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hyper-IgM syndrome - Clinical Profile, Genes & Research | Kisho | Kisho

Rare Disease

hyper-IgM syndrome

MONDO:0003947

Also known as:immunodeficiency with hyper-IgMhyperimmunoglobulin M syndrome

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Overview

A primary immune deficiency disorder characterized by defective CD40 signaling; via B cells affecting class switch recombination (CSR) and somatic hypermutation.

Clinical Trials2 registered · 1 recruiting

Clinical Presentation

Built from Human Phenotype Ontology (HPO) phenotype annotations and GeneReviews clinical descriptions. Features represent findings documented across known cases — not an exhaustive list of possible symptoms.

No HPO annotations are available for this condition.

GeneReviews

Clinical Guidance

CD40 ligand deficiency, a disorder of abnormal T- and B-cell function, is characterized by low serum concentrations of immunoglobulin (Ig) G, IgA, and IgE and normal or elevated serum concentrations of IgM. CD40 ligand deficiency is due to defects or deficiencies in the CD40 ligand (CD40L) protein that affect T cell communication with B lymphocytes. Mitogen proliferation may be normal but NK- and T-cell cytotoxicity can be impaired. Antigen-specific responses are usually decreased or absent.

Diagnosis

Drawn from GeneReviews diagnostic guidelines, newborn screening panel status (RUSP), and ClinGen gene-disease validity classifications. Reflects current clinical evidence and consensus where available.

GeneReviews

Diagnostic Criteria

Suggestive Findings

CD40 ligand deficiency should be suspected in any male presenting with Pneumocystis jirovecii pneumonia, persistent Cryptosporidium diarrhea, recurrent upper- and lower-respiratory tract bacterial infections, neutropenia, or sclerosing cholangitis and associated bile duct tumors with the following laboratory abnormalities:

Absent or low serum concentrations of immunoglobulin (Ig) G and IgA

Treatment

Compiled from FDA-approved drug records, orphan drug designations, and FDA Adverse Event Reporting System (FAERS) safety data. GeneReviews management guidance is included where available.

No approved treatments are currently available for hyper-IgM syndrome. The disease remains an area of unmet medical need.

GeneReviews

Management Guidelines

No clinical practice guidelines for CD40 ligand deficiency have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CD40 ligand deficiency, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Prognosis

Based on GeneReviews surveillance recommendations, HPO phenotype frequency and severity annotations, and published prevalence estimates from Orphanet and OMIM.

GeneReviews

Surveillance Guidelines

No guidelines have been published for ongoing surveillance in individuals with CD40 ligand deficiency. presents the current recommendations of the authors. Table 5. CD40 Ligand Deficiency: Recommended Surveillance

Research Landscape

Sourced from ClinicalTrials.gov and PubMed. Publication types are classified using NLM-curated article metadata; research type breakdowns reflect the nature of published work for this disease.

2 clinical trials registered, 1 recruiting. Interventions under study include drug therapy and other interventions. Pipeline includes 1 PHASE2. Research is primarily sponsored by academic and government institutions.

34 publications have been identified in PubMed for hyper-IgM syndrome. Research spans Case Report / Case Series (50%), Basic Science / Preclinical (18%), and Review / Meta-Analysis (15%).

Research Type	Count	% of Total
Patient case studies	17

Data assembled from 4 of 12 sources · Last updated Sep 18, 2026, 9:11 PM UTC

MONDOHPOClinicalTrials.govFDAPubMedHGNCClinVarClinGenGeneReviewsOrphanetOMIMRUSP

Medical References

Questions for Your Care Team

→Are any of the 2 active clinical trials a good fit for my situation?
→Are there specialists or centers of excellence for this condition in my area?
→Is there a patient registry I should consider joining?

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GeneReviews

Differential Diagnosis

Genetic disorders of interest in the differential diagnosis of CD40 ligand deficiency are listed in . Table 2. CD40 Ligand Deficiency: Differential Diagnosis

Gene(s)	Disorder1	MOI	Features of Disorder
Overlapping w/CD40 ligand deficiency	Distinguishing from CD40 ligand deficiency AICDA(AID)	AID deficiency (OMIM 605258)	AR
CD40	CD40 deficiency (OMIM 606843)	AR	Clinically indistinguishable w/recurrent bacterial infections opportunistic infections w/Pneumocystis jirovecii, Cryptosporidium, sclerosing cholangitis5
UNG	UNG deficiency (OMIM 608106)	AR	Recurrent bacterial infections
MSH6	MSH6 deficiency (constitutional mismatch repair deficiency; see Lynch Syndrome)	AR	or normal IgM, or normal IgG, normal B cell counts, normal memory B cells w/ class-switched B cells
PMS2	PMS2 deficiency (constitutional mismatch repair deficiency; see Lynch Syndrome)	AR	Recurrent infections; or normal IgM w/ IgG IgA; Normal B cell counts but memory B cells
TNFRSF13C	Common variable immunodeficiency (CVID; OMIM PS607594)	ARAD	Recurrent sinopulmonary infections; immunoglobulins incl IgG IgA; CD40L protein expression may be .
May be assoc w/ number of total T cells or T-cell function6 ADAAK2CD3DCD3ECD247CORO1ADCLRE1CIL2RGIL7RJAK3PRKDCPTPRCRAG1RAG27	Severe combined immunodeficiency (SCID; see X-Linked SCID Adenosine Deaminase Deficiency)	ARXL	All SCIDs must be considered in infants presenting w/Pneumocystis jirovecii pneumonia.

Source: GeneReviews — "CD40 Ligand Deficiency"

Kisho

hyper-IgM syndrome

Overview

Clinical Presentation

Clinical Guidance

Diagnosis

Diagnostic Criteria

Suggestive Findings

Treatment

Management Guidelines

Evaluations Following Initial Diagnosis

Prognosis

Surveillance Guidelines

Research Landscape

Medical References

Questions for Your Care Team

Questions for Your Care Team

Males

Establishing the Diagnosis

Differential Diagnosis

Immunology

Pulmonary

Gastrointestinal

Hepatobiliary

Transplantation

Genetic counseling

Clinical Guidance

Therapies Under Investigation

Clinical Trials

Recent Publications

hyper-IgM syndrome

Overview

Clinical Presentation

Clinical Guidance

Diagnosis

Diagnostic Criteria

Suggestive Findings

Treatment

Management Guidelines

Evaluations Following Initial Diagnosis

Prognosis

Surveillance Guidelines

Research Landscape

Medical References

Subtypes

Related Diseases

Questions for Your Care Team

Questions for Your Care Team

Males

Establishing the Diagnosis

Differential Diagnosis

Immunology

Pulmonary

Gastrointestinal

Hepatobiliary

Transplantation

Genetic counseling

Clinical Guidance

Therapies Under Investigation

Clinical Trials

Recent Publications