NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

X-Linked Hyper IgM Syndrome

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

, MD and , MD.

Author Information

Initial Posting: ; Last Update: February 20, 2020.

Estimated reading time: 25 minutes

Summary

Clinical characteristics.

X-linked hyper IgM syndrome (HIGM1), a disorder of abnormal T- and B-cell function, is characterized by low serum concentrations of IgG, 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 HIGM1 develop symptoms by age one year, and more than 90% are symptomatic by age four years. HIGM1 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 failure to thrive. 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 CNS infection, are seen in 5%-15% of affected males. Liver disease, a serious complication of HIGM1 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 X-linked hyper IgM syndrome 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.

Treatment of manifestations: Hematopoietic stem cell transplantation (HSCT) (the only curative treatment currently available), ideally performed before age ten years, prior to evidence of organ damage; immunoglobulin 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 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: CBC with differential to monitor for cytopenias, testing of IgG levels and lymphocyte subpopulations, pulmonary function tests after age seven years. Regular assessment of liver function, consider abdominal imaging; as well as 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 relatives of an affected individual in order to identify as early as possible those who would benefit from early diagnosis and prompt initiation of treatment and prevention of infections.

Genetic counseling.

By definition, X-linked hyper IgM syndrome (HIGM1) is inherited in an X-linked manner. Affected males transmit the pathogenic variant to all their daughters and none of their sons. Women with a CD40LG pathogenic variant have a 50% chance of transmitting the pathogenic variant in each pregnancy. Males who inherit the pathogenic variant will be affected. Female who inherit the pathogenic variant will typically be asymptomatic but may have a range of clinical manifestation 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, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing for HIGM1 are possible.

Diagnosis

Suggestive Findings

X-linked hyper IgM syndrome (HIGM1) should be suspected in any male presenting with Pneumocystis jirovecii pneumonia, persistent Cryptosporidium diarrhea, recurrent upper- and lower-respiratory tract bacterial infections, neutropenia, sclerosing cholangitis, and associated bile duct tumors with the following laboratory abnormalities:

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

Establishing the Diagnosis

The diagnosis of HIGM1 is established in a male proband with typical clinical and laboratory findings by identification of a hemizygous pathogenic variant in CD40LG on molecular genetic testing (see Table 1).

The diagnosis of HIGM1 is extremely rare in a female, as heterozygous females are typically asymptomatic unless there is skewed X-chromosome inactivation (see Clinical Description).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype and the family history.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of X-linked hyper IgM syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with immunodeficiency are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of HIGM1 syndrome, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

  • Single-gene testing. Sequence analysis of CD40LG is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. 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 at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants 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 this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
    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 (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.

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

Table 1.

Molecular Genetic Testing Used in X-Linked Hyper IgM Syndrome (HIGM1)

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
CD40LGSequence analysis 3, 485%-95% 5
Gene-targeted deletion/duplication analysis 65%-15% 5
1.
2.

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

3.

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

4.

Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.

5.
6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include 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 CD40 ligand (CD40L) protein expression after in vitro stimulation of T cells. In the resting state, only a low level of CD40L protein expression is seen on normal CD4+ T cells. After in vitro stimulation:

  • Controls show increased expression (up-regulation) of CD40L protein 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 protein [Gilmour et al 2003].
  • Persons with HIGM1 do not show increased expression of CD40L protein in CD4+ T cells.

NOTE: This testing should not be used as the only diagnostic test when HIGM1 is suspected. Up to 32% of individuals with HIGM1 may have normal extracellular domains of CD40L detected by this laboratory measure, which uses CD40L binding; but the intracellular signaling pathway from CD40L is nonfunctional, and thus genetic testing is required for diagnosis [Lee et al 2005].

Clinical Characteristics

Clinical Description

X-linked hyper IgM syndrome (HIGM1), a disorder of abnormal T- and B-cell function, is characterized by low serum concentrations of IgG, IgA, and IgE and normal or elevated serum concentrations of IgM. HIGM1 is due to defects or deficiencies in the 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 HIGM1 develop symptoms by age one year, and more than 90% are symptomatic by age four years [Winkelstein et al 2003].

Presentation. HIGM1 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 failure to thrive. 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].

Infection. Increased susceptibility to recurrent bacterial infections consisting of upper- and lower-respiratory tract infections is seen in 75%-80% of affected individuals (typically streptococcus pneumonia 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 HIGM1 are also at a significant risk for opportunistic infections from Pneumocystis jirovecii (PJP; formerly known as Pneumocystis carinii) and gastrointestinal infection with Cryptosporidium parvum.

Pneumocystis jirovecii pneumonia is the first clinical symptom of HIGM1 in more than 40% of infants with the disorder and is shown as the pathogenic organism in roughly 30% of individuals with HIGM1 [Levy et al 1997, Lee et al 2005, de la Morena 2016, Leven et al 2016] and accounts for 10%-15% of the mortality associated with HIGM1 [Levy et al 1997, Winkelstein et al 2003].

The presentation of HIGM1 across different ethnic backgrounds and in different countries has been shown to be consistent in the infectious organisms at present across all individuals with HIGM1 but they 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].

Gastrointestinal manifestations. Chronic diarrhea is the most frequent GI complication of HIGM1, occurring in approximately 20%-30% of affected males [Winkelstein et al 2003, Leven et al 2016]. 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].

