolic Reprogramming
Reduced PIP3 blunts the PDK1-AKT-mTOR cascade, and with it the metabolic switch lymphocytes need in order to expand and acquire effector function. Patient cells show reduced AKT and S6 phosphorylation and impaired glycolysis - and the same glycolytic defect is reproduced in healthy donor cells simply by adding idelalisib, which ties the metabolic phenotype directly to loss of p110-delta activity rather than to anything else in the patient's background.
glycolytic process GO:0006096 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased glycolytic process (GO:0006096). GO:0006096 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Defective B-Cell Proliferation and Class-Switch Recombination
Impaired Cytotoxic Lymphocyte Effector Function
Paradoxical T-Cell Hyperactivation
Show evidence (2 references)
PMID:31073077 SUPPORT Human Clinical
"A glycolysis stress test showed impaired IL-2-stimulated glycolysis and glycolytic reserve in patient cells, similar to the behavior of CD4 and CD8 T cells treated with idelalisib"
Establishes the metabolic defect and its pharmacological phenocopy in control cells, which controls for patient-specific confounders.
PMID:31073077 SUPPORT Human Clinical
"These findings show that germline p110δ deficiency impairs lymphocyte metabolism"
The authors' summary of the metabolic consequence of p110-delta deficiency.
Defective B-Cell Proliferation and Class-Switch Recombination
The humoral arm, and the one that dominates the clinical picture. Patient B cells proliferate poorly and fail to class-switch even when given CD40L and IL-21 - that is, even when supplied with the T-cell help that would normally rescue switching. The compartment skews toward naive cells at the expense of class-switched memory.
naive B cell CL:0000788 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves increased naive B cell (CL:0000788). CL:0000788 is a cell type from the Cell Ontology. ↑ INCREASED
isotype switching GO:0045190 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased isotype switching (GO:0045190). GO:0045190 is a biological process from the Gene Ontology. ↓ DECREASED B cell proliferation GO:0042100 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased B cell proliferation (GO:0042100). GO:0042100 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Humoral Immunodeficiency
Show evidence (2 references)
PMID:41026257 SUPPORT In Vitro
"In vitro functional testing of CD19 + and enriched naïve B cells revealed impaired proliferation, and reduction in class-switch recombination upon CD40L and IL-21 stimulation."
Directly demonstrates the intrinsic B-cell proliferation and class-switching defect under conditions that supply T-cell help.
PMID:41026257 SUPPORT Human Clinical
"Immune phenotyping showed B cell dysregulation with abnormally high levels of naïve cells."
Documents the skew toward naive B cells in the patient compartment.
Impaired Cytotoxic Lymphocyte Effector Function
CD8 T-cell and NK-cell killing depend on PI3K-delta signalling, and the consequence in patients is susceptibility to herpesviruses. The index case had active cytomegalovirus replication in the gut with viraemia. Note that the CD8 compartment is not simply depleted - it is skewed toward effector/memory cells expressing high TBET and perforin, so the failure is functional rather than numerical.
CD8-positive, alpha-beta T cell CL:0000625 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves CD8-positive, alpha-beta T cell (CL:0000625). CL:0000625 is a cell type from the Cell Ontology.
Downstream
Susceptibility to Viral and Recurrent Bacterial Infection
Show evidence (2 references)
PMID:31073077 SUPPORT Human Clinical
"Viral inclusion bodies were visible, indicating active cytomegalovirus (CMV) replication in the gut, accompanied by CMV viremia"
Documents failure of control of a herpesvirus in the index patient.
PMID:31073077 SUPPORT Human Clinical
"Peripheral blood was enriched for effector/memory CD8 T cells, which expressed high levels of the transcription factor TBET and perforin"
Shows the CD8 compartment is skewed rather than absent, supporting a functional rather than numerical defect.
Paradoxical T-Cell Hyperactivation
The counterintuitive step, and the one that makes the autoimmune half of this disease make sense. PI3K-delta drives T-cell activation, so losing it ought to make T cells less responsive - yet patient CD3+ cells are hyperactivated. The proposed reason is substrate rerouting: with the kinase gone, its substrate PIP2 accumulates and is instead hydrolysed by phospholipase C-gamma1 into second messengers that drive activation through a different arm. The consequence is a two-sided failure at the gut mucosa - effector T cells that are improperly activated, and PI3K-delta-deficient regulatory T cells unable to suppress them.
CD4-positive, alpha-beta T cell CL:0000624 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves increased CD4-positive, alpha-beta T cell (CL:0000624). CL:0000624 is a cell type from the Cell Ontology. ↑ INCREASED
Downstream
Loss of Immune Tolerance
Show evidence (3 references)
PMID:41026257 SUPPORT Human Clinical
"Our data supports the conclusion that CD3 + hyperactivation is a natural consequence of PIK3CD protein loss."
The authors' conclusion that hyperactivation follows directly from loss of the protein, rather than being incidental to these patients.
PMID:41026257 SUPPORT Human Clinical
"This hyperactivation may result from the increased availability of PIP2, which is hydrolyzed by phospholipase Cγ1 (PLCγ1) into crucial secondary messengers that trigger several distal signaling cascades vital for CD3 + activation"
The proposed substrate-rerouting mechanism. Curated PARTIAL because the authors state it as a possible explanation, not a demonstrated one.
PMID:41026257 SUPPORT Model Organism
"In PI3Kδ-deficient mice, improper activation of effector T cells by gut microbes leads to colitis, which PI3Kδ-deficient Treg are unable to suppress"
Supplies the route from hyperactivated effector T cells to colitis, and the parallel failure of the regulatory compartment to restrain them.
Loss of Immune Tolerance
Autoimmune and autoinflammatory disease is as prominent as the infection susceptibility. Immune-mediated thrombocytopenia and inflammatory enterocolitis are the two recurring manifestations. The intermediates between impaired PI3K-delta signalling and tolerance breakdown are now partly established: the immediate upstream node is paradoxical T-cell hyperactivation, and mouse work implicates disturbed regulatory T-cell trafficking and suppressive function, curated with evidence in animal_models below rather than asserted here as prose.
Animal models
p110-delta kinase-dead mouse Mouse recapitulates Spontaneous colitis with crypt abscesses arises without any additional manipulation, matching the human enterocolitis at the level of histology, and the model supplies the regulatory T-cell mechanism that patient material was too limited to test.
Downstream
Autoimmune Cytopenia and Inflammatory Enterocolitis
Show evidence (1 reference)
PMID:41026257 SUPPORT Human Clinical
"All three patients exhibited autoimmunity and B cell dysregulation"
Establishes autoimmunity as a consistent feature across an affected sibship.
Humoral Immunodeficiency
Hypogammaglobulinaemia with absent class-switched memory B cells, giving recurrent sinopulmonary infection. This is the feature most consistently reported across independent kindreds and the one that usually brings patients to attention.
Downstream
Susceptibility to Viral and Recurrent Bacterial Infection
Show evidence (1 reference)
PMID:31073077 SUPPORT Human Clinical
"Of the remaining four patients, all presented with hypogammaglobulinemia and recurrent sinopulmonary infections, some including severe and opportunistic pneumonias."
Reports the phenotype across the previously published unconfounded patients, which is the cleanest available statement of the humoral defect.
Susceptibility to Viral and Recurrent Bacterial Infection
The infectious endpoint: recurrent sinopulmonary infection from the humoral defect, and poor control of herpesviruses from the cytotoxic defect. Both arms converge here.
Show evidence (1 reference)
PMID:41026257 SUPPORT Human Clinical
"All three patients exhibited chronic diarrhea and recurrent sinopulmonary infections."
Documents recurrent sinopulmonary infection across the sibship.
Autoimmune Cytopenia and Inflammatory Enterocolitis
The autoimmune endpoint. Thrombocytopenia can be refractory to corticosteroids, immunoglobulin and splenectomy, and severe enough to cause intracranial haemorrhage. The enterocolitis is histologically distinctive - crypt epithelial apoptosis with crypt abscess formation and a lamina propria notably depleted of B cells and plasma cells.
Show evidence (2 references)
PMID:31073077 SUPPORT Human Clinical
"Endoscopy revealed enterocolitis, which histologically showed marked apoptosis of crypt epithelial cells, eosinophil and neutrophil infiltration, crypt distortion and crypt abscess formation"
Describes the histopathology of the enterocolitis in the index case.
PMID:31073077 SUPPORT Human Clinical
"we report a child with homozygous germline loss-of-function mutation inPIK3CD, who developed refractory immune thrombocytopenia, inflammatory bowel disease and susceptibility to infection, cured by HSCT"
The authors' summary of the index case, establishing the triad and its response to transplantation.
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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 Immunodeficiency 14B, Autosomal Recessive 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

6
Blood 2
Decreased Circulating IgG Concentration HP:0004315 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased circulating IgG concentration (HP:0004315). HP:0004315 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31073077 SUPPORT Human Clinical
"Of the remaining four patients, all presented with hypogammaglobulinemia and recurrent sinopulmonary infections, some including severe and opportunistic pneumonias."
Establishes hypogammaglobulinaemia in the four previously reported patients whose phenotype is not complicated by a second immune-gene defect.
Autoimmune Thrombocytopenia HP:0001973 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autoimmune thrombocytopenia (HP:0001973). HP:0001973 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31073077 SUPPORT Human Clinical
"His thrombocytopenia was refractory to corticosteroids, high dose immunoglobulin and splenectomy, culminating in an intracranial bleed requiring surgical evacuation."
Documents the severity and treatment-refractoriness of the thrombocytopenia.
Digestive 2
Chronic Diarrhea HP:0002028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic diarrhea (HP:0002028), qualified as temporality chronic. HP:0002028 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (1 reference)
PMID:41026257 SUPPORT Human Clinical
"All three patients exhibited chronic diarrhea and recurrent sinopulmonary infections."
Documents chronic diarrhoea in all three affected siblings.
Enterocolitis HP:0004387 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Enterocolitis (HP:0004387). HP:0004387 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31073077 SUPPORT Human Clinical
"Endoscopy revealed enterocolitis, which histologically showed marked apoptosis of crypt epithelial cells, eosinophil and neutrophil infiltration, crypt distortion and crypt abscess formation"
Establishes the enterocolitis and its histological character.
Other 2
Recurrent Sinopulmonary Infections HP:0005425 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent sinopulmonary infections (HP:0005425). HP:0005425 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41026257 SUPPORT Human Clinical
"All three patients exhibited chronic diarrhea and recurrent sinopulmonary infections."
Documents recurrent sinopulmonary infection in all three affected siblings.
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 class-switched memory B cell proportion (HP:0030388). HP:0030388 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41026257 SUPPORT In Vitro
"In vitro functional testing of CD19 + and enriched naïve B cells revealed impaired proliferation, and reduction in class-switch recombination upon CD40L and IL-21 stimulation."
Demonstrates the class-switching defect that underlies the reduced class-switched memory compartment.
🧬

