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CD40 Ligand Deficiency

Synonyms: CD154 Deficiency, HIGM1, X-Linked Hyper-IgM Immunodeficiency (XHIGM), X-Linked Hyper IgM Syndrome

, MD and , MD.

Author Information and Affiliations

Initial Posting: ; Last Update: December 4, 2025.

Estimated reading time: 35 minutes

Summary

Clinical characteristics.

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 with normal or elevated serum concentrations of IgM. Mitogen proliferation may be normal, but NK- and T-cell cytotoxicity can be impaired. Antigen-specific responses are usually decreased or absent. Total numbers of B cells are normal but there is a marked reduction of class-switched memory B cells. Defective oxidative burst of both neutrophils and macrophages has been reported. The range of clinical findings varies, even within the same family. More than 50% of males with CD40 ligand deficiency develop symptoms by age one year, and more than 90% are symptomatic by age four years. CD40 ligand deficiency usually presents in infancy with recurrent upper- and lower-respiratory tract bacterial infections, opportunistic infections including Pneumocystis jirovecii pneumonia, and recurrent or protracted diarrhea that can be infectious or noninfectious and is associated with faltering growth. Neutropenia is common; thrombocytopenia and anemia are less commonly seen. 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. Significant neurologic complications, often the result of a central nervous system infection, are seen in 5%-15% of affected males. 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.

Diagnosis/testing.

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.

Management.

Targeted therapy: Hematopoietic stem cell transplantation (the only curative treatment currently available) is ideally performed before age ten years or prior to evidence of organ dysfunction.

Treatment of manifestations: Ig replacement therapy (either intravenous or subcutaneous); appropriate antimicrobial therapy for acute infections; antimicrobial prophylaxis for opportunistic infection against Pneumocysitis jirovecii pneumonia; recombinant granulocyte colony-stimulating factor for chronic neutropenia; immunosuppressants for autoimmune disorders.

Agents/circumstances to avoid: Areas that place the affected individual at risk of contracting Cryptosporidium including pools, lakes, ponds, or certain water sources; drinking unpurified or unfiltered water; live vaccines such as rotavirus, MMR, varicella, live attenuated polio, and BCG.

Surveillance: At least annually, complete blood count with differential to monitor for cytopenias, testing of IgG levels and lymphocyte subpopulations, and pulmonary function tests after age seven years. Regular assessment of liver function, with consideration of abdominal imaging, and polymerase chain reaction-based testing for the presence of enteric pathogens including Cryptosporidium. Monitor growth and general health with a low threshold for lymph node biopsy given elevated oncologic risk.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of newborn at-risk male relatives of an affected individual to allow early diagnosis and prompt initiation of treatment and prevention of infections.

Genetic counseling.

CD40 ligand deficiency is inherited in an X-linked manner. The risk to sibs of a male proband depends on the genetic status of the mother. If the mother of the proband has a pathogenic variant in CD40LG, the chance of the mother transmitting it in each pregnancy is 50%: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes. Heterozygous females are typically asymptomatic but may have a range of clinical manifestations depending on X-chromosome inactivation. Once the CD40LG pathogenic variant has been identified in an affected family member, heterozygote testing for at-risk female relatives and prenatal/preimplantation genetic testing for CD40 ligand deficiency are possible.

Diagnosis

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
  • Normal or elevated serum concentrations of IgM
  • Normal number and distribution of T, B, and NK lymphocyte subsets
  • Normal T-cell proliferation in response to mitogens
  • Decreased expression of CD40 ligand (CD40L) on the surface of activated CD4 cells (not universal)

Establishing the Diagnosis

The diagnosis of CD40 ligand deficiency is established in a male proband with typical clinical and laboratory findings and a hemizygous pathogenic (or likely pathogenic) variant in CD40LG identified by molecular genetic testing (see Table 1).

The diagnosis of CD40 ligand deficiency is extremely rare in females, as heterozygous females are typically asymptomatic unless there is skewed X-chromosome inactivation (see Clinical Description, Heterozygous Females).

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a hemizygous CD40LG variant of uncertain significance does not establish or rule out the diagnosis. (3) Functional analysis by flow cytometry (see Additional Confirmatory Testing) and advanced computation analysis [Pazhanisamy et al 2023] have been used to clarify variants of uncertain significance.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of CD40 ligand deficiency syndrome, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.

