Hyper-IgM Syndrome Type 1

Genetic MONDO:0010626 Pathograph 25 Show in embeddings browser Hyper-IgM syndrome Combined immunodeficiency Primary immunodeficiency

Hyper-IgM syndrome type 1 (X-linked hyper-IgM syndrome, CD40 ligand deficiency) is an X-linked combined immunodeficiency caused by hemizygous loss-of-function variants in CD40LG, which encodes CD40 ligand (CD154), the activation-induced surface protein of CD4-positive T cells. Loss of CD40L abolishes engagement of CD40 on B cells, so B cells cannot undergo immunoglobulin class switch recombination and germinal centers fail to develop: serum IgG, IgA, and IgE are very low or absent while IgM is normal or elevated, and class-switched memory B cells are markedly reduced. The same molecular lesion abolishes CD40-dependent licensing of macrophages and dendritic cells, which is why the disorder behaves as a combined rather than a purely antibody deficiency and why affected boys are susceptible to opportunistic pathogens, most characteristically Pneumocystis jirovecii and Cryptosporidium. Most patients present in the first year of life with recurrent sinopulmonary infection, Pneumocystis pneumonia, and protracted diarrhea. Chronic neutropenia with oral ulceration is common, and Cryptosporidium-associated sclerosing cholangitis and biliary-tract malignancy dominate long-term morbidity and mortality. Management combines immunoglobulin replacement, Pneumocystis prophylaxis, and G-CSF for neutropenia; allogeneic hematopoietic cell transplantation is the only curative option.

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1
Inheritance
6
Pathophys.
13
Phenotypes
25
Pathograph
1
Genes
5
Medical Actions
1
References
🏷

Classifications

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

Inheritance

1
X-linked recessive HP:0001419
CD40LG lies at Xq26 and the disorder is transmitted as an X-linked recessive trait. Affected individuals are essentially always male hemizygotes; heterozygous female carriers are typically asymptomatic, although skewed X-chromosome inactivation can produce a range of manifestations.
X-linked recessive inheritance
Show evidence (2 references)
PMID:20301576 SUPPORT Human Clinical
"Heterozygous females are typically asymptomatic but may have a range of clinical manifestations depending on X-chromosome inactivation."
Documents the X-linked recessive transmission pattern, with carrier females generally unaffected.
PMID:7678782 SUPPORT Human Clinical
"The gene encoding gp39 was mapped to Xq26, the X chromosome region where the gene responsible for HIM had previously been mapped."
Maps the causative gene to the X chromosome, establishing the X-linked basis of the disorder.
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Pathophysiology

6
Loss of Functional CD40 Ligand on Activated CD4+ T Cells
Hemizygous loss-of-function variants in CD40LG leave activated CD4+ T cells unable to display functional CD40 ligand (CD154/gp39/TRAP) at the cell surface. Some variants abolish surface expression entirely; others permit normal transcription but encode extracellular-domain mutants that cannot bind CD40. Either way the T cell loses its principal contact-dependent helper signal, and every downstream defect in this entry follows from this single molecular lesion.
activated CD4+ T helper cell CL:0000896 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves activated CD4+ T helper cell, annotated with activated CD4-positive, alpha-beta T cell (CL:0000896). CL:0000896 is a cell type from the Cell Ontology.
CD40LG hgnc:11935 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves decreased CD40LG (hgnc:11935). hgnc:11935 is a gene from the HUGO Gene Nomenclature Committee. ↓ DECREASED
Genetic context CD40LG hgnc:11935 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns CD40LG (hgnc:11935). hgnc:11935 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HEMIZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Germline hemizygous CD40LG loss-of-function variants in males; the single X chromosome leaves no functional allele.
Downstream
Failed CD40 Engagement on B Cells Without functional CD40L on the T-cell surface, the cognate receptor CD40 on the B cell is never engaged during T-B collaboration.
Failed CD40-Dependent Licensing of Macrophages and Dendritic Cells CD40 is also expressed by macrophages and dendritic cells, so the same missing ligand removes the T-cell-derived activation signal for the mononuclear phagocyte compartment.
Chronic neutropenia Chronic or intermittent neutropenia is a well-documented consequence of CD40L deficiency, but the intervening steps between the CD40LG lesion and the granulocyte defect are not established; it responds to G-CSF, which is consistent with a myelopoietic rather than a purely peripheral-destruction mechanism.
Show evidence (2 references)
PMID:7679801 SUPPORT Human Clinical
"Activated T cells from the four affected patients failed to express wild-type CD40L, although their B cells responded normally to wild-type CD40L."
Localizes the primary lesion to the activated T cell and shows the B-cell compartment is intrinsically intact.
PMID:7679801 SUPPORT In Vitro
"Recombinant expression of two of the mutant CD40L complementary DNAs resulted in proteins incapable of binding to CD40 and unable to induce proliferation or IgE secretion from normal B cells."
Demonstrates directly that the mutant proteins are loss-of-function for CD40 binding, supporting the functional_impact_category assignment.
Failed CD40 Engagement on B Cells
CD40 is constitutively expressed on B cells and is functional in these patients, but it is never cross-linked because its ligand is absent. The B cell therefore never receives the contact-dependent second signal that, together with cytokines, drives activation, proliferation, differentiation, and isotype switching.
B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
CD40 signaling pathway GO:0023035 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased CD40 signaling pathway (GO:0023035). GO:0023035 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Defective Immunoglobulin Class Switch Recombination CD40 cross-linking is the signal that, in the presence of lymphokines, licenses the B cell to switch from IgM to the downstream isotypes.
Abortive Germinal Center Reaction with Follicular Dendritic Cell Depletion Ineffective CD40/CD40L interaction in the lymphoid follicle prevents the germinal center reaction from proceeding beyond a primary follicle.
Show evidence (2 references)
PMID:7678782 SUPPORT Human Clinical
"B cells from HIM patients express functional CD40, but their T cells do not bind CD40-Ig."
Shows the receptor side is intact and the failure is specifically in ligand-receptor engagement.
PMID:7539026 SUPPORT Human Clinical
"The CD40 ligand (CD40L) is an activation-induced surface membrane protein expressed by CD4+ T helper cells in lymphoid follicles, and is involved in the contact-dependent signaling-mediated activation, proliferation, and differentiation of CD40+ B cells."
Defines the contact-dependent CD40L-CD40 signal to B cells that is lost in this disorder.
Defective Immunoglobulin Class Switch Recombination
Deprived of the CD40 signal, the B cell cannot execute isotype switching from IgM to IgG, IgA, or IgE. IgM production continues - and is in fact sustained or amplified by ongoing antigenic stimulation, particularly at mucosal surfaces - so the serum picture is very low or absent IgG, IgA, and IgE with normal to elevated IgM. Class-switched memory B cells, which are the product of successful switching, are correspondingly reduced.
B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology. class switched memory B cell CL:0000972 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves class switched memory B cell (CL:0000972). CL:0000972 is a cell type from the Cell Ontology.
immunoglobulin class switch recombination (isotype switching) GO:0045190 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased immunoglobulin class switch recombination (isotype switching), annotated with isotype switching (GO:0045190). GO:0045190 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Decreased circulating IgG concentration IgG cannot be produced because the switch from IgM to IgG requires the CD40-dependent recombination step.
Decreased circulating IgA concentration IgA is one of the switched isotypes the block prevents, so serum IgA is low or absent alongside IgG and IgE.
Increased circulating IgM level IgM synthesis is preserved and sustained by continued antigenic stimulation while no isotype switching consumes the IgM-committed pool.
Recurrent sinopulmonary infections Absent IgG leaves patients unable to opsonize encapsulated bacteria, producing the recurrent upper- and lower-respiratory tract infections that typically bring them to attention.
Show evidence (3 references)
PMID:7679801 SUPPORT Human Clinical
"Thus, these CD40L defects lead to a T cell abnormality that results in the failure of patient B cells to undergo immunoglobulin class switching."
States the central mechanistic conclusion: the CD40L defect causes failure of B-cell class switching.
PMID:20301576 SUPPORT Human Clinical
"Total numbers of B cells are normal but there is a marked reduction of class-switched memory B cells."
Confirms that the defect is in switching rather than in B-cell development, and identifies the depleted class-switched memory compartment.
PMID:7539026 SUPPORT Human Clinical
"Recurrent or persisting antigenic stimulation in mucosal tissues is likely to play a major role in determining and maintaining elevated IgM serum levels."
Explains why IgM is normal to elevated rather than merely unswitched: ongoing mucosal antigenic drive sustains IgM-only plasma cells.
Abortive Germinal Center Reaction with Follicular Dendritic Cell Depletion
In patient lymph nodes and extranodal lymphoid tissue, B-cell follicles arrest as prominent primary follicles: germinal centers do not form, and the follicular dendritic cell network that normally supports affinity maturation is severely depleted and phenotypically abnormal. Intrafollicular CD4+ helper T cells are present in normal numbers and the paracortical T-cell area is architecturally intact, so the lesion is specific to the follicular B-cell compartment rather than a global lymphoid failure.
follicular dendritic cell CL:0000442 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves follicular dendritic cell (CL:0000442). CL:0000442 is a cell type from the Cell Ontology. B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
germinal center formation GO:0002467 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased germinal center formation (GO:0002467). GO:0002467 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Decreased class-switched memory B cell proportion The germinal center is where class-switched memory B cells are generated; an abortive germinal center reaction leaves this compartment markedly reduced.
Show evidence (2 references)
PMID:7539026 SUPPORT Human Clinical
"However, a severe depletion of follicular dendritic cells, recognized by Abs against NGFR, CD21 and CD23, and lack of expression of the Ag recognized by KiM4p on these cells, are noticed."
Documents the severe follicular dendritic cell depletion in patient lymphoid tissue.
PMID:7539026 SUPPORT Human Clinical
"Prominent primary B follicles are identified in the lymph nodes and in the extranodal lymphoid tissues from both cases"
Shows follicles arrested at the primary stage, i.e. germinal centers failing to form.
Failed CD40-Dependent Licensing of Macrophages and Dendritic Cells
CD40L is required not only for B-cell help but for T-cell-mediated activation of the mononuclear phagocyte system. In its absence, patient monocyte-derived macrophages show defective fungicidal activity, a reduced oxidative burst, impaired inflammatory cytokine production, a globally dysregulated transcriptome, and failure to control Mycobacterium tuberculosis. The rescue experiments separate two groups: fungicidal activity and the oxidative burst are restored in vitro by exogenous IFN-gamma but not by soluble CD40L, placing that block downstream of the T-cell-macrophage conversation, whereas impaired inflammatory cytokine production is ameliorated by both. This arm of the mechanism is why the disorder is a combined immunodeficiency and why the characteristic infections are opportunistic.
macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology. dendritic cell CL:0000451 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves dendritic cell (CL:0000451). CL:0000451 is a cell type from the Cell Ontology.
macrophage activation GO:0042116 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased macrophage activation (GO:0042116). GO:0042116 is a biological process from the Gene Ontology. ↓ DECREASED T cell costimulation GO:0031295 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased T cell costimulation (GO:0031295). GO:0031295 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Pneumocystis jirovecii pneumonia Impaired CD40-dependent activation of macrophages and dendritic cells degrades the cell-mediated defense against Pneumocystis jirovecii, which is frequently the presenting opportunistic infection.
Chronic diarrhea The same defect in cell-mediated mucosal defense permits protracted infectious diarrhea, characteristically caused by Cryptosporidium species.
Cryptosporidium-Associated Biliary Tract Injury Failure to clear Cryptosporidium from the gut and biliary tree allows persistent infection of the biliary epithelium, which is the initiating event for the cholangiopathy.
Show evidence (3 references)
PMID:27554817 SUPPORT In Vitro
"Macrophages from CD40L-deficient patients exhibited defective fungicidal activity and reduced oxidative burst, both of which improved in the presence of rhIFN-γ but not sCD40L."
Documents the specific macrophage functional defects caused by CD40L absence and their partial rescue by IFN-gamma.
PMID:27554817 SUPPORT In Vitro
"The absence of CD40L dysregulated the macrophage transcriptome, which was improved by rhIFN-γ."
Establishes a transcriptome-wide macrophage program defect attributable to CD40L loss.
PMID:27554817 SUPPORT In Vitro
"Studies of CD40L-deficient patients reveal the critical role of CD40L-CD40 interaction for the function of T, B, and dendritic cells."
Extends the licensing defect from macrophages to dendritic cells and T cells, supporting the cell-type annotations on this node.
Cryptosporidium-Associated Biliary Tract Injury
Persistent Cryptosporidium infection of the biliary epithelium drives chronic cholangiocyte injury and progressive fibro-obliterative bile duct disease (sclerosing cholangitis), and the resulting chronic inflammation is the presumed substrate for biliary-tract malignancy. Liver disease is the single strongest predictor of mortality in this disorder, and hematopoietic cell transplantation performed before its onset is the principal way to prevent it.
bile duct UBERON:0002394 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in bile duct (UBERON:0002394). UBERON:0002394 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Sclerosing cholangitis Chronic cryptosporidial cholangiocyte infection produces the sclerosing cholangitis phenotype.
Malignancy Chronic biliary inflammation is the presumed substrate for the hepatic and bile-duct malignancies that account for a disproportionate share of deaths; the intervening oncogenic steps are not established.
Liver disease Progressive biliary tract injury is what the aggregate "liver disease" of the registry cohorts measures — sclerosing cholangitis, hepatitis and cirrhosis recorded together.
Show evidence (2 references)
PMID:14663287 SUPPORT Human Clinical
"Sclerosing cholangitis occurred in 5 patients and in 4 of these was associated with Cryptosporidium infection."
Documents the association of sclerosing cholangitis with Cryptosporidium infection in a registry cohort.
PMID:27697500 SUPPORT Human Clinical
"Liver disease was a significant predictor of overall survival (hazard ratio, 4.9; 95% confidence limits, 2.2-10.8; P < .001)."
Quantifies the mortality impact of the hepatobiliary arm of the disease.
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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 Hyper-IgM Syndrome Type 1 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