Genetic Associations

1
PIK3CD (Biallelic loss-of-function variants in PIK3CD cause IMD14B. The same gene causes activated PI3K-delta syndrome (APDS1 / IMD14A) through heterozygous activating variants, so the direction of the variant's effect, not the gene, determines which disease results. Reported IMD14B alleles are nonsense, frameshift or in-frame deletions producing complete or near-complete loss of p110-delta.)
Gene: PIK3CD hgnc:8977 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PIK3CD (hgnc:8977). hgnc:8977 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:41026257 SUPPORT Human Clinical
"Mutations in PIK3CD, which encodes an immune-specific catalytic subunit of PI3K, cause both dominant (activating) and recessive (loss of function) immune deficiencies in humans."
Establishes the bidirectional gene-disease architecture at PIK3CD.
PMID:41026257 SUPPORT Human Clinical
"Our study substantially increases the limited number of patients known to have immune deficiency due to loss of PIK3CD."
Confirms loss of PIK3CD as an established cause of immune deficiency.
💊

Medical Actions

3
Hematopoietic Stem Cell Transplantation
Action: Hematopoietic Cell TransplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Hematopoietic Cell Transplantation (NCIT:C15431). NCIT:C15431 is a clinical intervention from the NCI Thesaurus. NCIT:C15431
Potentially curative, and the only intervention reported to resolve the disease rather than manage it. In the index case a first transplant was rejected with autologous lymphoid reconstitution; a second, with more myeloablative conditioning, achieved full donor chimerism and sustained remission of the enterocolitis. It is curated against the tolerance node because replacing the haematopoietic compartment replaces the p110-delta-deficient lymphocytes driving both arms of the disease.
Mechanism Target:
INHIBITS Loss of Immune Tolerance — Replacement of the patient's haematopoietic system with donor cells carrying functional PIK3CD removes the deficient lymphocyte compartment, and with it the immune dysregulation.
Show evidence (1 reference)
PMID:31073077 SUPPORT Human Clinical
"On this occasion he achieved 100% donor chimerism including lymphoid reconstitution and sustained remission of enterocolitis."
Documents resolution of the immune-mediated disease following engraftment.
Show evidence (1 reference)
PMID:31073077 SUPPORT Human Clinical
"Hematopoietic stem cell transplantation (HSCT) was therefore performed as a potentially curative procedure."
Establishes HSCT as the curative intent intervention in this disease.
Immunoglobulin Replacement and Antimicrobial Prophylaxis
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Standard management of the humoral defect in the previously reported patients: immunoglobulin replacement with antimicrobial therapy for acute infections. This treats the consequence of the humoral arm and does not engage the underlying signalling lesion, so no target_mechanisms link is asserted.
Show evidence (1 reference)
PMID:31073077 SUPPORT Human Clinical
"Their management involved immunoglobulin replacement and antimicrobial therapy for acute infections"
Reports the standard supportive management used across the reported patients.
Immunosuppressive and Anti-Inflammatory Therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Control of the immune-mediated enterocolitis. In the index case anti-inflammatory therapy alone failed, and the diarrhoea only came under control with corticosteroid, cyclosporine and infliximab; weaning the immunosuppression relapsed the gut disease. Other reported patients were managed with mesalazine, steroids or 6-mercaptopurine. It is curated against the tolerance node because it suppresses the dysregulated immune response rather than correcting the signalling lesion - which is also why it controls rather than cures.
Mechanism Target:
INHIBITS Loss of Immune Tolerance — Broad immunosuppression suppresses the dysregulated effector response driving the enterocolitis, without addressing the underlying PI3K-delta deficiency.
Show evidence (1 reference)
PMID:31073077 SUPPORT Human Clinical
"However, weaning of immunosuppressive treatment led to a relapse of his gut disease, indicating chronic immune-mediated inflammation."
Demonstrates the effect is suppressive and ongoing rather than curative - the disease returns when treatment stops.
Show evidence (1 reference)
PMID:31073077 SUPPORT Human Clinical
"but continued with torrential diarrhea (3L/day) until the addition of immunosuppression (corticosteroid, cyclosporine, infliximab)"
Documents the specific agents that brought the enterocolitis under control.
🔬

Diagnosis

1
Molecular Genetic Testing of PIK3CD
Sequencing of PIK3CD, with attention to zygosity and to the direction of the variant's effect - a PIK3CD variant report alone does not distinguish IMD14B from APDS1, and the two need opposite therapeutic approaches. Standard laboratory measures of T-cell number and function are frequently unremarkable, so a normal T-cell panel does not exclude the diagnosis.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:31073077 SUPPORT Human Clinical
"others had normal counts and standard laboratory measures of T cell number and function were generally unremarkable. Therefore a high index of suspicion for an underlying monogenic cause is required in this setting."
Supports the diagnostic caution that routine immunological testing may not flag the disorder.
📊

Prevalence

1
Worldwide, published cases
Cases In Literature Ultra Rare
Ten patients reported as of the 2025 sibship report, which then added three more. The count carries its own caveat: three of the ten had a concurrent mutation in another immune gene, so the number of patients whose phenotype can be attributed to PIK3CD alone is smaller than ten.
Show evidence (1 reference)
PMID:41026257 SUPPORT Human Clinical
"For LOF, only 10 patients have been reported to date with germline autosomal recessive deficiency of PIK3CD; however, phenotypic interpretation is complicated by the fact that three of them also had a concurrent mutation"
Gives both the published case count and the confounding that limits how many of those cases can support phenotype claims.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Immunodeficiency 14B, Autosomal Recessive:

Activated PI3K-delta syndrome (APDS1 / IMD14A)
Overlapping Features The same gene in the opposite direction. APDS1 arises from heterozygous activating PIK3CD variants and presents with lymphoproliferation, herpesvirus infection and CD4 lymphopenia; IMD14B arises from biallelic null variants and presents with humoral deficiency, autoimmunity and enterocolitis. Distinguishing them is not academic - a PI3K-delta inhibitor is rational therapy in APDS and would be expected to worsen IMD14B.
Distinguishing Features
  • APDS1 is autosomal dominant with gain-of-function variants; IMD14B is autosomal recessive with biallelic loss of function
  • APDS1 features chronic lymphoproliferation and CD4 lymphopenia
  • PI3K-delta inhibition is a therapeutic strategy in APDS and would aggravate the lesion in IMD14B
Show evidence (1 reference)
PMID:31073077 SUPPORT Human Clinical
"Activating germline mutations inPIK3CDcause the immune dysregulatory disease activated PI3Kδ syndrome (APDS), usually presenting with recurrent sinopulmonary infections in childhood, herpes virus infections and CD4 lymphopenia"
Gives the contrasting genotype and presentation of the dominant disease.
Idelalisib-associated immune-mediated colitis
Overlapping Features Not an inherited mimic but the acquired, pharmacological counterpart. Patients given the p110-delta-specific inhibitor idelalisib for haematological malignancy develop severe colitis - the same on-target loss of activity producing the same gut disease in adults with no PIK3CD variant. It belongs here because it is the strongest available evidence that the enterocolitis in IMD14B is caused by loss of p110-delta activity itself rather than by anything else in these patients' genomes.
Distinguishing Features
  • Acquired and drug-induced rather than germline, with onset during therapy in adults
  • No PIK3CD variant; the enzyme is inhibited rather than absent
  • Resolves or is managed by withdrawing the drug, an option unavailable in the genetic disease
Show evidence (1 reference)
PMID:31073077 SUPPORT Human Clinical
"In humans, immune dysregulation including severe colitis is present in many cancer patients who are treated with the p110δ-specific inhibitor idelalisib."
Establishes the pharmacological phenocopy of the enterocolitis in patients without a PIK3CD variant.
Common variable immunodeficiency
Overlapping Features The clinical bucket IMD14B patients are most likely to be placed in before genetic testing: hypogammaglobulinaemia, absent class-switched memory B cells, recurrent sinopulmonary infection and autoimmune cytopenia together describe a CVID phenotype. Routine T-cell testing is often normal, which does nothing to prompt a monogenic search.
Distinguishing Features
  • CVID is a clinical diagnosis of exclusion; IMD14B has a defined biallelic PIK3CD genotype
  • Consanguinity and affected siblings should prompt a monogenic search
  • Enterocolitis with crypt apoptosis and refractory immune thrombocytopenia are more suggestive of a monogenic defect
Show evidence (1 reference)
PMID:31073077 SUPPORT Human Clinical
"Therefore a high index of suspicion for an underlying monogenic cause is required in this setting."
The authors' own statement that this phenotype will not otherwise be recognised.
🐁

Animal Models

1
p110-delta kinase-dead mouse
The mouse that anticipated the human disease. p110-delta kinase-dead mice spontaneously develop inflammatory bowel disease with crypt abscesses - the same histological lesion later found in the index patient - and their regulatory T cells show normal thymic output but disturbed trafficking and suppressive function.
Species
Mouse
Genotype
Pik3cd kinase-dead knock-in
Publication
PMID:31073077
Pathograph links
Loss of Immune Tolerance recapitulates fidelity: moderate Spontaneous colitis with crypt abscesses arises without any additional manipulation, matching the human enterocolitis at the level of histology, and the model supplies the regulatory T-cell mechanism that patient material was too limited to test.
Limitations: A kinase-dead knock-in is not the human genotype: patients carry truncating alleles that remove the protein entirely, and loss of p110-delta protein also destabilises p85-alpha, which a catalytically inactive but present protein would not. The model also does not speak to the humoral arm, where human and mouse B cells are reported to differ in their class-switching requirement.
Show evidence (2 references)
PMID:31073077 SUPPORT Model Organism
"Similar to our patient, p110δ kinase-dead mice spontaneously develop inflammatory bowel disease with crypt abscesses."
Establishes that the model reproduces the human gut lesion, including its histological hallmark.
+ 1 more reference
{ }

Source YAML

click to show 
name: Immunodeficiency 14B, Autosomal Recessive
creation_date: "2026-08-21T00:00:00Z"
category: Mendelian
description: >-
  Immunodeficiency 14B (IMD14B, OMIM 619281) is an ultra-rare autosomal recessive
  inborn error of immunity caused by biallelic loss-of-function variants in PIK3CD,
  which encodes p110-delta, the leukocyte-restricted catalytic subunit of class IA
  phosphoinositide 3-kinase delta.

  It is the mirror image of a disease the knowledge base already holds. Heterozygous
  activating variants in the same gene cause activated PI3K-delta syndrome (APDS1 /
  IMD14A), a lymphoproliferative combined immunodeficiency; biallelic null variants
  cause this one, a predominantly humoral immunodeficiency with autoimmunity and
  enterocolitis. One gene, two directions, two diseases - which is why IMD14B is
  curated separately rather than as a subtype of the APDS entry.

  Roughly ten patients have been reported, and the literature carries its own health
  warning: three of them had a second, concurrent immune-gene mutation, so their
  phenotypes cannot be attributed to PIK3CD alone. The entry marks that confounding
  explicitly rather than pooling all reported features into one clean picture.

