Hyper IgM syndrome

Primary immunodeficiency where B cells cannot class-switch, leading to normal or elevated IgM but very low IgG, IgA, IgE levels.

• Leads to severe, often life-threatening infections in infancy (including opportunistic infections like Pneumocystis pneumonia). Highlights the critical role of T–B cell interactions (the CD40–CD40L handshake) in immune function and is a classic high-yield immunodeficiency.

• Usually presents in early childhood with recurrent sinopulmonary infections (e.g., otitis media, pneumonia) once maternal IgG wanes, often accompanied by poor growth (failure to thrive).
• Opportunistic infections are a hallmark: infants may develop Pneumocystis jirovecii pneumonia and chronic Cryptosporidium diarrhea (which can lead to cholangitis).
• Neutropenia is common in X-linked HIGM, causing mouth ulcers and skin infections. Lymphoid tissues (tonsils, lymph nodes) are often diminished due to lack of germinal centers in CD40L deficiency.

1. Measure immunoglobulin levels in any infant with recurrent infections: high IgM coupled with low IgG/IgA is the diagnostic pattern for Hyper IgM syndrome.
2. Confirm the cause by checking CD40 ligand (CD40L) expression on T cells (flow cytometry) and genetic testing. An absent CD40L in a boy indicates the X-linked form; other gene defects (AID, CD40) cause rare autosomal recessive forms.
3. Differentiate from other immunodeficiencies: X-linked agammaglobulinemia has low Ig of all types and absent B cells (vs. normal B cells and IgM in HIGM); SCID presents earlier with even more profound T-cell dysfunction (e.g., severe viral/fungal infections); CVID presents later in life.
4. Poor vaccine responses (due to inability to class-switch and form IgG antibodies) and lack of germinal centers on lymphoid biopsy are clues pointing to hyper IgM (especially the X-linked CD40L form).
5. Determine inheritance: X-linked HIGM (CD40L gene mutation) accounts for ~70% of cases and affects only boys. Autosomal recessive types (e.g., AID or CD40 mutations) affect both sexes and can show extremely high IgM with enlarged lymphoid tissues.

1. IVIG (intravenous Ig) replacement therapy to supply missing IgG and reduce infections.
2. Antimicrobial prophylaxis: e.g., daily TMP-SMX to prevent Pneumocystis pneumonia (especially in CD40L deficiency); plus precautions to avoid Cryptosporidium (boiled water, etc).
3. Hematopoietic stem cell transplant (bone marrow transplant) offers a potential cure and is recommended if an appropriate donor is available.
4. Treat neutropenia with G-CSF (filgrastim) if severe.

• Think M for Male and M for IgM: the most common HIGM is X-linked (affecting boys) and features high IgM with other isotypes Missing.
• No CD40L–CD40 handshake: without T-cell CD40 ligand, B cells never get the class-switch signal, so they remain stuck making IgM.

• Pneumocystis jirovecii pneumonia in an infant (unusual outside HIV/immunodeficiency) → evaluate for Hyper IgM or SCID.
• Recurrent severe bacterial infections starting at ~6–12 months old (after maternal IgG wanes) → suspect a primary immunodeficiency (like HIGM).

1. Recurrent infections in infancy (esp. with opportunistic pathogens) → suspect primary immunodeficiency.
2. Obtain quantitative immunoglobulin levels (IgG, IgA, IgM).
3. If IgM high with IgG/IgA low → likely Hyper IgM syndrome.
4. Confirm with CD40L protein testing and genetic analysis (to identify X-linked vs AR type).
5. Initiate therapy: IVIG infusions, antimicrobial prophylaxis (e.g., TMP-SMX), and refer for possible HSCT.

• Infant boy with recurrent ear infections, Pneumocystis pneumonia, and extremely low IgG/IgA but high IgM levels → X-linked Hyper IgM syndrome.
• Toddler with chronic Cryptosporidium diarrhea leading to cholangitis, found to have high IgM and low IgG/A levels → Hyper IgM immunodeficiency.