13
Blood 5
Chronic neutropenia Decreased total neutrophil count HP:0001875 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neutropenia, annotated with Decreased total neutrophil count (HP:0001875), qualified as temporality chronic. HP:0001875 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Sequelae: Oral ulcer
Show evidence (2 references)
PMID:9255191 SUPPORT Human Clinical
"Many patients had chronic neutropenia associated with oral and rectal ulcers."
Documents chronic neutropenia and its characteristic mucosal ulceration in a 56-patient cohort.
PMID:20301576 SUPPORT Human Clinical
"Neutropenia is common; thrombocytopenia and anemia are less commonly seen."
GeneReviews confirms neutropenia as a common finding and distinguishes it from the less common cytopenias.
Decreased circulating IgG concentration OBLIGATE 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:14663287 SUPPORT Human Clinical
"All of the patients had significant IgG deficiency and most had IgA deficiency, but only one-half had elevated IgM levels."
IgG deficiency was present in all 79 registry patients, supporting an obligate frequency assignment.
Decreased circulating IgA concentration VERY_FREQUENT HP:0002720 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased circulating IgA concentration (HP:0002720). HP:0002720 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:14663287 SUPPORT Human Clinical
"All of the patients had significant IgG deficiency and most had IgA deficiency, but only one-half had elevated IgM levels."
"Most" patients had IgA deficiency, supporting a very-frequent band.
Increased circulating IgM level FREQUENT HP:0003496 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased circulating IgM level (HP:0003496). HP:0003496 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:14663287 SUPPORT Human Clinical
"All of the patients had significant IgG deficiency and most had IgA deficiency, but only one-half had elevated IgM levels."
Elevated IgM in approximately half of registry patients supports the frequent (30-79%) band and the caveat that IgM is often normal.
PMID:20301576 SUPPORT Human Clinical
"characterized by low serum concentrations of immunoglobulin (Ig) G, IgA, and IgE with normal or elevated serum concentrations of IgM"
GeneReviews states the defining serum immunoglobulin pattern, including that IgM may be normal rather than elevated.
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:20301576 SUPPORT Human Clinical
"Total numbers of B cells are normal but there is a marked reduction of class-switched memory B cells."
Documents the reduced class-switched memory B-cell compartment with preserved total B-cell numbers.
Digestive 3
Chronic diarrhea FREQUENT 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 (2 references)
PMID:14663287 SUPPORT Human Clinical
"recurrent otitis (43%), recurrent/protracted diarrhea (34%), central nervous system infections (14%)"
Recurrent or protracted diarrhea in 34% of registry patients places this phenotype in the frequent (30-79%) band.
PMID:20301576 SUPPORT Human Clinical
"recurrent or protracted diarrhea that can be infectious or noninfectious and is associated with faltering growth"
GeneReviews characterizes the diarrhea and its association with growth failure.
Sclerosing cholangitis OCCASIONAL HP:0030991 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sclerosing cholangitis (HP:0030991), qualified as course progressive. HP:0030991 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:14663287 SUPPORT Human Clinical
"Sclerosing cholangitis occurred in 5 patients and in 4 of these was associated with Cryptosporidium infection."
Five of 79 registry patients (6%) developed sclerosing cholangitis, supporting the occasional (5-29%) frequency band.
PMID:9255191 SUPPORT Human Clinical
"Four patients underwent liver transplantation because of sclerosing cholangitis, which relapsed in there."
Documents sclerosing cholangitis severe enough to require transplantation, and its recurrence in the graft.
Liver disease Abnormality of the liver HP:0001392 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Liver disease, annotated with Abnormality of the liver (HP:0001392), qualified as course progressive. HP:0001392 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Bound to the broad liver-abnormality term deliberately: the source aggregates sclerosing cholangitis, hepatitis, cirrhosis, and cholangiocarcinoma under "liver disease", and the specific cholangiopathy is carried by its own phenotype and pathophysiology node.
Show evidence (2 references)
PMID:20301576 SUPPORT Human Clinical
"Liver disease, a serious complication of CD40 ligand deficiency once observed in more than 80% of affected males by age 20 years, may be decreasing with adequate screening and treatment of Cryptosporidium infection."
Documents the historical burden of liver disease and its dependence on Cryptosporidium control.
PMID:27697500 SUPPORT Human Clinical
"Liver disease was a significant predictor of overall survival (hazard ratio, 4.9; 95% confidence limits, 2.2-10.8; P < .001)."
Establishes liver disease as the significant independent predictor of survival in the largest reported cohort.
Head and Neck 1
Oral ulcer HP:0000155 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Oral ulcer (HP:0000155). HP:0000155 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9255191 SUPPORT Human Clinical
"Many patients had chronic neutropenia associated with oral and rectal ulcers."
Documents oral ulceration occurring in association with the neutropenia.
Immune 2
Recurrent sinopulmonary infections VERY_FREQUENT 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 (2 references)
PMID:14663287 SUPPORT Human Clinical
"The most prominent clinical infections were pneumonia (81% of patients), upper respiratory infections (49%) including sinusitis (43%) and recurrent otitis (43%)"
Pneumonia in 81% of registry patients places this phenotype in the very-frequent (80-100%) band.
PMID:9255191 SUPPORT Human Clinical
"Upper and lower respiratory tract infections (the latter frequently caused by Pneumocystis carinii), chronic diarrhea, and liver involvement (both often associated with Cryptosporidium infection) were common."
Independent European cohort confirming recurrent upper and lower respiratory tract infection as a common feature.
Pneumocystis jirovecii pneumonia HP:0020102 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pneumocystis jirovecii pneumonia (HP:0020102). HP:0020102 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301576 SUPPORT Human Clinical
"opportunistic infections including Pneumocystis jirovecii pneumonia"
GeneReviews lists Pneumocystis jirovecii pneumonia among the presenting opportunistic infections.
PMID:14663287 SUPPORT Human Clinical
"Most patients presented initially with a history of an increased susceptibility to infection including Pneumocystis carinii pneumonia."
Registry data documenting Pneumocystis pneumonia (reported under the older name P. carinii) as a common presenting infection.
Nervous System 1
Neurologic complications OCCASIONAL Abnormal nervous system physiology HP:0012638 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neurologic complications of CNS infection, annotated with Abnormal nervous system physiology (HP:0012638). HP:0012638 is a phenotype from the Human Phenotype Ontology.
Bound to the broad nervous-system-physiology term deliberately: the source reports "significant neurologic complications" without naming specific deficits, so a narrower binding would manufacture precision the cohort text does not carry. Also deliberately left without an incoming causal edge: the source attributes these complications to CNS infection generally rather than to any one organism or mechanism this entry models, and the registry's CNS-infection figure (14%) aggregates Pneumocystis, cytomegalovirus, ECHO virus and others, so an edge from a specific node would name a path the literature does not.
Show evidence (1 reference)
PMID:20301576 SUPPORT Human Clinical
"Significant neurologic complications, often the result of a central nervous system infection, are seen in 5%-15% of affected males."
GeneReviews quantifies neurologic complications at 5-15% of affected males and attributes most to CNS infection.
Neoplasm 1
Malignancy Neoplasm HP:0002664 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neoplasm (HP:0002664). HP:0002664 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301576 SUPPORT Human Clinical
"Autoimmune and/or inflammatory disorders (such as sclerosing cholangitis) as well as increased risk for neoplasms have been reported as medical complications of this disorder."
GeneReviews documents increased neoplasm risk as a recognized complication.
PMID:14663287 SUPPORT Human Clinical
"2 of malignancy (both hepatocellular carcinoma)"
Two of eight registry deaths were from hepatic malignancy, documenting malignancy as a cause of death.
🧬

