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Blood, 1 September 2001, Vol. 98, No. 5, pp. 1321-1325
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Alterations of the X-linked lymphoproliferative disease gene
SH2D1A in common variable immunodeficiency syndrome
Massimo Morra,
Olin Silander,
Silvia Calpe,
Michelle Choi,
Hans Oettgen,
Laurie Myers,
Amos Etzioni,
Rebecca Buckley, and
Cox Terhorst
From the Division of Immunology, Beth Israel Deaconess
Medical Center, and the Division of Immunology, Children's Hospital,
Harvard Medical School, Boston, MA; the Division of Allergy and
Immunology, Department of Pediatrics, Duke University School of
Medicine, Durham, NC; and the Division of Pediatrics, Rambam Medical
Center, B Rappaport School of Medicine, Technion, Haifa, Israel.
X-linked lymphoproliferative (XLP) disease is a primary
immunodeficiency caused by a defect in the SH2D1A gene. At
least 3 major manifestations characterize its clinical presentation:
fatal infectious mononucleosis (FIM), lymphomas, and immunoglobulin deficiencies. Common variable immunodeficiency (CVID) is a syndrome characterized by immunoglobulin deficiency leading to susceptibility to
infection. In some patients with CVID, a defective btk or
CD40-L gene has been found, but most often there is no
clearly identified etiology. Here, 2 unrelated families in whom male
members were affected by CVID were examined for a defect in the
XLP gene. In one family previously reported in the
literature as having progressive immunoglobulin deficiencies, 3 brothers were examined for recurrent respiratory infections, whereas
female family members showed only elevated serum immunoglobulin A
levels. A grandson of one of the brothers died of a severe
Aspergillus infection secondary to progressive immunoglobulin deficiency, FIM, aplastic anemia, and B-cell lymphoma. In the second family, 2 brothers had B lymphocytopenia and
immunoglobulin deficiencies. X-linked agammaglobulinemia syndrome was
excluded genetically, and they were classified as having CVID. The
occurrence of FIM in a male cousin of the brothers led to the XLP
diagnosis. Because the SH2D1A gene was found altered in
both families, these findings indicate that XLP must be considered when
more than one male patient with CVID is encountered in the same family,
and SH2D1A must be analyzed in all male patients with CVID.
Moreover, these data link defects in the SH2D1A gene to
abnormal B-lymphocyte development and to dysgammaglobulinemia in female
members of families with XLP disease.
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