DiagnosisClinical DiagnosisThe diagnosis of X-linked hyper IgM syndrome (HIGM1) should be considered in males with serum IgG concentration two or more SD below normal for age and any one or more of the following diagnostic criteria from the recommendations of the European Society for Immunodeficiencies [ESID Working Party 2005]:Definite diagnosis (decreased serum IgG and one of the following):Mutation in CD40LGFamily history of one or more maternally related males with an HIGM1 phenotype or diagnosis Probable diagnosis (decreased serum IgG and all of the following):Normal number of T cells and normal T cell proliferation to mitogensNormal or elevated numbers of B cells but no antigen-specific IgG antibodyOne or more of the following infections or complications:Recurrent bacterial infections in the first five years of lifePneumocystis carinii infection in the first year of lifeNeutropeniaCryptosporidium-related diarrheaSclerosing cholangitisParvovirus induced aplastic anemiaAbsent CD40 ligand expression Possible diagnosis (decreased serum IgG, normal numbers of T and B cells and one or more of the following):Serum IgM concentration two or more SD above normal for agePneumocystis carinii infection in the first year of lifeParvovirus induced aplastic anemiaCryptosporidium-related diarrheaSevere liver disease (typically sclerosing cholangitis) TestingAlthough no uniform abnormalities are observed on routine immunologic laboratory testing of males with HIGM1, the following test results suggest the diagnosis of HIGM1: Normal or elevated serum concentrations of IgM ¹ and IgD ^{2Absent or very low serum concentrations of IgG 2 and IgA 2Absent IgG specific antibodies Normal or increased number of B cells 2Normal number and distribution of CD4+ and CD8 + T-cell subsets 3Normal T-cell proliferation in response to mitogens 3Footnotes1.A minority of males with HIGM1 have decreased IgM concentrations.2.Serum concentrations of IgM, IgD, IgG, IgA, and B-cell markers are not reliable in a neonate. 3.Enumeration of lymphocyte subsets, mitogen responses, and other tests of cell-mediated immunity can vary from person to person and over time in a specific person. 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.
Note: Infants under 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. Molecular Genetic TestingGene. CD40LG (previously known as TNFSF5 or CD154) is the only gene in which mutation is known to cause X-linked hyper IgM syndrome (HIGM1). Clinical testing Table 1. Molecular Genetic Testing Used in X-Linked Hyper IgM Syndrome View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test Availability Affected MalesCarrier FemalesCD40LGSequence analysis Sequence variants 2, 395% 2, 395% 4ClinicalDeletion / duplication analysis 5Deletion / duplication of exon(s) or entire gene5% 5% 61. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. 3. Lack of amplification by PCR prior to sequence analysis can suggest a putative exonic, multiexonic, or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis. 4. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.6. Although it is technically feasible for this method to detect a deletion in a carrier female whether or not the deletion has previously been identified in the family, some laboratories may offer deletion testing only to those at-risk women whose family-specific deletion is known.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband with the following findings: Absent or very low serum concentrations of IgG and IgA
Note: These findings are not universal.Normal or elevated serum concentrations of IgM and IgDNormal: Number and distribution of CD4+ and CD8+ T-cell subsetsT-cell proliferation in response to mitogensNumber of B cellsPerform the following tests:Assay for absent or decreased CD40L protein expression Molecular genetic testing of CD40LG, first using sequence analysis. If lack of amplification suggests a deletion mutation, it must be confirmed by deletion/duplication analysis. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutation in the family.Note: (1) Carriers are heterozygotes for this X-linked disorder and typically do not develop clinical findings related to the disorder. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by methods to detect gross structural abnormalities.Predictive testing for at-risk asymptomatic males is facilitated by prior identification of the disease-causing mutation in the family. If a mutation has not been previously documented in the family, full sequence analysis of CD40LG in the at-risk newborn will detect a mutation. If lack of amplification suggests a deletion mutation, it must be confirmed by deletion/duplication analysis. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family. Genetically Related (Allelic) DisordersHIGM1 is the only disorder associated with mutations in CD40LG.}