Hematologic and immunologic abnormalities. Neutropenia occurs in roughly 45%-50% of males with HIGM1, 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]. Furthermore, some individuals with HIGM1 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 CD40LG [Cabral-Marques et al 2018].

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

Neurologic involvement. Significant neurologic complications, often the result of a CNS infection, are seen in 5%-15% of males with HIGM1 [Levy et al 1997, Cabral-Marques et al 2014, Leven et al 2016]. However, in at least half of affected individuals a specific infectious agent cannot be isolated [Winkelstein et al 2003].

Hepatobiliary disease. Liver disease, a serious complication of HIGM1, historically was observed in more than 80% of affected males by age 20 years [Hayward et al 1997] but with adequate screening and treatment of Cryptosporidium infections, that number may now be lower [Leven et al 2016]. Hepatitis and sclerosing cholangitis occur in 6%-10% of affected individuals. CD40, the receptor to which CD40Ligand (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 HIGM1 and are associated with high mortality [Winkelstein et al 2003, de la Morena 2016, Leven et al 2016]. Malignancies reported in individuals with HIGM1 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 HIGM1 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 HIGM1 include autoimmune retinopathy, cutaneous granulomas, and disseminated cutaneous warts [Gallerani et al 2004, Schuster et al 2005, Ho et al 2018].

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].

Hematopoietic stem cell transplant (HSCT) is the only curative therapy available for HIGM1. In a retrospective series of 130 affected individuals who had undergone HSCT, overall survival, event-free survival, and disease-free survival rates were respectively 78.2%, 58.1%, and 72.3% five years post HSCT [Ferrua et al 2019].

Heterozygous Females

Typically, heterozygous females are asymptomatic but on immunologic testing have been shown to have reduced expression of CD40L on activation of CD4+ T lymphocytes. Those females with more dramatic reduction in circulating lymphocytes with CD40L due to skewed X-chromosome inactivation can have a presentation similar to HIGM1 or common variable immunodeficiency [Hollenbaugh et al 1994, de Saint Basile et al 1999, Lobo et al 2002].

Genotype-Phenotype Correlations

Males with HIGM1 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 the pathogenic variant.

Prevalence

The estimated prevalence of HIGM is 1:1,000,000 males [Winkelstein et al 2003] with nearly 75% of these individuals having HIGM1 [Leven et al 2016].

HIGM1 has been reported in families of European, African, and Asian descent; thus, no evidence exists for a racial or ethnic predilection.

Differential Diagnosis

Table 2.

Disorders to Consider in the Differential Diagnosis of X-Linked Hyper IgM Syndrome (HIGM1)

Gene(s)Differential
Disorder
MOIClinical Features of Differential Disorder
Overlapping w/HIGM1Distinguishing from HIGM1
AICDA
(AID)
HIGM2 (OMIM 605258)ARAbnormalities in B-cell differentiation → recurrent URTI, LRTI, GI infections
  • Opportunistic infections rare
  • Lymphoid hyperplasia common; incl: hepatomegaly, splenomegaly, giant germinal centers, follicular hyperplasia.
  • Autoimmunity w/hemolytic anemia more common 1
Note: Clinical course milder in HIGM4 than in HIGM2 2
HIGM4 (OMIM 608184)AD 3
  • Recurrent URTI, LRTI
  • ↓ production of IgG, abnormalities in B cell differentiation 2
CD40HIGM3 (OMIM 606843)ARClinically indistinguishable w/recurrent bacterial infections & opportunistic infections w/P jirovecii, Cryptosporidium, & sclerosing cholangitis 4Clinically indistinguishable 4
UNGHIGM5 (OMIM 608106)ARRecurrent bacterial infectionsHIGM5 resembles HIGM2 in the ↑ in lymphoid hyperplasia compared to HIGM1. 2
MSH6Constitutional 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 cancers incl colorectal cancer, hereditary nonpolyposis colon cancer, & endometrial cancer
PMS2Constitutional mismatch repair deficiency (see Lynch Syndrome)AR
  • Recurrent infections
  • ↑ or normal IgM w/↓ IgG & IgA
  • Normal B cell counts but ↓ memory B cells
  • Café au lait spots
  • Colorectal adenocarcinoma
CD19
CD81
CR2
ICOS
IKZF1
IL21
IRF2BP2
LRBA
MS4A1
NFKB1
NFKB2
TNFRSF13B
TNFRSF13C
Common variable immunodeficiency (CVID) (OMIM PS607594)AR
AD
  • Recurrent sinopulmonary infections
  • ↓ immunoglobulins incl IgG & IgA
  • CD40LG protein may be ↓.
  • May be assoc w/↓ number of total T cells or ↓ T-cell function 5
ADA
AK2
CD3D
CD3E
CD247
CORO1A
DCLRE1C
IL2RG
IL7R
JAK3
PRKDC
PTPRC
RAG1
RAG2 6
Severe combined immunodeficiency (SCID)
(see X-Linked SCID & Adenosine Deaminase Deficiency)
AR
XL
All SCIDs must be considered in infants presenting w/P jirovecii pneumonia.
  • Most forms of SCID present w/absent T-cell function, quantitative abnormalities of T lymphocyte populations, & markedly ↓ mitogen function.
  • Hypomorphic RAG2 variants reported in a male w/clinical & immunologic studies suggestive of HIGM 7
AGMX2
BLNK
BTK
CD79A
CD79B
IGHM
IGLL1
LRRC8A
PIK3R1
TCF3
SLC39A7 8
Agammaglobulinemia
(see X-Linked Agammaglobulinemia [XLA])
AR
AD
XL
  • Males w/agammaglobulinemia should be considered in differential of HIGM1.
  • XLA typically presents in 1st yr of life w/recurrent bacterial infections
Most individuals w/agammaglobulinemia lack circulating B cells.
IKBKG
(NEMO)
Ectodermal dysplasia & immunodeficiency 1 (OMIM 300291)XL
  • Serious infections, incl opportunistic infections, are a common complication at any age.
  • Variable immunoglobulins from agammaglobulinemia to normal or ↑ IgM, ↓ IgG, & low/↑ IgA w/↓ memory B cells
  • IKBKG-related hyper IgM syndrome is generally assoc w/hypohydrotic ectodermal dysplasia. 9
  • Invasive disease by MRSA & MSSA; osteopetrosis, lymphedema; conical shaped teeth
PIK3CDActivated PI3 kinase-δ syndrome (OMIM 615513]AD
  • Recurrent infections w/S pneumoniae or H 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)
ATMAtaxia-telangiectasiaAR
  • Recurrent URTI/LRTI, malignancy
  • Normal/↑ IgM, normal to ↓ IgG/IgA, normal to ↓ T/B cells
  • Ataxia, telangiectasias, hypotonia, dysarthria, radiosensitivity
  • Lymphopenia, ↑ α-fetoprotein, variable mitogen & antigen response
NBNNijmegen breakage syndromeAR
  • Recurrent URTI/LRTI, malignancy, autoimmune conditions (primarily hemolytic anemia)
  • Variable immunoglobulins w/agammaglobulinemia to ↓ IgG/IgA & normal/↑ IgM
Microcephaly, facial features, short stature, café au lait spots, vitiligo, radiosensitivity
INO80INO80 deficiency 10 (OMIM 610169)
  • Recurrent bacterial infections
  • COPD
  • ↓ IgG & IgA
  • ↓ class-switched memory B cells
Normal CD40LG protein expression & no CD40LG pathogenic variant

