Clinical and Laboratory Findings in Hyper-IgM Syndrome with Novel CD40L and AICDA Mutations

Hyper-immunoglobulin M (HIGM) syndromes are a heterogeneous group of primary immunodeficiency disorders, characterized by recurrent infections associated with decreased serum levels of immunoglobulin G (IgG) and IgA and normal to increased serum levels of IgM. These patients have immunoglobulin class switch recombination defects, caused by mutations in several genes. In order to investigate clinical and immunological manifestations of HIGM in Iran, 23 Iranian patients with an age range of 5 months to 35 years, who were followed up over a period of 17 years, were studied. Fourteen of the 23 patients were screened for CD40L, AICDA, UNG, and CD40 gene mutations, using polymerase chain reaction followed by direct sequencing. All patients, except one, initially presented with infectious diseases; the most common manifestations were respiratory tract infections. Six different CD40L mutations were identified, five were novel, one splicing (IVS1+2T > C), three missense (T254M, G167R, L161P), and two frame shift deletions (T29fsX36 and D62fsX79). In addition, one novel AICDA mutation (E122X) was detected. No mutation was found in six out of 14 analyzed patients. CD40L mutations comprise the most common type of immunoglobulin class switch recombination defects. There are several patients with HIGM phenotype, in which the underlying genetic defects remain to be identified. Other defects such as those in components of the mismatch repair mechanism could be potential candidates for the latter.