 |
|
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Disease characteristics. X-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 are frequently impaired. Antigen-specific responses may be decreased or absent. The range of clinical findings varies, even within the same family. Over 50% of males with HIGM1 develop symptoms by age one year, and over 90% are symptomatic by age four years. HIGM1 usually presents in infancy with recurrent upper and lower respiratory tract bacterial infections, opportunistic infections, and recurrent or protracted diarrhea associated with failure to thrive. Neutropenia, thrombocytopenia, and anemia are common. Autoimmune and/or inflammatory disorders, such as sclerosing cholangitis, have been reported. Significant neurologic complications, often the result of a CNS infection, are seen in 10%-15% of affected males. Liver disease, including primary cirrhosis and carcinomas (bile duct carcinomas, hepatocellular carcinomas, adenocarcinomas of the liver and gall bladder), and tumors of the gastrointestinal tract (carcinoid of the pancreas, glucagonoma of the pancreas) are common life-threatening complications in adolescents and young adults with HIGM1. Affected males also have an increased risk of lymphoma, particularly Hodgkin's disease associated with Epstein-Barr virus (EBV) infection.
Diagnosis/testing. The diagnosis of HIGM1 is based on a combination of clinical findings, family history, absent or decreased expression of the CD40 ligand (CD40L) protein on flow cytometry following in vitro stimulation of white cells, and molecular genetic testing of CD40LG (also known as TNFSF5 or CD154), the only gene known to be associated with HIGM1. Direct sequencing of the entire coding region and intron/exon boundaries detects mutations in approximately 99% of affected males.
Management. Treatment of manifestations: Allogeneic hematopoietic cell transplantation (HCT), ideally performed prior to onset of life-threatening complications and organ damage, is the only curative treatment currently available; recombinant granulocyte colony-stimulating factor (G-CSF) for chronic neutropenia; appropriate antimicrobial therapy for infections; immunosuppressants for autoimmune disorders. Prevention of primary manifestations: prophylaxis for pneumonia secondary to Pneumocystis jiroveci; intravenous immune globulin (IVIG) by age six months to prevent overwhelming infection from encapsulated bacteria. Prevention of secondary complications: Drink only purified water in areas where cryptosporidium may be in the water supply. Surveillance: annual pulmonary function tests after age seven years; annual endoscopic evaluation. Testing of relatives at risk: Evaluate newborn at-risk male relatives with assay of CD40L protein expression by flow cytometry and CD40LG molecular genetic testing if the disease-causing mutation in the family is known so that morbidity and mortality can be reduced by early diagnosis and treatment.
Genetic counseling. X-linked hyper IgM syndrome (HIGM1) is inherited in an X-linked manner. Female carriers are asymptomatic and have no immunologic or biochemical markers of the disorder. Female carriers have a 50% chance of transmitting the disease-causing mutation in each pregnancy; males who inherit the mutation will be affected; females who inherit the mutation will be carriers. Affected males pass the disease-causing mutation to all their daughters and none of their sons. Prenatal testing is possible for pregnancies at increased risk if the disease-causing mutation has been identified in the family.
The diagnosis of X-linked hyper IgM syndrome (HIGM1) should be considered in males with serum IgG concentration at least two standard deviations (SD) below normal for age and any one or more of the following diagnostic criteria modified from the recommendations of the European Society for Immunodeficiencies (ESID).
Recurrent bacterial and opportunistic infections in infancy and early childhood
Parvovirus-induced aplastic anemia
Cryptosporidium-related diarrhea
Neutropenia (i.e., neutrophil count <2000/µL)
Liver disease including gastrointestinal (GI) carcinomas
Absent or decreased expression of the CD40 ligand (CD40L) protein as detection by flow cytometry following in vitro stimulation of white cells
Family history of one or more maternally related males with an HIGM1 phenotype or diagnosis
Although no uniform abnormalities are observed on laboratory testing of males with HIGM1, the following test results suggest the diagnosis of HIGM1:
Normal or elevated serum concentrations of IgM* and IgD*
Absent or very low serum concentrations of IgG* and IgA*
Absent IgG specific antibodies
Normal or increased number of B cells*
Normal number and distribution of CD4+ and CD8+ T-cell subsets**
Normal T-cell proliferation in response to mitogens**
* Serum concentrations of IgM, IgD, IgG, IgA, and B-cell markers are not reliable in a neonate.
** Enumeration of lymphocyte subsets, mitogen responses, and other tests of cell-mediated immunity can vary from patient to patient and over time in a specific patient.
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.
Persons with HIGM1 do not show increased expression of CD40L protein in CD4+ T cells
* Infants under age six months may not express normal amounts of CD40L protein [Gilmour et al 2003].