Natural HistoryX-linked hyper IgM syndrome (HIGM1), a disorder of abnormal T- and B-cell function, is characterized by low serum concentrations of IgG and IgA and normal or elevated serum concentrations of IgM. Mitogen proliferation may be normal but NK- and T-cell cytotoxicity is frequently impaired. Antigen-specific responses may be decreased or absent. 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].HIGM1 usually presents in infancy with recurrent upper- and lower-respiratory tract bacterial infections, opportunistic infections, and recurrent or protracted diarrhea. Hematologic disorders including neutropenia, thrombocytopenia, and anemia are common [Lee et al 2005]. Autoimmune and/or inflammatory disorders (e.g., sclerosing cholangitis) have been reported [Hayward et al 1997, Jesus et al 2008, Bussone & Mouthon 2009]. Liver disease (including primary cirrhosis and carcinomas) in addition to tumors of the gastrointestinal tract are common life-threatening medical complications in adolescents and young adults with HIGM1. Infection. Increased susceptibility to recurrent bacterial infections results in pneumonia, frequent sinopulmonary infections, and recurrent otitis media in infancy and childhood. Invasive fungal infections, primarily Candida, Cryptococcus, Histoplasma, present a significant risk in affected individuals [Antachopoulos 2010]. Boys with HIGM1 are also at a significant risk for opportunistic infections from Pneumocystis jeroveci (formerly known as Pneumocystis carinii (PCP) and Cryptosporidium parvum. Pneumocystis jeroveci pneumonia is the first clinical symptom of HIGM1 in more than 40% of infants with the disorder [Levy et al 1997, Lee et al 2005] and accounts for 10%-15% of the mortality associated with HIGM1 [Levy et al 1997, Winkelstein et al 2003]. Chronic diarrhea and malnutrition. Chronic diarrhea is a frequent complication of HIGM1, occurring in approximately one third of affected males [Winkelstein et al 2003]. 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]. Failure to thrive is a serious complication of chronic diarrhea. Hematologic abnormalities. Neutropenia, and, less frequently, anemia or thrombocytopenia, occurs in a majority of males with HIGM1 [Levy et al 1997, Lee et al 2005]. Neurologic involvement. Significant neurologic complications, often the result of a CNS infection, are seen in 10%-15% of males with HIGM1 [Levy et al 1997]. However, in at least one half of affected individuals a specific infectious agent cannot be isolated [Winkelstein et al 2003]. Liver disease and liver/gastrointestinal carcinoma. 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]. Hepatitis and sclerosing cholangitis are frequent and may or may not result from an identifiable infectious agent. Malignancies of the liver and gastrointestinal tract including bile duct carcinomas [Hayward et al 1997, Filipovich & Gross 2004], hepatocellular carcinomas [Hayward et al 1997], carcinoid of the pancreas [Winkelstein et al 2003], glucagonoma of the pancreas [Hayward et al 1997], and adenocarcinomas of the liver and gall bladder [Hayward et al 1997] are common complications of HIGM1 in adolescents and young adults and account for approximately 25% of the mortality associated with HIGM1 [Winkelstein et al 2003]. Less commonly, neuroendocrine carcinomas are also seen [Erdos et al 2008].Lymphoma. Males with HIGM1 have an increased risk for lymphoma, particularly Hodgkin's disease associated with Epstein-Barr virus infection [Filipovich & Gross 2004]. Other reported complications of HIGM1 include, rarely, autoimmune retinopathy [Schuster et al 2005] and cutaneous granulomas [Gallerani et al 2004]. Life span. The reported median survival of males with HIGM1 who do not undergo successful allogeneic bone marrow transplantation is less than 25 years [Levy et al 1997]. Pneumocystis jeroveci pneumonia in infancy, liver disease, and carcinomas of the liver and gastrointestinal tract in adolescence or young adulthood are the major causes of death [Levy et al 1997, Winkelstein et al 2003].

Genotype-Phenotype CorrelationsMales with HIGM1 show remarkable variability in clinical symptoms. In general, no good correlation between genotype and phenotype has been observed in HIGM1 [Notarangelo & Hayward 2000, Prasad et al 2005]. The p.Thr254Met mutation has been reported in three unrelated families with mild disease [Lee et al 2005]. Whether or not this is a true association needs to be evaluated with study of additional families with the mutation.

