SUMMARY

 

1. X-linked Hyper IgM syndrome (HIGM Type I) is a combined immune deficiency that is characterized by antibody deficiency as well as an impaired ability of T cells to activate monocytes and dendritic cells. 

 

2. This disease is caused by mutations in CD40 ligand (CD40L), a molecule that is expressed on the surface of activated T cells. CD40L interacts with CD40 on the surface of B cells to activate immunoglobulin class-switching (shifting antibody production from IgM to IgG, IgA, or IgE) and to establish B cell memory. 

 

3. Patients with CD40 deficiency (HIGM Type 3) have an autosomal recessive form of hyper IgM syndrome which can present with features identical to X-linked hyper IgM syndrome. 

 

4. CD40L interaction with CD40 expressed on dendritic cells leads to secretion of IL-12 (a key cytokine in Th1 immunity). The failure to secrete IL-12 impairs the ability of T cells to produce IFN-gamma and to activate monocytes. This defect in Th1 immunity may underlie the predisposition to opportunistic infections in these patients 

 

5. Clinically patients present early in life with a phenotype consistent with antibody immunodeficiency: recurrent pneumonia, otitis media, and sinusitis with encapsulated bacteria. However, patients also develop opportunistic infections including Pneumocystis jiroveci pneumonia (which occurs in more than one-half of patients). Chronic infectious diarrhea can occur from Cryptosporidium and Giardia. Cryptosporidium is also a major cause of sclerosing cholangitis in patients. 

 

6. Other reported infections include bacterial sepsis, enterovirus CNS infections, and skin cellulitis/abscess. 

 

7. Intermittent neutropenia is observed in over 60% of patients. This can be chronic and exacerbated by acute infections. Neutropenic patients can develop oral ulcers and gingivitis. Bone marrow analysis typically reveals a block in maturation at the pro-myelocyte to myelocyte stage. 

 

8. Classic laboratory findings include elevated IgM with very low serum IgG and IgA levels. It is important to note that one-half of patients actually have normal levels of IgM at initial presentation. Specific antibody responses to vaccine antigens are decreased. While the total numbers of B cells are normal, they have a naïve phenotype with expression of surface IgM and IgD. Patients lack switched memory B cells (CD27+IgM-IgD-) due to failed class-switch recombination. T cell numbers and function are normal. 

 

9. Rapid screening for X-linked Hyper IgM can be performed by flow cytometry to detect CD40L on activated T cells. Sequencing of the gene for CD40L (TNFSF5) can confirm the diagnosis. 

 

10. IVIG replacement therapy is indicated for patients as well as PJP prophylaxis with trimethoprim-sulfamethoxazole. G-CSF therapy may be useful for treatment of neutropenia. 

 

11. Despite supportive therapy, long-term survival is guarded. Hepatic disease can be a major cause of death. Some studies have shown only 40% survival beyond 25 years of age. As a result, HSCT is a serious consideration for patients if there is an HLA-identical sibling donor or a matched unrelated donor available (success rate is approximately 70%). 

 

 

 

 

OVERVIEW

 

       X-linked Hyper IgM syndrome (HIGM Type I) is a combined immunodeficiency that is characterized by antibody deficiency (elevated IgM but low IgG and low IgA, decreased specific antibody response) as well as a defect in cell-mediated immunity. 

 

       Clinically patients present early in life with a phenotype consistent with antibody immunodeficiency: recurrent pneumonia, otitis media, and sinusitis with encapsulated bacteria. However, patients also develop opportunistic infections including Pneumocystis jiroveci pneumonia (which occurs in more than one-half of patients). CMV, Cryptococcus, and mycobacterial infections can also occur. 

 

      Chronic infectious diarrhea can occur from Cryptosporidium and Giardia. Infections with Salmonella and Entamoeba histolytica have also been reported. Cryptosporidium is also a major cause of sclerosing cholangitis in patients. 

 

      CNS infections include meningitis or encephalitis from enterovirus, JC virus, cryptococcus, toxoplasma, and mycobacterial infection. 

 

      Unlike patients with XLA, X-linked hyper IgM patients have tonsillar tissue and lymph nodes. Hepatosplenomegaly may be present on physical examination. 

 

       Intermittent or chronic neutropenia is a common finding that develops in more than 60% of patients and can be exacerbated by acute infection. Neutropenia can lead to stomatitis, oral ulcers, and proctitis. Neutrophil development is typically arrested at the promyelocyte to myelocyte stage. 

 

       Classic laboratory features include very low IgG and IgA levels but markedly elevated IgM levels. However, it is important to note that normal IgM levels are noted in 50% of patients at initial presentation. Specific antibody responses to vaccine antigens are markedly reduced. While total B cell numbers are normal, the switched memory B cell population (CD27+IgD-IgM-) is very low. T cell numbers and function (proliferation to mitogens and antigens) are normal. CD40L expression on the surface of activated T cells is typically absent. 

       

 

 

PATHOGENESIS

 

       CD40 ligand is a type II transmembrane glycoprotein that is mainly expressed on activated T cells. CD40 is the receptor for CD40L and is expressed on the surface of B cells. CD40-CD40L signaling plays a critical role in B cell proliferation and differentiation. The interaction is responsible for inducing antibody class-switching (from IgM to IgG, IgA, and IgE) and generation of memory B cells. As a result, patients have very low IgG and IgA levels but markedly elevated IgM levels. Patients have a very low switched memory B cell population (CD27+IgD-IgM-). 

