immunodeficiency with hyper-IgM type 1

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#