Author: Luigi D Notarangelo, MD

Section Editor: E Richard Stiehm, MD

Deputy Editor: Elizabeth TePas, MD, MS

INTRODUCTION

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".)

EPIDEMIOLOGY

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.)

PATHOGENESIS

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: Sep 2019. | This topic last updated: Sep 18, 2019.

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