Clinical spectrum of X-linked hyper-IgM syndrome,☆☆

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Abstract

We report the clinical and immunologic features and outcome in 56 patients with X-linked hyper-IgM syndrome, a disorder caused by mutations in the CD40 ligand gene. Upper and lower respiratory tract infections (the latter frequently caused by Pneumocystis carinii ), chronic diarrhea, and liver involvement (both often associated with Cryptosporidium infection) were common. Many patients had chronic neutropenia associated with oral and rectal ulcers. The marked prevalence of infections caused by intracellular pathogens suggests some degree of impairment of cell-mediated immunity. Although lymphocyte counts and in vitro proliferation to mitogens were normal, a defective in vitro proliferative response to antigens was observed in some patients, and additional defects of cell-mediated immunity may be presumed on the basis of current knowledge of CD40-ligand function. All patients received regular infusions of immunoglobulins. Four patients underwent liver transplantation because of sclerosing cholangitis, which relapsed in three. Three patients underwent bone marrow transplantation. Thirteen patients (23%) died of infection and/or liver disease. X-linked hyper-IgM syndrome, once considered a clinical variant of hypogammaglobulinemia, is a severe immunodeficiency with significant cellular involvement and a high mortality rate. (J Pediatr 1997;131:47-54)

Section snippets

Methods

The names and addresses of European physicians taking care of patients with HIM were obtained from the Registry of Primary Immunodeficiencies of the European Society for Immune Deficiency (Huddinge, Sweden). The physicians answered a detailed questionnaire, and clinical, genetic, and immunologic data were gathered and analyzed with Excel (Microsoft Corp.) and SPSS (SPSS, Inc.) software. Data on immunoglobulin serum levels, total lymphocyte count, and enumeration of CD4 + and CD8 + T cells and

Results

Ninety-eight patients were identified as having HIM. Of these, 56 (from 47 families) fulfilled the criteria for XHIM. The inclusion criteria were evidence of specific CD40L gene mutation (48 patients) and/or clear X-linked inheritance (with multiple affected males in multiple generations) in association with defective CD40L expression (8 patients). An X-linked pattern of inheritance was evident from the pedigree of 32 patients, who belonged to 23 unrelated families. The mean age at presentation

Discussion

Although originally considered a humoral form of immunodeficiency, XHIM was suspected in 1986 to be due to defective T-cell function, when Mayer et al.

Figure. Kaplan-Meyer survival curve resulting from a retrospective analysis of 56 patients with X-linked hyper-IgM syndrome.

17 demonstrated that B cells in XHIM could be driven to undergo isotype switch if cocultured in the presence of CD4 + T cells derived from a patient with Sézary disease. More recently, XHIM was shown to be due to mutations

References (46)

  • JP DiSanto et al.

    CD40 ligand mutations in X-linked immunodeficiency with hyper-IgM

    Nature

    (1993)
  • R Korthauer et al.

    Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM

    Nature

    (1993)
  • R Fuleihan et al.

    Defective expression of the CD40 ligand in X chromosome–linked immunoglobulin deficiency with normal or elevated IgM

    Proc Natl Acad Sci U S A

    (1993)
  • P Macchi et al.

    Characterization of nine novel mutations in the CD40 ligand gene in patients with X-linked hyper-IgM syndrome of various ancestry

    Am J Hum Genet

    (1995)
  • D Hollenbaugh et al.

    The human T cell antigen gp39, a member of the TNF gene family, is a ligand for the CD40 receptor: expression of a soluble form of gp39 with B cell co-stimulatory activity

    EMBO J

    (1992)
  • P Lane et al.

    Activated human T cells express a ligand for the human B cell–associated antigen CD40, which participates in T cell–dependent acts of B lymphocytes

    Eur J Immunol

    (1992)
  • RJ Noelle et al.

    A 39-kDa protein on activated helper T cells binds CD40 and transduces the signal for cognate activation of B cells

    Proc Natl Acad U S A

    (1992)
  • N Banatvala et al.

    Hypogammaglobulinemia associated with normal or increased IgM (the hyper-IgM syndrome): a case series review

    Arch Dis Child

    (1994)
  • HD Ochs et al.

    Disorders of the B-cell system

  • M Benkerrou et al.

    Hypogammaglobulinemie G et A avec hypergammaglobulinemie M: a propos de 12 observations

    Arch Fr Pediatr

    (1990)
  • D Brugnoni et al.

    Ineffective expression of CD40 ligand on cord blood T cells may contribute to poor immunoglobulin production in the newborn

    Eur J Immunol

    (1994)
  • EL Kaplan et al.

    Nonparametric estimation from incomplete observations

    J Am Stat Assoc

    (1958)
  • C Thomas et al.

    Brief report: correction of X-linked hyper-IgM syndrome by allogeneic bone marrow transplantation

    N Engl J Med

    (1995)
  • Cited by (0)

    Reprint requests: Jacov Levy, MD, Department of Pediatrics, Soroka Medical Center, Beer Sheva 84101, Israel.

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