Neutropenia Associated with Hyperimmunoglobulin M Syndrome

Immunodeficiency with hyper-IgM may be caused by one of the following molecular genetic defects:

1. X-linked recessive trait, caused by mutations in the gene for the CD40 ligand, a molecule on T cells that binds to its receptor CD40 on B cells, to induce immunoglobulin class switching from production of IgM to IgG and IgA.

2. X-linked recessive form of the hyper-IgM syndrome caused by a mutation in IkB kinase y subunit/NF-KB essential modulator (NEMO) and associated with hypohidrotic ectodermal dysplasia (conical teeth, inadequate sweating, and poor antibody production to polysaccharide antigens).

3. An autosomal recessive form of hyper-IgM syndrome caused by a defect in the gene for activation-induced cytidine deaminase. This enzyme is needed for Ig class switch, recombination, and somatic hypermutation.

The mechanism of neutropenia is a decreased interaction between T cells and bone marrow stromal cells, resulting in reduced production of G-CSF.

Clinical Manifestations

• Severe recurrent pyogenic bacterial infections

• Infections by opportunistic organisms including Pneumocystis carinii, histoplasmosis, cryptosporidium, and Toxoplasma

• Neutropenia, transient, cyclic (10%), or chronic (50% of cases)

• Coombs' positive autoimmune hemolytic anemia

• Lymphoid hyperplasia

• Low serum immunoglobulin A (IgA), IgE, and IgG; elevated IgM

• Number of circulating B cells are normal or increased and T cells are normal.


IV immunoglobulin and G-CSF (mainstay of therapy); also HSCT.

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