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Autosomal recessive hyper IgM syndrome: causes, symptoms, diagnosis, treatment

 
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Last reviewed: 07.07.2025
 
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Autosomal recessive hyper IgM syndrome associated with activating cytidine deaminase deficiency (HIGM2)

Following the discovery of the molecular basis of X-linked hyper-IgM syndrome, descriptions of male and female patients with normal CD40L expression, increased susceptibility to bacterial but not opportunistic infections, and, in some families, an autosomal recessive inheritance pattern appeared. In 2000, Revy et al. published the results of a study of such a group of patients with hyper-IgM syndrome, which revealed a mutation in the gene encoding activation-inducible cytidine deaminase (AICDA).

The activation-inducible cytidine deaminase (AICDA) gene, located on chromosome 12p13, consists of 5 exons and codes for a protein consisting of 198 amino acids. Mutations, most often homozygous, rarely heterozygous, are found predominantly in exon 3.

AID belongs to the cytidine deaminase family. AID is an RNA-editing enzyme acting on one or more messenger RNA substrates. However, compelling evidence for a direct action of cytidine deaminase on DNA has recently been obtained. Following this model, it was proposed that AID converts deoxycytidine (dC) to deoxyuridine (dU) in one strand of DNA. It is now known that AID requires interaction with specific coenzyme(s) to induce class switch recombination. It has also been shown that the block to class switch recombination occurs before double-strand DNA breaks in the mu switch region. Thus, the precise mechanism of AID function is not well understood, although an important role for this enzyme in immunoglobulin class switch recombination and somatic hypermutation is evident.

Symptoms

Patients with AID deficiency present in early childhood, with a clinical picture dominated by recurrent bacterial infections of the respiratory and gastrointestinal tracts. However, due to a milder clinical phenotype due to the absence of opportunistic infections in this group of patients, many of them are diagnosed with immunodeficiency after 20 years of age. Similar to patients with a mutation in CD40, patients with AID deficiency have significantly reduced levels of IgG and IgA, and normal or elevated IgM. Specific IgG antibodies to T-dependent protein antigens are absent, while IgM isohemoagglutinins are present.

CD19 + B lymphocyte and CD27 + memory B cell counts are normal, and T cell immunity is usually preserved. The characteristic clinical finding in these patients is lymphoid hyperplasia, with giant germinal centers consisting of proliferating B lymphocytes simultaneously expressing IgM, IgD, and CD38.

Diagnostics

The diagnosis of AID deficiency should be suspected in patients with abnormal serum immunoglobulin levels consistent with hyper-IgM syndrome, in combination with normal CD40 ligand expression, and the inability of peripheral blood lymphocytes, when stimulated in vitro with anti-CD40 and lymphokines, to produce immunoglobulin classes other than IgM. Molecular confirmation of the diagnosis can only be achieved by detecting a mutation in the AID gene.

Treatment

Regular replacement therapy with intravenous immunoglobulin (400-600 mg/kg/month) reduces the frequency of infectious manifestations, but does not affect lymphoid hyperplasia.

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