Genetic Associations

1
CD40LG
Gene: CD40LG hgnc:11935 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CD40LG (hgnc:11935). hgnc:11935 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
X-linked recessive
Show evidence (3 references)
PMID:7679801 SUPPORT Human Clinical
"Abnormalities in the CD40L gene were associated with an X-linked immunodeficiency in humans [hyper-IgM (immunoglobulin M) syndrome]."
Establishes CD40LG as the gene whose defects cause X-linked hyper-IgM syndrome.
PMID:7679206 SUPPORT Human Clinical
"Here we present evidence that point mutations in the TRAP gene give rise to nonfunctional or defective expression of TRAP on the surface of T cells in patients with HIGM1."
Independent identification of loss-of-function point mutations in the CD40LG (TRAP) gene as the molecular cause.
PMID:7678782 SUPPORT Human Clinical
"These patients expressed normal levels of gp39 mRNA, but these mRNAs encode defective gp39 proteins owing to mutations in the extracellular domain of gp39."
Localizes the pathogenic variants to the extracellular (CD40-binding) domain, explaining the loss of function despite preserved transcription.
💊

Medical Actions

5
Immunoglobulin replacement therapy
Action: immunoglobulin replacement therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunoglobulin replacement therapy, annotated with Immunoglobulin Therapy (NCIT:C62710). NCIT:C62710 is a clinical intervention from the NCI Thesaurus. Ontology label: Immunoglobulin Therapy NCIT:C62710
Platform: Protein replacement
Intravenous or subcutaneous immunoglobulin replacement substitutes the IgG the patient cannot make and is the cornerstone of non-curative management. It was used in 95% of patients in the largest reported cohort.
Mechanism Target:
BYPASSES Defective Immunoglobulin Class Switch Recombination — Exogenous pooled IgG supplies the switched isotype the patient's B cells cannot generate. It does not restore class switch recombination; it substitutes for its product.
Show evidence (1 reference)
PMID:20301576 SUPPORT Human Clinical
"Ig replacement therapy (either intravenous or subcutaneous)"
GeneReviews identifies immunoglobulin replacement as treatment of manifestations, i.e. substitution for the missing switched isotypes.
Show evidence (1 reference)
PMID:9255191 SUPPORT Human Clinical
"All patients received regular infusions of immunoglobulins."
Documents universal use of immunoglobulin replacement in a 56-patient cohort.
Pneumocystis jirovecii pneumonia prophylaxis
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
Agent: trimethoprim CHEBI:45924 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses trimethoprim (CHEBI:45924). CHEBI:45924 is a therapeutic agent from Chemical Entities of Biological Interest. sulfamethoxazole CHEBI:9332 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses sulfamethoxazole (CHEBI:9332). CHEBI:9332 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Antimicrobial prophylaxis against Pneumocystis jirovecii, conventionally with trimethoprim-sulfamethoxazole, is standard from the time of diagnosis because Pneumocystis pneumonia is frequently the presenting and a potentially fatal infection. It was reported in 75% of patients in the largest cohort, including a quarter of patients who were not receiving it despite Pneumocystis having been their presenting illness.
Mechanism Target:
BYPASSES Failed CD40-Dependent Licensing of Macrophages and Dendritic Cells — Chemoprophylaxis suppresses the organism rather than repairing the macrophage and dendritic-cell activation defect that permits it.
Show evidence (1 reference)
PMID:20301576 SUPPORT Human Clinical
"antimicrobial prophylaxis for opportunistic infection against Pneumocysitis jirovecii pneumonia"
GeneReviews prescribes antimicrobial prophylaxis against Pneumocystis, an intervention aimed at the pathogen rather than the underlying immune defect. (The cached text carries the source's misspelling of the organism name.)
Target Phenotypes: Pneumocystis jirovecii pneumonia HP:0020102 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Pneumocystis jirovecii pneumonia (HP:0020102). HP:0020102 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301576 SUPPORT Human Clinical
"antimicrobial prophylaxis for opportunistic infection against Pneumocysitis jirovecii pneumonia"
Establishes Pneumocystis prophylaxis as a standard component of management. (The cached text carries the source's misspelling of the organism name.)
Recombinant G-CSF for chronic neutropenia
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
Agent: recombinant G-CSF NCIT:C1287 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses recombinant G-CSF, annotated with Recombinant Granulocyte Colony-Stimulating Factor (NCIT:C1287). NCIT:C1287 is a therapeutic agent from the NCI Thesaurus.
Platform: Protein replacement
Recombinant granulocyte colony-stimulating factor is used for the chronic neutropenia of CD40 ligand deficiency. Uptake is incomplete: fewer than half of neutropenic patients in the largest cohort received it.
Target Phenotypes: Neutropenia HP:0001875 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Neutropenia, annotated with Decreased total neutrophil count (HP:0001875). HP:0001875 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301576 SUPPORT Human Clinical
"recombinant granulocyte colony-stimulating factor for chronic neutropenia"
GeneReviews names recombinant G-CSF as the treatment for the chronic neutropenia of this disorder.
Allogeneic hematopoietic cell transplantation
Action: hematopoietic stem cell transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hematopoietic stem cell transplantation, annotated with Hematopoietic Cell Transplantation (NCIT:C15431). NCIT:C15431 is a clinical intervention from the NCI Thesaurus. Ontology label: Hematopoietic Cell Transplantation NCIT:C15431
Platform: Cell therapy
Allogeneic HCT replaces the CD40LG-mutant hematopoietic system with donor cells that express functional CD40 ligand, and is the only curative treatment. Outcome depends heavily on timing: it should be performed before age ten years and before liver disease develops. In the largest cohort, overall survival did not differ between transplanted and non-transplanted patients across all diagnosis years, though transplant-associated hazard fell markedly from the late 1990s and survivors of transplantation had better performance scores.
Mechanism Target:
RESTORES Loss of Functional CD40 Ligand on Activated CD4+ T Cells — Donor-derived T cells carry a wild-type CD40LG allele, restoring functional CD40 ligand expression and therefore both the B-cell help and the macrophage/dendritic-cell licensing arms of the mechanism.
Show evidence (1 reference)
PMID:20301576 SUPPORT Human Clinical
"Hematopoietic stem cell transplantation (the only curative treatment currently available) is ideally performed before age ten years or prior to evidence of organ dysfunction."
Identifies HCT as the only curative option, i.e. the only intervention that corrects rather than compensates for the underlying defect, and states the timing constraint.
Show evidence (3 references)
PMID:27697500 SUPPORT Human Clinical
"No difference in overall survival was observed between patients treated with or without HCT (P = .671)."
Qualifies the curative claim: across all diagnosis years the largest cohort found no overall survival advantage for transplantation.
PMID:27697500 SUPPORT Human Clinical
"However, risk associated with HCT decreased for diagnosis years 1987-1995; the hazard ratio was significantly less than 1 for diagnosis years 1995-1999."
Documents the improving risk profile of transplantation over time, which is the basis for continuing to offer it.
PMID:27697500 SUPPORT Human Clinical
"Among patients receiving HCT, 27 (40%) had graft-versus-host disease, and most deaths occurred within 1 year of transplantation."
Records the substantial transplant-related morbidity that qualifies the decision to transplant.
Live-vaccine avoidance
Action: live-vaccine avoidanceNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is live-vaccine avoidance, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Platform: Behavioral / lifestyle
Live vaccines are contraindicated pending immune reconstitution: with failed T-cell help, attenuated vaccine strains can cause disseminated disease. The avoid list spans rotavirus, MMR, varicella, live attenuated polio, and BCG.
Mechanism Target:
MODULATES Failed CD40-Dependent Licensing of Macrophages and Dendritic Cells — Removes attenuated-pathogen exposures that the unlicensed macrophage/dendritic-cell compartment cannot contain.
Show evidence (1 reference)
PMID:20301576 SUPPORT Human Clinical
"live vaccines such as rotavirus, MMR, varicella, live attenuated polio, and BCG"
GeneReviews' agents-to-avoid list enumerates the live vaccines this behavioral treatment withholds.
Show evidence (1 reference)
PMID:20301576 SUPPORT Human Clinical
"live vaccines such as rotavirus, MMR, varicella, live attenuated polio, and BCG"
Names the live vaccines to avoid in CD40 ligand deficiency.
🌍

Environmental Factors

1
Exposure to Cryptosporidium-contaminated water
exposure to Cryptosporidium-contaminated water ECTO:7000119 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to Cryptosporidium-contaminated water, annotated with exposure to contaminated water (ECTO:7000119). ECTO:7000119 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Bound to the general contaminated-water exposure term — ECTO has no Cryptosporidium-specific water term, and this is the KB's established binding for waterborne-pathogen exposures (Giardiasis and five other entries use the same CURIE); preferred_term carries the organism specificity.
Untreated or unfiltered water and recreational water sources (pools, lakes, ponds) are the recognized route of Cryptosporidium acquisition in CD40 ligand deficiency, where the organism cannot be cleared and drives chronic diarrhea and sclerosing cholangitis. Avoidance is a standard management measure.
Show evidence (1 reference)
PMID:20301576 SUPPORT Human Clinical
"Areas that place the affected individual at risk of contracting Cryptosporidium including pools, lakes, ponds, or certain water sources; drinking unpurified or unfiltered water"
GeneReviews' agents-to-avoid guidance identifies contaminated-water exposure as the risk route for Cryptosporidium in this disorder.
Mechanism Target:
TRIGGERS Cryptosporidium-Associated Biliary Tract Injury — Ingestion of contaminated water is the route by which Cryptosporidium reaches the gut and biliary tree; in the absence of CD40L-dependent macrophage licensing the infection persists and initiates the biliary epithelial injury this node describes.
Show evidence (1 reference)
PMID:20301576 SUPPORT INDIRECT Human Clinical
"Areas that place the affected individual at risk of contracting Cryptosporidium including pools, lakes, ponds, or certain water sources; drinking unpurified or unfiltered water"
Indirect: GeneReviews states the avoidance list, which encodes the recognized exposure route rather than reporting a cohort measurement of exposure-attributable disease.
🔬

