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CD40L deficiency

X-linked hyper-IgM syndrome, HIGM1, MIM.308230

Definition: 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

Etiology

- caused by mutations in 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