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immunodeficiency with hyper-IgM type 1

MIM.308230 Xq26

Monday 25 April 2005

Definition: The X-linked hyper-IgM (XHIGM) syndrome is an uncommon primary immunodeficiency disease caused by mutations in the gene for CD40 ligand (CD40L deficiency) and characterized by normal or elevated serum IgM, reduced levels of IgG and IgA, and defective T-cell function.

The X-linked hyper-IgM (XHIGM) syndrome is an uncommon primary immunodeficiency disease caused by mutations in the gene for CD40 ligand and characterized by normal or elevated serum IgM, reduced levels of IgG and IgA, and defective T-cell function.

The most prominent clinical infections were pneumonia (81% of patients), upper respiratory infections (49%) including sinusitis (43%) and recurrent otitis (43%), recurrent/protracted diarrhea (34%), central nervous system infections (14%), sepsis (13%), cellulitis (13%), hepatitis (9%), and osteomyelitis (1%).

Synopsis

- significant IgG deficiency
- +/- IgA deficiency
- +/- elevated IgM levels

- increased susceptibility to infection

  • Pneumocystis carinii pneumonia
  • infections caused by encapsulated bacteria
  • opportunistic infections
  • members of the herpes virus family (including cytomegalovirus)
  • Cryptosporidium
  • Cryptococcus
  • Candida
  • Histoplasma
  • Bartonella

- tonsillar hypertrophy
- gingivitis
- ulcerative stomatitis
- hepatomegaly
- chronic hepatitis
- splenomegaly
- diarrhea
- proctitis
- neutropenia, chronic or cyclic
- anemia
- hemolytic anemia
- thrombocytopenia
- immunodeficiency
- dysgammaglobulinemia
- primary dysfunction of B-lymphocyte isotype switching and memory B-cell generation
- lymph nodes lacking germinal centers
- normal or increased IgM
- serum IgA, IgG, and IgE severely deficient
- B-cell count normal
- decreased T cell activation
- recurrent bacterial infections with onset in the first or second year of life
- Pneumocystis carinii infection (12 to 42%)
- opportunistic infections
- sclerosing cholangitis

  • ascending Cryptosporidium sp. infection

- tumors

  • gallbladder tumors (#12790080#)
  • hepatocellular carcinoma (#14663287#)

- opportunistic infections

  • pneumonia
  • upper respiratory infections
    • sinusitis
    • recurrent otitis
  • recurrent/protracted diarrhea
  • central nervous system infections (14%),
  • systemic sepsis
  • osteomyelitis

- most frequent infectious agents

  • encapsulated bacteria
  • Pneumocystis carinii
  • Herpes virus family (including cytomegalovirus)
  • Cryptosporidium sp. (Cryptosporidium-associated sclerosing cholangitis)
  • Cryptococcus sp.
  • Candida sp.
  • Histoplasma sp.
  • Bartonella sp.

- cutaneous sarcoid-like granulomas (#14871324#)

Etiology

- mutations in the gene encoding CD40 ligand - CD40LG (MIM.300386)

  • X-linked hyper-IgM syndrome (HIGM1) is caused by mutation in the CD40LG gene (MIM.300386)
  • CD40L gene coding for the tumor necrosis factor ligand superfamily, member 5 gene (TNFSF5) or CD40-Ligand

References

- Winkelstein JA, Marino MC, Ochs H, Fuleihan R, Scholl PR, Geha R, Stiehm ER, Conley ME. The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients.Medicine (Baltimore). 2003 Nov;82(6):373-84. PMID: #14663287#