  The mechanism has an unusual external check. Idelalisib, a p110-delta-specific
  inhibitor used in haematological malignancy, causes severe colitis in treated
  patients - pharmacological loss of the same activity, in adults, producing the same
  gut disease. That is curated as a distinct line of supporting evidence.
disease_term:
  preferred_term: immunodeficiency 14b, autosomal recessive
  term:
    id: MONDO:0023655
    label: immunodeficiency 14b, autosomal recessive
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Disease requires biallelic loss-of-function variants. Reported genotypes are
    predominantly homozygous, reflecting consanguinity in the ascertained families.
    Heterozygous carriers are unaffected, which is what separates this from the
    dominant gain-of-function disease at the same locus.
  evidence:
  - reference: PMID:41026257
    reference_title: "Homozygous Loss of Function PIK3CD Mutation in Multiple Siblings Leading To B Cell Dysregulation and Autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in PIK3CD, which encodes an immune-specific catalytic subunit
      of PI3K, cause both dominant (activating) and recessive (loss of function) immune
      deficiencies in humans."
    explanation: >-
      States the two-mode architecture of PIK3CD disease and places IMD14B on the
      recessive loss-of-function side.

pathophysiology:
- name: Biallelic PIK3CD Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Homozygous or compound heterozygous null or severely hypomorphic PIK3CD alleles.
    Reported classes include nonsense, frameshift and in-frame deletion variants; the
    index case carried a homozygous 21 bp deletion with a 2 bp insertion in exon 5
    producing p.Q170Vfs*41 and no detectable full-length protein.
  downstream:
  - target: Loss of p110-delta Protein with Secondary p85-alpha Reduction
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:41026257
    reference_title: "Homozygous Loss of Function PIK3CD Mutation in Multiple Siblings Leading To B Cell Dysregulation and Autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report a family with three affected children carrying a novel
      bi-allelic, truncating mutation in PIK3CD."
    explanation: Documents a biallelic truncating genotype in three affected siblings.

- name: Loss of p110-delta Protein with Secondary p85-alpha Reduction
  biological_scale: MOLECULAR
  description: >-
    Truncating alleles abolish p110-delta protein. The consequence is not confined to
    the catalytic subunit: because p110-delta and the p85-alpha regulatory subunit
    associate constitutively, loss of p110-delta also reduces p85-alpha expression. The
    lesion therefore removes the holoenzyme rather than just half of it.
  molecular_functions:
  - preferred_term: 1-phosphatidylinositol-3-kinase activity
    term:
      id: GO:0016303
      label: 1-phosphatidylinositol-3-kinase activity
    modifier: LOSS_OF_FUNCTION
  downstream:
  - target: Failure of PIP3 Generation on Antigen and Cytokine Receptor Engagement
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:41026257
    reference_title: "Homozygous Loss of Function PIK3CD Mutation in Multiple Siblings Leading To B Cell Dysregulation and Autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunoblot confirmed loss of protein along with reduced expression of the
      associated p85α regulatory subunit."
    explanation: >-
      Demonstrates both the loss of p110-delta and the secondary reduction of its
      obligate regulatory partner.

- name: Failure of PIP3 Generation on Antigen and Cytokine Receptor Engagement
  biological_scale: CELLULAR
  description: >-
    PI3K-delta phosphorylates PIP2 to PIP3 at the leukocyte plasma membrane downstream
    of antigen and cytokine receptors. Patient T lymphoblasts fail to generate PIP3 on
    T-cell receptor engagement, which is the proximal signalling failure from which the
    rest of the disease follows.
  downstream:
  - target: Impaired AKT-mTOR Signalling and Lymphocyte Metabolic Reprogramming
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:31073077
    reference_title: "Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase δ."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patient-derived T lymphoblasts were profoundly impaired in their ability
      to generate PIP3 upon T cell receptor (TCR) engagement"
    explanation: Direct measurement of the proximal signalling defect in patient cells.

- name: Impaired AKT-mTOR Signalling and Lymphocyte Metabolic Reprogramming
  biological_scale: CELLULAR
  description: >-
    Reduced PIP3 blunts the PDK1-AKT-mTOR cascade, and with it the metabolic switch
    lymphocytes need in order to expand and acquire effector function. Patient cells
    show reduced AKT and S6 phosphorylation and impaired glycolysis - and the same
    glycolytic defect is reproduced in healthy donor cells simply by adding idelalisib,
    which ties the metabolic phenotype directly to loss of p110-delta activity rather
    than to anything else in the patient's background.
  biological_processes:
  - preferred_term: glycolytic process
    term:
      id: GO:0006096
      label: glycolytic process
    modifier: DECREASED
  downstream:
  - target: Defective B-Cell Proliferation and Class-Switch Recombination
    causal_link_type: DIRECT
  - target: Impaired Cytotoxic Lymphocyte Effector Function
    causal_link_type: DIRECT
  - target: Paradoxical T-Cell Hyperactivation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:31073077
    reference_title: "Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase δ."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A glycolysis stress test showed impaired IL-2-stimulated glycolysis and
      glycolytic reserve in patient cells, similar to the behavior of CD4 and CD8 T cells
      treated with idelalisib"
    explanation: >-
      Establishes the metabolic defect and its pharmacological phenocopy in control cells,
      which controls for patient-specific confounders.
  - reference: PMID:31073077
    reference_title: "Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase δ."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings show that germline p110δ deficiency impairs lymphocyte
      metabolism"
    explanation: The authors' summary of the metabolic consequence of p110-delta deficiency.

- name: Defective B-Cell Proliferation and Class-Switch Recombination
  biological_scale: CELLULAR
  description: >-
    The humoral arm, and the one that dominates the clinical picture. Patient B cells
    proliferate poorly and fail to class-switch even when given CD40L and IL-21 - that
    is, even when supplied with the T-cell help that would normally rescue switching.
    The compartment skews toward naive cells at the expense of class-switched memory.
  cell_types:
  - preferred_term: naive B cell
    term:
      id: CL:0000788
      label: naive B cell
    modifier: INCREASED
  biological_processes:
  - preferred_term: isotype switching
    term:
      id: GO:0045190
      label: isotype switching
    modifier: DECREASED
  - preferred_term: B cell proliferation
    term:
      id: GO:0042100
      label: B cell proliferation
    modifier: DECREASED
  downstream:
  - target: Humoral Immunodeficiency
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:41026257
    reference_title: "Homozygous Loss of Function PIK3CD Mutation in Multiple Siblings Leading To B Cell Dysregulation and Autoimmunity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro functional testing of CD19 + and enriched naïve B cells revealed
      impaired proliferation, and reduction in class-switch recombination upon CD40L and
      IL-21 stimulation."
    explanation: >-
      Directly demonstrates the intrinsic B-cell proliferation and class-switching defect
      under conditions that supply T-cell help.
  - reference: PMID:41026257
    reference_title: "Homozygous Loss of Function PIK3CD Mutation in Multiple Siblings Leading To B Cell Dysregulation and Autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immune phenotyping showed B cell dysregulation with abnormally high levels
      of naïve cells."
    explanation: Documents the skew toward naive B cells in the patient compartment.

- name: Impaired Cytotoxic Lymphocyte Effector Function
  biological_scale: CELLULAR
  description: >-
    CD8 T-cell and NK-cell killing depend on PI3K-delta signalling, and the consequence
    in patients is susceptibility to herpesviruses. The index case had active
    cytomegalovirus replication in the gut with viraemia. Note that the CD8 compartment
    is not simply depleted - it is skewed toward effector/memory cells expressing high
    TBET and perforin, so the failure is functional rather than numerical.
  cell_types:
  - preferred_term: CD8-positive, alpha-beta T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  downstream:
  - target: Susceptibility to Viral and Recurrent Bacterial Infection
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:31073077
    reference_title: "Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase δ."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Viral inclusion bodies were visible, indicating active cytomegalovirus (CMV)
      replication in the gut, accompanied by CMV viremia"
    explanation: Documents failure of control of a herpesvirus in the index patient.
  - reference: PMID:31073077
    reference_title: "Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase δ."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Peripheral blood was enriched for effector/memory CD8 T cells, which expressed
      high levels of the transcription factor TBET and perforin"
    explanation: >-
      Shows the CD8 compartment is skewed rather than absent, supporting a functional
      rather than numerical defect.

- name: Paradoxical T-Cell Hyperactivation
  biological_scale: CELLULAR
  description: >-
    The counterintuitive step, and the one that makes the autoimmune half of this disease
    make sense. PI3K-delta drives T-cell activation, so losing it ought to make T cells
    less responsive - yet patient CD3+ cells are hyperactivated. The proposed reason is
    substrate rerouting: with the kinase gone, its substrate PIP2 accumulates and is
    instead hydrolysed by phospholipase C-gamma1 into second messengers that drive
    activation through a different arm.

    The consequence is a two-sided failure at the gut mucosa - effector T cells that are
    improperly activated, and PI3K-delta-deficient regulatory T cells unable to suppress
    them.
  cell_types:
  - preferred_term: CD4-positive, alpha-beta T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
    modifier: INCREASED
  downstream:
  - target: Loss of Immune Tolerance
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:41026257
    reference_title: "Homozygous Loss of Function PIK3CD Mutation in Multiple Siblings Leading To B Cell Dysregulation and Autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our data supports the conclusion that CD3 + hyperactivation is a natural
      consequence of PIK3CD protein loss."
    explanation: >-
      The authors' conclusion that hyperactivation follows directly from loss of the
      protein, rather than being incidental to these patients.
  - reference: PMID:41026257
    reference_title: "Homozygous Loss of Function PIK3CD Mutation in Multiple Siblings Leading To B Cell Dysregulation and Autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This hyperactivation may result from the increased availability of PIP2, which
      is hydrolyzed by phospholipase Cγ1 (PLCγ1) into crucial secondary messengers that
      trigger several distal signaling cascades vital for CD3 + activation"
    explanation: >-
      The proposed substrate-rerouting mechanism. Curated PARTIAL because the authors state
      it as a possible explanation, not a demonstrated one.
  - reference: PMID:41026257
    reference_title: "Homozygous Loss of Function PIK3CD Mutation in Multiple Siblings Leading To B Cell Dysregulation and Autoimmunity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In PI3Kδ-deficient mice, improper activation of effector T cells by gut
      microbes leads to colitis, which PI3Kδ-deficient Treg are unable to suppress"
    explanation: >-
      Supplies the route from hyperactivated effector T cells to colitis, and the parallel
      failure of the regulatory compartment to restrain them.

- name: Loss of Immune Tolerance
  biological_scale: ORGANISM
  description: >-
    Autoimmune and autoinflammatory disease is as prominent as the infection
    susceptibility. Immune-mediated thrombocytopenia and inflammatory enterocolitis are
    the two recurring manifestations. The intermediates between impaired PI3K-delta
    signalling and tolerance breakdown are now partly established: the immediate upstream
    node is paradoxical T-cell hyperactivation, and mouse work implicates disturbed
    regulatory T-cell trafficking and suppressive function, curated with evidence in
    animal_models below rather than asserted here as prose.
  downstream:
  - target: Autoimmune Cytopenia and Inflammatory Enterocolitis
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:41026257
    reference_title: "Homozygous Loss of Function PIK3CD Mutation in Multiple Siblings Leading To B Cell Dysregulation and Autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All three patients exhibited autoimmunity and B cell dysregulation"
    explanation: Establishes autoimmunity as a consistent feature across an affected sibship.

- name: Humoral Immunodeficiency
  biological_scale: ORGANISM
  description: >-
    Hypogammaglobulinaemia with absent class-switched memory B cells, giving recurrent
    sinopulmonary infection. This is the feature most consistently reported across
    independent kindreds and the one that usually brings patients to attention.
  downstream:
  - target: Susceptibility to Viral and Recurrent Bacterial Infection
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:31073077
    reference_title: "Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase δ."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the remaining four patients, all presented with hypogammaglobulinemia and
      recurrent sinopulmonary infections, some including severe and opportunistic pneumonias."
    explanation: >-
      Reports the phenotype across the previously published unconfounded patients, which is
      the cleanest available statement of the humoral defect.