AD = autosomal dominant; AR = autosomal recessive; COPD = chronic obstructive pulmonary disease; GI = gastrointestinal; H = Haemophilus; HIGM = hyper IgM syndrome; LRTI = lower respiratory tract infection; MOI = mode of inheritance; P = Pneumocystis; S = Streptococcus; URTI = upper respiratory tract infection; XL = X-linked

1.
2.
3.

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

4.
5.

See Park et al [2011], Yong et al [2011], and Abbott & Gelfand [2015] for current reviews of CVID.

6.

Note: 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, ZAP70.

7.
8.
9.
10.

The differential diagnosis of HIGM1 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. Transient hypogammaglobulinemia of infancy is characterized by normal antibody production, normal growth patterns, and lack of opportunistic infections. Neonates and young infants may have diminished CD40L expression that improves with time [Nonoyama et al 1995].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with X-linked hyper IgM syndrome, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with X-Linked Hyper IgM Syndrome

System/ConcernEvaluationComment
Hematology/
Immunology
  • CBC w/differential
  • IgG levels
  • T, B, & NK cell numbers
For evidence of cytopenias
PulmonaryBaseline chest radiograph & pulmonary function testingFor chronic lung changes due to infection; if present, consider pulmonology evaluation.
GastrointestinalPCR-based testing of stoolsFor presence of Cryptosporodium or other enteric pathogens; if present, partner w/gastroenterologist.
Nutritional assessment
HepatobiliaryBaseline liver function testing & liver / biliary tree ultrasoundFor evidence of hepatocyte dysfunction & developing biliary dilation
TransplantationAll individuals should be offered HLA typing at diagnosis.For consideration of HSCT
OtherConsultation w/clinical geneticist &/or genetic counselor

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

Treatment of Manifestations

For a concise summary of current clinical management practices in this disorder, see Davies & Thrasher [2010] and de la Morena et al [2017].

Hematopoietic stem cell transplant (HSCT). Currently HSCT is the only curative therapy available for HIGM1. Best outcomes are reported for those individuals transplanted before age ten years and without evidence of end organ damage, especially liver disease [de la Morena et al 2017, Ferrua et al 2019]. Myeloablative conditioning regimens result in better survival; 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, among 130 transplanted individuals with HIGM1, a third required ongoing immunoglobulin replacement five years after transplantation [Ferrua et al 2019].

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

Table 4.

Treatment of Manifestations in Individuals with X-Linked Hyper IgM Syndrome

Manifestation/
Concern
TreatmentConsiderations/Other
Recurrent
infections
  • Immunoglobulin replacement w/intravenous or subcutaneous immunoglobulin 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 P 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 individuals 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.
ImmunodeficiencyOnly current curative treatment is HSCT, preferably at age <10 yrs.Modified conditioning regimens may be needed in those w/preexisting liver disease, & hepatic transplant along w/HSCT may be required.
Chronic
neutropenia
Recombinant GCSF
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 bone marrow transplantation. Infectious etiologies need to be pursued & treated prior to transplantation.
Autoimmune
disorders
Treatment of autoimmune disorders usually involves judicious use of immunosuppressants tailored to individual's diagnosis.
CancerTreatment should follow standard protocols/therapies for individual cancers in conjunction w/immunologist.

