Hyper-IgM syndrome

Hyper-IgM syndrome typically presents in infancy, with more than 50% of affected males symptomatic by age one year and more than 90% by age four years. Recurrent upper and lower respiratory tract bacterial infections, predominantly with Streptococcus pneumoniae and Pseudomonas species, occur in 75-80% of affected individuals; otitis is reported in 42% and sinusitis in 36%. Opportunistic infections, in particular Pneumocystis jirovecii pneumonia, are characteristic and frequently occur in the first year of life. Recurrent or protracted diarrhoea (infectious or non-infectious) with poor weight gain is common. Neutropenia is frequent; thrombocytopenia and anaemia occur less often. Autoimmune and inflammatory complications, such as sclerosing cholangitis, and an increased risk of neoplasms have been reported. Progressive liver disease, historically observed in more than 80% of affected males by age 20 years, remains an important contributor to morbidity.

Hyper-IgM syndromes are very rare disorders, with individual forms typically occurring in fewer than 1/1,000,000. Collectively, they account for roughly 0.3–2.9% of all primary immunodeficiency cases worldwide.

Hyper-IgM syndrome is caused by germline pathogenic variants in genes encoding components of the CD40-CD40 ligand signalling pathway or downstream class-switch recombination machinery. CD40LG (Xq26.3) accounts for ~75% of cases (CD40 ligand deficiency); AICDA (12p13.31), encoding activation-induced cytidine deaminase, is the second most common cause; CD40 (20q13.12) and UNG (12q24.11) are rare causes that resemble CD40 ligand and AID deficiency clinically. The shared molecular consequence is impaired immunoglobulin isotype switching from IgM to IgG, IgA, and IgE, with absent germinal-centre formation in lymph nodes.

Hyper-IgM syndrome is inherited in an X-linked recessive manner when caused by CD40LG pathogenic variants (CD40 ligand deficiency, the most common form). Autosomal recessive inheritance occurs when the condition is caused by pathogenic variants in AICDA, CD40, or UNG; a rare autosomal dominant form of AICDA-related disease has also been reported. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The diagnosis is established primarily by molecular genetic testing. Supporting findings include low or absent serum IgG, IgA, and IgE with normal or elevated IgM, normal T, B, and NK cell subsets, and reduced class-switched memory B cells. Flow-cytometric measurement of CD40 ligand expression on activated CD4+ T cells contributes diagnostic information, although up to 32% of affected individuals retain normal extracellular CD40 ligand binding.

Main differential diagnoses include:

• : reduced IgG and IgA with recurrent sinopulmonary infections, without elevated IgM; TNFRSF13B and others
• EDA-ID due to NEMO/IKBKG deficiency: X-linked disorder with hypohidrotic ectodermal dysplasia and invasive staphylococcal disease; IKBKG
• Activated PI3K delta syndrome (APDS): elevated IgM, lymphoid hyperplasia, and severe herpes-virus infections; PIK3CD, PIK3R1

• Establishing the diagnosis: identification of the underlying pathogenic variant confirms a clinical suspicion and provides a definitive genetic diagnosis.
• Specific and individualised surveillance: knowledge of the causal variant provides the prerequisite for targeted medical care, including individualised surveillance for infectious, hepatic, haematological, and neoplastic complications, which is decided by the treating physicians in consultation with the affected individual.
• Family member testing: once the familial pathogenic variant has been identified, at-risk relatives can be tested to clarify their genetic status.

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