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. CD40LG (also known as TNFSF5 or CD154) is the only gene known to be associated with X-linked hyper IgM syndrome (HIGM1).
Clinical testing
Sequence analysis. Direct sequencing of the entire coding region and intron/exon boundaries detects approximately 99% of CD40LG mutations in males.
Mutation scanning. The sensitivity of mutation scanning is generally less than that of sequence-based analysis.
Deletion/duplication testing. Large deletions, which comprise 5% of CD40LG mutations, are not detected by PCR-based sequence analysis in females. Quantitative PCR methods (e.g., MLPA, RT-PCR) are able to detect large deletions in at-risk females.
Note: Although it is technically possible 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.
Table 1 summarizes molecular genetic testing for this disorder.
| Test Method | Mutations Detected | Mutation Detection Frequency 1 | Test Availability | |
|---|---|---|---|---|
| Males | Females | |||
| Sequence analysis | CD40LG sequence variants | ~99% 2 | ~95% | Clinical
 |
| Deletion/duplication testing | CD40LG deletions | NA 2 | ~5% | |
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
Confirmatory diagnostic testing for HIGM1. If:
Serum concentrations of IgG and IgA are absent or very low (but these findings are not universal)
Serum concentrations of IgM and IgD are normal or elevated
Number and distribution of CD4+ and CD8+ T-cell subsets are normal
T-cell proliferation in response to mitogens is normal
Number of B cells is normal
Then:
Assay for absent or decreased CD40L protein expression.
Perform molecular genetic testing of CD40LG.
Identification of female carriers requires either:
Prior identification of the disease-causing mutation in the family
Or:
If an affected male is not available for testing, molecular genetic testing by full sequence analysis. If a mutation is not identified by sequence analysis, deletion testing if it is offered under these circumstances by a clinical laboratory
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 the CD40LG gene and assay of CD40L protein expression by flow cytometry in the at-risk newborn is diagnostic.
Prenatal diagnosis/preimplantation genetic diagnosis (PGD) for at-risk pregnancies requires prior identification of the disease-causing mutation in the family.
HIGM1 is the only disorder associated with mutations in CD40LG.
X-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 are frequently impaired. Antigen-specific responses may be decreased or absent. The range of clinical findings varies, even within the same family. Over 50% of males with HIGM1 develop symptoms by age one year, and over 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, such as sclerosing cholangitis, have been reported [Hayward et al 1997]. 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. Boys with HIGM1 are also at an increased 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 over 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 microorganism; 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 over 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 a common complication of HIGM1 in adolescents and young adultsf and account for approximately 25% of the mortality associated with HIGM1 [Winkelstein et al 2003].
Lymphoma. Males with HIGM1 have an increased risk of lymphoma, particularly Hodgkin's disease associated with Epstein-Barr virus (EBV) infection [Filipovich & Gross 2004].
Other. Recently 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].
Males 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 this mutation.
Penetrance is complete in males with a CD40LG mutation.
Anticipation has not been documented in HIGM1.
The estimated prevalence of HIGM1 is 2:1,000,000 males [Winkelstein et al 2003].
HIGM1 has been reported in families of European, African, and Asian descent; thus, no evidence exists for a racial or ethnic predilection.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
The differential diagnosis of X-linked hyper IgM syndrome (HIGM1) includes the following:
Non X-linked forms of HIGM
HIGM2. Mutations in the activation-induced cytidine deaminase (AICDA) gene 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 [Durandy et al 2005].
HIGM3. Mutations in the CD40 gene, the receptor of CD40 LG, 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. Mutations in the UNG gene 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), and Salzer & Grimbacher (2006) 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 the IL2RG gene. Biallelic mutations in multiple other genes result in autosomal recessive forms of SCID. See Fischer et al (2005) for a current review of these disorders.
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 the gene IfKBKG (also 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.
To establish the extent of disease in an individual diagnosed with X-linked hyper IgM syndrome (HIGM1), the GI and respiratory tracts should be evaluated for overt or occult infections.
For a concise summary of current clinical management practices in this disorder, see Notarangelo & Hayward (2000).
Total parental nutrition may be required.
The 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 [Thomas et al 1995, 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 2005].
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].
The 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 pentamidinef by intravenous or inhalation therapy.
Intravenous immune globulin (IVIG). IVIG replacement should be considered by the time the child is six months old, 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 may be safely administered but do not preclude the need for IVIG replacement.
In areas where cryptosporidium may be present in the water supply, only purified water should be ingested.
Monitor and treat pulmonary complications:
Annual pulmonary function tests for those over age seven years
Follow-up with a high-resolution chest CT scan pulmonary infiltrates which may represent lymphoid aggregates.
Perform 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
It is appropriate to perform molecular genetic testing of CD40LG if the disease-causing mutation in the family is known and assay CD40L protein expression by flow cytometry of newborn at-risk male relatives 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.