Diagnosis

1
Molecular genetic testing
The diagnosis is established in a male proband with the typical clinical and laboratory picture — recurrent and opportunistic infections with normal-to-elevated IgM and low IgG and IgA — by identifying a hemizygous pathogenic CD40LG variant.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:20301576 SUPPORT Human Clinical
"The diagnosis of CD40 ligand deficiency is established in a male proband with typical clinical and laboratory findings and a hemizygous pathogenic variant in CD40LG identified by molecular genetic testing."
GeneReviews states the diagnostic criterion: typical clinical and laboratory findings plus a hemizygous CD40LG pathogenic variant.
📊

Prevalence

1
United States (national XHIGM registry, 79 patients from 60 families)
Birth Prevalence 0.097 per 100,000 <1 in 1,000,000 (births)
Registry-derived minimal incidence of approximately 1 per 1,030,000 live births, normalized to 0.097 cases per 100,000 live births. Because live births include both sexes and essentially only hemizygous males are affected, this corresponds to roughly 2 per million male births. The registry figure is a minimal estimate and undercounts undiagnosed cases.
Show evidence (1 reference)
PMID:14663287 SUPPORT Human Clinical
"The estimated minimal incidence was approximately 1/1,030,000 live births."
Provides the registry-based occurrence estimate underlying this prevalence record.
{ }