GCSF = granulocyte colony-stimulating factor; HSCT = hematopoietic stem-cell transplantation; P = Pneumocystis

1.

The following methods are used to prevent infection:
Antibiotic prophylaxis. Prophylaxis for pneumonia secondary to Pneumocystis jirovecii (PJP) is indicated for all children with HIGM1 due to the high risk of developing PJP during the first two years of life. There is no standard-of-care approach established for length of PJP prophylaxis. However, individuals with HIGM1 who develop PJP 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 replacement should be considered at the time of diagnosis, as individuals with HIGM1 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 with ongoing questions regarding Cryptosporidum prophylaxis not yet being standardized.
Routine childhood immunizations (killed vaccines) may be safely administered but do not preclude the need for immunoglobulin replacement. Live vaccines (e.g., rotavirus, MMR, varicella, live attenuated polio, and BCG) should not be given to individuals with HIGM1.
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 HIGM1. Table 5 presents the current recommendations of the authors.

Table 5.

Recommended Surveillance for Individuals with X-Linked Hyper IgM Syndrome

System/ConcernEvaluationFrequency
HematologyCBC w/differential to monitor for cytopeniasAt least every 6 mos to yrly if stable or w/any change in clinical status
ImmunologyIgG levels
  • IgG frequency depends on time needed to achieve adequate IgG levels; similar to those w/primary antibody deficiency syndromes.
  • Adults: at least yrly
Lymphocyte subpopulations: T, B, & NK cell numbersGiven progressive T, B, & NK loss over time, consider obtaining yrly in nontransplanted adolescents & adults.
CD40L expression in transplanted individualsMonitor CD40L expression in activated T-cells at least yrly in those who have had HSCT, or if any change in clinical status.
PulmonaryPulmonary function testsYrly for those age >7 yrs or if change in clinical status
Chest radiograph w/follow up of pulmonary infiltrates w/high-resolution CT scanAs clinically indicated
GastrointestinalPCR-based testing of stools for infectious etiologiesAt least every 6 mos or if diarrhea 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 at least 2x/yr
  • Children: at every visit; at least every 4-6 mos
  • Adolescents/adults: at least 2x/yr
  • If any change in clinical status
OncologyPhysical exam
  • Children: at least every 4-6 mos
  • Adolescents/adults: at least 1-2x/yr
  • Low threshold for lymph node biopsy

CBC = complete blood count; 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 (e.g., rotavirus, MMR, varicella, live attenuated polio, and BCG) should not be given to individuals with HIGM1.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of newborn at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from 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

Research into autologous gene corrective therapy is ongoing [Hubbard et al 2016, Kuo et al 2018].

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, 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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

X-linked hyper IgM syndrome (HIGM1) is inherited in an X-linked manner.

Risk to Family Members

Parents of a male proband

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:

Other family members

  • A male proband's maternal aunts or other maternal relatives and their offspring may be at risk of being heterozygous for a CD40LG pathogenic variant (if female) or of being affected with a CD40LG-related disorder (if male). The precise risk to the proband's maternal relatives depends on the family relationships.
  • 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 of at-risk female relatives to determine their genetic status is most informative if the pathogenic variant has been identified in an affected male relative.

If an affected male is not available for testing, perform molecular genetic testing first by sequence analysis, and if no pathogenic variant is identified, by gene-targeted deletion/duplication analysis.

Note: CD40L expression by flow cytometry may be helpful but is not a diagnostic test for the detection of heterozygotes.

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, clarification of genetic status, and discussion of the availability of prenatal 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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the CD40LG pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for HIGM1 are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

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
    215 West 101st Street
    Suite 7B
    New York NY 10025
    Phone: 646-883-4446
    Email: info@hyperigm.org
  • Canadian Immunodeficiencies Patient Organization (CIPO)
    362 Concession Road 12
    RR #2
    Hastings Ontario K0L 1Y0
    Canada
    Phone: 877-262-2476 (toll-free)
    Fax: 866-942-7651 (toll-free)
    Email: info@cipo.ca
  • Immune Deficiency Foundation
    110 West Road
    Suite 300
    Towson MD 21204
    Email: idf@primaryimmune.org
  • Jeffrey Modell Foundation/National Primary Immunodeficiency Resource Center
    747 Third Avenue
    New York NY 10017
    Phone: 866-463-6474 (toll-free); 212-819-0200
    Fax: 212-764-4180
    Email: info@jmfworld.org
  • European Society for Immunodeficiencies (ESID) Registry
    Dr. Gerhard Kindle
    University Medical Center Freiburg Centre of Chronic Immunodeficiency
    Engesserstr. 4
    79106 Freiburg
    Germany
    Phone: 49-761-270-34450
    Email: esid-registry@uniklinik-freiburg.de
  • Primary Immunodeficiency Diseases Registry at USIDNET
    40 West Chesapeake Avenue
    Suite 308
    Towson MD 21204-4803
    Phone: 866-939-7568
    Fax: 410-321-0293
    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.

X-Linked Hyper IgM Syndrome: Genes and Databases

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 X-Linked Hyper IgM Syndrome (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 CD40 ligand protein. 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. The HIGM1 syndrome 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 HIGM1 [Lee et al 2005].