 

       CD40 is also expressed on the surface of monocytes and dendritic cells. Defective CD40-CD40L signaling leads to impaired IL-12 secretion from dendritic cells, which results in decreased IFN-gamma secretion from T cells and impaired macrophage activation. This likely explains the susceptibility of patients to opportunistic infections such as Pneumocystis jiroveci. 

         

 

 

 

DIFFERENTIAL DIAGNOSIS

 

It is important to consider other primary causes of hypogammaglobulinemia as well as combined immunodeficiencies (given the high incidence of opportunistic infections) 

 

1. X-linked or AR agammaglobulinemia 

2. Autosomal recessive Hyper IgM syndromes 

3. WHIM syndrome (this can present with neutropenia and hypogammaglobulinemia) 

4. NEMO deficiency 

5. Transient Hypogammaglobulinemia of Infancy 

6. Other combined immunodeficiencies 

7. Severe Combined Immunodeficiency (SCID) 

 

 

 

EVALUATION

 

An evaluation for this disease should be considered for patients suffering from bacterial sinopulmonary infections as well as opportunistic infections (Pneumocystis jiroveci pneumonia) at an early age.   


Step 1: Quantitative and Functional Humoral Evaluation 

 

 -Quantitative immunoglobulins (IgG, IgM, IgA) 
 -Antibody titers to vaccine antigens 
 -Flow cytometry for B, T, and NK cell numbers 
 -CBC with differential 

 

 -Classically patients present with low IgG and IgA but elevated IgM. However, one-half of patients have normal IgM at initial presentation. 

 -Protein and polysaccharide vaccine antibody (IgG) responses should be evaluated (ex. Tetanus, Diphtheria, and Pneumococcus). These will typically be very low in patients. 

 -Absolute B, T, and NK cell numbers are typically normal. The presence of appropriate lymphocyte subsets distinguishes this condition from SCID. 

 -A CBC with differential may reveal the presence of neutropenia, a common finding in patients. 


Step 2: Additional Immune Evaluation 

 

-Lymphocyte flow cytometry for B-cell subpopulations (including switched memory B-cell numbers: CD27+ IgD- IgM-). 
-T cell proliferation to mitogens
-Bone Marrow Aspiration (if neutropenia is present) 

 

-Patients have a very low switched memory B cell population (CD27+IgD-IgM-) 

-T cell proliferation to mitogens is typically normal. However, this is a useful evaluation to consider because opportunistic infections can be seen in SCID and other combined immune deficiencies. 

-In patients with neutropenia, bone marrow aspiration typically reveals an arrest in neutrophil development at the promyelocyte to myelocyte stage. 


Step 3: Screening for CD40L expression 

 

-Flow Cytometry for CD40 ligand (CD154) expression 

 

-Flow cytometry to assess expression of CD40 ligand on the surface of activated T cells can be useful for rapid diagnosis. However, in rare cases, anti-CD40L antibody can bind to mutant forms of the protein resulting in a normal test. 


Step 4: CD40L gene sequencing 


-CD40L gene sequencing (TNFSF5) 

 

-Sequencing of the CD40L gene (TNFSF5) is commercially available and can confirm the diagnosis. Sequencing typically takes 4-6 weeks. 

 

 

 

 

MANAGEMENT

 

1. Monthly immunoglobulin (IVIG) therapy 

Starting doses should be 400-600mg/kg/month for IV therapy. 
 

2. Antibiotic prophylaxis for Pneumocystis jiroveci pneumonia 

Trimethoprim-sulfamethoxazol 4-6 mg/kg (TMP component) divided twice daily 3 days a week. Maximum one double strength tablet (sulfamethoxazole 800 mg; trimethoprim 160 mg) once daily 3 days a week. 


3. Treatment of Neutropenia 

Patients with persistent neutropenia may respond to therapy with GCSF (granulocyte colony stimulating factor). 


4. Hematopoietic Stem Cell Transplantation (HSCT) 
Despite the use of the above supportive measures, the survival rate is poor. Opportunistic infections and liver disease are major causes of death. HSCT is a curative therapy for patients and should be considered if there is an appropriate HLA-identical sibling or a matched unrelated donor. The overall success rate is approximately 70% for HLA-identical sibling or matched unrelated donor transplants. Transplantation is more successful if performed prior to significant lung or liver damage. 

 

 

 

 

RESOURCES

 

Diagnostic Resources      (LAB ORDER FORMS)

 

1. B cell panel  - CHOP & Cincinnati 

2. CD40L flow cytometry - Cincinnati 

3. CD40L gene sequencing - Correlagen

 

Literature Resources

 

1.  Notarangelo 2006 
     Defects of class-switch recombination
     

2.  Winkelstein 2003 
     X-linked Hyper IgM syndrome  - features of 79 patients
     

3.  Levy 1997 
     Clinical spectrum of X-linked Hyper IgM syndrome
     

4.  Lee 2005 
     Molecular Analysis of a 140 patient Hyper IgM cohort
     

5.  Cunningham CK 1999 
     Enteroviral meningoencephalitis in X-linked Hyper IgM
     

6.  Han 2005 
     JC virus and BK virus in a X-linked HIGM patient with PML
     

7.  Aschermann 2007 
     XL HIGM and PML (case report)
     

8.  Gennery 2003 
     HSCT for XL HIGM - European Experience (38 patients)
     

9.  Jacobsohn 2004 
     Nonmyeloablative HSCT for 2 patients with XL HIGM