- name: Susceptibility to Viral and Recurrent Bacterial Infection
  biological_scale: ORGANISM
  description: >-
    The infectious endpoint: recurrent sinopulmonary infection from the humoral defect,
    and poor control of herpesviruses from the cytotoxic defect. Both arms converge here.
  evidence:
  - reference: PMID:41026257
    reference_title: "Homozygous Loss of Function PIK3CD Mutation in Multiple Siblings Leading To B Cell Dysregulation and Autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All three patients exhibited chronic diarrhea and recurrent sinopulmonary
      infections."
    explanation: Documents recurrent sinopulmonary infection across the sibship.

- name: Autoimmune Cytopenia and Inflammatory Enterocolitis
  biological_scale: ORGANISM
  description: >-
    The autoimmune endpoint. Thrombocytopenia can be refractory to corticosteroids,
    immunoglobulin and splenectomy, and severe enough to cause intracranial haemorrhage.
    The enterocolitis is histologically distinctive - crypt epithelial apoptosis with
    crypt abscess formation and a lamina propria notably depleted of B cells and plasma
    cells.
  evidence:
  - reference: PMID:31073077
    reference_title: "Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase δ."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Endoscopy revealed enterocolitis, which histologically showed marked apoptosis
      of crypt epithelial cells, eosinophil and neutrophil infiltration, crypt distortion and
      crypt abscess formation"
    explanation: Describes the histopathology of the enterocolitis in the index case.
  - reference: PMID:31073077
    reference_title: "Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase δ."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we report a child with homozygous germline loss-of-function mutation inPIK3CD,
      who developed refractory immune thrombocytopenia, inflammatory bowel disease and
      susceptibility to infection, cured by HSCT"
    explanation: >-
      The authors' summary of the index case, establishing the triad and its response to
      transplantation.

phenotypes:
- category: Immunological
  name: Recurrent Sinopulmonary Infections
  description: >-
    Recurrent infections of the upper and lower respiratory tract, in some patients
    including severe or opportunistic pneumonia. Reported in essentially every
    unconfounded patient.
  phenotype_term:
    preferred_term: Recurrent sinopulmonary infections
    term:
      id: HP:0005425
      label: Recurrent sinopulmonary infections
  evidence:
  - reference: PMID:41026257
    reference_title: "Homozygous Loss of Function PIK3CD Mutation in Multiple Siblings Leading To B Cell Dysregulation and Autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All three patients exhibited chronic diarrhea and recurrent sinopulmonary
      infections."
    explanation: Documents recurrent sinopulmonary infection in all three affected siblings.

- category: Immunological
  name: Decreased Circulating IgG Concentration
  description: >-
    Hypogammaglobulinaemia. Reported consistently across the previously published
    unconfounded patients. Note that the index case's immunoglobulin measurements are
    confounded - see notes.
  phenotype_term:
    preferred_term: Decreased circulating IgG concentration
    term:
      id: HP:0004315
      label: Decreased circulating IgG concentration
  evidence:
  - reference: PMID:31073077
    reference_title: "Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase δ."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the remaining four patients, all presented with hypogammaglobulinemia and
      recurrent sinopulmonary infections, some including severe and opportunistic pneumonias."
    explanation: >-
      Establishes hypogammaglobulinaemia in the four previously reported patients whose
      phenotype is not complicated by a second immune-gene defect.

- category: Immunological
  name: Decreased Class-Switched Memory B Cell Proportion
  description: >-
    Class-switched memory B cells are absent or markedly reduced, consistent with the
    demonstrated in vitro class-switch recombination defect.
  phenotype_term:
    preferred_term: Decreased class-switched memory B cell proportion
    term:
      id: HP:0030388
      label: Decreased class-switched memory B cell proportion
  evidence:
  - reference: PMID:41026257
    reference_title: "Homozygous Loss of Function PIK3CD Mutation in Multiple Siblings Leading To B Cell Dysregulation and Autoimmunity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro functional testing of CD19 + and enriched naïve B cells revealed
      impaired proliferation, and reduction in class-switch recombination upon CD40L and
      IL-21 stimulation."
    explanation: >-
      Demonstrates the class-switching defect that underlies the reduced class-switched
      memory compartment.

- category: Gastrointestinal
  name: Chronic Diarrhea
  description: >-
    Chronic diarrhoea, which in the index case was intractable, reaching three litres a
    day with roughly 30% body weight loss.
  phenotype_term:
    preferred_term: Chronic diarrhea
    term:
      id: HP:0002028
      label: Chronic diarrhea
    temporality: CHRONIC
  evidence:
  - reference: PMID:41026257
    reference_title: "Homozygous Loss of Function PIK3CD Mutation in Multiple Siblings Leading To B Cell Dysregulation and Autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All three patients exhibited chronic diarrhea and recurrent sinopulmonary
      infections."
    explanation: Documents chronic diarrhoea in all three affected siblings.

- category: Gastrointestinal
  name: Enterocolitis
  description: >-
    Inflammatory enterocolitis with crypt epithelial apoptosis, crypt abscesses and a
    lamina propria depleted of B cells and plasma cells. Relapses on withdrawal of
    immunosuppression, indicating chronic immune-mediated inflammation rather than a
    purely infectious process.
  phenotype_term:
    preferred_term: Enterocolitis
    term:
      id: HP:0004387
      label: Enterocolitis
  evidence:
  - reference: PMID:31073077
    reference_title: "Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase δ."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Endoscopy revealed enterocolitis, which histologically showed marked apoptosis
      of crypt epithelial cells, eosinophil and neutrophil infiltration, crypt distortion and
      crypt abscess formation"
    explanation: Establishes the enterocolitis and its histological character.

- category: Hematological
  name: Autoimmune Thrombocytopenia
  description: >-
    Immune-mediated thrombocytopenia, refractory in the index case to corticosteroids,
    high-dose immunoglobulin and splenectomy, and complicated by intracranial haemorrhage
    requiring surgical evacuation.
  phenotype_term:
    preferred_term: Autoimmune thrombocytopenia
    term:
      id: HP:0001973
      label: Autoimmune thrombocytopenia
  evidence:
  - reference: PMID:31073077
    reference_title: "Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase δ."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His thrombocytopenia was refractory to corticosteroids, high dose immunoglobulin
      and splenectomy, culminating in an intracranial bleed requiring surgical evacuation."
    explanation: Documents the severity and treatment-refractoriness of the thrombocytopenia.

genetic:
- name: PIK3CD
  gene_term:
    preferred_term: PIK3CD
    term:
      id: hgnc:8977
      label: PIK3CD
  relationship_type: CAUSATIVE
  association: >-
    Biallelic loss-of-function variants in PIK3CD cause IMD14B. The same gene causes
    activated PI3K-delta syndrome (APDS1 / IMD14A) through heterozygous activating
    variants, so the direction of the variant's effect, not the gene, determines which
    disease results. Reported IMD14B alleles are nonsense, frameshift or in-frame
    deletions producing complete or near-complete loss of p110-delta.
  evidence:
  - reference: PMID:41026257
    reference_title: "Homozygous Loss of Function PIK3CD Mutation in Multiple Siblings Leading To B Cell Dysregulation and Autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in PIK3CD, which encodes an immune-specific catalytic subunit of
      PI3K, cause both dominant (activating) and recessive (loss of function) immune
      deficiencies in humans."
    explanation: Establishes the bidirectional gene-disease architecture at PIK3CD.
  - reference: PMID:41026257
    reference_title: "Homozygous Loss of Function PIK3CD Mutation in Multiple Siblings Leading To B Cell Dysregulation and Autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our study substantially increases the limited number of patients known to have
      immune deficiency due to loss of PIK3CD."
    explanation: Confirms loss of PIK3CD as an established cause of immune deficiency.

prevalence:
- population: Worldwide, published cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Ten patients reported as of the 2025 sibship report, which then added three more. The
    count carries its own caveat: three of the ten had a concurrent mutation in another
    immune gene, so the number of patients whose phenotype can be attributed to PIK3CD
    alone is smaller than ten.
  evidence:
  - reference: PMID:41026257
    reference_title: "Homozygous Loss of Function PIK3CD Mutation in Multiple Siblings Leading To B Cell Dysregulation and Autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For LOF, only 10 patients have been reported to date with germline autosomal
      recessive deficiency of PIK3CD; however, phenotypic interpretation is complicated by
      the fact that three of them also had a concurrent mutation"
    explanation: >-
      Gives both the published case count and the confounding that limits how many of those
      cases can support phenotype claims.

diagnosis:
- name: Molecular Genetic Testing of PIK3CD
  description: >-
    Sequencing of PIK3CD, with attention to zygosity and to the direction of the
    variant's effect - a PIK3CD variant report alone does not distinguish IMD14B from
    APDS1, and the two need opposite therapeutic approaches. Standard laboratory
    measures of T-cell number and function are frequently unremarkable, so a normal
    T-cell panel does not exclude the diagnosis.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:31073077
    reference_title: "Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase δ."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "others had normal counts and standard laboratory measures of T cell number and
      function were generally unremarkable. Therefore a high index of suspicion for an
      underlying monogenic cause is required in this setting."
    explanation: >-
      Supports the diagnostic caution that routine immunological testing may not flag the
      disorder.

treatments:
- name: Hematopoietic Stem Cell Transplantation
  description: >-
    Potentially curative, and the only intervention reported to resolve the disease
    rather than manage it. In the index case a first transplant was rejected with
    autologous lymphoid reconstitution; a second, with more myeloablative conditioning,
    achieved full donor chimerism and sustained remission of the enterocolitis. It is
    curated against the tolerance node because replacing the haematopoietic compartment
    replaces the p110-delta-deficient lymphocytes driving both arms of the disease.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: Hematopoietic Cell Transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Loss of Immune Tolerance
    treatment_effect: INHIBITS
    description: >-
      Replacement of the patient's haematopoietic system with donor cells carrying
      functional PIK3CD removes the deficient lymphocyte compartment, and with it the
      immune dysregulation.
    evidence:
    - reference: PMID:31073077
      reference_title: "Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase δ."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "On this occasion he achieved 100% donor chimerism including lymphoid
        reconstitution and sustained remission of enterocolitis."
      explanation: Documents resolution of the immune-mediated disease following engraftment.
  evidence:
  - reference: PMID:31073077
    reference_title: "Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase δ."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hematopoietic stem cell transplantation (HSCT) was therefore performed as a
      potentially curative procedure."
    explanation: Establishes HSCT as the curative intent intervention in this disease.

- name: Immunoglobulin Replacement and Antimicrobial Prophylaxis
  description: >-
    Standard management of the humoral defect in the previously reported patients:
    immunoglobulin replacement with antimicrobial therapy for acute infections. This
    treats the consequence of the humoral arm and does not engage the underlying
    signalling lesion, so no target_mechanisms link is asserted.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:31073077
    reference_title: "Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase δ."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Their management involved immunoglobulin replacement and antimicrobial therapy
      for acute infections"
    explanation: Reports the standard supportive management used across the reported patients.

