HyperIgM

Hyper-IgM syndrome refers to a group of primary immunodeficiency disorders characterized by normal or elevated serum IgM in combination with low or absent IgG, IgA, and IgE due to defects in immunoglobulin class switch recombination or CD40-CD40L signaling. The most common form is X-linked and results from mutations in the CD40 ligand (CD40LG).

Genetic causes include X-linked CD40LG deficiency and autosomal recessive forms caused by mutations in CD40, AICDA (activation-induced cytidine deaminase, AID), and UNG, among other CSR-related genes. These defects disrupt germinal center reactions and somatic hypermutation, leading to impaired isotype switching and poor antibody responses despite normal or increased B cell numbers.

Clinical features typically involve recurrent bacterial infections, especially of the sinuses and lungs, and can include opportunistic infections such as Pneumocystis jirovecii, Cryptosporidium, and Giardia, particularly in CD40LG deficiency. Patients have low IgG and IgA with normal or elevated IgM, poor responses to vaccines (including polysaccharide antigens), and may develop autoimmunity or lymphoid abnormalities.

Diagnosis is suspected in patients with elevated or normal IgM and low IgG/IgA. Evaluation includes quantitative immunoglobulins, assessment of vaccine responses, flow cytometry for CD40L expression, and genetic sequencing to identify causative mutations.

Management centers on immunoglobulin replacement therapy to maintain IgG levels, prophylactic antibiotics, and appropriate vaccination with non-live vaccines. Infections and complications are treated as they arise. Allogeneic hematopoietic stem cell transplantation can be curative in some patients, particularly for severe X-linked disease; gene therapy remains an area of ongoing research.