  • Single-gene testing. Sequence analysis of CD40LG can detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
  • An immunodeficiency multigene panel that includes CD40LG and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype is indistinguishable from many other inherited disorders characterized by immunodeficiency, comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

CD40 Ligand Deficiency: Molecular Genetic Testing

Gene 1MethodProportion of Pathogenic Variants 2 Identified by Method
CD40LG Sequence analysis 385%-95% 4
Gene-targeted deletion/duplication analysis 55%-15% 4
1.
2.

See Molecular Genetics for information on variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Lee et al [2005], Prasad et al [2005], Cabral-Marques et al [2014], Leven et al [2016], França et al [2022], Banday et al [2023], Pazhanisamy et al [2023], and data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Additional Confirmatory Testing

Measurement by flow cytometry of CD40L protein expression after in vitro stimulation of T cells. In the resting state, only a low level of CD40L expression is seen on normal CD4+ T cells. After in vitro stimulation:

  • Individuals with CD40 ligand deficiency do not show increased expression of CD40L in CD4+ T cells.
  • Controls show increased expression (upregulation) of CD40L in the majority of CD4+ T cells, which is determined by monoclonal anti-human IgG to CD40L.
    Note: Infants younger than age six months may not express normal amounts of CD40L [Gilmour et al 2003].

Note: This testing should not be used as the only diagnostic test when CD40 ligand deficiency is suspected. Up to 32% of individuals with CD40 ligand deficiency may have normal extracellular domains of CD40L detected by this laboratory measure, which uses CD40L binding. In CD40 ligand deficiency the intracellular signaling pathway from CD40L is nonfunctional, and thus genetic testing is required for diagnosis [Lee et al 2005].

Clinical Characteristics

Clinical Description

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.

Males

The range of clinical findings varies, even within the same family. More than 50% of males with CD40 ligand deficiency develop symptoms by age one year, and more than 90% are symptomatic by age four years [Winkelstein et al 2003, França et al 2022, Banday et al 2023].

Presentation. CD40 ligand deficiency usually presents in infancy with recurrent upper- and lower-respiratory tract bacterial infections, opportunistic infections including Pneumocystis jirovecii pneumonia, and recurrent or protracted diarrhea that can be infectious or noninfectious and is associated with poor weight gain. Neutropenia is common; thrombocytopenia and anemia are also (though less commonly) seen. 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 [Lee et al 2005, Leven et al 2016, de la Morena et al 2017, Banday et al 2023].

Infection. Infectious concerns are often the initial presentation for individuals with CD40 ligand deficiency [França et al 2022]. Increased susceptibility to recurrent bacterial infections consisting of upper- and lower-respiratory tract infections is seen in 75%-80% of affected individuals (typically Streptococcus pneumoniae and Pseudomonas), otitis in 42%, and sinusitis in 36% [Leven et al 2016]. Susceptibility to invasive fungal infections (primarily Candida, Cryptococcus, and Histoplasma) is also increased. Boys with CD40 ligand deficiency are also at significant risk for opportunistic infections from Pneumocystis jirovecii (formerly known as Pneumocystis carinii) and gastrointestinal (GI) infection from Cryptosporidium parvum.

Pneumocystis jirovecii pneumonia is the first clinical symptom of CD40 ligand deficiency in more than 40% of infants with the disorder and is shown as the pathogenic organism in roughly 30% of individuals with CD40 ligand deficiency [Levy et al 1997, Lee et al 2005, de la Morena 2016, Leven et al 2016]. It accounts for 10%-15% of the mortality associated with CD40 ligand deficiency [Levy et al 1997, Winkelstein et al 2003, França et al 2022].

The presentation of CD40 ligand deficiency across different ethnic backgrounds and in different countries has been shown to be consistent in the infectious organisms present across all individuals with CD40 ligand deficiency; however, individuals are also at risk for the pathogens that are endemic to their specific region [Cabral-Marques et al 2014, Wang et al 2014, Rawat et al 2018, Tafakori Delbari et al 2019].

GI manifestations. Chronic diarrhea is the most frequent GI complication of CD40 ligand deficiency, occurring in approximately 20%-30% of affected males [Winkelstein et al 2003, Leven et al 2016, Banday et al 2023]. Recurrent or protracted diarrhea may result from infection with Cryptosporidium parvum or other microorganisms; however, in at least 50% of males with recurrent or protracted diarrhea, no infectious agent can be detected [Winkelstein et al 2003, Leven et al 2016]. Poor growth is a serious complication of chronic diarrhea. Additionally, aphthous ulcers can be present in 21% of affected males [Leven et al 2016]. Intramural intestinal hematomas have been reported [Chandola et al 2024].