- name: Immunosuppressive and Anti-Inflammatory Therapy
  description: >-
    Control of the immune-mediated enterocolitis. In the index case anti-inflammatory
    therapy alone failed, and the diarrhoea only came under control with corticosteroid,
    cyclosporine and infliximab; weaning the immunosuppression relapsed the gut disease.
    Other reported patients were managed with mesalazine, steroids or 6-mercaptopurine.
    It is curated against the tolerance node because it suppresses the dysregulated immune
    response rather than correcting the signalling lesion - which is also why it controls
    rather than cures.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Loss of Immune Tolerance
    treatment_effect: INHIBITS
    description: >-
      Broad immunosuppression suppresses the dysregulated effector response driving the
      enterocolitis, without addressing the underlying PI3K-delta deficiency.
    evidence:
    - reference: PMID:31073077
      reference_title: "Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase δ."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "However, weaning of immunosuppressive treatment led to a relapse of his gut
        disease, indicating chronic immune-mediated inflammation."
      explanation: >-
        Demonstrates the effect is suppressive and ongoing rather than curative - the disease
        returns when treatment stops.
  evidence:
  - reference: PMID:31073077
    reference_title: "Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase δ."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "but continued with torrential diarrhea (3L/day) until the addition of
      immunosuppression (corticosteroid, cyclosporine, infliximab)"
    explanation: Documents the specific agents that brought the enterocolitis under control.

differential_diagnoses:
- name: Activated PI3K-delta syndrome (APDS1 / IMD14A)
  description: >-
    The same gene in the opposite direction. APDS1 arises from heterozygous activating
    PIK3CD variants and presents with lymphoproliferation, herpesvirus infection and CD4
    lymphopenia; IMD14B arises from biallelic null variants and presents with humoral
    deficiency, autoimmunity and enterocolitis. Distinguishing them is not academic - a
    PI3K-delta inhibitor is rational therapy in APDS and would be expected to worsen
    IMD14B.
  distinguishing_features:
  - APDS1 is autosomal dominant with gain-of-function variants; IMD14B is autosomal recessive with biallelic loss of function
  - APDS1 features chronic lymphoproliferation and CD4 lymphopenia
  - PI3K-delta inhibition is a therapeutic strategy in APDS and would aggravate the lesion in IMD14B
  evidence:
  - reference: PMID:31073077
    reference_title: "Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase δ."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Activating germline mutations inPIK3CDcause the immune dysregulatory disease
      activated PI3Kδ syndrome (APDS), usually presenting with recurrent sinopulmonary
      infections in childhood, herpes virus infections and CD4 lymphopenia"
    explanation: Gives the contrasting genotype and presentation of the dominant disease.

- name: Idelalisib-associated immune-mediated colitis
  description: >-
    Not an inherited mimic but the acquired, pharmacological counterpart. Patients given
    the p110-delta-specific inhibitor idelalisib for haematological malignancy develop
    severe colitis - the same on-target loss of activity producing the same gut disease
    in adults with no PIK3CD variant. It belongs here because it is the strongest
    available evidence that the enterocolitis in IMD14B is caused by loss of p110-delta
    activity itself rather than by anything else in these patients' genomes.
  distinguishing_features:
  - Acquired and drug-induced rather than germline, with onset during therapy in adults
  - No PIK3CD variant; the enzyme is inhibited rather than absent
  - Resolves or is managed by withdrawing the drug, an option unavailable in the genetic disease
  evidence:
  - reference: PMID:31073077
    reference_title: "Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase δ."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In humans, immune dysregulation including severe colitis is present in many
      cancer patients who are treated with the p110δ-specific inhibitor idelalisib."
    explanation: >-
      Establishes the pharmacological phenocopy of the enterocolitis in patients without a
      PIK3CD variant.

- name: Common variable immunodeficiency
  description: >-
    The clinical bucket IMD14B patients are most likely to be placed in before genetic
    testing: hypogammaglobulinaemia, absent class-switched memory B cells, recurrent
    sinopulmonary infection and autoimmune cytopenia together describe a CVID phenotype.
    Routine T-cell testing is often normal, which does nothing to prompt a monogenic
    search.
  distinguishing_features:
  - CVID is a clinical diagnosis of exclusion; IMD14B has a defined biallelic PIK3CD genotype
  - Consanguinity and affected siblings should prompt a monogenic search
  - Enterocolitis with crypt apoptosis and refractory immune thrombocytopenia are more suggestive of a monogenic defect
  evidence:
  - reference: PMID:31073077
    reference_title: "Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase δ."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therefore a high index of suspicion for an underlying monogenic cause is
      required in this setting."
    explanation: The authors' own statement that this phenotype will not otherwise be recognised.

animal_models:
- name: p110-delta kinase-dead mouse
  species: Mouse
  genotype: Pik3cd kinase-dead knock-in
  publication: PMID:31073077
  description: >-
    The mouse that anticipated the human disease. p110-delta kinase-dead mice spontaneously
    develop inflammatory bowel disease with crypt abscesses - the same histological lesion
    later found in the index patient - and their regulatory T cells show normal thymic
    output but disturbed trafficking and suppressive function.
  modeled_mechanisms:
  - target: Loss of Immune Tolerance
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Spontaneous colitis with crypt abscesses arises without any additional manipulation,
      matching the human enterocolitis at the level of histology, and the model supplies the
      regulatory T-cell mechanism that patient material was too limited to test.
    limitations: >-
      A kinase-dead knock-in is not the human genotype: patients carry truncating alleles
      that remove the protein entirely, and loss of p110-delta protein also destabilises
      p85-alpha, which a catalytically inactive but present protein would not. The model
      also does not speak to the humoral arm, where human and mouse B cells are reported to
      differ in their class-switching requirement.
    evidence:
    - reference: PMID:31073077
      reference_title: "Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase δ."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Similar to our patient, p110δ kinase-dead mice spontaneously develop
        inflammatory bowel disease with crypt abscesses."
      explanation: >-
        Establishes that the model reproduces the human gut lesion, including its
        histological hallmark.
    - reference: PMID:31073077
      reference_title: "Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase δ."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In these mice, thymic output of Tregs was normal, but Treg trafficking and
        suppressive activity including IL-10 secretion were disturbed."
      explanation: >-
        Supplies the regulatory T-cell mechanism invoked for the tolerance node, sourced
        rather than asserted.

discussions:
- discussion_id: mismatch_human_b_cell_class_switching_versus_mouse
  kind: HUMAN_MODEL_MISMATCH
  attaches_to:
  - pathophysiology#Defective B-Cell Proliferation and Class-Switch Recombination
  prompt: >-
    Why do human PIK3CD-deficient B cells fail to class-switch even when supplied with
    CD40L and IL-21, when mouse B cells lacking p110-delta can still class-switch given
    external T-cell help?
  rationale: >-
    Most of what is known about PI3K-delta in immunity comes from mice, and the mouse
    predicts that T-cell help should rescue class-switch recombination. Human patient B
    cells do not behave that way: proliferation and switching remain impaired under CD40L
    and IL-21 stimulation, which is precisely the help that should have rescued them. The
    authors of the sibling study raise this themselves. If the human B-cell requirement
    for PI3K-delta is genuinely broader than the mouse's, then mouse models will
    systematically understate the humoral severity of this disease, and a therapy
    validated on murine class-switching would not translate. The alternative is that the
    in vitro stimulation conditions do not reproduce germinal-centre help faithfully
    enough, in which case the discrepancy is methodological rather than biological.
  proposed_experiments:
  - experiment_id: exp_side_by_side_human_mouse_csr
    name: Matched-protocol class-switch recombination in human and murine p110-delta-null B cells
    description: >-
      Run identical stimulation protocols on patient-derived and p110-delta-null murine B
      cells in the same laboratory, varying CD40L and IL-21 dose and timing. A species
      difference that survives protocol matching is biological; one that disappears is an
      artefact of how the two literatures were generated.
  - experiment_id: exp_germinal_centre_organoid_switching
    name: Class-switching in a germinal-centre organoid supplied with autologous T-cell help
    description: >-
      Test patient B cells in a three-dimensional germinal-centre system with autologous T
      cells rather than recombinant CD40L, to establish whether physiological help rescues
      switching where soluble stimulation does not.

- discussion_id: gap_confounded_phenotype_attribution
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Loss of Immune Tolerance
  prompt: >-
    Which features of the reported IMD14B phenotype are attributable to PIK3CD loss
    alone, given that a third of published patients carry a second immune-gene defect and
    the index case was immunophenotyped after rituximab?
  rationale: >-
    This is a small-numbers problem with a specific and unusually well-documented shape.
    Of roughly ten reported patients, three also carry a concurrent mutation in another
    immune gene, so their phenotypes cannot be assigned to PIK3CD. Separately, the index
    case's B-cell findings - low B cells, absent class-switched memory, low
    immunoglobulins - were measured after treatment with the B-cell-depleting antibody
    rituximab, and the reporting authors say explicitly that these are consistent with
    either the drug or a primary B-cell abnormality. The unconfounded evidence for the
    humoral phenotype therefore rests on a smaller set of patients than the headline count
    suggests, and the 2025 sibship is valuable precisely because it is untreated and
    unconfounded. Until more such families are reported, any frequency estimate for this
    disease would be assembled from a denominator that does not really exist.
  proposed_experiments:
  - experiment_id: exp_unconfounded_imd14b_registry
    name: Registry of biallelic PIK3CD patients stratified by confounder status
    description: >-
      Collect reported and unreported biallelic PIK3CD patients into a single registry
      that records, per patient, whether a second immune-gene variant is present and
      whether immunophenotyping preceded or followed B-cell-depleting or immunosuppressive
      therapy. Only the untreated, single-locus subset can support statements about the
      disease's intrinsic phenotype.

notes: >-
  No GeneReviews chapter exists for IMD14B. This was checked and verified by reading rather
  than assumed. A PubMed search for PIK3CD in GeneReviews returns exactly one chapter,
  PMID:39899769, and that chapter was fetched and read: it is "Activated PI3K Delta
  Syndrome", it defines APDS1 as caused by a heterozygous gain-of-function PIK3CD variant
  and APDS2 by a heterozygous PIK3R1 variant, and it contains no occurrence of "recessive",
  "biallelic" or "homozygous". It is therefore a chapter about a different disease and is
  not cited here; using it as the phenotype baseline for IMD14B would be evidence from the
  wrong disorder. Note also that APDS2 is described as a loss-of-function variant, but in
  PIK3R1, the inhibitory regulatory subunit - so that loss of function produces pathway
  hyperactivation, the opposite of what loss of function in PIK3CD does. The phrase "PIK3CD
  loss of function" alone is not enough to identify which disease is meant.

  Confounded evidence, flagged deliberately. The index case (PMID:31073077) received
  rituximab before immunophenotyping, and the reporting authors state that the low B cells,
  absent class-switched memory and subnormal immunoglobulins are "consistent with prior
  rituximab therapy and/or a primary B-cell abnormality". This entry therefore sources the
  humoral phenotype to the four previously reported unconfounded patients and to the 2025
  untreated sibship, not to the index case's own B-cell numbers. Separately, three of the
  roughly ten reported patients carry a concurrent mutation in another immune gene.

  No frequency bands are assigned to any phenotype. With about ten reported patients, a
  third of them confounded by a second genetic defect, there is no denominator to band
  against.

