Immunoglobulin M Deficiency

Article Last Updated: Jun 8, 2006
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Synonyms and related keywords: selective IgM deficiency, SIgMD, hypogammaglobulinemia, IgM, IgM deficiency

INTRODUCTION


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.


CLINICAL


History

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.


DIFFERENTIALS


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.


WORKUP


Lab Studies

Imaging Studies

Other Tests

Procedures


TREATMENT


Medical Care

Consultations


MEDICATION


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.


FOLLOW-UP


Further Outpatient Care

Complications

Prognosis

Patient Education


MISCELLANEOUS


Medical/Legal Pitfalls