Flow cytometry using anti-CD40L monoclonal antibodies can confirm the diagnosis of HIGM1 in some affected individuals:

  • Those who produce no CD40L protein 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.

Notable CD40LG Pathogenic Variants

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.

References

Literature Cited

  • Abbott JK, Gelfand EW. Common variable immunodeficiency: diagnosis, management, and treatment. Immunol Allergy Clin North Am. 2015;35:637–58. [PubMed: 26454311]
  • Agematsu K, Nagumo H, Shinozaki K, Hokibara S, Yasui K, Terada K, Kawamura N, Toba T, Nonoyama S, Ochs HD, Komiyama A. Absence of IgD-CD27 (+) memory B cell population in X-linked hyper-IgM Syndrome. J Clin Invest. 1998;102:853–60. [PMC free article: PMC508949] [PubMed: 9710455]
  • Anzilotti C, Swan DJ, Boisson B, Deobagkar-Lele M, Oliveira C, Chabosseau P, Engelhardt KR, Xu X, Chen R, Alvarez L, Berlinguer-Palmini R, Bull KR, Cawthorne E, Cribbs AP, Crockford TL, Dang TS, Fearn A, Fenech EJ, de Jong SJ, Lagerholm BC, Ma CS, Sims D, van den Berg B, Xu Y, Cant AJ, Kleiner G, Leahy TR, de la Morena MT, Puck JM, Shapiro RS, van der Burg M, Chapman JR, Christianson JC, Davies B, McGrath JA, Przyborski S, Santibanez Koref M, Tangye SG, Werner A, Rutter GA, Padilla-Parra S, Casanova JL, Cornall RJ, Conley ME, Hambleton S. An essential role for the Zn2+ transporter ZIP7 in B cell development. Nat Immunol. 2019;20:350–61. [PMC free article: PMC6561116] [PubMed: 30718914]
  • Bucciol G, Nicholas SK, Calvo PL, Cant A, Edgar JDM, Espanol T, Ferrua F, Galicchio M, Gennery AR, Hadzic N, Hanson I E, Kusminsky G, Lange A, Lanternier F, Mahlaoui N, Moshous D, Nademi Z, Neven B, Oleastro M, Porta F, Quarello P, Silva M, Slatter MA, Soncini E, Stefanowicz M, Tandoi F, Teisseyre M, Torgerson TR, Veys P, Weinacht KG, Wolska-Kuśnierz B, Pirenne J, de la Morena MT, Meyts I. Combined liver and hematopoietic stem cell transplantation in patients with X-linked hyper-IgM syndrome. J Allergy Clin Immunol. 2019;143:1952–6.e6. [PubMed: 30682461]
  • Cabral-Marques O, Klaver S, Schimke LF, Ascendino ÉH, Khan TA, Pereira PV, Falcai A, Vargas-Hernández A, Santos-Argumedo L, Bezrodnik L, Moreira I, Seminario G, Di Giovanni D, Raccio AG, Porras O, Weber CW, Ferreira JF, Tavares FS, de Carvalho E, Valente CF, Kuntze G, Galicchio M, King A, Rosário-Filho NA, Grota MB, dos Santos Vilela MM, Di Gesu RS, Lima S, de Souza Moura L, Talesnik E, Mansour E, Roxo-Junior P, Aldave JC, Goudouris E, Pinto-Mariz F, Berrón-Ruiz L, Staines-Boone T, Calderón WO, del Carmen Zarate-Hernández M, Grumach AS, Sorensen R, Durandy A, Torgerson TR, Carvalho BT, Espinosa-Rosales F, Ochs HD, Condino-Neto A. First report of the Hyper IgM Syndrome Registry of the Latin American Society for Immunodeficiencies: novel mutations, unique infections, and outcomes. J Clin Immunol. 2014;34:146–56. [PubMed: 24402618]
  • Cabral-Marques O, França TT, Al-Sbiei A, Schimke LF, Khan TA, Feriotti C, da Costa TA, Junior OR, Weber CW, Ferreira JF, Tavares FS, Valente C, Di Gesu RSW, Iqbal A, Riemekasten G, Amarante-Mendes GP, Marzagão Barbuto JA, Costa-Carvalho BT, Pereira PVS, Fernandez-Cabezudo MJ, Calich VLG, Notarangelo LD, Torgerson TR, Al-Ramadi BK, Ochs HD, Condino-Neto A. CD40 ligand deficiency causes functional defects of peripheral neutrophils that are improved by exogenous IFN-γ. J Allergy Clin Immunol. 2018;142:1571–88.e9. [PMC free article: PMC6123297] [PubMed: 29518426]
  • Chou J, Hanna-Wakim R, Tirosh I, Kane J, Fraulino D, Lee Y N, Ghanem S, Mahfouz I, Megarbane A, Lefranc G, Inati A, Dbaibo G, Giliani S, Notarangelo LD, Geha R S, Massaad MJ. A novel homozygous mutation in recombination activating gene 2 in two relatives with different clinical phenotypes: Omenn syndrome and hyper-IgM syndrome. J Allergy Clin Immunol. 2012;130:1414–6. [PMC free article: PMC3511613] [PubMed: 22841008]
  • Davies EG, Thrasher AJ. Update on the hyper immunoglobulin M syndromes. Br J Haematol. 2010;149:167–80. [PMC free article: PMC2855828] [PubMed: 20180797]