Hematologic and immunologic abnormalities. Neutropenia occurs in roughly 45%-50% of males with CD40 ligand deficiency, with anemia seen in 10%-15% and thrombocytopenia in 5% [Levy et al 1997, Lee et al 2005, Cabral-Marques et al 2014, Leven et al 2016]. Severe aplastic anemia secondary to parvovirus B19 has been found, but was reported as the initial finding in individuals with a milder phenotype and later age of presentation [Seyama et al 1998, Leven et al 2016, de la Morena 2016].

The total number of B cells in circulation is normal, however, there is a marked reduction of class-switched memory B cells [Agematsu et al 1998, Banday et al 2023]. Furthermore, some individuals with CD40 ligand deficiency may show progressive loss of B and NK cell populations over time, which can contribute to the increased morbidity [Lougaris et al 2018]. Defective oxidative burst of both neutrophils and macrophages have been reported – the result of impaired interaction between neutrophils, macrophages and, activated T lymphocytes through CD40 and CD40L [Cabral-Marques et al 2018].

CD40 ligand deficiency has been seen with anti-phospholipid syndrome typically associated with other infectious sequelae [Phan et al 2021].

Histologic examination of lymph nodes shows absence of germinal center formation.

Neurologic involvement. Significant neurologic complications, both infectious and noninfectious and including progressive cognitive decline, are seen in 5%-15% of males with CD40 ligand deficiency [Levy et al 1997, Bishu et al 2009, Cabral-Marques et al 2014, Leven et al 2016, de la Morena et al 2017]. However, in at least half of affected individuals with evidence of neurodegeneration a specific infectious agent cannot be isolated except in those with acute fulminant encephalopathy [Winkelstein et al 2003]. Additionally, involuntary hyperkinetic or chorea movements have been described in individuals with CD40 ligand deficiency [Coulter et al 2020, Škorvánek et al 2022].

Hepatobiliary disease. Liver disease, a serious complication of CD40 ligand deficiency, historically was observed in more than 80% of affected males by age 20 years [Hayward et al 1997, Grunebaum & Avitzur 2019], but with adequate screening and treatment of Cryptosporidium infections, that number may now be lower [Leven et al 2016]. Liver disease and infectious etiologies contribute to the highest mortality rates, although liver disease can be prevented with early hematopoietic stem cell transplantation (HSCT) [Azzu et al 2018]. Hepatitis and sclerosing cholangitis occur in 6%-10% of affected individuals. CD40, the receptor to which CD40L binds, has been shown to be expressed on bile duct epithelium; chronic infection with Cryptosporidium or other inflammatory changes are thought to contribute to sclerosing cholangitis and malignant transformation [Hayward et al 1997, de la Morena 2016, Leven et al 2016].

Oncologic disease. Malignancies occur in approximately 5% of individuals with CD40 ligand deficiency and are associated with high mortality [Winkelstein et al 2003, de la Morena 2016, Leven et al 2016]. Malignancies reported in individuals with CD40 ligand deficiency include neuroendocrine tumors of the GI tract, colon cancer, bile duct carcinomas, hepatocellular carcinomas, hepatoma, adrenal adenomas, and adenocarcinomas of the liver and gall bladder [Hayward et al 1997, Winkelstein et al 2003, Filipovich & Gross 2004, Erdos et al 2008, Leven et al 2016, Nicolaides & de la Morena 2017].

Males with CD40 ligand deficiency are also at increased risk for acute myelogenous leukemia and lymphoma, particularly Hodgkin disease associated with Epstein-Barr virus infection [Filipovich & Gross 2004].

Other (rarely) reported complications of CD40 ligand deficiency include autoimmune retinopathy, cutaneous granulomas, pulmonary alveolar proteinosis, and disseminated cutaneous warts [Gallerani et al 2004, Schuster et al 2005, Ho et al 2018, Xu et al 2023].

Life span. The current reported median survival time from diagnosis is 25 years [de la Morena et al 2017]. Pneumocystis jirovecii pneumonia in infancy, liver disease, and malignancies in adolescence or young adulthood are important contributors to mortality [Levy et al 1997, Winkelstein et al 2003, de la Morena 2016, Leven et al 2016].

HSCT is the only curative therapy available for CD40 ligand deficiency. In a retrospective series of 130 affected individuals who had undergone HSCT, overall survival, event-free survival, and disease-free survival rates were 78.2%, 58.1%, and 72.3%, respectively, five years post HSCT [Ferrua et al 2019, Uygun et al 2020, Wang et al 2021, Chandrakasan et al 2022].

