Hyper IgM-Syndrome D80.5

Hyper-immunoglobulin M syndromes (HIGM) are a heterogeneous group of genetic disorders resulting from immunoglobulin class switch recombination (CSR) defects associated with or without somatic hypermutation (SHM) defects.

The phenoytp hyper IgM syndrome is characterized by genetic heterogeneity. To date, 5 HIGM subtypes have been described:

X-linked HIGM (about 70% of cases; mutations in the CD40L gene).

• HIGM1a: CD40LG gene (X-linked): HIGM1 is the most common form of HIGM and is present in approximately 70-of males affected. The CD40 ligand is expressed on T cells after antigen stimulation; its interaction with the CD40 receptor on B cells is essential for class switching from IgM to IgG, IgE, or IgA. Patients with X-linked HIGM are also prone to neutropenia as well as a high rate of gastrointestinal and central nervous system infections, often leading to severe liver disease and/or neurodegeneration.
• HIGM1b: Another X-linked inherited defect with a phenotype of hyper-IgM syndrome is caused by hypomorphic genetic mutations in the IKBKG gene. These lead to a partial loss of gene function and cause the occurrence of "Anhidrotic ectodermal dysplasia with immunodeficiency (OMIM: 300291)

Autosomal recessive HIGM (about 30% of cases; true B-cell defects):

• HIGM2 (OMIM: 605258): AICDA gene (autosomal recessive): Defects of activation-induced cytidine deaminase lead to defects in Ig class switching and somatic hypermutation, so that specific and high-affinity antibodies cannot be formed. Opportunistic infections as in combined immunodeficiencies have not been described so far, nor has an accumulation of malignancies; in contrast, autoimmune diseases are common. In addition, there is lymphoproliferation with lymphadenopathy.
• HIGM3 (OMIM: 606843): CD40 gene (autosomal recessive): The CD40 receptor is constitutively expressed on B cells/antigen presenting cells. HIGM3 corresponds to HIGM1 in clinic and severity.
• HIGM4 (OMIM: 608184): HIGM4 forms a group of patients who cannot be molecularly assigned to any of the other subtypes. HIGM4 is associated with restricted subclass switching but rather mild courses. Somatic hypermutation is preserved. Clinic comparable to HiGM2, but gene defect unknown (Imai K et al. 2003).
• HHIGM5 (OMIM: 608106): UNG gene (autosomal recessive): The UNG gene encodes uracil DNA glycosylase, which initiates the DNA repair mechanism during class switching. The HIGM5 phenotype is similar to HIGM2.

These immunodeficiency syndromes are caused by mutations in the following genes: AICDA, CD40, CD40LG, UNG; IKBKG. They can be classified as defects in signal transduction by CD40, causing both humoral immunodeficiency and susceptibility to opportunistic infections, or as intrinsic defects in B cells of the CSR mechanism, leading to pure humoral immunodeficiency. Initially, a humoral immunodeficiency develops with increased susceptibility to bacterial sino-pulmonary infections. In some forms of the disease (HIGM1, HIGM3), there is an additional deficiency of T-cell functions, so that opportunistic infections and an increased risk of malignancy also occur.

Symptoms develop in most children with HIGM syndrome during the first or second year of life. The most common problem is an increased risk of infection, especially recurrent bacterial, viral, or even mycotic infections of the upper and lower respiratory tract. Some patients also experience gastrointestinal symptoms such as diarrhea and malabsorption. Approximately 50% of patients with XHIGM syndrome develop neutropenia combined with oral ulcers, inflammation and ulceration of the rectum, and infections of the skin. Patients with autosomal recessive HIGM syndrome are more likely to develop lymphadenopathy with enlarged pharyngeal and palatine tonsils .Autoimmune diseases are observed more frequently in HIGM patients.

HIGM syndrome is suspected when a patient has recurrent severe respiratory infections or opportunistic infection. Additionally, blood tests indicate normal or elevated IgM levels and little to no IgG. Ultimately, the diagnosis is made by molecular genetics.

CD40 signaling defects may require corrective therapy with bone marrow transplantation. People with a defective CSR mechanism generally do well with immunoglobulin replacement therapy. Complications may include autoimmunity, lymphoid hyperplasia, and in some cases, predisposition to malignant lymphoid disease.

Varies according to the expressivity of the immunodeficiency.

In X-linked hyper IgM syndrome, only 20% of patients reach the third decade of life without treatment.

Complicating the disease is the occurrence of various gastrointestinal cancers, including cholangiocarcinoma, hepatocellular carcinoma, and adenocarcinoma often in combination with Cryptosporidium parvum (protozoa causing intestinal infections, usually in the setting of X-linked hyper-IgM syndrome of immunosuppression or immunodeficiency).

1. Allen RC et al (1993) CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome. Science 259: 990-993.
2. Andre P et al (2002) CD40L stabilizes arterial thrombi by a beta(3) integrin-dependent mechanism. Nature Med. 8: 247-252.
3. Aruffo A et al (1993) The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome. Cell 72: 291-300.
4. Aschermann Z et al (2007) X-linked hyper-IgM syndrome associated with a rapid course of multifocal leukoencephalopathy. Arch. Neurol. 64: 273-276.
5. Davies EG et al (2010) Update on the hyper immunoglobulin M syndromes. Br J Haematol 149:167-180.
6. Hasegawa S et al (2014) Whole-exome sequence analysis of ataxia telangiectasia-like phenotype. J Neurol Sci 340: 86-90.
7. Imai K et al (2003) Hyper-IgM syndrome type 4 with a B lymphocyte-intrinsic selective deficiency in Ig class-switch recombination. J Clin Invest 112: 136-142.
8. Kawai T et al (2012) Diagnosis and treatment in anhidrotic ectodermal dysplasia with immunodeficiency. Allergol Int 61:207-217.
9. Kraakman ME et al (1995) Identification of a CD40L gene mutation and genetic counselling in a family with immunodeficiency with hyperimmunoglobulinemia M. Clin Genet 48: 46-48.
10. van Zelm MC et al. (2014) Human CD19 and CD40L deficiencies impair antibody selection and differentially affect somatic hypermutation. J Allergy Clin. Immun 134: 135-144.