The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients.
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. Because of its rarity, it has been difficult for any single investigator or institution to develop a comprehensive clinical picture of this disorder. Accordingly, a national registry was developed in the United States to provide demographic, genetic, immunologic, and clinical information on a relatively large number of patients with the XHIGM syndrome.A total of 79 patients from 60 unrelated families were registered between January 1997 and July 2002. The estimated minimal incidence was approximately 1/1,030,000 live births. All of the patients had significant IgG deficiency and most had IgA deficiency, but only one-half had elevated IgM levels. Most patients presented initially with a history of an increased susceptibility to infection including Pneumocystis carinii pneumonia. The average age of diagnosis was significantly earlier in patients born into a family with a previously affected individual. However, only one-third of the patients born into a family with a previously affected individual were diagnosed exclusively because of the presence of the positive family history before any clinical symptoms developed. Over half the patients developed symptoms of immunodeficiency and were diagnosed by 1 year of age, and over 90% by 4 years of age. 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%). In addition to infections caused by encapsulated bacteria, opportunistic infections were relatively common and were caused by P. carinii, members of the herpes virus family (including cytomegalovirus), Cryptosporidium, Cryptococcus, Candida, Histoplasma, and Bartonella. Sclerosing cholangitis occurred in 5 patients and in 4 of these was associated with Cryptosporidium infection. Eight patients had died at the time of their entry into the Registry; 2 of pneumonia (1 P. carinii and 1 cytomegalovirus), 2 of encephalitis (1 ECHO virus and 1 cytomegalovirus), 2 of malignancy (both hepatocellular carcinoma), 1 of sclerosing cholangitis caused by Cryptosporidium, and 1 of hemolytic uremic syndrome.
Winkelstein
Jerry A
JA
Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Marino
Mary C
MC
Ochs
Hans
H
Fuleihan
Ramsey
R
Scholl
Paul R
PR
Geha
Raif
R
Stiehm
E Richard
ER
Conley
Mary Ellen
ME
D000293:Adolescent; D023201:CD40 Ligand / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D041321:Chromosomes, Human, X; D003967:Diarrhea / Q000150:complications; D008040:Genetic Linkage; D006801:Humans; D006942:Hypergammaglobulinemia / Q000150:complications / Q000235:genetics* / Q000276:immunology* / Q000628:therapy; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood*; D007075:Immunoglobulin M / Q000097:blood; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D007153:Immunologic Deficiency Syndromes / Q000150:complications / Q000235:genetics* / Q000276:immunology* / Q000628:therapy; D007223:Infant; D007239:Infections / Q000150:complications; D008297:Male; D009154:Mutation; D009369:Neoplasms / Q000150:complications; D009503:Neutropenia / Q000150:complications; D012042:Registries
D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D016756:Immunoglobulins, Intravenous; D023201:CD40 Ligand