Heterozygous Females

Typically, heterozygous females are asymptomatic but on functional activation testing of CD4+ T lymphocytes may have reduced expression of CD40L. Those females with more dramatic reduction in circulating lymphocytes with CD40L due to skewed X-chromosome inactivation can have a presentation similar to CD40 ligand deficiency or common variable immunodeficiency [Hollenbaugh et al 1994, de Saint Basile et al 1999, Lobo et al 2002].

Genotype-Phenotype Correlations

Males with CD40 ligand deficiency show remarkable variability in clinical symptoms.

No specific genotype-phenotype correlations for CD40LG have been identified [Notarangelo & Hayward 2000, Prasad et al 2005]. However, the p.Thr254Met and p.Arg11Ter pathogenic variants have been reported in unrelated families with milder and later-onset disease [Seyama et al 1998, Lee et al 2005]. Whether or not this is a true association needs to be evaluated with study of additional families with these pathogenic variants.

Prevalence

The estimated prevalence of hyper IgM syndrome is 1:1,000,000 males [Winkelstein et al 2003] with nearly 75% of these individuals having CD40 ligand deficiency [Leven et al 2016].

Differential Diagnosis

Genetic disorders of interest in the differential diagnosis of CD40 ligand deficiency are listed in Table 2.

Table 2.

CD40 Ligand Deficiency: Differential Diagnosis

Gene(s)Disorder 1MOIFeatures of Disorder
Overlapping w/CD40 ligand deficiencyDistinguishing from CD40 ligand deficiency
AICDA
(AID)		AID deficiency (OMIM 605258)ARAbnormalities in B-cell differentiation leading to recurrent URT, LRT, & GI infections
  • Opportunistic infections are rare.
  • Lymphoid hyperplasia is common, incl hepatomegaly, splenomegaly, giant germinal centers, & follicular hyperplasia.
  • Autoimmunity w/hemolytic anemia is more common. 4
  • Note: Clinical course is milder in AD AID deficiency than in AR AID deficiency. 3
AD 2
  • Recurrent URT & LRT infections
  • ↓ production of IgG; abnormalities in B-cell differentiation 3
CD40 CD40 deficiency (OMIM 606843)ARClinically indistinguishable w/recurrent bacterial infections & opportunistic infections w/Pneumocystis jirovecii, Cryptosporidium, & sclerosing cholangitis 5Clinically indistinguishable 5
UNG UNG deficiency (OMIM 608106)ARRecurrent bacterial infectionsUNG deficiency resembles AID deficiency in the ↑ in lymphoid hyperplasia compared to CD40 ligand deficiency. 3
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
  • No recurrent infections
  • ↑ risk for cancer incl colorectal cancer & cancer of small intestine
  • Café au lait macules
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
  • ↑ risk for cancer incl colorectal cancer & cancer of small intestine
  • Café au lait macules
CD19
CD81
CR2
ICOS
IKZF1
IL21
IRF2BP2
LRBA
MS4A1
NFKB1
NFKB2
SEC61A1
TNFRSF13B
TNFRSF13C 		Common variable immunodeficiency (CVID; OMIM PS607594)AR
AD
  • Recurrent sinopulmonary infections
  • ↓ immunoglobulins incl IgG & IgA
  • CD40L protein expression may be ↓.
  • May be assoc w/↓ number of total T cells or ↓ T-cell function 6
ADA
AK2
CD3D
CD3E
CD247
CORO1A
DCLRE1C
IL2RG
IL7R
JAK3
PRKDC
PTPRC
RAG1
RAG2 7		Severe combined immunodeficiency (SCID; see X-Linked SCID & Adenosine Deaminase Deficiency)AR
XL		All SCIDs must be considered in infants presenting w/Pneumocystis jirovecii pneumonia.
  • Most forms of SCID present w/absent T-cell function, quantitative abnormalities of T lymphocyte populations, & markedly ↓ mitogen function.
  • Hypomorphic RAG2 variants were reported in a male w/clinical & immunologic studies suggestive of HIGMS. 8
BLNK
BTK
CD79A
CD79B
IGHM
IGLL1
LRRC8A
PIK3R1
SH3KBP1 (AGMX2)
SLC39A7
SPI1
TCF3 9		Agammaglobulinemia
(OMIM PS601495; see X-Linked Agammaglobulinemia [XLA])		AR
AD
XL		XLA typically presents in early childhood w/recurrent bacterial infections.Most persons w/agammaglobulinemia lack circulating B cells.
IKBKG
(NEMO)		EDA-ID due to NEMO/IKBKG deficiency (ectodermal dysplasia, immune deficiency; OMIM 300291)XL
  • Serious infections, incl opportunistic infections, are a common complication at any age.
  • Variable Igs from agammaglobulinemia to normal or ↑ IgM, ↓ IgG, & low/↑ IgA w/↓ memory B cells
  • Generally assoc w/hypohidrotic ectodermal dysplasia 10
  • Invasive disease by MRSA & MSSA; osteopetrosis, lymphedema; conical-shaped teeth
PIK3CD
PIK3R1 		Activated PI3K delta syndrome AD
  • Recurrent infections w/Streptococcus pneumoniae or Haemophilus influenzae
  • Chronic lung disease
  • ↑ IgM, ↓/normal IgG/IgA
  • ↓ class-switched memory B cells
  • Lymphoid hyperplasia
  • Lymphopenia, ↓ T/B cell counts
  • Severe response to herpes family virus (EBV, CMV, HSV, VZV)
ATM Ataxia-telangiectasia AR
  • Recurrent URT/LRT infections, malignancy
  • Normal/↑ IgM, normal to ↓ IgG/IgA, normal to ↓ T/B cells
  • Ataxia, telangiectasias, hypotonia, dysarthria, radiosensitivity
  • Lymphopenia, ↑ AFP, variable mitogen & antigen response
NBN Nijmegen breakage syndrome AR
  • Recurrent URT/LRT infections, malignancy, autoimmune conditions (primarily hemolytic anemia)
  • Variable Igs w/agammaglobulinemia to ↓ IgG/IgA & normal/↑ IgM
Microcephaly, facial features, short stature, hyperpigmented or hypopigmented macules, radiosensitivity
INO80 INO80 deficiency 11 (OMIM 610169)AR
  • Recurrent bacterial infections
  • COPD
  • ↓ IgG & IgA
  • ↓ class-switched memory B cells
Normal CD40L expression & no CD40LG pathogenic variant