Source YAML

click to show 
name: Hyper-IgM Syndrome Type 1
creation_date: "2026-08-27T01:46:30Z"
category: Genetic
synonyms:
- X-linked hyper-IgM syndrome
- XHIM
- XHIGM
- HIGM1
- CD40 ligand deficiency
- CD40L deficiency
- hyper-IgM syndrome due to CD40 ligand deficiency
- immunodeficiency with hyper IgM type 1
- immunodeficiency 3
- IHIS
description: >-
  Hyper-IgM syndrome type 1 (X-linked hyper-IgM syndrome, CD40 ligand deficiency)
  is an X-linked combined immunodeficiency caused by hemizygous loss-of-function
  variants in CD40LG, which encodes CD40 ligand (CD154), the activation-induced
  surface protein of CD4-positive T cells. Loss of CD40L abolishes engagement of
  CD40 on B cells, so B cells cannot undergo immunoglobulin class switch
  recombination and germinal centers fail to develop: serum IgG, IgA, and IgE are
  very low or absent while IgM is normal or elevated, and class-switched memory B
  cells are markedly reduced. The same molecular lesion abolishes CD40-dependent
  licensing of macrophages and dendritic cells, which is why the disorder behaves
  as a combined rather than a purely antibody deficiency and why affected boys are
  susceptible to opportunistic pathogens, most characteristically Pneumocystis
  jirovecii and Cryptosporidium. Most patients present in the first year of life
  with recurrent sinopulmonary infection, Pneumocystis pneumonia, and protracted
  diarrhea. Chronic neutropenia with oral ulceration is common, and
  Cryptosporidium-associated sclerosing cholangitis and biliary-tract malignancy
  dominate long-term morbidity and mortality. Management combines immunoglobulin
  replacement, Pneumocystis prophylaxis, and G-CSF for neutropenia; allogeneic
  hematopoietic cell transplantation is the only curative option.
disease_term:
  preferred_term: X-linked hyper-IgM syndrome (CD40 ligand deficiency)
  term:
    id: MONDO:0010626
    label: hyper-IgM syndrome type 1
parents:
- Hyper-IgM syndrome
- Combined immunodeficiency
- Primary immunodeficiency
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
    notes: >-
      CD40 ligand deficiency is an inborn error of immunity (primary
      immunodeficiency) and belongs with the disorders of the immune system.
    evidence:
    - reference: PMID:27697500
      reference_title: "Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        X-linked hyper-IgM syndrome (XHIGM) is a primary immunodeficiency with
        high morbidity and mortality compared with those seen in healthy
        subjects.
      explanation: >-
        Establishes XHIGM as a primary immunodeficiency, an immune-system
        disorder under the immunology/rheumatology Part.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A single-gene X-linked Mendelian disorder caused by hemizygous CD40LG
      pathogenic variants, with genetic counseling and carrier testing central to
      management.
    evidence:
    - reference: PMID:20301576
      reference_title: CD40 Ligand Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        CD40 ligand deficiency is inherited in an X-linked manner.
      explanation: >-
        GeneReviews states the Mendelian X-linked basis of the disorder,
        supporting placement in the genetics Part.
  iuis_category:
    classification_value: combined immunodeficiency
    notes: >-
      The IUIS 2022 update places CD40 ligand (CD154) deficiency in Table 1,
      section 3, "Combined Immunodeficiency (CID), Generally Less Profound than
      SCID" - NOT among the predominantly antibody deficiencies of Table 3.
      Despite the immunoglobulin-centric name, the disorder is classified as a
      CID because CD40L is also required to license macrophages and dendritic
      cells, so cell-mediated immunity is impaired alongside the antibody defect.
    evidence:
    - reference: PMID:35748970
      reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        CD40 ligand (CD154) deficiency CD40LG XL 308230
      explanation: >-
        The IUIS classification-table row assigning CD40 ligand (CD154)
        deficiency, gene CD40LG, X-linked, OMIM 308230, within the section
        "3. Combined Immunodeficiency (CID), Generally Less Profound than SCID".
        The quoted row comes from the classification tables in the cached full
        text rather than from the abstract.
    - reference: PMID:27554817
      reference_title: "Human CD40 ligand deficiency dysregulates the macrophage transcriptome causing functional defects that are improved by exogenous IFN-γ."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        CD40 ligand (CD40L) deficiency predisposes to opportunistic infections,
        including those caused by fungi and intracellular bacteria.
      explanation: >-
        Susceptibility to fungal and intracellular bacterial pathogens is a
        cell-mediated-immunity defect, which is the substantive basis for the
        combined-immunodeficiency rather than antibody-deficiency assignment.
inheritance:
- name: X-linked recessive
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  description: >-
    CD40LG lies at Xq26 and the disorder is transmitted as an X-linked recessive
    trait. Affected individuals are essentially always male hemizygotes;
    heterozygous female carriers are typically asymptomatic, although skewed
    X-chromosome inactivation can produce a range of manifestations.
  evidence:
  - reference: PMID:20301576
    reference_title: CD40 Ligand Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heterozygous females are typically asymptomatic but may have a range of
      clinical manifestations depending on X-chromosome inactivation.
    explanation: >-
      Documents the X-linked recessive transmission pattern, with carrier females
      generally unaffected.
  - reference: PMID:7678782
    reference_title: "The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The gene encoding gp39 was mapped to Xq26, the X chromosome region where
      the gene responsible for HIM had previously been mapped.
    explanation: >-
      Maps the causative gene to the X chromosome, establishing the X-linked
      basis of the disorder.
prevalence:
- population: United States (national XHIGM registry, 79 patients from 60 families)
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_per_100000: 0.097
  notes: >-
    Registry-derived minimal incidence of approximately 1 per 1,030,000 live
    births, normalized to 0.097 cases per 100,000 live births. Because live
    births include both sexes and essentially only hemizygous males are affected,
    this corresponds to roughly 2 per million male births. The registry figure is
    a minimal estimate and undercounts undiagnosed cases.
  evidence:
  - reference: PMID:14663287
    reference_title: "The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The estimated minimal incidence was approximately 1/1,030,000 live births.
    explanation: >-
      Provides the registry-based occurrence estimate underlying this prevalence
      record.
genetic:
- name: CD40LG
  gene_term:
    preferred_term: CD40LG
    term:
      id: hgnc:11935
      label: CD40LG
  relationship_type: CAUSATIVE
  inheritance:
  - name: X-linked recessive
    inheritance_term:
      preferred_term: X-linked recessive inheritance
      term:
        id: HP:0001419
        label: X-linked recessive inheritance
  notes: >-
    CD40LG encodes CD40 ligand (CD154, gp39, TRAP), a type II transmembrane
    member of the TNF superfamily expressed on the surface of activated CD4+ T
    cells. Pathogenic variants are hemizygous and loss-of-function: point
    mutations in the extracellular domain that abolish CD40 binding, as well as
    variants causing absent or non-functional surface expression. B cells are
    intrinsically normal and respond to wild-type CD40L, so the defect is a T-cell
    lesion with B-cell consequences.
  evidence:
  - reference: PMID:7679801
    reference_title: "CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Abnormalities in the CD40L gene were associated with an X-linked
      immunodeficiency in humans [hyper-IgM (immunoglobulin M) syndrome].
    explanation: >-
      Establishes CD40LG as the gene whose defects cause X-linked hyper-IgM
      syndrome.
  - reference: PMID:7679206
    reference_title: "Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we present evidence that point mutations in the TRAP gene give rise to
      nonfunctional or defective expression of TRAP on the surface of T cells in
      patients with HIGM1.
    explanation: >-
      Independent identification of loss-of-function point mutations in the
      CD40LG (TRAP) gene as the molecular cause.
  - reference: PMID:7678782
    reference_title: "The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These patients expressed normal levels of gp39 mRNA, but these mRNAs encode
      defective gp39 proteins owing to mutations in the extracellular domain of
      gp39.
    explanation: >-
      Localizes the pathogenic variants to the extracellular (CD40-binding)
      domain, explaining the loss of function despite preserved transcription.
pathophysiology:
- name: Loss of Functional CD40 Ligand on Activated CD4+ T Cells
  biological_scale: MOLECULAR
  description: >-
    Hemizygous loss-of-function variants in CD40LG leave activated CD4+ T cells
    unable to display functional CD40 ligand (CD154/gp39/TRAP) at the cell
    surface. Some variants abolish surface expression entirely; others permit
    normal transcription but encode extracellular-domain mutants that cannot bind
    CD40. Either way the T cell loses its principal contact-dependent helper
    signal, and every downstream defect in this entry follows from this single
    molecular lesion.
  gene:
    preferred_term: CD40LG
    modifier: DECREASED
    term:
      id: hgnc:11935
      label: CD40LG
  genetic_context:
    gene:
      preferred_term: CD40LG
      term:
        id: hgnc:11935
        label: CD40LG
    variant_origin: GERMLINE
    zygosity: HEMIZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Germline hemizygous CD40LG loss-of-function variants in males; the single X
      chromosome leaves no functional allele.
  cell_types:
  - preferred_term: activated CD4+ T helper cell
    term:
      id: CL:0000896
      label: activated CD4-positive, alpha-beta T cell
  evidence:
  - reference: PMID:7679801
    reference_title: "CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Activated T cells from the four affected patients failed to express
      wild-type CD40L, although their B cells responded normally to wild-type
      CD40L.
    explanation: >-
      Localizes the primary lesion to the activated T cell and shows the B-cell
      compartment is intrinsically intact.
  - reference: PMID:7679801
    reference_title: "CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Recombinant expression of two of the mutant CD40L complementary DNAs
      resulted in proteins incapable of binding to CD40 and unable to induce
      proliferation or IgE secretion from normal B cells.
    explanation: >-
      Demonstrates directly that the mutant proteins are loss-of-function for
      CD40 binding, supporting the functional_impact_category assignment.
  downstream:
  - target: Failed CD40 Engagement on B Cells
    causal_link_type: DIRECT
    description: >-
      Without functional CD40L on the T-cell surface, the cognate receptor CD40
      on the B cell is never engaged during T-B collaboration.
    evidence:
    - reference: PMID:7679206
      reference_title: "Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The resultant failure of TRAP to interact with CD40 on functionally
        intact B cells is responsible for the observed immunoglobulin isotype
        defect in HIGM1.
      explanation: >-
        States the direct causal step from absent CD40L to failed CD40
        engagement on otherwise normal B cells.
  - target: Failed CD40-Dependent Licensing of Macrophages and Dendritic Cells
    causal_link_type: DIRECT
    description: >-
      CD40 is also expressed by macrophages and dendritic cells, so the same
      missing ligand removes the T-cell-derived activation signal for the
      mononuclear phagocyte compartment.
    evidence:
    - reference: PMID:27554817
      reference_title: "Human CD40 ligand deficiency dysregulates the macrophage transcriptome causing functional defects that are improved by exogenous IFN-γ."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Absence of CD40L impairs macrophage development and function.
      explanation: >-
        Establishes that loss of CD40L directly compromises macrophage
        development and function, independent of the antibody defect.
  - target: Chronic neutropenia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Chronic or intermittent neutropenia is a well-documented consequence of
      CD40L deficiency, but the intervening steps between the CD40LG lesion and
      the granulocyte defect are not established; it responds to G-CSF, which is
      consistent with a myelopoietic rather than a purely peripheral-destruction
      mechanism.
    evidence:
    - reference: PMID:20301576
      reference_title: CD40 Ligand Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Neutropenia is common; thrombocytopenia and anemia are less commonly
        seen.
      explanation: >-
        Documents neutropenia as a common consequence of CD40 ligand deficiency
        without specifying the intermediate mechanism.
- name: Failed CD40 Engagement on B Cells
  biological_scale: CELLULAR
  description: >-
    CD40 is constitutively expressed on B cells and is functional in these
    patients, but it is never cross-linked because its ligand is absent. The
    B cell therefore never receives the contact-dependent second signal that,
    together with cytokines, drives activation, proliferation, differentiation,
    and isotype switching.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: CD40 signaling pathway
    term:
      id: GO:0023035
      label: CD40 signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:7678782
    reference_title: "The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      B cells from HIM patients express functional CD40, but their T cells do not
      bind CD40-Ig.
    explanation: >-
      Shows the receptor side is intact and the failure is specifically in
      ligand-receptor engagement.
  - reference: PMID:7539026
    reference_title: "Immunohistologic analysis of ineffective CD40-CD40 ligand interaction in lymphoid tissues from patients with X-linked immunodeficiency with hyper-IgM. Abortive germinal center cell reaction and severe depletion of follicular dendritic cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The CD40 ligand (CD40L) is an activation-induced surface membrane protein
      expressed by CD4+ T helper cells in lymphoid follicles, and is involved in
      the contact-dependent signaling-mediated activation, proliferation, and
      differentiation of CD40+ B cells.
    explanation: >-
      Defines the contact-dependent CD40L-CD40 signal to B cells that is lost in
      this disorder.
  downstream:
  - target: Defective Immunoglobulin Class Switch Recombination
    causal_link_type: DIRECT
    description: >-
      CD40 cross-linking is the signal that, in the presence of lymphokines,
      licenses the B cell to switch from IgM to the downstream isotypes.
    evidence:
    - reference: PMID:7679206
