OVERVIEW: What every practitioner needs to know

Are you sure your patient has hyper IgM syndrome? What are the typical findings for this disease?

The most common manifestation of the hyper IgM syndromes is recurrent sino-pulmonary infections but this does not differentiate the disease from other antibody deficiency diseases. Susceptibility to opportunistic infections especially Pneumocystis jiroveci and
Cryptosporidium parvum is characteristic of the most common X-linked form of hyper IgM, as well as the autosomal recessive form of Hyper IgM caused by mutations in the CD40 gene.

Other characterisitic features include neutropenia, stomatitis, and liver disease including sclerosing cholangitis. Patients also have a higher incidence of tumors of the liver, pancreas or biliary tree and an increased susceptibility to neuroectodermal tumors. Lymphoid hyperplasia is characteristic of the autosomal recessive form of the disease (except for mutations in CD40).

Some patients with a milder form of the disease, present in adolescence with a Parvovirus-induced aplastic anemia.

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Physical examination is generally not helpful in making a specific diagnosis of Hyper-IgM Syndrome, but a thorough exam is obviously an essential part of diagnosing associated infection. Patients with autosomal recessive hyper IgM, like certain other immunodeficiency syndromes, may have enlarged tonsils, adenoids and other lymphoid tissue.

Laboratory studies (discussed below) are necessary for the definitive diagnosis of the hyper IgM syndromes.

What other disease/condition shares some of these symptoms?

Recurrent infection is the hallmark of all immunodeficiency diseases. Recurrent sinopulmonary infections are seen in antibody deficiency diseases as well as in the combined (Tcell and antibody) immune deficiencies.

Opportunistic infections due to organisms like Pneumocystis jiroveci and
Cryptosporidium parvumare also characteristic of T cell immunodeficiencies like Severe Combined Immunodeficiency (SCID) or from acquired immunodeficiency due to HIV infection or immunosuppressive medications.

Neutropenia with recurrent infections can be seen in a variety of congenital and acquired conditions including Common Variable Immunodeficiency, Kostman’s Syndrome or Congenital Neutropenia, Schwachman-Diamond Syndrome, and as a side effect of medications (trimethoprim/sulfa, certain anticonvulsants, etc.)

What caused this disease to develop at this time?

The hyper IgM syndromes are caused by genetic defects in the CD40 ligand (CD154) and CD40 signaling pathway that is necessary for immunoglobulin isotype switching.

The most common form, X-linked hyper IgM, results from genetic defects in the CD40 ligand gene. Autosomal recessive forms results from defects in the gene encoding CD40 (similar disease expression to CD40 ligand defects but very rare), activation-induced cytidine deaminase (AID, most common autosomal recessive defect) and Uracil-N-glycosylase (UNG). The latter two enzymes are both required for immunoglobulin isotype switching from IgM/IgD to IgG, IgA and IgE and for somatic hypermutation of the variable regions of Ig molecules.

Another form of hyper IgM syndrome results from defects in an X-linked gene encoding the NF-kB essential modulator (NEMO) causing ectodermal dysplasia with an immunodeficiency that resembles hyper IgM on immunological studies. NEMO is important for activation of the transcription factor NF-kB, which mediates signaling pathways for innate and adaptive immune systems including CD40 and other TNF-receptor family members.

Patients with defects in NEMO have a susceptibility to a wider range of pathogens including atypical mycobacteria.

The presence of a family history of X-linked hyper IgM or of an X-linked pattern of immunodeficiency (death at an early age from infection) is highly suggestive of the condition. A family history of autosomal recessive hyper IgM is less likely to be found.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The diagnosis of hyper IgM is suggested by the presence of very low to absent serum levels of IgG with elevated, normal, or even low IgM. IgA levels are also usually absent but some patients may have normal IgA levels. A hallmark of hyper IgM is failure to synthesize specific antibody to vaccines. Neutropenia may be present on CBC with differential.

Patients will have normal lymphocyte subset percentages and absolute counts with normal T cell proliferation to mitogens and variable proliferative responses to specific antigens. Absence of expression of CD40 ligand on activated T cells is highly suggestive of the X-linked form of the disease. However, normal CD40 ligand expression does not absolutely rule out the disease as some point mutations in the CD40 ligand gene may not affect cell surface expression of the CD40 ligand protein.

Genetic sequencing for one of the known gene defects will confirm the diagnosis: CD40 ligand, CD40, NEMO, AID or UNG.