AD = autosomal dominant; AFP = alpha-fetoprotein; AR = autosomal recessive; CD40L = CD40 ligand; CMV = cytomegalovirus; COPD = chronic obstructive pulmonary disease; EBV = Epstein-Barr virus; GI = gastrointestinal; HIGMS = hyper IgM syndrome; HSV = herpes simplex virus; Ig = immunoglobulin; LRT = lower-respiratory tract; MOI = mode of inheritance; MRSA = methicillin-resistant Staphylococcus aureus; MSSA = methicillin-susceptible Staphylococcus aureus; URT = upper-respiratory tract; VZV = varicella-zoster virus; XL = X-linked

1.
2.

An autosomal dominant form of hyper IgM syndrome has been reported in four unrelated families with an identical pathogenic nonsense variant (NM_020661​.2:p.Arg190Ter) in AICDA [Durandy et al 2005].

3.
4.
5.
6.
7.

A growing list of rare causes of SCID-like phenotypes include pathogenic variants in the following additional genes: CD3G, CD8A, CHD7, CIITA, DOCK8, FOXN1, LCK, LIG4, MTHFD1, NHEJ1, ORAI1, PGM3, PNP, PRKDC, RFXANK (RFX-B), RFX5, RFXAP, RMRP, SLC46A1, STIM1, TBX1, TTC7A, and ZAP70.

8.
9.
10.
11.

The differential diagnosis of CD40 ligand deficiency also includes the following disorders:

  • HIV infection. Infection with HIV should be considered in any infant presenting with Pneumocystis jirovecii pneumonia.
  • Transient hypogammaglobulinemia of infancy is characterized by reduced antibody production including immunoglobulin (Ig) G and IgM at a young age followed by progressively normalizing antibody production, normal growth patterns, and lack of opportunistic infections. Neonates and young infants may have diminished CD40L expression that improves with time [Justiz-Vaillant et al 2023].

Management

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 in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

CD40 Ligand Deficiency: Recommended Evaluations Following Initial Diagnosis

System/ConcernEvaluationComment
Hematology/
Immunology
  • CBC w/differential
  • IgG levels
  • T, B, & NK cell numbers
For evidence of cytopenias
Pulmonary Baseline chest radiograph & pulmonary function testingFor chronic lung changes due to infection; if present, consider pulmonology eval.
Gastrointestinal PCR-based testing of stoolsFor presence of Cryptosporodium or other enteric pathogens; if present, partner w/gastroenterologist.
Nutritional assessment
Hepatobiliary Baseline liver function testing & liver / biliary tree ultrasoundFor evidence of hepatocyte dysfunction & developing biliary dilatation
Transplantation All affected persons should be offered HLA typing at diagnosis.For consideration of HSCT
Genetic counseling By genetics professionals 1To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of CD40 ligand deficiency to facilitate medical & personal decision making
Family support
& resources 		By clinicians, wider care team, & family support organizationsAssessment of family & social structure to determine need for:

CBC = complete blood count; HLA = human leukocyte antigen; HSCT = hematopoietic stem cell transplant; Ig = immunoglobulin; PCR = polymerase chain reaction

1.

Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

Treatment of Manifestations

For a concise summary of current clinical management practices in hyper immunoglobulin (Ig) M syndromes, see Davies & Thrasher [2010] and de la Morena et al [2017].

Targeted Therapy

In GeneReviews, a targeted therapy is one that addresses the specific underlying mechanism of disease causation (regardless of whether the therapy is significantly efficacious for one or more manifestation of the genetic condition); would otherwise not be considered without knowledge of the underlying genetic cause of the condition; or could lead to a cure. —ED

Hematopoietic stem cell transplant (HSCT). Currently HSCT is the only curative therapy available for CD40 ligand deficiency. Best outcomes are reported for those individuals transplanted before age ten years and without evidence of end-stage organ damage, especially liver disease [de la Morena et al 2017, Ferrua et al 2019, Uygun et al 2020, Wang et al 2021, Banday et al 2023]. Myeloablative conditioning regimens result in better survival [Carruthers et al 2022]; mismatched-related-donor and matched-unrelated-donor transplants were associated with increased morbidity compared to matched-sib donors. Approximately 15% of individuals may reject the graft (mainly after matched-unrelated transplant and reduced-intensity conditioning) and require a second or third transplant. In one series, of 130 transplanted individuals with CD40 ligand deficiency, one third required ongoing Ig replacement five years after transplantation [Ferrua et al 2019, Chandrakasan et al 2022].

Note: Liver transplantation has been performed successfully for end-stage liver disease but for best outcome requires concomitant HSCT be performed following the liver allograft [Bucciol et al 2019].

Supportive Care

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4).

Table 4.

CD40 Ligand Deficiency: Treatment of Manifestations

Manifestation/
Concern		TreatmentConsiderations/Other
Recurrent
infections
  • Ig replacement w/IV or subcutaneous Ig starting at diagnosis
  • Initial dosing for IgG replacement: 0.4-0.6 g/kg every 3-4 wks for IV, or ≥100 mg/kg dose weekly for subcutaneous Ig.
  • Titrate IgG levels as for primary antibody deficiency syndromes.
  • Prophylactic antibiotics against opportunistic infections incl Pneumocystis jirovecii
  • Institute appropriate antimicrobial therapy for acute infections.
  • Aggressively evaluate pulmonary infections (incl use of diagnostic bronchoalveolar lavage) to define specific etiology.
  • Prevention of infections 1
Discussion re prophylactic use of azithromycin or nitazoxanide for all affected persons for prevention of Crypstosporidium is ongoing. While not standard of care, it should be considered for those living in / traveling to an area w/↑ Cryptosporidium rates.
Immunodeficiency Only current curative treatment is HSCT, preferably at age <10 yrs.Modified conditioning regimens may be needed in those w/preexisting liver disease, & liver transplant along w/HSCT may be required.
Chronic
neutropenia 		Recombinant G-CSF
Malnutrition &
poor growth 		Total parenteral nutrition & consultation w/clinical dietary nutritionist may be required to optimize caloric intake.
Sclerosing
cholangitis 		Some males w/end-stage sclerosing cholangitis have been treated successfully w/orthotopic liver transplantation closely assoc w/allogeneic HSCT. Infectious etiologies need to be pursued & treated prior to transplantation.
Autoimmune
disorders 		Treatment of autoimmune disorders usually involves judicious use of immunosuppressants tailored to person's diagnosis.
Cancer Treatment should follow standard protocols/therapies for individual cancers in conjunction w/immunologist.

G-CSF = granulocyte colony-stimulating factor; HSCT = hematopoietic stem cell transplantation; Ig = immunoglobulin

1.