  The founding clinical description of PI3K-delta deficiency, Sogkas et al. 2018
  (PMID:30040974, J Allergy Clin Immunol), is a Letter that caches with no abstract and no
  retrievable full text, so it carries no evidence item here and is cited only as context.
  It is not listed in the references block because nothing in this entry is quoted from it.

references:
- reference: PMID:31073077
  title: Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal
    recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase delta.
- reference: PMID:41026257
  title: Homozygous Loss of Function PIK3CD Mutation in Multiple Siblings Leading To B Cell
    Dysregulation and Autoimmunity.
📚

References & Deep Research

References

2
PMID:31073077
Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase delta.
No top-level findings curated for this source.
PMID:41026257
Homozygous Loss of Function PIK3CD Mutation in Multiple Siblings Leading To B Cell Dysregulation and Autoimmunity.
No top-level findings curated for this source.

Deep Research

1
Claude Code ▸
Immunodeficiency 14B, Autosomal Recessive (IMD14B) — Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 15 citations 2026-08-21T12:48:44.296315

Immunodeficiency 14B, Autosomal Recessive (IMD14B) — Comprehensive Research Report

1. Disease Information

Overview. Immunodeficiency 14B, Autosomal Recessive (IMD14B) is a rare inborn error of immunity caused by biallelic (homozygous or compound heterozygous) loss-of-function variants in PIK3CD, the gene encoding the p110δ catalytic subunit of class IA phosphoinositide 3-kinase (PI3Kδ). It is the recessive, loss-of-function counterpart of the much more extensively characterized autosomal dominant gain-of-function PIK3CD disorder, Activated PI3K-delta Syndrome 1 (APDS1 / IMD14A, OMIM #615513) — the same gene, opposite direction of dysregulation, and a substantially different clinical picture. Whereas APDS1 (heterozygous activating variants) causes a combined immunodeficiency with lymphoproliferation and hyperactive PI3Kδ signaling, IMD14B (biallelic loss-of-function variants) produces PI3Kδ deficiency/haploinsufficiency-below-threshold, presenting mainly with humoral immunodeficiency, defective cytotoxic lymphocyte function, and autoimmune/autoinflammatory features including autoimmune thrombocytopenia and enterocolitis.

Key identifiers: - OMIM: #619281 — "IMMUNODEFICIENCY 14B, AUTOSOMAL RECESSIVE; IMD14B" (gene-disease relationship curated at OMIM 602839, PIK3CD) - Related/contrasted entries: OMIM #615513 (IMD14A, autosomal dominant, same gene, GOF); OMIM #616005 (IMD36/APDS2, PIK3R1, AD); ClinGen gene-disease validity record SGC-104693.2 (PIK3CD, autosomal recessive) - Gene: PIK3CD (HGNC:8977), chromosome 1p36.22 - MONDO ID: not directly located in this search session — recommend cross-checking the MONDO term server directly before curation (candidate: a MONDO term mapping to OMIM:619281) - Suggested MONDO/Mondo cross-ref: should resolve via OMIM 619281 xref - Inheritance: Autosomal recessive - Category:* Inborn error of immunity — predominantly antibody deficiency / combined immunodeficiency with immune dysregulation (IUIS classification)

Synonyms/alternative names: Autosomal recessive PI3Kδ deficiency; PIK3CD deficiency (loss-of-function type); p110δ deficiency; PI3K-delta underactivation; biallelic PIK3CD deficiency. Should not be confused with "PIK3CD deficiency" used loosely in some older literature to mean APDS1 (gain-of-function).

Evidence basis: This entry is derived almost entirely from aggregated case-series/case-report literature (family and cohort reports of small numbers of patients, typically from consanguineous kindreds), not large-cohort EHR/registry data — reflecting genuine disease rarity. As of the founding 2019 report only ~9 patients from 6 families had been described with germline biallelic PI3Kδ-pathway loss-of-function; a further multi-sibling family was reported in 2025.

Sources: OMIM #619281, OMIM #615513 (IMD14A), ClinGen SGC-104693.2, PMC6886442 (Swan et al. 2019)

2. Etiology

Disease Causal Factors

IMD14B is a monogenic, purely genetic disorder. Disease requires biallelic loss-of-function (LOF) variants in PIK3CD — i.e., both alleles carry null or severely hypomorphic mutations, consistent with autosomal recessive Mendelian inheritance. This is mechanistically the inverse lesion from APDS1: APDS1 variants (e.g., E1021K, the classic "hotspot") increase PI3Kδ lipid-kinase activity (gain-of-function, dominant), while IMD14B variants abolish or severely reduce p110δ protein expression or catalytic function (loss-of-function, recessive — a single functional allele is sufficient for near-normal PI3Kδ signaling, consistent with autosomal recessive rather than dominant-negative behavior at the heterozygous carrier level).

Genetic Risk Factors

  • Causal variants: Biallelic (homozygous or compound heterozygous) null/hypomorphic PIK3CD alleles. Reported variant types across the described families include:
  • c.703_723delinsGT (exon 5), producing a frameshift and premature stop codon p.Q170Vfs*41, resulting in absent full-length p110δ protein — the index case in the Swan et al. 2019 Haematologica report (homozygous, from consanguineous parents)
  • Nonsense variants: Q116, Q721
  • Frameshift: V552Sfs*26
  • In-frame deletion: I899del (These four — Q116, I899del, V552Sfs26, Q721* — represent the mutation spectrum reported across the original 6-family cohort of biallelic PI3Kδ-pathway LOF cases.)
  • Consanguinity is strongly overrepresented among reported families, consistent with the rarity of biallelic LOF alleles at population frequency and typical of autosomal recessive Mendelian disease ascertainment.
  • Population allele frequency / constraint: PIK3CD is a gene with population-level constraint against loss-of-function variation in gnomAD (constraint metrics — pLI/LOEUF — were not independently retrieved in this session and should be pulled directly from gnomAD before finalizing a KB entry, but the extreme rarity of reported biallelic-null patients is consistent with a haploinsufficient/constrained gene where homozygous null genotypes are strongly selected against or embryonic-lethal-adjacent in some genetic backgrounds).
  • Modifier/digenic context: At least one report describes a patient with concomitant partial defects in PIK3CD and RAB27A (two hypomorphic genetic lesions) that together predisposed to hemophagocytic lymphohistiocytosis (HLH) upon viral challenge — illustrating that partial (hypomorphic, not fully null) PI3Kδ pathway dysfunction can act as a genetic modifier/second hit rather than causing IMD14B outright on its own (Ghosh et al., J Exp Med 2018, "Concomitant PIK3CD and TNFRSF9 deficiencies cause chronic active Epstein-Barr virus infection of T cells" — note: this specific title concerns TNFRSF9, and a related HLH/RAB27A digenic report was also identified in search but not independently verified in this session; treat as a lead requiring primary-source confirmation before citation).

Environmental Risk Factors

None established as causal — this is a purely monogenic disorder. However, as with other primary antibody/cytotoxic immunodeficiencies, infectious triggers (particularly EBV and CMV) appear to precipitate or exacerbate the clinical phenotype in affected patients (CMV viremia and gut CMV replication were documented in the index Swan et al. case; norovirus and post-transplant HSV were also noted), consistent with the known role of PI3Kδ in cytotoxic lymphocyte (CD8+ T cell, NK cell) antiviral function.

Protective Factors

None specifically established. By analogy to other antibody-deficiency PIDs, timely diagnosis enabling immunoglobulin replacement and prophylactic antimicrobials likely reduces infection-related morbidity, but this has not been formally studied as a "protective factor" in IMD14B specifically.

Gene-Environment Interactions

The core biological interaction is infection as a functional stress-test of an already-deficient cytotoxic/humoral immune system — e.g., CMV/EBV exposure unmasking failure of PI3Kδ-dependent CD8+ T-cell and NK-cell cytotoxic effector function, and gut viral/bacterial exposure precipitating the enterocolitis phenotype in a background of PI3Kδ-dependent epithelial/mucosal immune dysregulation.

Sources: PMC6886442, PMC6082933 (CD8+ T cell PI3Kδ), JEM: Concomitant PIK3CD and TNFRSF9 deficiencies

3. Phenotypes

Reported cases converge on a triad of recurrent infection, humoral immunodeficiency, and autoimmune/autoinflammatory gut and hematologic disease — clinically distinct from the lymphoproliferative, herpesvirus-viremic phenotype of APDS1 (gain-of-function).

Phenotype Type Onset Severity/Course Suggested HP term
Recurrent sinopulmonary/respiratory infections Symptom/clinical sign Early childhood Variable; some patients had severe pneumonia HP:0002205 (Recurrent respiratory infections)
Hypogammaglobulinemia Laboratory abnormality Childhood Reported as IgG 2.5 g/L, IgM 0.25 g/L in the index case HP:0004313 (Hypogammaglobulinemia)
Decreased/absent class-switched memory B cells Laboratory abnormality — — HP:0005361 or a B-cell subset abnormality term (candidate: HP:0010976, Decreased proportion of memory B cells)
Low-normal circulating B-cell numbers Laboratory abnormality — — HP:0010976 / HP:0012183 (B lymphocytopenia) — verify exact term with OAK before curating
Inflammatory bowel disease / enterocolitis Clinical sign Childhood Can be intractable — index case had ~30% body weight loss from diarrhea; histology showed crypt epithelial apoptosis, eosinophil/neutrophil infiltration, crypt abscesses HP:0002037 (Inflammatory abnormality of the intestine) / HP:0100280 (IBD)
Autoimmune (immune-mediated) thrombocytopenia Clinical sign, hematologic Childhood Refractory to corticosteroids, IVIG, and splenectomy in the index case; complicated by intracranial hemorrhage requiring neurosurgical evacuation HP:0001973 (Autoimmune thrombocytopenia)
Osteomyelitis Clinical sign Childhood Reported in a subset of patients HP:0002754 (Osteomyelitis)
Impaired cell-mediated cytotoxicity Laboratory/functional abnormality — Affects NK and CD8+ T-cell killing HP:0025387 (Impaired natural killer cell cytotoxicity) or related
Defective T-cell function Laboratory abnormality — Normal T-cell numbers but functionally impaired HP:0002647 or a T-cell dysfunction term
CMV/EBV susceptibility Clinical sign, infectious — CMV gut viremia documented in index case HP:0032101 or general viral-susceptibility term
Skewed CD8+ effector/memory T-cell compartment Laboratory abnormality — Elevated TBET and perforin expression reported (candidate GO/CL-level annotation rather than HP)

Frequency caveat: because the disease has been described in only a handful of families, formal frequency bands (FREQUENT/OCCASIONAL) cannot be assigned from large-cohort statistics; per dismech evidence discipline, frequency claims for this entry should either be omitted or explicitly qualified as derived from a small case series (n≈9–15 patients across all published reports as of this research).

Quality of life impact: Not formally studied with validated instruments (EQ-5D/SF-36) in this ultra-rare population; qualitatively, the index case required repeated hospitalizations, splenectomy, neurosurgical intervention for intracranial hemorrhage, and ultimately curative HSCT — indicating substantial morbidity in severe presentations.

Sources: PMC6886442, OMIM #619281 search summary

4. Genetic/Molecular Information

Causal gene: PIK3CD (HGNC:8977; OMIM 602839), chromosome 1p36.22, encoding p110δ, the catalytic subunit of class IA phosphoinositide 3-kinase delta (PI3Kδ). p110δ binds the p85 regulatory subunit (encoded by PIK3R1*) to form the heterodimeric PI3Kδ enzyme, which phosphorylates PIP2 to PIP3 downstream of antigen and cytokine receptors, driving AKT/mTOR pathway activation.

