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Synonyms and related keywords: selective IgM deficiency, SIgMD, hypogammaglobulinemia, IgM, IgM deficiency

Background

Selective immunoglobulin M deficiency (SIgMD) is a rare form of dysgammaglobulinemia characterized by an isolated low level of serum immunoglobulin M (IgM). Reported IgM concentrations in SIgMD vary from 40 mg/dL (though some sources say 20 mg/dL) to undetectable levels (reference range 45-150 mg/dL in adults) (Sorenson, 2000). Values in children must be compared with reference range values for age (Ballow, 2002). The levels of other immunoglobulin classes are within reference ranges.

SIgMD may occur as a primary or secondary condition. Secondary SIgMD is much more common than primary SIgMD and may be seen in association with malignancy, autoimmune disease, gastrointestinal disease, and in patients treated with immunosuppressive agents.

Some patients are asymptomatic, whereas others (often infants and small children) develop serious infections. Patients may develop prolonged or life-threatening infections caused by both encapsulated bacteria and viruses, especially in infancy. In older children and adults, SIgMD is usually discovered during the investigation of other conditions, such as autoimmune disease or malignancy.

Serum immunoglobulin levels are controlled by intricate immunological regulatory mechanisms, and heterogeneity is believed to exist in the pathogenesis of SIgMD. Little is known about the pathological features of SIgMD at a cellular level, given that the condition is so uncommon.

Pathophysiology

The cause of SIgMD is unknown. Increased regulatory T-cell activity specific for IgM has been described (Ohno, 1987). The absence of IgM in the presence of immunoglobulin G (IgG) and immunoglobulin A (IgA) has yet to be explained, as this appears to contradict the theory of sequential immunoglobulin gene rearrangement. Normal mature B cells are expected to have IgM and immunoglobulin D (IgD) on their surfaces, and, with proper stimulation, rearrange their immunoglobulin genes to switch from expressing IgM to IgG, IgA, or immunoglobulin E (IgE).

Having normal levels of IgG and IgA in the face of a low IgM is thus counterintuitive. However, few studies are available to determine whether only the serum IgM level is low or whether the number of B cells with surface IgM is also decreased in most patients. Most of the studies in the literature on this subject were performed before current understanding of the rules governing B-cell switching was elucidated. Gradually, current state-of-the-art laboratory technology is being applied in studying patients with SIgMD, though much remains to be learned at this point.

The currently available literature suggests a heterogeneous population of patients of SIgMD. Some patients are capable of normal antibody responses of other immunoglobulin classes following specific immunization, whereas others respond poorly. Certain patients have been described who have decreased helper T-cell activity (De la Concha, 1982). Cell-mediated immunity appears to be intact, but an insufficient number of detailed studies are available to confirm this. Suggested etiologies include rapid isotype switching of B cells from production of IgM to production of other isotypes and hypercatabolism of IgM.

Frequency

International

SIgMD is rare, with an incidence of less than 0.03% in the general population and 1% in hospitalized patients (Inoue, 1986).

Mortality/Morbidity

Infants can succumb to overwhelming infections such as meningitis, pneumonia, and gram-negative sepsis.

Patients with SIgMD are susceptible to overwhelming infection with encapsulated bacteria (eg, Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae). They may also have autoimmune disease, malignancies, chronic dermatitis, diarrhea, and upper respiratory infections.

Race

The incidence of SIgMD in various races has not been reported, given the low overall incidence.

Sex

The disorder occurs in both males and females, with no known discrepancies between the sexes.

Age

Infants can present with severe and overwhelming infections. Older children may present with recurrent sinopulmonary infections secondary to encapsulated organisms and an increased incidence of gram-negative septicemia.

History

• Patients may be asymptomatic, with a decreased IgM level noted during the investigation of other diseases, such as malignancies or autoimmune diseases.



• Prolonged or life-threatening infections also occur, especially in infancy. Recurrent infections (eg, sinusitis and pneumonia) are caused by encapsulated bacteria. Infections with gram negative bacteria are also more common, especially with Pseudomonas aeruginosa.



• Associated disorders or symptoms may include atopic or chronic dermatitis, allergic rhinitis, wheezing, and diarrhea. Patients may have a history of splenectomy.

Physical

Failure to thrive may be present, due at least in part to frequent infections. Other associated signs may include features of dermatitis, allergic rhinitis, wheezing, and splenomegaly, as well as those of other primary conditions associated with secondary SIgMD, such as malignant or autoimmune disorders.

Causes

The cause of SIgMD is unknown, and any pattern of inheritance appears to be variable.