Differential DiagnosisTable 2. Immunodeficiency with Hyper-IgM: OMIM Phenotypic SeriesView in own windowPhenotypePhenotype
MIM NumberGene/LocusGene/Locus
MIM NumberImmunodeficiency, X-linked, with hyper-IgM 308230TNFSF5, CD40LG, HIGM1, IGM 300386 Immunodeficiency with hyper-IgM, type 2 605258 AICDA, AID, HIGM2 605257 Immunodeficiency with hyper IgM, type 5 608106 UNG, DGU, HIGM5 191525 Immunodeficiency with hyper-IgM, type 3 606843 CD40, TNFRSF5 109535 Immunodeficiency with hyper-IgM, type 4 608184 HIGM4 608184 From Online Mendelian Inheritance in ManThe differential diagnosis of X-linked hyper IgM syndrome (HIGM1) includes the following:Non X-linked forms of HIGM HIGM2Mutations in the activation-induced cytidine deaminase gene (AICDA) result in HIGM2, characterized by abnormalities in B-cell differentiation resulting in recurrent bacterial, respiratory, and gastrointestinal infections, but rarely opportunistic infections. Lymphoid hyperplasia is common [Minegishi et al 2000, Revy et al 2000, Lee et al 2005]. Inheritance is autosomal recessive.An autosomal dominant form of hyper IgM syndrome has been reported in four unrelated families with an identical nonsense mutation (p.Arg190X) in AICDA (reference sequence NM_020661.2) [Durandy et al 2005]. HIGM3. Biallelic mutations in CD40, the receptor of CD40LG, are causative. HIGM3 is clinically indistinguishable from HIGM1 [Ferrari et al 2001]. Inheritance is autosomal recessive. HIGM4. Fifteen individuals with an unidentified form of HIGM with decreased production of IgG and a somewhat milder clinical course than HIGM2 have been reported [Imai et al 2003]. The genetic defect(s) underlying HIGM4 has not been determined. HIGM5. Biallelic mutations in UNG are causative. HIGM5 resembles HIGM2. Inheritance is autosomal recessive [Imai et al 2003]. Common variable immunodeficiency (CVID), particularly hypogammaglobulinemia identified in the first decade of life. As in HIGM1, CD40LG protein may be reduced in individuals with CVID. In contrast to HIGM1, CVID may be associated with a decreased number of total T cells or decreased T-cell function. The genetic etiology of most cases of CVID is currently unknown. See Common Variable Immune Deficiency Overview, Goldacker & Warnatz [2005], Salzer & Grimbacher [2006], Park et al [2011], Yong et al [2011] for current reviews of CVID. Severe combined immunodeficiency. Any one of the severe combined immunodeficiencies (SCIDs) must be considered in infants presenting with Pneumocystis jeroveci pneumonia. SCID usually presents with absent T-cell function, quantitative abnormalities of T lymphocyte populations, and markedly decreased mitogen function irrespective of SCID genotype. X-linked SCID is caused by mutations in IL2RG. Biallelic mutations in multiple other genes result in autosomal recessive forms of SCID. See Sponzilli & Notarangelo [2011] and Aloj et al [2012]. Agammaglobulinemia. Any one of the disorders associated with agammaglobulinemia should be considered as part of the differential diagnosis of HIGM1. X-linked agammaglobulinemia (XLA) typically presents in the first year of life with recurrent bacterial infections. Opportunistic viral infections such as Pneumocystis jeroveci pneumonia are rare, as are hematologic disorders such as neutropenia. In contrast to HIGM1, XLA typically presents with absence of CD19+ B cells. XLA is caused by mutations in BTK. Mutations in several other genes result in autosomal dominant and autosomal recessive forms of agammaglobulinemia. See Bonilla & Geha [2006] for a current review of these disorders. HIV infection. Infection with HIV should be considered in any infant presenting with Pneumocystis jeroveci pneumonia. Transient hypogammaglobulinemia of infancy. Transient hypogammaglobulinemia of infancy is characterized by normal antibody production, normal growth patterns, and lack of opportunistic infections. IKBKG. Mutations in IKBKG (formerly known as NEMO) may result in a hyper IgM syndrome, generally associated with hypohydrotic ectodermal dysplasia [Jain et al 2001]. Serious infections, including opportunistic infections, are a common complication at any age. Inheritance is X-linked. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisFollowing the diagnosis of X-linked hyper IgM syndrome (HIGM1), the GI and respiratory tracts should be evaluated for overt or occult infections.Treatment of ManifestationsThe only curative treatment currently available for HIGM1 is allogeneic hematopoietic cell transplantation (HCT), ideally prior to onset of a life-threatening complication and organ damage [Levy et al 1997]. Currently, boys with HIGM1 who receive allogeneic HCT have a 70%-75% long-term survival rate [Tomizawa et al 2004, Tsuji et al 2006]. Modified conditioning regimens prior to HCT may be necessary in individuals with preexisting liver disease [Dogu et al 2011]. For a concise summary of current clinical management practices in this disorder, see Davies & Thrasher [2010].Other Total parenteral nutrition may be required. Treat chronic neutropenia with recombinant granulocyte colony-stimulating factor (G-CSF). Institute appropriate antimicrobial therapy for infections. Aggressively evaluate pulmonary infections, including the use of diagnostic