Pathogenic variant classes described in IMD14B (loss-of-function, biallelic): - Nonsense: c.[346C>T] p.Gln116 (Q116); p.Gln721 (Q721) - Frameshift: c.703_723delinsGT, p.Gln170Valfs*41 (Q170Vfs41); p.Val552Serfs26 (V552Sfs*26) - In-frame deletion: p.Ile899del** (I899del)

All produce complete or near-complete loss of p110δ protein expression or catalytic function when biallelic. Zygosity in reported cases is predominantly homozygous, reflecting consanguinity in the ascertained families; compound heterozygosity is also biologically plausible and consistent with autosomal recessive inheritance.

Functional consequences (mechanistic, patient-derived cell data): - Patient T lymphoblasts show profoundly impaired PIP3 generation upon T-cell receptor (TCR) engagement - Reduced AKT and mTOR phosphorylation - Impaired glycolysis and glycolytic reserve in activated T cells - The functional phenotype of patient cells parallels pharmacologic PI3Kδ inhibition (e.g., idelalisib) in healthy donor cells — i.e., the genetic lesion phenocopies chemical PI3Kδ blockade - Absent full-length p110δ protein on Western blot in the index frameshift case

Contrast with APDS1 (gain-of-function, same gene): APDS1 variants (classic hotspot E1021K, and others such as E525K) enhance membrane recruitment/kinase activity of p110δ, causing constitutively elevated PIP3/AKT/mTOR signaling, T-cell senescence, and impaired B-cell class-switching from hyperactivity, whereas IMD14B produces the same downstream signaling defect (impaired terminal effector output) via the opposite biochemical mechanism (absence rather than excess of activity) — both converge on defective adaptive antiviral immunity and B-cell dysfunction, but with very different accompanying phenotypes (lymphoproliferation/herpesvirus viremia in APDS1 vs. autoimmune cytopenia/enterocolitis in IMD14B).

Variant frequency/pathogenicity resources: ClinVar and gnomAD should be queried directly per-variant during curation; this session did not retrieve specific gnomAD allele frequency or pLI/LOEUF constraint values for PIK3CD and these should be sourced from gnomad.broadinstitute.org before finalizing KB entries.

Modifier genes: Digenic/oligogenic modulation has been reported — concomitant hypomorphic defects in a second gene (e.g., in the setting of HLH-susceptibility or chronic active EBV) appear to potentiate the phenotype of partial PI3Kδ pathway dysfunction; this should be flagged in the entry as a MODIFIER/COOPERATING relationship_type rather than curated as the primary causal mechanism.

Epigenetic/chromosomal information: No epigenetic mechanism or chromosomal-abnormality mechanism has been reported for IMD14B; this is a classic biallelic small-variant Mendelian disorder.

Sources: PMC6886442, OMIM *602839, Nature Immunology — activating PIK3CD variants, T-cell senescence

5. Environmental Information

No non-genetic environmental, lifestyle, or occupational factors have been described as causal for IMD14B — it is a Mendelian monogenic disease. The only environmental modulators identified in the literature are infectious triggers (CMV, EBV, norovirus, HSV) that precipitate or exacerbate clinical episodes against the background of underlying immune deficiency, rather than acting as disease-initiating exposures.

Sources: PMC6886442

6. Mechanism / Pathophysiology

Causal chain (proposed for pathograph modeling)

  1. Trigger: Biallelic loss-of-function PIK3CD variant (nonsense/frameshift/in-frame deletion) →
  2. Molecular: Absent or non-functional p110δ catalytic subunit protein → failure to form functional PI3Kδ heterodimer with p85 (PIK3R1) →
  3. Molecular: Loss of PIP2→PIP3 conversion upon antigen receptor (BCR/TCR) and cytokine receptor engagement →
  4. Molecular: Failure of AKT and mTORC1 (and downstream S6/4E-BP1) phosphorylation cascade →
  5. Cellular: Impaired T-cell and B-cell activation-induced metabolic reprogramming (reduced glycolysis/glycolytic reserve) →
  6. Cellular: Defective B-cell development, survival, and class-switch recombination → hypogammaglobulinemia, reduced class-switched memory B cells →
  7. Cellular: Defective cytotoxic effector differentiation/function in CD8+ T cells and NK cells → impaired viral clearance (CMV, EBV) →
  8. Organismal: Recurrent infections (sinopulmonary, opportunistic) →
  9. Parallel branch — immune dysregulation: Loss of a normally PI3Kδ-dependent regulatory/tolerogenic checkpoint (mechanism less well defined than the infection-susceptibility arm) → breakdown of peripheral tolerance → autoimmune thrombocytopenia, enterocolitis (with crypt epithelial apoptosis, eosinophil/neutrophil infiltration) →
  10. Organismal: Multisystem disease — hematologic (bleeding, intracranial hemorrhage), gastrointestinal (malnutrition, weight loss), skeletal (osteomyelitis) complications

Suggested ontology terms for pathograph nodes

  • Molecular function: GO:0004430 (1-phosphatidylinositol 4-kinase activity) / more precisely the phosphatidylinositol-4,5-bisphosphate 3-kinase activity term (GO:0035005, phosphatidylinositol-4,5-bisphosphate 3-kinase activity) — verify exact GO ID/label via OAK before curating
  • Biological process: GO:0043491 (protein kinase B signaling / AKT signaling), GO:0038202 (TORC1 signaling), GO:0050853 (B cell receptor signaling pathway), GO:0050852 (T cell receptor signaling pathway), GO:0002250 (adaptive immune response)
  • Cell types (CL): CL:0000236 (B cell), CL:0000818 (memory B cell / class-switched memory B cell subtype), CL:0000625 (CD8-positive, alpha-beta T cell), CL:0000623 (natural killer cell), CL:0000897 (CD4-positive, alpha-beta memory T cell)
  • Protein dysfunction category: loss of function (p110δ absent/non-functional) — use functional_impact_category: LOSS_OF_FUNCTION per the dismech GeneticContext slot guidance, contrasting with the GAIN_OF_FUNCTION classification used for the allelic APDS1 disorder

Molecular profiling

No transcriptomic, proteomic, or single-cell atlas dataset specific to IMD14B was identified in this research session (unlike APDS1, which has been studied with bulk and single-cell approaches). Functional characterization has relied on patient-derived primary lymphocyte assays (PIP3 flux by flow cytometry, phospho-AKT/phospho-S6 immunoblotting, Seahorse extracellular flux glycolysis assays) rather than omics datasets.

Tissue damage / immune dysregulation mechanisms

Gut histopathology in the index case showed crypt epithelial apoptosis, eosinophil and neutrophil infiltration, and crypt abscess formation — consistent with an inflammatory bowel disease-like process superimposed on immunodeficiency, analogous mechanistically to other monogenic very-early-onset IBD (VEO-IBD) syndromes with primary immunodeficiency etiology.

Sources: PMC6886442, PMC6082933, JACI review — PI3K pathway defects

7. Anatomical Structures Affected

  • Organ level (primary): Immune system broadly — lymphoid organs (spleen — splenectomy performed in index case; bone marrow — site of B-cell development); gastrointestinal tract (small/large intestine — enterocolitis); respiratory tract (lungs — recurrent pneumonia); skeletal system (bone — osteomyelitis); central nervous system (secondary — intracranial hemorrhage as a complication of severe thrombocytopenia, not a primary target organ)
  • Body systems: Hematologic/immune system (primary), digestive system, respiratory system, skeletal system, secondarily nervous system (hemorrhagic complication)
  • UBERON candidates: UBERON:0002106 (spleen), UBERON:0002371 (bone marrow), UBERON:0002108 (small intestine), UBERON:0002106, UBERON:0002048 (lung)
  • Tissue/cell level: Lymphoid tissue — B lymphocytes (bone marrow and peripheral development), T lymphocytes (thymic/peripheral), NK cells; intestinal crypt epithelium (site of apoptosis/damage in enterocolitis)
  • Subcellular level: Plasma membrane (site of PI3Kδ lipid kinase activity and PIP3 generation upon receptor engagement); cytoplasm (AKT/mTOR signaling cascade) — GO Cellular Component candidates: GO:0005886 (plasma membrane), GO:0005942 (phosphatidylinositol 3-kinase complex, class IA)
  • Localization/laterality: Not applicable — systemic/multisystem disease, not laterality-specific

Sources: PMC6886442

8. Temporal Development

  • Onset: Early childhood (recurrent infections typically the presenting feature); the index HSCT case was diagnosed/treated by age 9
  • Onset pattern: Chronic with acute exacerbations (infectious episodes, thrombocytopenic crises, IBD flares)
  • Progression: Can be progressive and life-threatening without intervention — the index case progressed to refractory autoimmune thrombocytopenia complicated by intracranial hemorrhage requiring surgical evacuation, and intractable enterocolitis causing ~30% weight loss, ultimately requiring curative allogeneic HSCT
  • Disease course pattern: Chronic, with episodic/relapsing autoimmune manifestations (thrombocytopenia refractory to first-line therapies) superimposed on a baseline of chronic humoral immunodeficiency
  • Duration: Chronic/lifelong unless treated definitively (HSCT reported curative in at least one case, achieving 100% donor chimerism after a second transplant with myeloablative conditioning)
  • Remission patterns: Spontaneous remission not described; disease was treatment (HSCT)-induced remission/cure in the reported case
  • Critical periods: Early recognition appears critical given the severity of complications (intracranial hemorrhage) that can occur if autoimmune thrombocytopenia is not adequately controlled

Sources: PMC6886442

9. Inheritance and Population

  • Epidemiology: Extremely rare — as of the founding literature (Swan et al. 2019), only 9 patients from 6 families had been reported with germline biallelic PI3Kδ-pathway loss-of-function causing this phenotype; a further family with multiple affected siblings was reported in 2025 (Journal of Clinical Immunology). No formal population prevalence/incidence estimate exists; this contrasts with APDS1/APDS2 (gain-of-function), for which >200–250 patients have been reported and an early prevalence estimate of ~1 in 1,000,000 live births was proposed (likely an underestimate given limited genetic screening) — no comparable prevalence estimate is available for the recessive LOF disorder given its still smaller reported case count.
  • Inheritance pattern: Autosomal recessive (biallelic — homozygous or compound heterozygous)
  • Penetrance: Appears to be high/complete in reported homozygous null cases, though the small number of reported families limits confident penetrance estimation
  • Expressivity: Variable — reported patients range from severe multisystem disease (the index HSCT case) to milder presentations dominated by recurrent infection and hypogammaglobulinemia without necessarily manifesting the severe autoimmune/enterocolitis phenotype
  • Consanguinity: Strongly overrepresented among reported families — most/all published pedigrees involve consanguineous unions, consistent with autosomal recessive disease requiring biallelic rare LOF alleles
  • Founder effects: Not specifically documented; variants reported to date appear to be private/family-specific (e.g., the c.703_723delinsGT frameshift was described as a "private homozygous frameshift variant")
  • Carrier frequency: Not established; would require gnomAD-derived allele frequency data per specific variant (not retrieved in this session)
  • Affected populations / geographic distribution: Not systematically characterized; reported families derive from multiple, geographically dispersed consanguineous kindreds rather than a single founder population
  • Sex ratio: Not established as skewed — autosomal recessive inheritance predicts equal sex distribution, consistent with expectation for an autosomal (non-X-linked) gene

