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Hyperimmunoglobulin M syndromes

Luigi D Notarangelo, MD
Section Editor
E Richard Stiehm, MD
Deputy Editor
Elizabeth TePas, MD, MS


The hyperimmunoglobulin M (hyper-IgM or HIGM) syndromes include a heterogeneous group of conditions characterized by defective class-switch recombination (CSR), resulting in normal or increased levels of serum IgM associated with deficiency of immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin E (IgE) and poor antibody function [1]. Hyper-IgM syndrome includes several genetically determined diseases [2,3] but may also be secondary to congenital rubella syndrome [4], use of phenytoin, T cell leukemia, or lymphomas [1]. This topic review discusses in detail only genetically determined forms of hyper-IgM syndrome. (See "Congenital rubella syndrome: Clinical features and diagnosis".)


All forms of hyper-IgM syndrome are rare. The estimated frequency of CD40 ligand (CD40L) deficiency is 2:1,000,000 males [5]. Although no data are available on the frequency of activation-induced cytidine deaminase (AID) deficiency, this disorder is estimated to affect fewer than 1:1,000,000 individuals. In contrast, there are only a few reported cases of CD40 [6-9] and uracil N-glycosylase (UNG) [10] deficiencies. There is parental consanguinity in several families with autosomal recessive forms of hyper-IgM syndrome. (See 'Genetics' below.)


Maturation of antibody responses is marked by a series of events that include (see "Immunoglobulin genetics"):

Class-switch recombination (CSR, also called class-switching), whereby the immunoglobulin mu heavy chain is replaced by other heavy chain isotypes with distinct biologic properties, resulting in production of immunoglobulin isotypes other than IgM.

Somatic hypermutation (SHM), by which somatic mutations are introduced in the variable region of actively transcribed immunoglobulin genes, thereby allowing production of high-affinity antibodies.

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Literature review current through: Nov 2017. | This topic last updated: Oct 04, 2017.
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