      reference_title: "Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Crosslinking of CD40 on B cells induces, in the presence of lymphokines,
        immunoglobulin class switching from IgM to IgG, IgA or IgE.
      explanation: >-
        States the direct dependence of class switching on CD40 cross-linking,
        which is what fails here.
  - target: Abortive Germinal Center Reaction with Follicular Dendritic Cell Depletion
    causal_link_type: DIRECT
    description: >-
      Ineffective CD40/CD40L interaction in the lymphoid follicle prevents the
      germinal center reaction from proceeding beyond a primary follicle.
    evidence:
    - reference: PMID:7539026
      reference_title: "Immunohistologic analysis of ineffective CD40-CD40 ligand interaction in lymphoid tissues from patients with X-linked immunodeficiency with hyper-IgM. Abortive germinal center cell reaction and severe depletion of follicular dendritic cells."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        these data support the idea that ineffective CD40/CD40L interactions
        determine both abortive germinal center cell reaction as well as severe
        depletion and phenotypical abnormalities of follicular dendritic cells,
        thus impairing the functional development of B follicles.
      explanation: >-
        Directly links failed CD40/CD40L engagement to the abortive germinal
        center reaction in patient lymphoid tissue.
- name: Defective Immunoglobulin Class Switch Recombination
  biological_scale: CELLULAR
  description: >-
    Deprived of the CD40 signal, the B cell cannot execute isotype switching from
    IgM to IgG, IgA, or IgE. IgM production continues - and is in fact sustained
    or amplified by ongoing antigenic stimulation, particularly at mucosal
    surfaces - so the serum picture is very low or absent IgG, IgA, and IgE with
    normal to elevated IgM. Class-switched memory B cells, which are the product
    of successful switching, are correspondingly reduced.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: class switched memory B cell
    term:
      id: CL:0000972
      label: class switched memory B cell
  biological_processes:
  - preferred_term: immunoglobulin class switch recombination (isotype switching)
    term:
      id: GO:0045190
      label: isotype switching
    modifier: DECREASED
  evidence:
  - reference: PMID:7679801
    reference_title: "CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, these CD40L defects lead to a T cell abnormality that results in the
      failure of patient B cells to undergo immunoglobulin class switching.
    explanation: >-
      States the central mechanistic conclusion: the CD40L defect causes failure
      of B-cell class switching.
  - reference: PMID:20301576
    reference_title: CD40 Ligand Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Total numbers of B cells are normal but there is a marked reduction of
      class-switched memory B cells.
    explanation: >-
      Confirms that the defect is in switching rather than in B-cell development,
      and identifies the depleted class-switched memory compartment.
  - reference: PMID:7539026
    reference_title: "Immunohistologic analysis of ineffective CD40-CD40 ligand interaction in lymphoid tissues from patients with X-linked immunodeficiency with hyper-IgM. Abortive germinal center cell reaction and severe depletion of follicular dendritic cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recurrent or persisting antigenic stimulation in mucosal tissues is likely
      to play a major role in determining and maintaining elevated IgM serum
      levels.
    explanation: >-
      Explains why IgM is normal to elevated rather than merely unswitched:
      ongoing mucosal antigenic drive sustains IgM-only plasma cells.
  downstream:
  - target: Decreased circulating IgG concentration
    causal_link_type: DIRECT
    description: >-
      IgG cannot be produced because the switch from IgM to IgG requires the
      CD40-dependent recombination step.
    evidence:
    - reference: PMID:7679206
      reference_title: "Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        X chromosome-linked immunodeficiency with hyper-IgM (HIGM1, MIM number
        308230) is a rare disorder characterized by recurrent bacterial
        infections, very low or absent IgG, IgA and IgE, and normal to increased
        IgM and IgD serum levels.
      explanation: >-
        Documents the serum immunoglobulin pattern that results from the
        switching defect.
  - target: Decreased circulating IgA concentration
    causal_link_type: DIRECT
    description: >-
      IgA is one of the switched isotypes the block prevents, so serum IgA is
      low or absent alongside IgG and IgE.
    evidence:
    - reference: PMID:7679801
      reference_title: "CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This disease is characterized by elevated concentrations of serum IgM and
        decreased amounts of all other isotypes.
      explanation: >-
        "All other isotypes" includes IgA, which the switching block prevents
        the B cell from producing.
  - target: Increased circulating IgM level
    causal_link_type: DIRECT
    description: >-
      IgM synthesis is preserved and sustained by continued antigenic stimulation
      while no isotype switching consumes the IgM-committed pool.
    evidence:
    - reference: PMID:7679801
      reference_title: "CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This disease is characterized by elevated concentrations of serum IgM and
        decreased amounts of all other isotypes.
      explanation: >-
        Documents elevated IgM with reduction of all switched isotypes, the
        signature of the switching block.
  - target: Recurrent sinopulmonary infections
    causal_link_type: DIRECT
    description: >-
      Absent IgG leaves patients unable to opsonize encapsulated bacteria,
      producing the recurrent upper- and lower-respiratory tract infections that
      typically bring them to attention.
    evidence:
    - reference: PMID:20301576
      reference_title: CD40 Ligand Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        CD40 ligand deficiency usually presents in infancy with recurrent upper-
        and lower-respiratory tract bacterial infections
      explanation: >-
        Links the humoral defect to the recurrent sinopulmonary bacterial
        infections that are the usual presentation.
- name: Abortive Germinal Center Reaction with Follicular Dendritic Cell Depletion
  biological_scale: TISSUE
  description: >-
    In patient lymph nodes and extranodal lymphoid tissue, B-cell follicles arrest
    as prominent primary follicles: germinal centers do not form, and the
    follicular dendritic cell network that normally supports affinity maturation
    is severely depleted and phenotypically abnormal. Intrafollicular CD4+ helper
    T cells are present in normal numbers and the paracortical T-cell area is
    architecturally intact, so the lesion is specific to the follicular B-cell
    compartment rather than a global lymphoid failure.
  cell_types:
  - preferred_term: follicular dendritic cell
    term:
      id: CL:0000442
      label: follicular dendritic cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: germinal center formation
    term:
      id: GO:0002467
      label: germinal center formation
    modifier: DECREASED
  evidence:
  - reference: PMID:7539026
    reference_title: "Immunohistologic analysis of ineffective CD40-CD40 ligand interaction in lymphoid tissues from patients with X-linked immunodeficiency with hyper-IgM. Abortive germinal center cell reaction and severe depletion of follicular dendritic cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, a severe depletion of follicular dendritic cells, recognized by
      Abs against NGFR, CD21 and CD23, and lack of expression of the Ag
      recognized by KiM4p on these cells, are noticed.
    explanation: >-
      Documents the severe follicular dendritic cell depletion in patient lymphoid
      tissue.
  - reference: PMID:7539026
    reference_title: "Immunohistologic analysis of ineffective CD40-CD40 ligand interaction in lymphoid tissues from patients with X-linked immunodeficiency with hyper-IgM. Abortive germinal center cell reaction and severe depletion of follicular dendritic cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prominent primary B follicles are identified in the lymph nodes and in the
      extranodal lymphoid tissues from both cases
    explanation: >-
      Shows follicles arrested at the primary stage, i.e. germinal centers failing
      to form.
  downstream:
  - target: Decreased class-switched memory B cell proportion
    causal_link_type: DIRECT
    description: >-
      The germinal center is where class-switched memory B cells are generated;
      an abortive germinal center reaction leaves this compartment markedly
      reduced.
    evidence:
    - reference: PMID:20301576
      reference_title: CD40 Ligand Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Total numbers of B cells are normal but there is a marked reduction of
        class-switched memory B cells.
      explanation: >-
        Documents the depleted class-switched memory B-cell compartment that
        results from the failed germinal center reaction.
- name: Failed CD40-Dependent Licensing of Macrophages and Dendritic Cells
  biological_scale: CELLULAR
  description: >-
    CD40L is required not only for B-cell help but for T-cell-mediated activation
    of the mononuclear phagocyte system. In its absence, patient monocyte-derived
    macrophages show defective fungicidal activity, a reduced oxidative burst,
    impaired inflammatory cytokine production, a globally dysregulated
    transcriptome, and failure to control Mycobacterium tuberculosis. The
    rescue experiments separate two groups: fungicidal activity and the
    oxidative burst are restored in vitro by exogenous IFN-gamma but not by
    soluble CD40L, placing that block downstream of the T-cell-macrophage
    conversation, whereas impaired inflammatory cytokine production is
    ameliorated by both. This arm of the mechanism is why the disorder is a combined
    immunodeficiency and why the characteristic infections are opportunistic.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: dendritic cell
    term:
      id: CL:0000451
      label: dendritic cell
  biological_processes:
  - preferred_term: macrophage activation
    term:
      id: GO:0042116
      label: macrophage activation
    modifier: DECREASED
  - preferred_term: T cell costimulation
    term:
      id: GO:0031295
      label: T cell costimulation
    modifier: DECREASED
  evidence:
  - reference: PMID:27554817
    reference_title: "Human CD40 ligand deficiency dysregulates the macrophage transcriptome causing functional defects that are improved by exogenous IFN-γ."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Macrophages from CD40L-deficient patients exhibited defective fungicidal
      activity and reduced oxidative burst, both of which improved in the presence
      of rhIFN-γ but not sCD40L.
    explanation: >-
      Documents the specific macrophage functional defects caused by CD40L
      absence and their partial rescue by IFN-gamma.
  - reference: PMID:27554817
    reference_title: "Human CD40 ligand deficiency dysregulates the macrophage transcriptome causing functional defects that are improved by exogenous IFN-γ."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The absence of CD40L dysregulated the macrophage transcriptome, which was
      improved by rhIFN-γ.
    explanation: >-
      Establishes a transcriptome-wide macrophage program defect attributable to
      CD40L loss.
  - reference: PMID:27554817
    reference_title: "Human CD40 ligand deficiency dysregulates the macrophage transcriptome causing functional defects that are improved by exogenous IFN-γ."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Studies of CD40L-deficient patients reveal the critical role of CD40L-CD40
      interaction for the function of T, B, and dendritic cells.
    explanation: >-
      Extends the licensing defect from macrophages to dendritic cells and T
      cells, supporting the cell-type annotations on this node.
  downstream:
  - target: Pneumocystis jirovecii pneumonia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Impaired CD40-dependent activation of macrophages and dendritic cells
      degrades the cell-mediated defense against Pneumocystis jirovecii, which is
      frequently the presenting opportunistic infection.
    evidence:
    - reference: PMID:20301576
      reference_title: CD40 Ligand Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        opportunistic infections including Pneumocystis jirovecii pneumonia
      explanation: >-
        Documents Pneumocystis jirovecii pneumonia as a characteristic
        opportunistic infection of the disorder, i.e. a cell-mediated-immunity
        failure.
  - target: Chronic diarrhea
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The same defect in cell-mediated mucosal defense permits protracted
      infectious diarrhea, characteristically caused by Cryptosporidium species.
    evidence:
    - reference: PMID:9255191
      reference_title: Clinical spectrum of X-linked hyper-IgM syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The marked prevalence of infections caused by intracellular pathogens
        suggests some degree of impairment of cell-mediated immunity.
      explanation: >-
        Attributes the intracellular-pathogen susceptibility, including the
        Cryptosporidium-associated diarrhea in this cohort, to impaired
        cell-mediated immunity.
  - target: Cryptosporidium-Associated Biliary Tract Injury
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Failure to clear Cryptosporidium from the gut and biliary tree allows
      persistent infection of the biliary epithelium, which is the initiating
      event for the cholangiopathy.
    evidence:
    - reference: PMID:9255191
      reference_title: Clinical spectrum of X-linked hyper-IgM syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        chronic diarrhea, and liver involvement (both often associated with
        Cryptosporidium infection) were common.
      explanation: >-
        Links persistent Cryptosporidium infection to the hepatobiliary
        involvement in this cohort.
- name: Cryptosporidium-Associated Biliary Tract Injury
  biological_scale: TISSUE
  description: >-
    Persistent Cryptosporidium infection of the biliary epithelium drives chronic
    cholangiocyte injury and progressive fibro-obliterative bile duct disease
    (sclerosing cholangitis), and the resulting chronic inflammation is the
    presumed substrate for biliary-tract malignancy. Liver disease is the single
    strongest predictor of mortality in this disorder, and hematopoietic cell
    transplantation performed before its onset is the principal way to prevent it.
  locations:
  - preferred_term: bile duct
    term:
      id: UBERON:0002394
      label: bile duct
  evidence:
  - reference: PMID:14663287
    reference_title: "The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sclerosing cholangitis occurred in 5 patients and in 4 of these was
      associated with Cryptosporidium infection.
    explanation: >-
      Documents the association of sclerosing cholangitis with Cryptosporidium
      infection in a registry cohort.
  - reference: PMID:27697500