Sources: PMC6886442, Frontiers — Activated PI3Kinase Delta Syndrome, multifaceted disease

10. Diagnostics

Clinical/laboratory tests

  • Immunoglobulin levels: Quantitative IgG, IgA, IgM — hypogammaglobulinemia is a hallmark (index case IgG 2.5 g/L, IgM 0.25 g/L)
  • Lymphocyte immunophenotyping (flow cytometry): B-cell enumeration (low-normal total B cells; markedly reduced/absent class-switched memory B cells [CD27+IgD-IgM-]); T-cell and NK-cell enumeration (typically normal numbers despite functional defects)
  • Functional PI3Kδ pathway assays (research/reference-lab level): PIP3 generation assay upon BCR/TCR engagement; phospho-AKT and phospho-S6/phospho-mTOR flow cytometry or immunoblot following receptor stimulation — these directly demonstrate the loss-of-function biochemical defect
  • Metabolic functional assays: Seahorse extracellular flux analysis showing impaired glycolysis/glycolytic reserve in activated lymphocytes
  • Viral load monitoring: CMV and EBV PCR/viremia surveillance given documented susceptibility
  • Histopathology: Intestinal biopsy in cases with enterocolitis — crypt epithelial apoptosis, eosinophil/neutrophil infiltration, crypt abscesses

Genetic testing

  • Recommended approach: Given the phenotypic overlap with other combined immunodeficiencies and antibody deficiencies, a primary immunodeficiency gene panel or whole exome/genome sequencing is the practical diagnostic approach, particularly given consanguinity (which favors homozygosity mapping/WES in an autosomal recessive framework)
  • Single-gene PIK3CD sequencing is reasonable when the biochemical/functional phenotype (impaired PI3Kδ signaling by flow-cytometric PIP3/pAKT assay) already points to the PI3Kδ pathway
  • Chromosomal microarray/karyotype: Not indicated as a primary diagnostic tool — this is a small-variant (not structural) disorder
  • No specific mention of newborn screening applicability was identified (TREC-based SCID newborn screening would not reliably detect this humoral/cytotoxic-predominant phenotype, since T-cell numbers are typically normal)

Clinical criteria / differential diagnosis

Differential diagnosis should include: - APDS1 (heterozygous gain-of-function PIK3CD) and APDS2 (PIK3R1) — distinguished by inheritance pattern (dominant vs. recessive), lymphoproliferation/splenomegaly and chronic herpesvirus viremia (more typical of APDS), and opposite functional PI3Kδ assay results (hyperactive vs. hypoactive signaling) - Common variable immunodeficiency (CVID) and other predominantly antibody deficiencies - Very-early-onset inflammatory bowel disease (VEO-IBD) monogenic causes - Other causes of autoimmune cytopenia with immunodeficiency (ALPS, CTLA4 haploinsufficiency, LRBA deficiency)

Sources: PMC6886442, JACI PI3K pathway review

11. Outcome/Prognosis

  • Survival/mortality: No formal survival statistics exist given the extremely small reported case numbers; the index case's course (refractory thrombocytopenia, intracranial hemorrhage, severe enterocolitis with major weight loss, opportunistic infection) illustrates that the disease can be life-threatening without definitive treatment
  • Curative option: Allogeneic hematopoietic stem cell transplantation (HSCT) was reported curative in the index case, achieving 100% donor chimerism after a second (myeloablative) transplant — directly paralleling the curative role HSCT plays in APDS1/APDS2 for patients with life-threatening complications
  • Morbidity: Substantial in severe cases — intracranial hemorrhage requiring neurosurgical evacuation, splenectomy, malnutrition from intractable diarrhea, recurrent severe infections (pneumonia, CMV viremia, norovirus, post-transplant HSV)
  • Prognostic factors: Severity appears to correlate with degree of p110δ loss (complete absence of protein in the frameshift/nonsense cases) and the presence of refractory autoimmune complications; earlier recognition and treatment (immunoglobulin replacement, prophylaxis, and timely consideration of HSCT for severe/refractory cases) likely improves outcomes, by analogy with APDS management paradigms

Sources: PMC6886442

12. Treatment

Pharmacotherapy

  • Immunoglobulin replacement therapy (IVIG/SCIG): Standard supportive treatment for the hypogammaglobulinemia component, as used across PI3Kδ pathway disorders — NCIT candidate term: NCIT:C15986 (Pharmacotherapy) with therapeutic_agent bound to immunoglobulin product classes
  • Antibiotic/antimicrobial prophylaxis: Standard supportive measure for recurrent infection risk
  • Immunosuppressive therapy: Used for autoimmune thrombocytopenia (corticosteroids reported, though refractory in the index case) — NCIT:C15986 with an appropriate corticosteroid therapeutic_agent
  • Note: unlike APDS1 (gain-of-function), where sirolimus/rapamycin (mTOR inhibition) and selective PI3Kδ inhibitors (e.g., leniolisib) are mechanistically rational targeted therapies, these agents would be mechanistically inappropriate or contraindicated in the loss-of-function IMD14B disorder, since further inhibiting an already-deficient pathway would be expected to worsen, not improve, the immunodeficiency. This is an important curation distinction — do not apply APDS1/APDS2 targeted-therapy target_mechanisms patterns to IMD14B entries.

Surgical/Interventional

  • Splenectomy — was attempted (unsuccessfully) for refractory autoimmune thrombocytopenia in the index case — NCIT:C15329 (Surgical Procedure) / a more specific splenectomy term if available
  • Neurosurgical evacuation of intracranial hemorrhage — performed as an emergency intervention for the thrombocytopenia-related bleeding complication

Advanced/curative therapeutics

  • Allogeneic hematopoietic stem cell transplantation (HSCT) — curative in the reported index case (myeloablative conditioning, second transplant needed to achieve full donor chimerism) — NCIT:C15289 (Organ Transplantation) is the closest general term; a more specific HSCT-mapped NCIT code should be verified (candidate: NCIT:C15431, Hematopoietic Cell Transplantation)

Supportive care

  • Nutritional support given severe diarrhea/weight loss (~30% body weight loss documented) — NCIT:C15433/C15447-family terms as appropriate
  • Antiviral management for CMV/EBV/HSV reactivation/infection

Experimental / investigational

No disease-specific clinical trials (NCT-registered) for IMD14B were identified in this research session — reflecting the extreme rarity of the condition. Management is extrapolated largely from broader primary immunodeficiency and APDS-family treatment paradigms, adjusted for the opposite direction of the underlying molecular lesion.

Sources: PMC6886442, Frontiers — Activated PI3Kδ syndrome, diagnosis/treatment review

13. Prevention

  • Primary prevention: Not applicable in the traditional sense (monogenic recessive disease) — the relevant preventive intervention is genetic counseling and carrier/prenatal testing for consanguineous families with a known proband, given the autosomal recessive inheritance pattern and demonstrated overrepresentation of consanguinity
  • Secondary prevention: Early diagnosis via genetic testing in symptomatic infants/children with recurrent infection plus hypogammaglobulinemia, particularly from consanguineous unions, to enable early initiation of immunoglobulin replacement and infection prophylaxis before severe autoimmune/enterocolitis complications develop
  • Genetic counseling: Recommended for families with an identified proband — recurrence risk 25% for future pregnancies in carrier x carrier matings, consistent with standard autosomal recessive counseling
  • Screening: No population-level newborn screening protocol identified as applicable (TREC-based SCID screening would not detect this phenotype); targeted carrier screening would only be relevant in populations/families with a known pathogenic allele
  • Prophylaxis: Antimicrobial and immunoglobulin prophylaxis, as discussed under Treatment, functions as tertiary/ongoing prevention of infectious complications once diagnosed

Sources: PMC6886442

14. Other Species / Natural Disease

No naturally occurring veterinary/animal disease analog of biallelic PIK3CD loss-of-function was identified in this research session. This appears to be a human-specific reported condition to date (in contrast to some PIDs with described veterinary correlates).

15. Model Organisms

  • Mouse models: Pik3cd-knockout and kinase-dead knock-in mice have been used extensively to study p110δ loss-of-function biology (largely in the context of dissecting normal PI3Kδ physiology and, separately, APDS-related gain-of-function models). Search results retrieved in this session confirmed active mouse-model literature on p110δ's role in B-cell development, survival, and germinal center reactions (e.g., B-cell-specific PIK3CD gain-of-function mouse models — Mb1-aPIK3CD — and p110δ-selective inhibitor studies in murine B cells), but a specific, disease-matched loss-of-function Pik3cd knockout mouse phenocopying IMD14B was not independently retrieved with full phenotypic detail in this session and should be sourced directly from MGI (Mouse Genome Informatics) before citing in a KB entry — historically, Pik3cd germline-null mice are known (from foundational PI3Kδ immunology literature predating this specific human disease description) to show B-cell developmental block, reduced serum immunoglobulin, and impaired T-cell-dependent and -independent antibody responses, consistent with a translatable phenotype, but this claim requires direct primary-source (PMID) verification before curation into a dismech entry (do not curate from this summary without confirming the source).
  • Functional cellular models: Patient-derived primary T lymphoblasts and B cells (ex vivo, human) constitute the principal "model system" used to demonstrate the molecular loss-of-function phenotype (PIP3 generation assays, phospho-flow, Seahorse metabolic assays) — these are IN_VITRO human primary cell studies, not animal models, and should be tagged evidence_source: IN_VITRO accordingly if reused for the KB.
  • Resources for follow-up: MGI (Mouse Genome Informatics) for Pik3cd allele records; IMPC (International Mouse Phenotyping Consortium) for any systematic Pik3cd-null phenotyping data.

Sources: PMC6886442, search results on Mb1-aPIK3CD and p110δ B-cell biology (not independently fetched in full)

Curation Notes and Flags for the dismech Entry

  1. Primary anchor reference: Swan DJ, Aschenbrenner D, Lamb CA, et al. "Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase δ." Haematologica 2019. Full text at PMC6886442 — fetch this via just fetch-reference and extract the exact PMID before writing any evidence snippet; this report only had indirect access to the PMC full text and did not independently confirm the PMID number, which must be verified directly (e.g., via PubMed search for the exact title) rather than assumed.
  2. NEC risk: This disease sits in a numbered-series / gene-shared-eponym risk class per the dismech NEC guidance — "Immunodeficiency 14A" (dominant, same gene, OMIM #615513) and "Immunodeficiency 14B" (recessive, same gene, OMIM #619281) are adjacent entries in the same phenotypic series, and APDS1/APDS2/IMD36 literature vastly outnumbers IMD14B literature in any generic "PIK3CD immunodeficiency" search. Run just preflight-dr against MONDO's causal-gene record for the correct MONDO ID once identified, and manually confirm any DR-tool output actually discusses biallelic/homozygous loss-of-function variants and recessive inheritance, not the far more common heterozygous gain-of-function APDS1 literature, before curating.
  3. MONDO ID not confirmed in this session — must be resolved via MONDO/OMIM xref lookup (OMIM:619281) before curation.
  4. Several claims flagged above ("should be verified," "not independently retrieved," "requires primary-source confirmation") are explicitly marked as leads, not verified facts — per the dismech evidence SOP, these must not be curated into evidence: blocks without independent PMID fetch and snippet verification via just fetch-reference / just count-verified-snippets.

Sources

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