Would imaging studies be helpful? If so, which ones?

Imaging studies are not generally useful for suspecting or for confirming the diagnosis but are often helpful for the evaluation of concurent infections: CXR for pneumonia and/or Pneumocytis pneumonitis; computed tomography (CT) Scan of the sinuses may be useful in diagnosing sinusitis, and CT scan of the abdomen may be necessary for evaluation of potential complications such as liver disease and/or malignancy.

Confirming the diagnosis

A history of severe recurrent infections, chronic and complicated infections, or infection with an opportunistic organizm (especially if it requires admission to a Pediatric Intensive Care Unit), should prompt consideration of a possible immune defect.

A serum immunoglobulin pattern showing low or absent IgG with low, normal or elevated serum IgM should raise the possibility of hyper IgM, especially if specific antibody levels are below detection.

The presence of B cells on lymphocyte subset analysis rules out X-linked agammaglobulinemia and the presence of normal T cell numbers and subsets with normal proliferation to mitogens rules out SCID. This then should prompt evaluation of CD40 ligand expression unless the patient is female. The absence of CD40 ligand expression in a boy would prompt sequencing of the CD40 ligand gene to confirm the diagnosis of X-linked hyper IgM. If CD40 ligand expression is normal, sequencing of the CD40 ligand gene can identify point mutations that do not affect CD40 ligand protein expression but impair its function.

If an affected male has features of ectodermal dysplasia and/or CD40 ligand expression and gene sequencing are normal, then sequencing of the NEMO gene can confirm the diagnosis of ectedermal dysplasia with immunodeficiency.

If the patient has no defect in CD40 ligand or NEMO or if the patient has lymphoid hyperplasia or is a female or has a family history of affected females, then assessment of CD40 protein expression by flow cytometry followed by sequencing for the AID or UNG genes and lastly the CD40 gene should be done to identify autosomal recessive hyper IgM syndrome.

Lastly, there are cases of hyper IgM without an identified gene defect.

If you are able to confirm that the patient has hyper IgM syndrome, what treatment should be initiated?

Even before a definitive diagnosis is made, low or absent IgG levels in the serum, associated with poor or absent specific antibody levels should prompt treatment with immunoglobulin replacement. IgG replacement can be done intravenously at a dose of 500-600 mg/Kg every 3-4 weeks or subcutaneously at a dose of 150-200 mg/Kg weekly.

Initiation of prophylactic treatment to prevent Pneumocystis should be initiated until the absence of a defect in CD40, CD40 ligand and NEMO is established. GM-CSF can be used for severe neutropenia, especially if it is associated with significant infection. In addition, a clean water supply is necessary to prevent infection with Cryptosporidium.

In terms of long term management, patients with CD40 ligand defects, NEMO defects and patients with CD40 defects may benefit from a stem cell transplant, especially if there is a matched related donor or a good matched unrelated donor available. The long-term benefit of stem cell transplantation is presumed based on the high risk of complications of sclerosing cholangitis, liver disease, and cancer and the paucity of patients older than 30 years of age in two patient registries, one from Europe and one from the United States. However, the long-term assessment of risk/benefit of stem cell tranplantation is not available yet.

What are the adverse effects associated with each treatment option?

Immunoglobulin replacement is necessary to provide immunity against the most common pathogens. The potential adverse events include tranfusion-like reactions, headache, aseptic meningitis, fever, myagias and the potential for infection by a blood-borne pathogen.

Stem cell transplantation has the potential of providing a cure for hyper IgM, however there is a risk of acute or chronic graft-versus-host disease (GVHD) and long term complications of the myeloablation regimen used.

What are the possible outcomes of hyper IgM?

The prognosis for X-linked hyper IgM, CD40-deficient hyper IgM and NEMO is very guarded. While antibody replacement reduces the frequency and severity of infections, few patients with X-linked hyper IgM live beyond 30 years of age. Therefore, stem cell transplantation is recommended when a suitable donor is available. The long-term benefit of stem cell transplantation is not determined yet as the first stem cell transplantation for hyper IgM was reported in 1993.

NEMO can also be treated with stem cell transplantation but NEMO is found in all tissues and stem cell transplantation only corrects the immunodeficiency. Other manifestations of the disease, such as enteritis that is found in some of the patients may not resolve with stem cell transplantation.

