Immunodeficiency With Hyper-Igm, Type 3

A number sign (#) is used with this entry because autosomal recessive hyper-IgM immunodeficiency type 3 (HIGM3) results from homozygous mutation in the CD40 gene (109535) on chromosome 20q12-q13.2.

Description

HIGM3, first described in humans by Ferrari et al. (2001), is characterized by hypogammaglobulinemia with normal or elevated levels of IgM.

For a general phenotypic description and a discussion of genetic heterogeneity of immunodeficiency with hyper-IgM, see HIGM1 (308230).

Clinical Features

The clinical features of HIGM3 are similar to those of X-linked HIGM1 and include an inability of B cells to undergo isotype switching, one of the final differentiation steps in the humoral immune system, an inability to mount an antibody-specific immune response, and a lack of germinal center formation (Castigli et al., 1994; Ferrari et al., 2001). The result is susceptibility to bacterial and opportunistic infections, such as Pneumocystis carinii. Revy et al. (1998) suggested that the opportunistic infections, usually indicating a defect in cellular immunity, may be the result of defective macrophages, which also utilize the CD40-CD40L pathway of activation.

Ferrari et al. (2001) described 3 female patients with HIGM3. They pointed out that the immunologic profile of their patients closely resembled that of CD40-knockout mice (Kawabe et al., 1994; Castigli et al., 1994). Two of their patients suffered from severe interstitial pneumonia, and the other had severe neutropenia. This increased susceptibility to opportunistic infections, well-documented in HIGM1 but not in HIGM2 (605258) patients, who instead suffer mainly from recurrent bacterial infections, confirmed the critical role for CD40/CD40L interaction in immune defense mechanisms toward both extracellular and intracellular pathogens.

Kutukculer et al. (2003) reported a fourth female patient with HIGM3, who presented with respiratory distress, hepatomegaly, failure to thrive, and a history of severe respiratory syncytial virus infection. A necrotizing pneumonia due to Pseudomonas aeruginosa and evidence of a systemic Cryptosporidium parvum infection confirmed the clinical severity of the disorder. Hematopoietic stem cell transplantation in this patient failed to engraft (Kutukculer et al., 2003).

Clinical Management

Mazzolari et al. (2007) reported a 2-year-old Turkish girl, born of consanguineous parents, with HIGM3 who underwent successful bone marrow transplantation at age 3, resulting in stable multilineage full chimerism and normal immune function. Genetic analysis identified a homozygous mutation in the CD40 gene (109535.0004) as the cause of the disorder.

Pathogenesis

Mutation in the CD40 gene renders the interaction with CD40 ligand defective, thereby preventing subsequent signaling (Fuleihan, 2001).

Molecular Genetics

Ferrari et al. (2001) described 2 mutations in the CD40 gene in 3 patients with HIGM3. One patient carried a homozygous silent mutation at the fifth basepair position of exon 5 (109535.0001), involving an exonic splicing enhancer and leading to exon skipping and premature termination; the other 2 patients showed a homozygous point mutation in exon 3, resulting in a cysteine-to-arginine substitution (109535.0002).

In a Turkish female infant with HIGM3, Kutukculer et al. (2003) identified a novel homozygous splice site mutation (IVS3-2A-T; 109535.0003) in the CD40 gene.