bronchoalveolar lavage, to define the specific etiology. Some males with end-stage sclerosing cholangitis have been treated successfully with orthotropic liver transplantation closely associated with allogeneic bone marrow transplantation. Treat lymphomas and GI cancer. Treatment of autoimmune disorders usually involves judicious use of immunosuppressants tailored to the individual's diagnosis. Liver disease, including primary cirrhosis and carcinomas, in addition to tumors of the gastrointestinal tract, complicate the management of older individuals with HIGM1 [Lee et al 2005].Prevention of Primary ManifestationsThe following methods are used to prevent infection:Antibiotic prophylaxis. Prophylaxis for pneumonia secondary to Pneumocystis jiroveci (PCP) is indicated because infants with HIGM1 are at high risk of developing PCP during the first two years of life. Typical prophylaxis is Bactrim® (trimethoprim-sulfamethoxazole) orally or pentamidine by intravenous or inhalation therapy. Intravenous immune globulin (IVIG). IVIG replacement should be considered by the time the child is age six months, as individuals with HIGM1 cannot generate antibodies to encapsulated bacteria naturally and are at risk for overwhelming infection from these organisms. IVIG 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. Routine childhood immunizations (killed vaccines) may be safely administered but do not preclude the need for IVIG replacement. Prevention of Secondary ComplicationsIn areas where cryptosporidium may be present in the water supply, only purified water should be ingested.SurveillanceMonitor and treat pulmonary complications:Annual pulmonary function tests for those older than age seven years Follow-up of pulmonary infiltrates with a high-resolution chest CT scan, as they may represent lymphoid aggregatesBronchoscopic evaluations as indicatedPerform annual endoscopic evaluation.At routine visits, monitor for the following:Chronic neutropenia Chronic diarrhea and resulting malnutrition. If present, screen for ova and parasites. Liver disease with biochemical liver function tests, especially in individuals with documented history of cryptosporidiosis Lymphomas and GI cancers by history of new symptoms that could be suggestive of malignancy Autoimmune disorders with history, physical examination, and CBC Neurologic complications with neurologic examinations and brain MRI, as indicated Evaluation of Relatives at RiskIt is appropriate to perform molecular genetic testing of CD40LG if the disease-causing mutation in the family is known so that morbidity and mortality can be reduced by early diagnosis and treatment. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCD40LGXq26​.3CD40 ligandCD40Lbase: Mutation registry for X-linked Hyper-IgM syndrome
CD40LG @ LOVD
CCHMC - Human Genetics Mutation DatabaseCD40LGData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for X-Linked Hyper IgM Syndrome (View All in OMIM) View in own window 300386CD40 LIGAND; CD40LG 308230IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1; HIGM1Normal allelic variants. CD40LG has five coding exons and four introns that span over 13 kb. To date, no normal allelic variants of CD40LG are associated with a change in the amino acid sequence of this protein. Population studies of DNA from 50 normal females from southern Ohio identified several variants in the intronic sequence, but these are highly unlikely to have any pathologic effect on CD40 ligand [Zhang et al, unpublished]. Pathologic allelic variants. To date, about 170 pathologic CD40LG mutations have been published. A database of published CD40LG mutations can be found at www.hgmd.cf.ac.uk (registration required). Mutations have been described throughout the five exons of the gene but are particularly common in the TNF-homology domain (exon 5): 26% of these are missense mutations which may affect core packaging, prevent binding to CD40L, or affect trimer formation [Seyama et al 1998]. 20% are nonsense mutations that predict premature protein truncation. The remaining mutations are small deletions/insertions, splicing mutations, and partial- or whole-gene deletions or large insertions. Table 3. Selected CD40LG Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.-239A>C--NM_000074​.2
NP_000065​.1c.761C>Tp.Thr254MetSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).Normal gene product. CD40 ligand (CD40L) 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. CD40 ligand, expressed primarily on CD4+ T cells, binds with CD40 on the surface of B cells to promote immunoglobulin isotype switching. CD40L also plays an important role in T-cell function, particularly in the interaction with monocyte-derived antigen-presenting cells [Jain et al 1999]. Abnormal gene product. Mutations 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 mutations in CD40LG are unable to make high-affinity functional antibodies and cytokines, resulting in a high incidence of opportunistic infections. Inactivation of CD40LG by an AluYb8 element insertion in exon 1 has been reported in a young affected individual [Apoil et al 2007]. A mutation at position -123 of the promoter region has been reported to be responsible for the reduction of CD40L protein [van Hoeyveld et al 2007].