Background
Selective immunoglobulin M (SIgM) deficiency is a rare form of dysgammaglobulinemia characterized by an isolated low level of serum immunoglobulin M (IgM). [1] Reported IgM concentrations in SIgM deficiency vary from 40 mg/dL (though some sources say 20 mg/dL) to undetectable levels (reference range 45-150 mg/dL in adults). [2] Recent series report IgM levels of 29.7±8.7 mg/dL (mean±SD) for adults and 16.5±13.8 (mean±SD) in children. [3, 4] In this context, remember that 2.1% of "normal" individuals have values < 2 SD below the mean and that values in children must be compared with reference range values for age. [5] The levels of other immunoglobulin classes are within reference ranges.
SIgM deficiency may occur as a primary or secondary condition. [6] Secondary SIgM deficiency is much more common than primary SIgM deficiency and may be seen in association with malignancy, autoimmune disease, gastrointestinal disease, and immunosuppressive treatment. [1]
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, SIgM deficiency is usually discovered during the investigation of other conditions, such as autoimmune disease or malignancy. [1]
Serum immunoglobulin levels are controlled by intricate immunological regulatory mechanisms, and heterogeneity is believed to exist in the pathogenesis of SIgM deficiency. Little is known about the pathological features of SIgM deficiency at a cellular level, given that the condition is so uncommon. Processes that control the survival of IgM in the circulation and may otherwise regulate its concentration in serum have not been well described; alterations in clearance mechanisms, in addition to altered production of IgM by lymphocytes, may contribute to selective deficiency of this immunoglobulin isotype.
Pathophysiology
The cause of SIgM deficiency is unknown. Increased regulatory T-cell activity specific for IgM has been described. [7] The absence of IgM in the presence of normal levels 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 low IgM is thus counterintuitive. One could speculate that failure to regenerate B-cell precursors could lead first to depletion of IgM, with gradual loss of IgG and other isotypes occurring later as class-switched memory B-cells and plasma cells fail to be replaced. This hypothesis has not been tested, and 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 patients with selective IgM deficiency. Gradually, current state-of-the-art laboratory technology is being applied in studying patients with SIgM deficiency, though much remains to be learned.
The currently available literature suggests a heterogeneous population of patients of SIgM deficiency. Some patients are capable of normal antibody responses of other immunoglobulin classes following specific immunization, whereas others respond poorly. Certain patients with decreased helper T-cell activity have been described. [8] 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.
Epidemiology
Frequency
United States
In a retrospective study of a large allergy practice (20,000 patients) database, Goldstein et al reported prevalences of SIgM deficiency of 0.26% among adults and 0.03% among children. [3, 4]
International
SIgM deficiency is rare, with an incidence of less than 0.03% in the general population and 1% in hospitalized patients. [9]
Mortality/Morbidity
Since IgM may have a different range of specificities than placentally-transferred maternal IgG, infants can succumb to overwhelming infections such as meningitis, pneumonia, and gram-negative sepsis.
Patients with SIgM deficiency are susceptible to recurrent sepsis and overwhelming infection with encapsulated bacteria (eg, Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae). [10, 11, 12] They may also have autoimmune disease including glomerulonephritis and osteomyelitis from which organisms are not recoverable, [13, 14, 15] as well as malignancies, chronic dermatitis, diarrhea, and upper respiratory infections.
Race-, sex-, and age-related characteristics
The incidence of SIgM deficiency in various races has not been reported, given the low overall incidence.
The disorder occurs in both males and females, with no known discrepancies between the sexes.
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.