The following methods are used to prevent infection:
Antibiotic prophylaxis. Prophylaxis for pneumonia secondary to Pneumocystis jirovecii is indicated for all children with CD40 ligand deficiency due to the high risk of developing Pneumocystis jirovecii pneumonia during the first two years of life. There is no standard-of-care approach established for duration of Pneumocystis jirovecii pneumonia prophylaxis. However, individuals with CD40 ligand deficiency who develop Pneumocystis jirovecii pneumonia after age two years should continue prophylaxis for life or until after HSCT transplant when normal immune function is established. Typical prophylaxis is trimethoprim-sulfamethoxazole orally, pentamidine by intravenous or inhalation therapy, dapsone, and atovaquone.
Immunoglobulin (either subcutaneous or intravenous). Immunoglobulin (Ig) replacement should be considered at the time of diagnosis, as individuals with CD40 ligand deficiency cannot generate antibodies to encapsulated bacteria naturally and are at risk for overwhelming infection from these organisms. IgG replacement is a highly purified blood derivative (a combination of many specific antimicrobial antibodies) that is typically given every three to four weeks or can be given subcutaneously, usually on a weekly basis.
Additional antibiotic prophylaxis should be evaluated on a case-by-case basis; Cryptosporidum prophylaxis is not yet standardized.
Routine childhood immunizations (killed vaccines) may be safely administered but do not preclude the need for Ig replacement. Live vaccines (e.g., rotavirus, MMR, varicella, live attenuated polio, and BCG) should not be given to individuals with CD40 ligand deficiency.
Only boiled and/or filtered water should be ingested. Avoid swimming in non-chlorinated pools. Avoid swimming in lakes and ponds. Children should avoid water parks and farm animals.

Surveillance

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

Table 5.

CD40 Ligand Deficiency: Recommended Surveillance

System/ConcernEvaluationFrequency
Hematology CBC w/differential to monitor for cytopeniasAt least every 6-12 mos if stable or w/any change in clinical status
Immunology IgG levels
  • Depends on time needed to achieve adequate IgG levels; similar to those w/primary antibody deficiency syndromes
  • Adults: at least annually
Lymphocyte subpopulations: T, B, & NK cell numbersConsider annually in nontransplanted adolescents & adults given progressive T, B, & NK loss over time.
CD40L expression in activated T cellsAt least annually in those who have had HSCT, or if any change in clinical status
Pulmonary Pulmonary function testsAnnually for those age >7 yrs or if change in clinical status
Chest radiograph w/follow up of pulmonary infiltrates w/high-res CT scanAs clinically indicated
Gastrointestinal PCR-based testing of stools for infectious etiologiesAt least every 6 mos or if diarrhea is present or exposure occurs
Liver function tests
  • Children: at least every 4-6 mos or if change in clinical status
  • Adults: at least 1-2x/yr or if change in clinical status
Liver ultrasound≥1x/yr or if change in clinical status
  • Monitor growth in children.
  • Measure weight in adolescents & adults.
  • Children: at every visit; at least every 4-6 mos
  • Adolescents/adults: at least 2x/yr
  • If any change in clinical status
Oncology Physical exam w/low threshold for lymph node biopsy
  • Children: at least every 4-6 mos
  • Adolescents/adults: at least 1-2x/yr

CBC = complete blood count; HSCT = hematopoietic stem cell transplantation; Ig = immunoglobulin; PCR = polymerase chain reaction

Agents/Circumstances to Avoid

Avoid areas that place the individual at risk of contracting Cryptosporidium including pools, lakes, ponds, or certain water sources. Avoid drinking unpurified or unfiltered water.

Live vaccines such as rotavirus, MMR (measles, mumps, and rubella), varicella, live attenuated polio, and BCG (bacillus Calmette-Guérin for tuberculosis) should not be given to individuals with CD40 ligand deficiency.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of newborn at-risk male relatives of an affected individual to allow early diagnosis and prompt initiation of treatment and prevention of infections.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

CD40 ligand deficiency is inherited in an X-linked manner.

Risk to Family Members

Parents of a male proband

  • The father of an affected male will not have the disorder nor will he be hemizygous for the CD40LG pathogenic variant; therefore, he does not require further evaluation/testing.
  • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the CD40LG pathogenic variant cannot be detected in her leukocyte DNA, she most likely has gonadal mosaicism.
  • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a de novo CD40LG pathogenic variant (in which case the mother is not a heterozygote), or the mother may have somatic/gonadal mosaicism. Approximately one third of males who represent simplex cases have the disorder as the result of a de novo CD40LG pathogenic variant.
  • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother:

Offspring of a male proband. Affected males transmit the CD40LG pathogenic variant to all of their daughters and none of their sons.

Other family members. If the mother of a male proband is heterozygous for a CD40LG pathogenic variant, maternally related relatives may be at risk of having a CD40LG pathogenic variant.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo pathogenic variant arose, information that could help determine genetic risk status of the extended family.

Heterozygote Detection

Molecular genetic testing to identify female heterozygotes requires prior identification of the CD40LG pathogenic variant in the family.

