X-linked Immunodeficiency With Hyper IgM Workup

Updated: Oct 23, 2019
  • Author: C Lucy Park, MD; Chief Editor: Harumi Jyonouchi, MD  more...
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Laboratory Studies

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  • Most early descriptions of X-linked immunodeficiency with hyper–immunoglobulin M (XHIGM) reported that patients had elevated serum immunoglobulin (Ig)M levels but markedly reduced IgG, IgA, and IgE levels. According to the US XHIGM Registry report in 2003, elevated IgM levels were found in less than one third of patients. [4] All patients had reduced levels of IgG. More than three fourths of patients had reduced levels of IgA.

  • Diagnosis is confirmed by demonstrating a deficient expression of CD40L on activated CD4+ T lymphocytes using flow cytometric analysis with anti–CD40L monoclonal antibody. Phenotypical analysis of circulating lymphocytes (CD3, CD4, CD8, and CD19 expression) generally shows normal counts of T and B cells.

  • A few case reports described a man with normal expression of CD40L on activated T cells who was found to have hypomorphic mutations of the CD40LG or deletion of several nucleotides and frameshift mutation. Therefore genetic diagnosis should be performed when clinical data support this diagnosis and CD40L protein is present on activated T cells. (ref.11, 36)

  • Diagnostic criteria used for the US XHIGM Registry consisted of 2 of the following: (1) mutation of CD40LG, (2) a positive family history of a lateral male relative with the HIGM syndrome, and (3) defective expression of CD40L on activated T lymphocytes. Patients with reduced CD40L expression only, without positive family history or mutation of CD40LG, cannot be included because this reduced expression can occur in some patients with common variable immunodeficiency (CVID).

  • Functional antibody production that requires T-cell and B-cell interaction (T-cell dependent) is markedly impaired. Antibodies against T-cell–dependent antigens, such as antibodies to tetanus-toxoid, diphtheria-toxoid, and protein-conjugated H influenzae type b antigens, are absent. Although pneumococcal polysaccharide antigens are T-cell independent, IgG antibodies against these antigens are not produced. Antibodies to T-cell–independent antigens in the IgM class, such as isohemagglutinin (antibodies against ABO blood group antigens), are often normal.

  • Despite decreased or absent functional antibody production, these patients may produce a large amount of autoantibodies against erythrocytes, platelets, and other organs, such as antiparietal cells and antithyroid microsomal autoantibodies.

  • In vitro lymphocyte stimulation with T-cell mitogens (phytohemagglutinin or concanavalin A) was normal in over 90% of patients with XHIGM. A minority of patients had a reduced in vitro proliferative response to tetanus toxoid.

  • B cells from patients with XHIGM can be driven to secrete immunoglobulins of various isotypes in the presence of pokeweed mitogens when cocultured with helper T lymphoblasts from a patient with a Sézary-like syndrome. This finding illustrates a primary T-cell defect in XHIGM.

  • Neutropenia frequently accompanies XHIGM and can be chronic, cyclic, or occasional. Bone marrow studies show maturation arrest of the myeloid lineage at the promyelocyte-myelocyte stage. Autoantibodies to neutrophils are not detected.

  • Evaluation of infection by appropriate culture and determination of antibiotic sensitivities are integral to managing any immune deficiency disease. Sputum and stool cultures are commonly needed, and obtaining a culture at any acute infection site before administering antibiotics is crucial.

  • Perform liver function tests at diagnosis and yearly thereafter because subclinical hepatitis is not uncommon. Viral hepatitis (B and C) testing requires antigen detection because most patients are unable to produce antibodies. Perform biopsies on patients with hepatic disease to best delineate the extent of disease.

  • Gene mutation analysis should be performed for the final confirmation of diagnosis. If the precise mutation in CD40LG is known in a given family, and if the fetus is male, a prenatal diagnosis is possible. Women in the family can be tested to see if they carry the mutation and are, therefore, at risk for having an affected son.

  • About 20% of patients with XHIGM express nonfunctional CD40L on T cells that can bind anti–CD40L monoclonal antibodies. Therefore, these patients may require testing to determine whether their T cells can bind to CD40 molecules using CD40-Ig fusion protein. The final molecular diagnosis may depend on sequence analysis of CD40LG using cDNA or genomic DNA.

  • A physician consultation service is available through the Immune Deficiency Foundation.


Imaging Studies

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  • Chest radiographs and sinus radiographs or CT scans are initially needed for baseline studies. Patients with chronic sinopulmonary disease are customarily reevaluated at intervals with CT imaging.

  • Abdominal CT imaging or MRI is indicated in patients with hepatomegaly, cholangitis, or abnormal liver function test findings.


Other Tests

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  • Pulmonary function tests are essential at diagnosis and yearly thereafter to monitor for chronic lung disease. Approximately one fourth of patients with XHIGM have bronchiectasis; the risk of bronchiectasis is higher if the initiation of intravenous immunoglobulin (IVIG) therapy is delayed.



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  • Bronchoscopy and bronchoalveolar lavage may be required in patients with severe pulmonary disease that does not respond to usual antibiotic therapy or patients who may have P jiroveci pneumonia in order to obtain a specimen for identification of pathogens.

  • Patients with chronic diarrhea may require endoscopy and biopsy to rule out inflammatory bowel disease.

  • Patients with abnormal liver function may require percutaneous liver biopsy.


Histologic Findings

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  • Lymph node biopsy findings reveal a lack of germinal centers, attributed to ineffective CD40L-CD40 interaction in the extrafollicular areas, resulting in poor recruitment of germinal center precursors.