  • de la Morena MT. Clinical phenotypes of hyper IgM syndromes. J Allergy Clin Immunol Pract. 2016;4:1023–36. [PubMed: 27836054]
  • de la Morena MT, Leonard D, Torgerson TR, Cabral-Marques O, Slatter M, Aghamohammadi A, Chandra S, Murguia-Favela L, Bonilla FA, Kanariou M, Damrongwatanasuk R, Kuo CY, Dvorak CC, Meyts I, Chen K, Kobrynski L, Kapoor N, Richter D, DiGiovanni D, Dhalla F, Farmaki E, Speckmann C, Español T, Shcherbina A, Hanson IC, Litzman J, Routes JM, Wong M, Fuleihan R, Seneviratne SL, Small TN, Janda A, Bezrodnik L, Seger R, Raccio AG, Edgar JD, Chou J, Abbott JK, van Montfrans J, González-Granado LI, Bunin N, Kutukculer N, Gray P, Seminario G, Pasic S, Aquino V, Wysocki C, Abolhassani H, Dorsey M, Cunningham-Rundles C, Knutsen AP, Sleasman J, Costa Carvalho BT, Condino-Neto A, Grunebaum E, Chapel H, Ochs HD, Filipovich A, Cowan M, Gennery A, Cant A, Notarangelo LD, Roifman CM. Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation. J Allergy Clin Immunol. 2017;139:1282–92. [PMC free article: PMC5374029] [PubMed: 27697500]
  • de Saint Basile G, Tabone MD, Durandy A, Phan F, Fischer A, Le Deist F. CD40 ligand expression deficiency in a female carrier of the X-linked hyper-IgM syndrome as a result of X chromosome lyonization. Eur J Immunol. 1999;29:367–73. [PubMed: 9933119]
  • Durandy A, Revy P, Imai K, Fischer A. Hyper-immunoglobulin M syndromes caused by intrinsic B-lymphocyte defects. Immunol Rev. 2005;203:67–79. [PubMed: 15661022]
  • Erdos M, Garami M, Rákóczi E, Zalatnai A, Steinbach D, Baumann U, Kropshofer G, Tóth B, Maródi L. Neuroendocrine carcinoma associated with X-linked hyper-immunoglobulin M syndrome: report of four cases and review of the literature. Clin Immunol. 2008;129:455–61. [PubMed: 18805740]
  • Ferrari S, Giliani S, Insalaco A, Al-Ghonaium A, Soresina AR, Loubser M, Avanzini MA, Marconi M, Badolato R, Ugazio AG, Levy Y, Catalan N, Durandy A, Tbakhi A, Notarangelo LD, Plebani A. Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM. Proc Natl Acad Sci U S A. 2001;98:12614–9. [PMC free article: PMC60102] [PubMed: 11675497]
  • Ferrua F, Galimberti S, Courteille V, Slatter MA, Booth C, Moshous D, Neven B, Blanche S, Cavazzana A, Laberko A, Shcherbina A, Balashov D, Soncini E, Porta F, Al-Mousa H, Al-Saud B, Al-Dhekri H, Arnaout R, Formankova R, Bertrand Y, Lange A, Smart J, Wolska-Kusnierz B, Aquino VM, Dvorak CC, Fasth A, Fouyssac F, Heilmann C, Hoenig M, Schuetz C, Kelečić J, Bredius RGM, Lankester AC, Lindemans CA, Suarez F, Sullivan KE, Albert MH, Kałwak K, Barlogis V, Bhatia M, Bordon V, Czogala W, Alonso L, Dogu F, Gozdzik J, Ikinciogullari A, Kriván G, Ljungman P, Meyts I, Mustillo P, Smith AR, Speckmann C, Sundin M, Keogh SJ, Shaw PJ, Boelens JJ, Schulz AS, Sedlacek P, Veys P, Mahlaoui N, Janda A, Davies EG, Fischer A, Cowan MJ, Gennery AR, et al. Hematopoietic stem cell transplantation for CD40 Ligand deficiency: Results from an EBMT/ESID-IEWP-SCETIDE-PIDTC study. J Allergy Clin Immunol. 2019;143:2238–53. [PubMed: 30660643]
  • Filipovich L, Gross T. Immunodeficiency and cancer. In: Abeloff M, Armitage J, Niederhuber J, Kastan M, McKenna WG, eds. Clinical Oncology. 3 ed. London, UK: Elsevier/Churchill Livingstone; 2004:287-98.
  • Gallerani I, Innocenti DD, Coronella G, Berti S, Amato L, Moretti S, Fabbri P. Cutaneous sarcoid-like granulomas in a patient with X-linked hyper-IgM syndrome. Pediatr Dermatol. 2004;21:39–43. [PubMed: 14871324]
  • Gilmour KC, Walshe D, Heath S, Monaghan G, Loughlin S, Lester T, Norbury G, Cale CM. Immunological and genetic analysis of 65 patients with a clinical suspicion of X linked hyper-IgM. Mol Pathol. 2003;56:256–62. [PMC free article: PMC1187335] [PubMed: 14514918]
  • Hayward AR, Levy J, Facchetti F, Notarangelo L, Ochs HD, Etzioni A, Bonnefoy JY, Cosyns M, Weinberg A. Cholangiopathy and tumors of the pancreas, liver, and biliary tree in boys with X-linked immunodeficiency with hyper-IgM. J Immunol. 1997;158:977–83. [PubMed: 8993019]
  • Ho HE, Byun M, Cunningham-Rundles C. Disseminated cutaneous warts in X-linked hyper IgM syndrome. J Clin Immunol. 2018;38:454–6. [PMC free article: PMC6030472] [PubMed: 29730845]