Note: Analysis of CD40 ligand (CD40L) expression by flow cytometry may be helpful in identifying heterozygotes. Typically, heterozygous females are asymptomatic but on functional activation testing of CD4+ T lymphocytes may have reduced expression of CD40L.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.

Prenatal Testing and Preimplantation Genetic Testing

Once the CD40LG pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for CD40 ligand deficiency are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Hyper IgM Foundation
  • Immune Deficiency Foundation
    Phone: 800-296-4433
    Fax: 410-321-9165
    Email: idf@primaryimmune.org
  • ImmUnity Canada
    Canada
    Phone: 250-381-7134; 877 -607­-2476
    Email: info@immunitycanada.org
  • Jeffrey Modell Foundation/National Primary Immunodeficiency Resource Center
    Email: info@jmfworld.org
  • European Society for Immunodeficiencies (ESID) Registry
    Email: esid-registry@uniklinik-freiburg.de
  • United States Immunodeficiency Network (USIDNET) Registry
    Email: contact@usidnet.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

CD40 Ligand Deficiency: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
CD40LG Xq26​.3 CD40 ligand CD40LG @ LOVD
CCHMC - Human Genetics Mutation Database (CD40LG)
CD40Lbase: Mutation registry for X-linked Hyper-IgM syndrome (CD40LG) 		CD40LG CD40LG

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for CD40 Ligand Deficiency (View All in OMIM)

300386CD40 LIGAND; CD40LG
308230IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1; HIGM1

Molecular Pathogenesis

CD40LG encodes CD40 ligand (CD40L), which is a small, 261-amino-acid transmembrane protein. The protein has three functional domains: an intracytoplasmic domain, a transmembrane domain, and an extracellular domain that shares considerable sequence homology to tumor necrosis factor alpha. CD40L, expressed primarily on CD4+ T cells, binds to CD40 on the surface of B cells to promote immunoglobulin isotype switching in B lymphocytes. CD40L also plays an important role in T-cell function, particularly in the interaction with monocyte-derived antigen-presenting cells [Jain et al 1999].

Pathogenic variants in CD40LG lead to changes in the amino acid sequence, abnormal splicing of the protein, premature truncation of the protein, or complete absence of CD40L. Persons with pathogenic variants in CD40LG are unable to make high-affinity functional antibodies and cytokines, resulting in a high incidence of opportunistic infections.

Mechanism of disease causation. CD40 ligand deficiency is caused by loss of function as evidenced by multiple partial- or whole-gene deletion and gross-insertion pathogenic variants of CD40LG. Missense pathogenic variants may affect core packaging, prevent binding to CD40L, or affect trimer formation [Seyama et al 1998].

CD40LG-specific laboratory technical considerations. The presence of CD40L based on flow cytometry alone does not rule out a diagnosis of CD40 ligand deficiency [Lee et al 2005].

Flow cytometry using anti-CD40L monoclonal antibodies can confirm the diagnosis of CD40 ligand deficiency in some affected individuals:

  • Those who produce no CD40L on the surface of CD4+ cells due to missense or frameshift variants
  • Those who produce an altered protein structure of CD40L, preventing anti-CD40L antibody binding

Anti-CD40L antibody testing will not identify affected individuals with pathogenic variants in the intracellular tail or those producing reduced amounts of normal CD40L.

Table 6.

CD40LG Pathogenic Variants Referenced in This GeneReview

Reference SequencesDNA Nucleotide ChangePredicted Protein ChangeComment [Reference]
NM_000074​.2
NP_000065​.1 		c.31C>Tp.Arg11TerAssoc w/milder clinical phenotype [Seyama et al 1998, Lee et al 2005]
c.761C>Tp.Thr254Met

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Chapter Notes

Author History

M Teresa de la Morena, MD (2020-present)
Clinton P Dunn, MD (2020-present)
Alexandra H Filipovich, MD; Cincinnati Children's Hospital Medical Center (2007-2020)
Judith Johnson, MS; Cincinnati Children's Hospital Medical Center (2007-2020)
Kejian Zhang, MD, MBA; Cincinnati Children's Hospital Medical Center (2007-2020)

Revision History

  • 4 December 2025 (sw) Comprehensive update posted live
  • 20 February 2020 (ha) Comprehensive update posted live
  • 21 June 2012 (me) Comprehensive update posted live
  • 2 February 2010 (me) Comprehensive update posted live
  • 31 May 2007 (me) Review posted live
  • 20 February 2007 (jj) Original submission

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