title: X-linked hyper-immunoglobulin M syndrome: molecular genetic study and long-time follow-up of three generations of a Chinese family.
abstract: BACKGROUND
  X-linked hyper-immunoglobulin M (IgM) syndrome (XHIGM) is a rare immunodeficiency disease caused by mutations of the CD40 ligand gene. Patients are subject to recurrent infections and have normal or elevated levels of IgM but markedly decreased serum IgG.
  
  
  OBJECTIVE
  We describe molecular genetic studies and clinical manifestations in three generations of one family, as well as results of long-term treatment of 2 young men with the disorder.
  
  
  METHODS
  Of 37 living family members, mutational analysis of the CD40 ligand gene was performed in 36 members. Laboratory data for patients and carriers were reviewed.
  
  
  RESULTS
  Four male family members had died of unexplained causes. The 3 patients with XHIGM syndrome and the 5 carriers all had a novel mutation located at Tyr 169 Asn (T526A) in exon 5, the tumor necrosis factor domain of the CD40 ligand gene. In the 3 patients, CD40 ligand expression in activated CD4+ T cells was below 1%. In the carriers, about half of activated CD4+ cells expressed CD40 ligand. One carrier had malignant lymphoma. Long-term (>20 years) intravenous immunoglobulin therapy in 2 patients improved IgG levels but did not fully suppress the high levels of IgM, nor did it prevent late complications (bronchiectasis and sclerosing cholangitis).
  
  
  CONCLUSIONS
  Diagnosis of a genetic immunodeficiency, especially an X-linked disease such as XHIGM syndrome, should prompt a survey of the entire family.
authors.affiliation: Department of Pediatrics, Divisions of Allergy and Immunology, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Sheng-Chieh
authors.initials: SC
authors.lastname: Lin
authors.forename: Shyh-Dar
authors.initials: SD
authors.lastname: Shyur
authors.forename: Wen-I
authors.initials: WI
authors.lastname: Lee
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Ma
authors.forename: Li-Hsin
authors.initials: LH
authors.lastname: Huang
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D044466:Asian People / Q000235:genetics; D023201:CD40 Ligand / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D017074:Common Variable Immunodeficiency / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000628:therapy; D004252:DNA Mutational Analysis; D005260:Female; D005500:Follow-Up Studies; D006580:Genetic Carrier Screening; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood*; D007223:Infant; D008297:Male; D010375:Pedigree; D013577:Syndrome
chemical_list: D007074:Immunoglobulin G; D007075:Immunoglobulin M; D023201:CD40 Ligand