    reference_title: "Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Liver disease was a significant predictor of overall survival (hazard
      ratio, 4.9; 95% confidence limits, 2.2-10.8; P < .001).
    explanation: >-
      Quantifies the mortality impact of the hepatobiliary arm of the disease.
  downstream:
  - target: Sclerosing cholangitis
    causal_link_type: DIRECT
    description: >-
      Chronic cryptosporidial cholangiocyte infection produces the sclerosing
      cholangitis phenotype.
    evidence:
    - reference: PMID:14663287
      reference_title: "The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Sclerosing cholangitis occurred in 5 patients and in 4 of these was
        associated with Cryptosporidium infection.
      explanation: >-
        Directly connects Cryptosporidium infection to sclerosing cholangitis in
        affected patients.
  - target: Malignancy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Chronic biliary inflammation is the presumed substrate for the hepatic and
      bile-duct malignancies that account for a disproportionate share of deaths;
      the intervening oncogenic steps are not established.
    evidence:
    - reference: PMID:14663287
      reference_title: "The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        2 of malignancy (both hepatocellular carcinoma)
      explanation: >-
        Documents fatal hepatic malignancy in the registry cohort, downstream of
        the chronic hepatobiliary disease.
  - target: Liver disease
    causal_link_type: DIRECT
    description: >-
      Progressive biliary tract injury is what the aggregate "liver disease" of
      the registry cohorts measures — sclerosing cholangitis, hepatitis and
      cirrhosis recorded together.
    evidence:
    - reference: PMID:14663287
      reference_title: "The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Sclerosing cholangitis occurred in 5 patients and in 4 of these was
        associated with Cryptosporidium infection.
      explanation: >-
        Ties the biliary injury of this node directly to Cryptosporidium in four
        of five affected patients; sclerosing cholangitis is the dominant
        component of the liver disease this edge points at.
phenotypes:
- name: Recurrent sinopulmonary infections
  category: Clinical
  description: >-
    Recurrent upper- and lower-respiratory tract bacterial infections are the
    usual presenting problem. In the US registry, pneumonia affected 81% of
    patients, with upper respiratory infections in 49%, sinusitis in 43%, and
    recurrent otitis in 43%.
  phenotype_term:
    preferred_term: Recurrent sinopulmonary infections
    term:
      id: HP:0005425
      label: Recurrent sinopulmonary infections
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:14663287
    reference_title: "The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most prominent clinical infections were pneumonia (81% of patients),
      upper respiratory infections (49%) including sinusitis (43%) and recurrent
      otitis (43%)
    explanation: >-
      Pneumonia in 81% of registry patients places this phenotype in the
      very-frequent (80-100%) band.
  - reference: PMID:9255191
    reference_title: Clinical spectrum of X-linked hyper-IgM syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Upper and lower respiratory tract infections (the latter frequently caused
      by Pneumocystis carinii), chronic diarrhea, and liver involvement (both
      often associated with Cryptosporidium infection) were common.
    explanation: >-
      Independent European cohort confirming recurrent upper and lower
      respiratory tract infection as a common feature.
- name: Pneumocystis jirovecii pneumonia
  category: Clinical
  description: >-
    Pneumocystis jirovecii pneumonia is the signature opportunistic infection and
    is frequently the presenting manifestation, reflecting the cell-mediated
    rather than the antibody arm of the immunodeficiency.
  phenotype_term:
    preferred_term: Pneumocystis jirovecii pneumonia
    term:
      id: HP:0020102
      label: Pneumocystis jirovecii pneumonia
  evidence:
  - reference: PMID:20301576
    reference_title: CD40 Ligand Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      opportunistic infections including Pneumocystis jirovecii pneumonia
    explanation: >-
      GeneReviews lists Pneumocystis jirovecii pneumonia among the presenting
      opportunistic infections.
  - reference: PMID:14663287
    reference_title: "The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most patients presented initially with a history of an increased
      susceptibility to infection including Pneumocystis carinii pneumonia.
    explanation: >-
      Registry data documenting Pneumocystis pneumonia (reported under the older
      name P. carinii) as a common presenting infection.
- name: Chronic diarrhea
  category: Clinical
  description: >-
    Recurrent or protracted diarrhea, which may be infectious (characteristically
    Cryptosporidium) or noninfectious, occurred in 34% of registry patients and is
    associated with faltering growth.
  phenotype_term:
    preferred_term: Chronic diarrhea
    term:
      id: HP:0002028
      label: Chronic diarrhea
    temporality: CHRONIC
  frequency: FREQUENT
  evidence:
  - reference: PMID:14663287
    reference_title: "The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      recurrent otitis (43%), recurrent/protracted diarrhea (34%), central
      nervous system infections (14%)
    explanation: >-
      Recurrent or protracted diarrhea in 34% of registry patients places this
      phenotype in the frequent (30-79%) band.
  - reference: PMID:20301576
    reference_title: CD40 Ligand Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      recurrent or protracted diarrhea that can be infectious or noninfectious
      and is associated with faltering growth
    explanation: >-
      GeneReviews characterizes the diarrhea and its association with growth
      failure.
- name: Chronic neutropenia
  category: Laboratory
  description: >-
    Chronic or intermittent neutropenia is common and is characteristically
    accompanied by oral and rectal ulceration. It responds to recombinant G-CSF.
  phenotype_term:
    preferred_term: Neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
    temporality: CHRONIC
  evidence:
  - reference: PMID:9255191
    reference_title: Clinical spectrum of X-linked hyper-IgM syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Many patients had chronic neutropenia associated with oral and rectal
      ulcers.
    explanation: >-
      Documents chronic neutropenia and its characteristic mucosal ulceration in
      a 56-patient cohort.
  - reference: PMID:20301576
    reference_title: CD40 Ligand Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neutropenia is common; thrombocytopenia and anemia are less commonly seen.
    explanation: >-
      GeneReviews confirms neutropenia as a common finding and distinguishes it
      from the less common cytopenias.
  sequelae:
  - target: Oral ulcer
    causal_link_type: DIRECT
    description: >-
      The oral and rectal ulceration that characteristically accompanies the
      neutropenia; the cohort reports the two together.
    evidence:
    - reference: PMID:9255191
      reference_title: Clinical spectrum of X-linked hyper-IgM syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Many patients had chronic neutropenia associated with oral and rectal
        ulcers.
      explanation: >-
        States the association between the neutropenia and the ulceration this
        edge connects.
- name: Oral ulcer
  category: Clinical
  description: >-
    Oral (and rectal) ulceration accompanies the neutropenia and is a
    characteristic mucosal manifestation of the disorder.
  phenotype_term:
    preferred_term: Oral ulcer
    term:
      id: HP:0000155
      label: Oral ulcer
  evidence:
  - reference: PMID:9255191
    reference_title: Clinical spectrum of X-linked hyper-IgM syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Many patients had chronic neutropenia associated with oral and rectal
      ulcers.
    explanation: >-
      Documents oral ulceration occurring in association with the neutropenia.
- name: Sclerosing cholangitis
  category: Clinical
  description: >-
    Sclerosing cholangitis is a serious complication, strongly associated with
    Cryptosporidium infection. It occurred in 5 of 79 US registry patients, and in
    the European cohort four patients required liver transplantation for it, with
    relapse in the graft.
  phenotype_term:
    preferred_term: Sclerosing cholangitis
    term:
      id: HP:0030991
      label: Sclerosing cholangitis
    clinical_course: PROGRESSIVE
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:14663287
    reference_title: "The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sclerosing cholangitis occurred in 5 patients and in 4 of these was
      associated with Cryptosporidium infection.
    explanation: >-
      Five of 79 registry patients (6%) developed sclerosing cholangitis,
      supporting the occasional (5-29%) frequency band.
  - reference: PMID:9255191
    reference_title: Clinical spectrum of X-linked hyper-IgM syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Four patients underwent liver transplantation because of sclerosing
      cholangitis, which relapsed in there.
    explanation: >-
      Documents sclerosing cholangitis severe enough to require transplantation,
      and its recurrence in the graft.
- name: Liver disease
  category: Clinical
  description: >-
    Hepatobiliary involvement is the dominant long-term complication and the only
    clinical variable at diagnosis that independently predicts mortality. Liver
    disease was once seen in more than 80% of affected males by age 20 years,
    though this may be falling with Cryptosporidium screening and treatment.
  phenotype_term:
    preferred_term: Liver disease
    term:
      id: HP:0001392
      label: Abnormality of the liver
    clinical_course: PROGRESSIVE
  notes: >-
    Bound to the broad liver-abnormality term deliberately: the source
    aggregates sclerosing cholangitis, hepatitis, cirrhosis, and
    cholangiocarcinoma under "liver disease", and the specific cholangiopathy
    is carried by its own phenotype and pathophysiology node.
  evidence:
  - reference: PMID:20301576
    reference_title: CD40 Ligand Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Liver disease, a serious complication of CD40 ligand deficiency once
      observed in more than 80% of affected males by age 20 years, may be
      decreasing with adequate screening and treatment of Cryptosporidium
      infection.
    explanation: >-
      Documents the historical burden of liver disease and its dependence on
      Cryptosporidium control.
  - reference: PMID:27697500
    reference_title: "Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Liver disease was a significant predictor of overall survival (hazard
      ratio, 4.9; 95% confidence limits, 2.2-10.8; P < .001).
    explanation: >-
      Establishes liver disease as the significant independent predictor of
      survival in the largest reported cohort.
- name: Malignancy
  category: Clinical
  description: >-
    Neoplasms, particularly of the liver and biliary tract, are an established
    complication and carry very high mortality. The IUIS classification lists
    cholangiocarcinoma and peripheral neuroectodermal tumors among the associated
    features of CD40 ligand deficiency.
  phenotype_term:
    preferred_term: Neoplasm
    term:
      id: HP:0002664
      label: Neoplasm
  evidence:
  - reference: PMID:20301576
    reference_title: CD40 Ligand Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autoimmune and/or inflammatory disorders (such as sclerosing cholangitis) as
      well as increased risk for neoplasms have been reported as medical
      complications of this disorder.
    explanation: >-
      GeneReviews documents increased neoplasm risk as a recognized complication.
  - reference: PMID:14663287
    reference_title: "The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      2 of malignancy (both hepatocellular carcinoma)
    explanation: >-
      Two of eight registry deaths were from hepatic malignancy, documenting
      malignancy as a cause of death.
- name: Decreased circulating IgG concentration
  category: Laboratory
  description: >-
    Serum IgG is very low or absent, the direct consequence of the class-switch
    recombination block. All 79 US registry patients had significant IgG
    deficiency.
  phenotype_term:
    preferred_term: Decreased circulating IgG concentration
    term:
      id: HP:0004315
      label: Decreased circulating IgG concentration
  frequency: OBLIGATE
  evidence:
  - reference: PMID:14663287
    reference_title: "The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All of the patients had significant IgG deficiency and most had IgA
      deficiency, but only one-half had elevated IgM levels.
    explanation: >-
      IgG deficiency was present in all 79 registry patients, supporting an
      obligate frequency assignment.
- name: Decreased circulating IgA concentration
  category: Laboratory
  description: >-
    Serum IgA is very low or absent alongside IgG, since IgA also requires
    CD40-dependent class switching. Most registry patients had IgA deficiency.
  phenotype_term:
    preferred_term: Decreased circulating IgA concentration
    term:
      id: HP:0002720
      label: Decreased circulating IgA concentration
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:14663287
    reference_title: "The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All of the patients had significant IgG deficiency and most had IgA
      deficiency, but only one-half had elevated IgM levels.
    explanation: >-
      "Most" patients had IgA deficiency, supporting a very-frequent band.
- name: Increased circulating IgM level
  category: Laboratory
  description: >-
    Serum IgM is normal to elevated, the finding that gives the syndrome its name.
    Importantly it is normal rather than raised in a substantial fraction of
    patients - only about half of US registry patients had frankly elevated IgM -
    so a normal IgM does not exclude the diagnosis.
  phenotype_term:
    preferred_term: Increased circulating IgM level
    term:
      id: HP:0003496
      label: Increased circulating IgM level
  frequency: FREQUENT
  evidence:
  - reference: PMID:14663287
    reference_title: "The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All of the patients had significant IgG deficiency and most had IgA
      deficiency, but only one-half had elevated IgM levels.
    explanation: >-
      Elevated IgM in approximately half of registry patients supports the
      frequent (30-79%) band and the caveat that IgM is often normal.
  - reference: PMID:20301576
    reference_title: CD40 Ligand Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      characterized by low serum concentrations of immunoglobulin (Ig) G, IgA, and
      IgE with normal or elevated serum concentrations of IgM
    explanation: >-
      GeneReviews states the defining serum immunoglobulin pattern, including that
      IgM may be normal rather than elevated.
- name: Decreased class-switched memory B cell proportion
  category: Laboratory
  description: >-
    Total B-cell numbers are normal, but class-switched memory B cells - the