  • Hollenbaugh D, Wu LH, Ochs HD, Nonoyama S, Grosmaire LS, Ledbetter JA, Noelle RJ, Hill H, Aruffo A. The Random Inactivation of the X Chromosome Carrying the Defective Gene Responsible for X-linked Hyper IgM Syndrome (X-HIM) in Female Carriers of HIGM1. J Clin Invest. 1994;94:616–22. [PMC free article: PMC296138] [PubMed: 7518839]
  • Hubbard N, Hagin D, Sommer K, Song Y, Khan I, Clough C, Ochs H D, Rawlings D J, Scharenberg A M, Torgerson TR. Targeted gene editing restores regulated CD40L function in X-linked hyper-IgM syndrome. Blood. 2016;127:2513–22. [PubMed: 26903548]
  • Imai K, Catalan N, Plebani A, Maródi L, Sanal O, Kumaki S, Nagendran V, Wood P. Hyper-IgM syndrome type 4 with a B lymphocyte-intrinsic selective deficiency in Ig class switch recombination. J Clin Invest. 2003;112:136–42. [PMC free article: PMC162294] [PubMed: 12840068]
  • Jain A, Atkinson TP, Lipsky PE, Slater JE, Nelson DL, Strober W. Defects of T-cell effector function and post-thymic maturation in X-linked hyper-IgM syndrome. J Clin Invest. 1999;103:1151–8. [PMC free article: PMC408278] [PubMed: 10207167]
  • Jain A, Ma CA, Liu S, Brown M, Cohen J, Strober W. Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia. Nat Immunol. 2001;2:223–8. [PubMed: 11224521]
  • Kracker S, Di Virgilio M, Schwartzentruber J, Cuenin C, Forveille M, Deau MC, McBride KM, Majewski J, Gazumyan A, Seneviratne S, Grimbacher B, Kutukculer N, Herceg Z, Cavazzana M, Jabado N, Nussenzweig MC, Fischer A, Durandy A. An Inherited immunoglobulin class-switch recombination deficiency associated with a defect in the INO80 Chromatin Remodeling Complex. J Allergy Clin Immunol. 2015;2015;135:998–1007.e6. [PMC free article: PMC4382329] [PubMed: 25312759]
  • Kuo C Y, Long J D, Campo-Fernandex B, de Oliveira S, Cooper AR, Romero Z, Hoban MD, Joglekar AV, Lill GR, Kaufman ML, Fitz-Gibbon S, Wang X, Hollis RP, Kohn DB. Site-specific gene editing of human hematopoietic stem cells for X-linked hyper-IgM syndrome. Cell Rep. 2018;23:2606–16. [PMC free article: PMC6181643] [PubMed: 29847792]
  • Le Coz C, Trofa M, Syrett CM, Martin A, Jyonouchi H, Jyonouchi S, Anguera MC, Romberg N. CD40LG duplication-associated autoimmune disease is silenced by nonrandom X-chromosome inactivation. J Allergy Clin Immunol. 2018;141:2308–11.e7. [PMC free article: PMC5994181] [PubMed: 29499223]
  • Lee WI, Torgerson TR, Schumacher MJ, Yel L, Zhu Q, Ochs HD. Molecular analysis of a large cohort of patients with the hyper immunoglobulin M (IgM) syndrome. Blood. 2005;105:1881–90. [PubMed: 15358621]
  • Leven EA, Maffucci P, Ochs H, Scholl PR, Buckley RB, Fuleihan RL, Geha RS, Cunningham CK, Bonilla FA, Conley ME, Ferdman RM, Hernandez-Trujilo V, Puck JM, Sullivan K, Secord EA, Ramesh M, Cunningham-Rundles C. Hyper IgM syndrome: a report from the USIDNET Registry. J Clin Immunol. 2016;36:490–501. [PMC free article: PMC5039943] [PubMed: 27189378]
  • Levy J, Espanol-Boren T, Thomas C, Fischer A, Tovo P, Bordigioni P, Resnick I, Fasth A, Baer M, Gomez L, Sanders EAM, Tabone MD, Plantaz D, Etzioni A, Monafo V, Abinun M, Hammarstrom L, Abrahamsen T, Jones A, Finn A, Klemola T, DeVries E, Sanal O, Peitsch MC, Notarangelo LD. Clinical spectrum of X-linked hyper IgM syndrome. J Pediatr. 1997;131:47–54. [PubMed: 9255191]
  • Lobo FM, Scholl PR, Fuleihan RL. CD40 ligand-deficient T cells from X-linked hyper-IgM syndrome carriers have intrinsic priming capability. J Immunol. 2002;168:1473–8. [PubMed: 11801691]
  • Lougaris V, Lanzi G, Manuela B, Gazzurelli L, Vairo D, Lorenzini T, Badolato R, Notarangelo LD, Boschi A, Moratto D, Plebani A. Progressive severe B cell and NK cell deficiency with T cell senescence in adult CD40L deficiency. Clin Immunol. 2018;190:11–14. [PubMed: 29476811]
  • Minegishi Y, Lavoie A, Cunningham-Rundles C, Bedard PM, Hebert J, Cote L, Dan K, Sedlak D, Buckley RH, Fischer A, Durandy A, Conley ME. Mutations in activation-induced cytidine deaminase in patients with hyper IgM syndrome. Clin Immunol. 2000;97:203–10. [PubMed: 11112359]