• Patients with malignant neoplasms (eg, clear cell sarcoma, Bloom syndrome, promyelocytic leukemia), autoimmune diseases (eg, rheumatoid arthritis, Hashimoto's thyroiditis, systemic lupus erythematosus, autoimmune hemolytic anemia), infections (eg, Brucella), or those given immunosuppressive agents may develop secondary SIgMD (Yamasaki, 1992; Herrod, 2001).



• As cited by Zaka-ur-Rab (2005), associations exist between SIgMD and gastrointestinal conditions, including Crohn disease, chronic diarrhea, lymphoid nodular hyperplasia, Whipple disease, and splenomegaly.



• Infants with permanent congenital hypothyroidism were shown to have undetectable or lower concentrations of IgA and lower concentrations of IgM than normal controls (Stagi, 2005).



• A report of 13 multiple myeloma patients in a phase 2 study showed that the 7 patients who received rituximab following autologous stem cell transplantation developed severely depressed levels of IgM that were persistent with continued rituximab therapy. When compared to the 6 myeloma patients who had received autologous stem cell transplantation without rituximab, not only were IgM levels significantly decreased, but those in the rituximab group experienced far more infections, including 21 cases of pneumonia, 2 cases of sepsis, and one death during the first 12 months (Lim, 2004).



• One case report describes a 15-year-old female with 22q11.2 deletion syndrome (in her case, partial DiGeorge Syndrome) who presented with recurrent and chronic otitis media who was found to have SIgMD, associated with no other immunologic defects (Al-Herz, 2004).

DiGeorge Syndrome
Hypocomplementemia
Hypogammaglobulinemia
Immunoglobulin A Deficiency
Immunoglobulin G Deficiency
Wiskott-Aldrich Syndrome

Other Problems to be Considered

Common variable immunodeficiency
Defects in B lymphocytes and T lymphocytes

Wiskott-Aldrich syndrome (WAS) also presents with low levels of IgM, but levels of IgA and IgE are often elevated. WAS is an X-linked disorder manifesting in infancy with eczema, thrombocytopenia, and recurrent pyogenic infections.

Lab Studies

• Quantitative levels of IgM, IgG, IgA, and IgE, along with IgG subclasses, are measured. This is done to exclude more common immunodeficiency disorders, such as common variable immunodeficiency and IgA deficiency.



• The biological significance of a seemingly isolated low IgM level may be assessed by immunizing the patient with protein (eg, tetanus) and polysaccharide (eg, unconjugated Streptococcus pneumoniae) vaccines and assessing whether antigen-specific IgG responses are normal.

Imaging Studies

• Imaging studies are not required routinely for SIgMD. However, if patients give a history of recurrent sinopulmonary infection, CT scans of the sinuses and chest may be helpful for diagnosing chronic sinusitis and bronchiectasis, respectively.

Other Tests

• Flow cytometry for B cells with surface IgM may be helpful.
• Other tests are not required routinely for SIgMD. However, other tests may be needed for further evaluation of associated diseases.

Procedures

• Diagnostic procedures are not routinely required for SIgMD. They may be needed for diagnosis of infections, complications, or associated diseases.

Medical Care

• Replacement of IgM is not an option, as IgM is not a significant component of therapeutic preparations of intravenous immunoglobulin. However, defective antigen-specific IgG responses have been demonstrated in some patients. For such patients, IVIG replacement may be an option.



• Prophylactic and therapeutic antibiotics may be beneficial.



• Fresh frozen plasma may be considered for severe infections (Zaka-ur-Rab, 2005).



• In a patient who is asymptomatic and in whom a decreased IgM level has been noted incidentally, prophylactic antibiotics are not needed.

Consultations

• Patients with SIgMD should be under the care of a clinical immunologist, as a workup to exclude other immunodeficiencies is essential.
• Consultation with an infectious disease specialist may also be helpful in the patient with recurrent infections.

Infections should be treated promptly with appropriate broad-spectrum antibiotics, depending on the suspected pathogen.

Intravenous immunoglobulin is a therapeutic consideration for patients with SIgMD who have demonstrated findings of defective antigen-specific IgG responses.

Further Outpatient Care

• Determination of quantitative immunoglobulins (IgM, IgG, IgA, IgE) and IgG subclasses should be performed at periodic intervals (ie, every 1-2 y).

Complications

• Prompt treatment of infections helps to decrease morbidity and mortality.

Prognosis

• Patients with severe life-threatening infections clearly have poor prognoses. Other patients who are asymptomatic may have excellent prognoses.

Patient Education

• Educate patients to promptly report any symptoms of infection.

Medical/Legal Pitfalls

• Patients should be promptly referred to a clinical immunologist. Quantitative measurements of other immunoglobulin isotypes (in order to exclude other humoral immunodeficiencies) upon discovering low IgM levels must also be done.