    product of a successful germinal center reaction - are markedly reduced.
  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:20301576
    reference_title: CD40 Ligand Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Total numbers of B cells are normal but there is a marked reduction of
      class-switched memory B cells.
    explanation: >-
      Documents the reduced class-switched memory B-cell compartment with
      preserved total B-cell numbers.
- name: Neurologic complications
  category: Neurologic
  description: >-
    Significant neurologic complications, most often the consequence of a
    central nervous system infection, occur in 5-15% of affected males.
  phenotype_term:
    preferred_term: Neurologic complications of CNS infection
    term:
      id: HP:0012638
      label: Abnormal nervous system physiology
  notes: >-
    Bound to the broad nervous-system-physiology term deliberately: the source
    reports "significant neurologic complications" without naming specific
    deficits, so a narrower binding would manufacture precision the cohort
    text does not carry. Also deliberately left without an incoming causal
    edge: the source attributes these complications to CNS infection generally
    rather than to any one organism or mechanism this entry models, and the
    registry's CNS-infection figure (14%) aggregates Pneumocystis,
    cytomegalovirus, ECHO virus and others, so an edge from a specific node
    would name a path the literature does not.
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:20301576
    reference_title: "CD40 Ligand Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Significant neurologic complications, often the result of a central nervous system infection, are seen in 5%-15% of affected males."
    explanation: >-
      GeneReviews quantifies neurologic complications at 5-15% of affected
      males and attributes most to CNS infection.
environmental:
- name: Exposure to Cryptosporidium-contaminated water
  description: >-
    Untreated or unfiltered water and recreational water sources (pools,
    lakes, ponds) are the recognized route of Cryptosporidium acquisition in
    CD40 ligand deficiency, where the organism cannot be cleared and drives
    chronic diarrhea and sclerosing cholangitis. Avoidance is a standard
    management measure.
  exposure_term:
    preferred_term: exposure to Cryptosporidium-contaminated water
    term:
      id: ECTO:7000119
      label: exposure to contaminated water
  notes: >-
    Bound to the general contaminated-water exposure term — ECTO has no
    Cryptosporidium-specific water term, and this is the KB's established
    binding for waterborne-pathogen exposures (Giardiasis and five other
    entries use the same CURIE); preferred_term carries the organism
    specificity.
  influences_mechanisms:
  - target: Cryptosporidium-Associated Biliary Tract Injury
    environmental_effect: TRIGGERS
    description: >-
      Ingestion of contaminated water is the route by which Cryptosporidium
      reaches the gut and biliary tree; in the absence of CD40L-dependent
      macrophage licensing the infection persists and initiates the biliary
      epithelial injury this node describes.
    evidence:
    - reference: PMID:20301576
      reference_title: "CD40 Ligand Deficiency."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Areas that place the affected individual at risk of contracting Cryptosporidium including pools, lakes, ponds, or certain water sources; drinking unpurified or unfiltered water"
      explanation: >-
        Indirect: GeneReviews states the avoidance list, which encodes the
        recognized exposure route rather than reporting a cohort measurement
        of exposure-attributable disease.
  evidence:
  - reference: PMID:20301576
    reference_title: "CD40 Ligand Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Areas that place the affected individual at risk of contracting Cryptosporidium including pools, lakes, ponds, or certain water sources; drinking unpurified or unfiltered water"
    explanation: >-
      GeneReviews' agents-to-avoid guidance identifies contaminated-water
      exposure as the risk route for Cryptosporidium in this disorder.
treatments:
- name: Immunoglobulin replacement therapy
  description: >-
    Intravenous or subcutaneous immunoglobulin replacement substitutes the IgG the
    patient cannot make and is the cornerstone of non-curative management. It was
    used in 95% of patients in the largest reported cohort.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: immunoglobulin replacement therapy
    term:
      id: NCIT:C62710
      label: Immunoglobulin Therapy
  target_mechanisms:
  - target: Defective Immunoglobulin Class Switch Recombination
    treatment_effect: BYPASSES
    description: >-
      Exogenous pooled IgG supplies the switched isotype the patient's B cells
      cannot generate. It does not restore class switch recombination; it
      substitutes for its product.
    evidence:
    - reference: PMID:20301576
      reference_title: CD40 Ligand Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Ig replacement therapy (either intravenous or subcutaneous)
      explanation: >-
        GeneReviews identifies immunoglobulin replacement as treatment of
        manifestations, i.e. substitution for the missing switched isotypes.
  evidence:
  - reference: PMID:9255191
    reference_title: Clinical spectrum of X-linked hyper-IgM syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients received regular infusions of immunoglobulins.
    explanation: >-
      Documents universal use of immunoglobulin replacement in a 56-patient
      cohort.
- name: Pneumocystis jirovecii pneumonia prophylaxis
  description: >-
    Antimicrobial prophylaxis against Pneumocystis jirovecii, conventionally with
    trimethoprim-sulfamethoxazole, is standard from the time of diagnosis because
    Pneumocystis pneumonia is frequently the presenting and a potentially fatal
    infection. It was reported in 75% of patients in the largest cohort, including
    a quarter of patients who were not receiving it despite Pneumocystis having
    been their presenting illness.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: trimethoprim
      term:
        id: CHEBI:45924
        label: trimethoprim
    - preferred_term: sulfamethoxazole
      term:
        id: CHEBI:9332
        label: sulfamethoxazole
  target_phenotypes:
  - preferred_term: Pneumocystis jirovecii pneumonia
    term:
      id: HP:0020102
      label: Pneumocystis jirovecii pneumonia
  target_mechanisms:
  - target: Failed CD40-Dependent Licensing of Macrophages and Dendritic Cells
    treatment_effect: BYPASSES
    description: >-
      Chemoprophylaxis suppresses the organism rather than repairing the
      macrophage and dendritic-cell activation defect that permits it.
    evidence:
    - reference: PMID:20301576
      reference_title: CD40 Ligand Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        antimicrobial prophylaxis for opportunistic infection against Pneumocysitis
        jirovecii pneumonia
      explanation: >-
        GeneReviews prescribes antimicrobial prophylaxis against Pneumocystis, an
        intervention aimed at the pathogen rather than the underlying immune
        defect. (The cached text carries the source's misspelling of the organism
        name.)
  evidence:
  - reference: PMID:20301576
    reference_title: CD40 Ligand Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      antimicrobial prophylaxis for opportunistic infection against Pneumocysitis
      jirovecii pneumonia
    explanation: >-
      Establishes Pneumocystis prophylaxis as a standard component of management.
      (The cached text carries the source's misspelling of the organism name.)
  notes: >-
    GeneReviews does not name the prophylactic agent in the cached abstract; the
    therapeutic_agent binding to trimethoprim and sulfamethoxazole reflects
    standard practice for Pneumocystis prophylaxis and is not separately quoted
    from the cited source.
- name: Recombinant G-CSF for chronic neutropenia
  description: >-
    Recombinant granulocyte colony-stimulating factor is used for the chronic
    neutropenia of CD40 ligand deficiency. Uptake is incomplete: fewer than half
    of neutropenic patients in the largest cohort received it.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: recombinant G-CSF
      term:
        id: NCIT:C1287
        label: Recombinant Granulocyte Colony-Stimulating Factor
  target_phenotypes:
  - preferred_term: Neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  evidence:
  - reference: PMID:20301576
    reference_title: CD40 Ligand Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      recombinant granulocyte colony-stimulating factor for chronic neutropenia
    explanation: >-
      GeneReviews names recombinant G-CSF as the treatment for the chronic
      neutropenia of this disorder.
- name: Allogeneic hematopoietic cell transplantation
  description: >-
    Allogeneic HCT replaces the CD40LG-mutant hematopoietic system with donor
    cells that express functional CD40 ligand, and is the only curative treatment.
    Outcome depends heavily on timing: it should be performed before age ten years
    and before liver disease develops. In the largest cohort, overall survival did
    not differ between transplanted and non-transplanted patients across all
    diagnosis years, though transplant-associated hazard fell markedly from the
    late 1990s and survivors of transplantation had better performance scores.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Loss of Functional CD40 Ligand on Activated CD4+ T Cells
    treatment_effect: RESTORES
    description: >-
      Donor-derived T cells carry a wild-type CD40LG allele, restoring functional
      CD40 ligand expression and therefore both the B-cell help and the
      macrophage/dendritic-cell licensing arms of the mechanism.
    evidence:
    - reference: PMID:20301576
      reference_title: CD40 Ligand Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Hematopoietic stem cell transplantation (the only curative treatment
        currently available) is ideally performed before age ten years or prior to
        evidence of organ dysfunction.
      explanation: >-
        Identifies HCT as the only curative option, i.e. the only intervention
        that corrects rather than compensates for the underlying defect, and
        states the timing constraint.
  evidence:
  - reference: PMID:27697500
    reference_title: "Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No difference in overall survival was observed between patients treated
      with or without HCT (P = .671).
    explanation: >-
      Qualifies the curative claim: across all diagnosis years the largest cohort
      found no overall survival advantage for transplantation.
  - reference: PMID:27697500
    reference_title: "Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, risk associated with HCT decreased for diagnosis years 1987-1995;
      the hazard ratio was significantly less than 1 for diagnosis years
      1995-1999.
    explanation: >-
      Documents the improving risk profile of transplantation over time, which is
      the basis for continuing to offer it.
  - reference: PMID:27697500
    reference_title: "Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among patients receiving HCT, 27 (40%) had graft-versus-host disease, and
      most deaths occurred within 1 year of transplantation.
    explanation: >-
      Records the substantial transplant-related morbidity that qualifies the
      decision to transplant.
- name: Live-vaccine avoidance
  description: >-
    Live vaccines are contraindicated pending immune reconstitution: with
    failed T-cell help, attenuated vaccine strains can cause disseminated
    disease. The avoid list spans rotavirus, MMR, varicella, live attenuated
    polio, and BCG.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: live-vaccine avoidance
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Failed CD40-Dependent Licensing of Macrophages and Dendritic Cells
    treatment_effect: MODULATES
    description: >-
      Removes attenuated-pathogen exposures that the unlicensed
      macrophage/dendritic-cell compartment cannot contain.
    evidence:
    - reference: PMID:20301576
      reference_title: "CD40 Ligand Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "live vaccines such as rotavirus, MMR, varicella, live attenuated polio, and BCG"
      explanation: >-
        GeneReviews' agents-to-avoid list enumerates the live vaccines this
        behavioral treatment withholds.
  evidence:
  - reference: PMID:20301576
    reference_title: "CD40 Ligand Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "live vaccines such as rotavirus, MMR, varicella, live attenuated polio, and BCG"
    explanation: >-
      Names the live vaccines to avoid in CD40 ligand deficiency.
diagnosis:
- name: Molecular genetic testing
  description: >-
    The diagnosis is established in a male proband with the typical clinical
    and laboratory picture — recurrent and opportunistic infections with
    normal-to-elevated IgM and low IgG and IgA — by identifying a hemizygous
    pathogenic CD40LG variant.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:20301576
    reference_title: "CD40 Ligand Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of CD40 ligand deficiency is established in a male proband with typical clinical and laboratory findings and a hemizygous pathogenic variant in CD40LG identified by molecular genetic testing."
    explanation: >-
      GeneReviews states the diagnostic criterion: typical clinical and
      laboratory findings plus a hemizygous CD40LG pathogenic variant.
references:
- reference: PMID:20301576
  title: CD40 Ligand Deficiency.
  tags:
  - GeneReviews
notes: >-
  Naming and scope. This entry covers hyper-IgM syndrome type 1 specifically -
  the X-linked, CD40LG-mutant form (MONDO:0010626, OMIM 308230). It is one member
  of the broader "hyper-IgM syndrome" grouping (MONDO:0003947), which also
  includes autosomal recessive forms caused by AICDA, UNG, CD40, and others.
  Those are distinct diseases and are out of scope here.

  Classification caveat. The name is misleading about where this disorder sits
  nosologically. IUIS 2022 places CD40 ligand deficiency in Table 1 among the
  combined immunodeficiencies, not in Table 3 with the predominantly antibody
  deficiencies, because CD40L is required for macrophage and dendritic-cell
  licensing as well as for B-cell help. The opportunistic-infection profile
  (Pneumocystis, Cryptosporidium) is the clinical expression of that second arm.

  Diagnostic caveat. Only about half of patients in the US registry had frankly
  elevated serum IgM; a normal IgM does not exclude the diagnosis. IgG deficiency,
  present in all registry patients, is the more reliable laboratory finding.

  Mechanistic gap. The chronic neutropenia of CD40 ligand deficiency is well
  documented and G-CSF-responsive, but the causal path from the CD40LG lesion to
  the granulocyte defect is not established; the corresponding edge is curated as
  INDIRECT_UNKNOWN_INTERMEDIATES rather than assigned a mechanism the literature
  does not support.
📚

References & Deep Research

References

1
PMID:20301576
CD40 Ligand Deficiency.
No top-level findings curated for this source.