Hyper-IgM syndrome
Hyper-IgM syndrome is a class-switch recombination defect, most often X-linked CD40 ligand deficiency, causing normal or high IgM with very low IgG, IgA, and IgE and severe pyogenic and opportunistic infections early in life. Diagnosis rests on the immunoglobulin pattern with impaired switching, and treatment is immunoglobulin replacement, Pneumocystis prophylaxis, and consideration of stem cell transplantation.
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What this article covers
- Overview
Definition: hyper-IgM syndrome is a primary immunodeficiency caused by a defect in immunoglobulin class-switch recombination, most commonly X-linked deficiency of CD40 ligand (CD40L) on helper T cells.
- Epidemiology
Rare and usually X-linked: the CD40 ligand form affects boys and presents in infancy; autosomal recessive forms (CD40, AID, UNG defects) also occur.
- Risk factors
CD40 ligand (or CD40) mutation: the defining cause; X-linked inheritance means affected males and carrier mothers.
- Pathophysiology
CD40-CD40L interaction failure: helper T cells cannot deliver the CD40 ligand signal that B cells need to undergo class-switch recombination.
- Clinical features
Recurrent pyogenic infections: sinopulmonary infections and otitis from the antibody defect.
- Differential diagnosis
X-linked agammaglobulinemia: absent B cells and all low immunoglobulins including IgM, without opportunistic infection.
- Diagnosis
Establish by the immunoglobulin pattern with impaired class switching: normal or elevated IgM together with markedly low IgG, IgA, and IgE, plus impaired specific antibody responses, in an infant boy…
- Management
Start immunoglobulin replacement first-line: intravenous immunoglobulin (IVIG) 400 to 600 mg/kg IV every 3 to 4 weeks, titrated to trough IgG and infection control, continued indefinitely (this also lowers the elevated IgM).
- Complications
Pneumocystis pneumonia: a leading cause of early death.
- Prognosis
Guarded without transplantation: the X-linked form has high mortality by early adulthood despite replacement and prophylaxis.
- Prevention
Pneumocystis prophylaxis with trimethoprim-sulfamethoxazole from diagnosis, three times weekly.
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