  • Nicolaides RE, de la Morena MT. Inherited and acquired clinical phenotypes associated with neuroendocrine tumors. Curr Opin Allergy Clin Immunol. 2017;17:431–42. [PubMed: 29040209]
  • Nonoyama S, Penix LA, Edwards CP, Lewis DB, Ito S, Aruffo A, Wilson CB, Ochs HD. Diminished Expression of CD40 ligand by activated neonatal T cells. J Clin Invest. 1995;95:66–75. [PMC free article: PMC295372] [PubMed: 7814647]
  • Notarangelo LD, Hayward AR. X-linked immunodeficiency with hyper-IgM (XHIM). Clin Exp Immunol. 2000;120:399–405. [PMC free article: PMC1905564] [PubMed: 10844515]
  • Park JH, Resnick ES, Cunningham-Rundles C. Perspectives on common variable immune deficiency. Ann N Y Acad Sci. 2011;1246:41–9. [PMC free article: PMC3428018] [PubMed: 22236429]
  • Prasad ML, Velickovic M, Weston SA, Benson EM. Mutational screening of the CD40 ligand (CD40L) gene in patients with X linked hyper-IgM syndrome (XHIM) and determination of carrier status in female relatives. J Clin Pathol. 2005;58:90–2. [PMC free article: PMC1770534] [PubMed: 15623492]
  • Rawat A, Mathew B, Pandiarajan V, Jindal A, Sharma M, Suri D, Gupta A, Goel S, Karim A, Saikia B, Minz RW, Imai K, Nonoyama S, Ahara O, Giliani SC, Notarangelo LD, Chan KW, Lau YL, Singh S. Clinical and molecular features of X-linked hyper IgM syndrome - an experience from North India. Clin Immunol. 2018;195:59–66. [PMC free article: PMC6666391] [PubMed: 30053428]
  • Revy P, Muto T, Levy Y, Geissmann F, Plebani A, Sanal O, Catalan N, Forveille M, Dufourcq-Labelouse R, Gennery A, Tezcan I, Ersoy F, Kayserili H, Ugazio AG, Brousse N, Muramatsu M, Notarangelo LD, Kinoshita K, Honjo T, Fischer A, Durandy A. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the hyper-IgM syndrome (HIGM2). Cell. 2000;102:565–75. [PubMed: 11007475]
  • Schuster A, Apfelstedt-Sylla E, Pusch CM, Zrenner E, Thirkill CE. Autoimmune retinopathy with RPE hypersensitivity and "negative ERG" in X-linked hyper-IgM syndrome. Ocul Immunol Inflamm. 2005;13:235–43. [PubMed: 16019685]
  • Seyama K, Nonoyama S, Gangsaas I, Hollenbaugh D, Pabst HF, Aruffo A, Ochs HD. Mutations of the CD40 ligand gene and its effect on CD40 ligand expression in patients with X-linked hyper IgM syndrome. Blood. 1998;92:2421–34. [PubMed: 9746782]
  • Tafakori Delbari M, Cheraghi T, Yazdani R, Fekrvand S, Delavari S, Azizi G, Chavoshzadeh Z, Mahdaviani SA, Ahanchian H, Khoshkhui M, Behmanesh F, Aleyasin S, Esmaeilzadeh H, Jabbari-Azad F, Fallahpour M, Zamani M, Madani SP, Moazzami B, Habibi S, Rezaei A, Lotfalikhani A, Movahed M, Shariat M, Kalantari A, Babaei D, Darabi M, Parvaneh N, Rezaei N, Abolhassani H, Aghamohammadi A. Clinical manifestations, immunological characteristics and genetic analysis of patients with hyper-immunoglobulin M syndrome in Iran. Int Arch Allergy Immunol. 2019;180:52–63. [PubMed: 31117086]
  • Wang LL, Zhou W, Zhao W, Tian Z, Wang W, Wang X, Chen T. Clinical features and genetic analysis of 20 Chinese patients with X-linked hyper-IgM syndrome. J Immunol Res. 2014;2014:683160 [PMC free article: PMC4158165] [PubMed: 25215306]
  • Winkelstein JA, Marino MC, Ochs H, Fuleihan R, Scholl PR, Geha R, Stiehm ER, Conley ME. The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients. Medicine (Baltimore). 2003;82:373–84. [PubMed: 14663287]
  • Yong PF, Thaventhiran JE, Grimbacher B. "A rose is a rose is a rose," but CVID is not CVID common variable immune deficiency (CVID), what do we know in 2011? Adv Immunol. 2011;111:47–107. [PubMed: 21970952]

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

  • 20 February 2020 (ha) Comprehensive update posted live
  • 24 January 2013 (cd) Revision: deletion/duplication analysis available clinically
  • 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
Copyright © 1993-2020, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2020 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK1402PMID: 20301576

Views

Tests in GTR by Gene

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...