Hyper-IgM syndrome (HIGM) is a group of rare, genetically diverse conditions characterized by low or absent serum IgG and IgA levels with normal or elevated IgM and normal B cell counts. It is caused by a disorder of immunoglobulin class switching that is sometimes combined with a disturbance of somatic hypermutation. As a result, an initial humoral immune defect with an increased susceptibility to bacterial sinopulmonary infections develops. In some forms of the disease (HIGM1, HIGM3), there is also a T cell function deficiency, so that opportunistic infections and an increased risk of malignancy also occur.
To date, five HIGM subtypes have been documented:
HIGM1: CD40LG gene (X-chromosomal)
HIGM1 is the most common form of HIGM and is present in about 80% of male patients. The CD40 ligand is expressed on T cells after antigen stimulation; its interaction with the CD40 receptor on B cells is essential for class change from IgM to IgG, IgE or IgA. Another X-linked defect with the phenotype of HIGM is caused by pathogenic variants in the IKBKG gene, which codes for the NF-kB essential modulator (NEMO). However, in the case of the NEMO defect, anhidrotic ectodermal dysplasia is also present.
HIGM2: AICDA gene (autosomal recessive)
Defects in activation-induced cytidine deaminase lead to disturbances in immunoglobulin class switching and somatic hypermutation, so that no specific and high-affinity antibodies can be produced. Although opportunistic infections as seen in combined immunodeficiencies and an increase in malignancies have not been described so far, autoimmune diseases are frequent. There is also lymphoproliferation with lymphadenopathy.
HIGM3: CD40 gene (autosomal recessive)
The CD40 receptor is constitutively expressed on B cells/antigen presenting cells. HIGM3 corresponds to HIGM1 clinically and in severity level.
HIGM4 forms a group of patients that cannot be assigned to any of the other subtypes on a molecular level. HIGM4 is associated with limited subclass switching but usually mild disease courses. The somatic hypermutation is preserved.
HIGM5: UNG gene (autosomal recessive)
The UNG gene codes for uracil DNA glycosylase, which initiates the DNA repair mechanism during class switching. The HIGM5 phenotype is similar to HIGM2.
Johnson et al. 2013, GeneReviews® [Internet] https://www.ncbi.nlm.nih.gov/books/NBK1402/ / Yazdani et al. 2019, Clin Immunol. 198:19 / Qamar et al, Clinic Rev Allerg Immunol 46:120 (2014)