Search 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.
There is no evidence that C-section reduces the risk of morbidity or mortality in newborns with HIGM1.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
X-linked hyper IgM syndrome (HIGM1) is inherited in an X-linked manner.
Parents of a proband
The father of an affected male will not have HIGM1 nor will he be a carrier of a CD40LG mutation.
In a family with more than one affected individual, the mother of an affected male is an obligate carrier. Female carriers of a mutation in CD40LG are asymptomatic and have no immunologic or biochemical markers of the disorder.
If pedigree analysis reveals that the proband is the only affected family member, the mother may be a carrier or the affected male may have a de novo gene mutation, in which case the mother is not a carrier. De novo mutations occur in approximately one-third of affected individuals with no previous family history of the disorder. Therefore, the mother of an affected male who has no family history of HIGM1 has a 2/3 chance of being a carrier of the gene mutation.
Sibs of a proband
The risk to sibs depends upon the carrier status of the mother.
If the mother is a carrier of the CD40LG mutation, the chance of transmitting the disease-causing mutation in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers.
Female carriers of CD40LG mutations are asymptomatic and have no immunologic or biochemical markers of the disorder.
Germline mosaicism has been demonstrated in this condition. Thus, even if the proband's disease-causing mutation has not been identified in DNA extracted from the mother's leukocytes, the sibs remain at increased risk.
Offspring of a proband
Males will pass the disease-causing mutation to all of their daughters and none of their sons.
Female carriers of a CD40LG mutation are asymptomatic and have no immunologic or biochemical markers of the disorder.
Other family members of a proband. The proband's maternal aunts or other maternal relatives and their offspring may be at risk of being carriers of a CD40LG mutation, 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.
Carrier testing of at-risk female relatives is available if the family-specific mutation has been identified in an affected male relative.
If sequence analysis has not been performed on an affected male in the family, direct sequencing of the coding regions of CD40LG detects mutations in approximately 95% of female carriers. If a mutation is not identified by sequence analysis, it would be necessary to determine if deletion testing is available from a clinical laboratory.
See Testing of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.
Family planning
The optimal time for determination of genetic risk, clarification of carrier 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, carriers, or at risk of being carriers.
DNA banking. 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.
If the CD40LG mutation has been identified in the family, prenatal testing is possible for pregnancies at increased risk. The usual procedure is to determine fetal sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (CVS) at about ten to 12 weeks' gestation or by amniocentesis usually performed at about 15-18 weeks' gestation. If the karyotype is 46,XY, DNA from fetal cells can be analyzed for the known disease-causing mutation.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified in an affected family member. For laboratories offering PGD, see
.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|
| CD40LG | Xq26 | CD40 ligand |
Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
| Gene Symbol | Locus Specific | Entrez Gene | HGMD |
|---|---|---|---|
| CD40LG | CD40LG | 959 (MIM No. 300386) | CD40LG |
For a description of the genomic databases listed, click here.
Normal 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, over 127 pathologic CD40LG mutations have been published. A database of published CD40LG mutations can be found at www.hgmd.cf.ac.uk
Mutations have been described throughout the five exons of the gene but are particularly common in the TNF-homology domain (exon 5):
Twenty-six percent of these are missense mutations which may affect core packaging, prevent binding to CD40L, or affect trimer formation [Seyama et al 1998].
Twenty percent are nonsense mutations which lead to premature protein truncation.
The remaining mutations are small deletions/insertions, splicing mutations, and gross deletions or insertions.
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 the CD40LG gene by an AluYb8 element insertion in exon 1 has been reported in a young affected individual [Apoil et al 2007].
Most recently a mutation at position -123 of the promoter region has been reported to be responsible for the reduction of CD40L protein [Shimadzu et al 1995, van Hoeyveld et al 2007].
Note: Standard mutation designation of promoter region mutation is NM_000074.2: c.-239A>C (or chrX:135455710A>C, May, 2004 assembly at genome.ucsc.edu).
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
Immune Deficiency Foundation
40 W Chesapeake Ave Suite 308
Towson MD 21204
Phone: 800-296-4433; 410-321-6647
Fax: 410-321-9165
Email: idf@primaryimmune.org
www.primaryimmune.org
Jeffrey Modell Foundation/National Primary Immunodeficiency Resource Center
747 Third Avenue 34A
New York NY 10017
Phone: 800-533-3844; 212-819-0200
Fax: 212-764-4180
Email: info@jmfworld.org
www.info4pi.org
Primary Immunodeficiency Diseases Registry (PIDR)
Phone: 800-296-4433
Primary Immunodeficiency Registry
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
31 May 2007 (me) Review posted to live Web site
20 February 2007 (jj) Original submission
