X-linked Immunodeficiency With Hyper IgM Differential Diagnoses

Updated: Oct 05, 2016
  • Author: C Lucy Park, MD; Chief Editor: Harumi Jyonouchi, MD  more...
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Diagnostic Considerations

Other forms of hyper-IgM syndrome (HIGM)

Since the first description of X-linked immunodeficiency with hyper-immunoglobulin M (XHIGM) in a patient with markedly reduced serum levels of other isotypes in 1961, several other gene mutations that result in defective Ig class-switch recombination with normal or elevated serum IgM and recurrent infection have been reported. (ref. 38)

The most common form is XHIGM (or HIGM1), which accounts for approximately 88% of all HIGMs reported to USIDNET registry and is inherited through an X-linked recessive (XR) trait. (ref 38)

Another XR form of the syndrome is associated with hypohidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) and is due to defects in the gene that encodes for nuclear factor (NF)-κB essential modulator (IKBKG/NEMO). Thus, this genetic deficiency is also referred to as NEMO syndrome. In addition, several autosomal recessive (AR) forms of HIGM have been reported, including activation-induced cytidine deaminase (AICDA) deficiency (HIGM2), defects in CD40 expressed on B cells (HIGM3), and uracil N glycosylase (UNG) deficiency (HIGM5). Some cases of HIGM syndrome with unknown genetic defects have been reported, including HIGM with class-switch recombination (CSR) defects and unclassified HIGM. A subtype of AID deficiency (AID with c-terminal deletions) is inherited through autosomal dominant trait. One fermaile patient with autosomal dominant gain of function mutations in phosphoinositide 3-kinase catalytic delta component (PIK3CD) has been reported. (ref 38)

All patients with HIGHM present with recurrent bacterial infections. Only CD40L defect (XHIGM) and CD40 defect are associated with significant T & B cell defect and are susceptible to opportunistic infections. Most HIGM cases due to intrinsic B-cell defects are not due to AID or UNG deficiency. The molecular basis of these cases has not been elucidated, but CSR defect was noted in either upstream or downstream from the DNA cleavage site.

Table 1. Clinical and Immunologic Features of Hyper-IgM Syndromes [12] (Open Table in a new window)

  XHIGM CD40 defect EDA-ID AR-AID AID- Cter AID-Δ C UNG defect CSR defect- upstream from DNA cleavage CSR defect-downstream from DNA cleavage
Inheritance XL AR XL AR AR AD AR AR AR
Lymphadenopathy - - - ++ ++ ++ + + +
Opportunistic Infection + + - - - - - - -
Autoimmunity ± ± + + + + - - +
Serum IgM N or ↑ N or ↑ N or ↑ ↑ ↑ ↑ ↑ ↑ ↑ N or ↑ N or ↑
CD40-induced CSR N UD Variable UD UD UD UD UD UD
SHM Variable ↓ ↓ N N N but biased N N

Note. AID-Cter = Mutations in the c-terminal region of AID; AID-Δ C = AID c-terminal deletions; AD = Autosomal dominant; N = normal; EDA-ID = Hypohidrotic ectodermal dysplasia with immunodeficiency; SHM = Somatic hypermutation; UD = Undetected

Differential Diagnoses