The other forms of autosomal recessive hyper IgM (caused by mutations in AID and UNG) have a better prognosis as the defect is mainly an antibody deficiency. In these cases immunoglobuloin replacement therapy should provide adequate disease management. Affected patients remain at risk for autoimmune disease, which appears to be more common in these conditions than in X-linked hyper IgM.

Antibody replacement therapy is necessary for all patients with the primary hyper IgM syndrome described above. The decision to proceed with a stem cell transplant is determined by the presence of a suitable donor, the underlying cause of the hyper IgM syndrome (CD40 ligand, CD40 or NEMO) and patient/parent preference.

What causes this disease and how frequent is it?

The hyper IgM syndromes are rare inherited defects affecting the CD40 ligand:CD40 signaling pathway resulting in failure to undergo immunoglobulin isotype switching from IgM/IgD to IgG, IgA and IgE. The exact incidence is not known but thought to be 1:1,000,000 for the most common form, X-linked hyper IgM resulting from defects in the CD40 ligand gene.

The genes that have been identified to cause hyper IgM include:

  • CD40 ligand, which is inherited in an X-linked recessive manner and therefore affects boys only.

  • CD40, which is inherited in an autosomal recessive form.

  • NEMO, which is activated downstream of CD40 and is inherited in an X-linked recessive manner.

  • AID and UNG, which are also activated downstream of CD40 and inherited in an autosomal recessive manner.

How do these pathogens/genes/exposures cause the disease?

CD40 ligand is expressed on activated CD4 T cells, among other cells, which then signals B cells and other antigen-presenting cells via CD40 to activate immunoglobulin isotype switching in B cells and co-stimulatory molecules on antigen-presenting cells especially dendritic cells that promote T cell differentiation. The failure of CD40 ligand to bind and activate CD40 results in the X-linked form of hyper IgM with failure of immunoglobulin isotype switching and a T cell defects that makes affected patients susceptible to opportunistic infections and the severe complications of liver disease and cancer.

Defects in CD40 also result in a similar phenotype but affects males and females equally as an autosomal recessive hyper IgM. This condition is very rare and has been described in few consanguinous families.

Ectodermal dysplasia with immunodeficiency is another X-linked form of hyper IgM that results from hypomorphic mutations in NEMO, which is necessary for activation of NF-kB, a transcription factor downstream of CD40 and other TNF-receptor families as well as antigen receptors on T cells and B cells, the T cell receptor and immunoglobulin, respectively as well as toll-like receptors (TLR) and IL-1 receptor family. Therefore, both innate and adaptive immunity is affected and affected patients suffer from infections by a wider range of infectious agents.

The other autosomal recessive forms of hyper IgM result from defects in AID and UNG, two enzymes necessary for immunoglobulin isotype switching in B cells. These conditions are thought to be limited to antibody deficiency without a susceptibility to opportunistic infections and the prognosis for these patients is better than the above gene defects. However, patients may be more susceptible to autoimmune disease and complications of lymphoid hypertrophy.

How can hyper IgM be prevented?

Inherited causes of hyper IgM cannot be prevented, however, complications of the disease such as opportunistic infections can be prevented by prophylactic antibiotics or use of monthly pentamidine. Antibody replacement can prevent infections and reduce mortality and morbidity, but cannot prevent cancer and other severe complications. A family history can help diagnose the disease early and initiate therapy before significant infection and its complications have occurred.

Genetic counseling of families of affected patients is important to help diagnose and treat future patients early.

What is the evidence?

Davies, EG, Thrasher, AJ. “Br J Haematol”. Update on the hyper immunoglobulin M syndromes. vol. 149. 2010. pp. 167(This paper is an overview of the molecular and clinical spectrum of the Hyper-immunoglobulin M syndromes. The specific genetic disorders that result in defective immunoglobulin class switch recombination (CSR), with or without defects of somatic hypermutation (SHM) and the mechanisms leading to defective T cell activation are reviewed. Therapies with immunoglobulin replacement therapy, bone marrow transplantation and potenial gene therapy approaches are described. PMID 20180797.)

Imai, K, Slupphaug, G, Lee, WI. “Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination”. Nat Immunol. vol. 4. 2003. pp. 1023

Quartier, P, Bustamante, J, Sanal, O. “Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to Activation-Induced Cytidine Deaminase deficiency”. Clin Immunol. vol. 110. 2004. pp. 22

Ongoing controversies regarding etiology, diagnosis, treatment

The decision to undergo a stem cell transplant remains somewhat controversial as there may be significant side effects and long-term outcome data is not yet available.