137 Hypogammaglobulinemia in a Boy: Consider Also X-linked Lymphoproliferative Disease

BACKGROUND: X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency presenting with a variety of clinical manifestations, the most common being dysgammaglobulinemia and B-cell lymphoma. The first gene causing XLP, when defective, was termed SH2D1A or SAP for signaling lymphocyte activation molecule (SLAM)-associated protein. The absence of SH2D1A leads to an overwhelming and uncontrolled TH1- shifted cytotoxic immune response, which might, at least in part, explain the severe clinical picture. A second gene, XIAP (X-linked inhibitor of apoptosis), was later identified. METHODS: An 8 year old Mexican boy was admitted in June 2008 for bronchopneumonia, with no previous history of recurrent or severe infections. He had a family history of a brother deceased at 7 years from fulminate hepatitis, who was diagnosed with agammaglobulinemia. A laboratory evaluation for primary immunodeficiency was made, including serum immunoglobulins: IgG 30 mg/dL, IgA <5 mg/dL IgM 8.6 mg/dL; and flow citometry for lymphocyte subpopulations: CD3+ 2590 mm(3) (56%) CD4+ 1004 mm(3) (42%), CD8+ 1267 mm(3)(53%) CD16/56 171mm(3) (41%) CD19+ 1493 mm(3) (35%). The patient was started on monthly intravenous gammaglobulin (IVIG) therapy. He was admitted in December 2008 with fever and severe abdominal pain; an exploratory laparotomy revealed a rectal-sigmoid tumor. The biopsy reported an atypical Burkitt lymphoma (Immunophenotype “B”: Bcl 2+, CD10+) with surgical margins negative for malignancy. Bone marrow aspirate and biopsy were negative for malignancy. In February 2009, management with chemotherapy was started with the diagnosis of Burkitt's lymphoma stage III. Patient received 6 courses of chemotherapy with complete response to induction; for consolidation, 4 doses of rituximab were given. PCR amplification and direct automated sequencing by the Sanger method was performed in both genes known to be responsible for XLP in chromosome X. RESULTS: A hemizygous splice-site deletion in SAP was found, in intron 2: c.187_201+10del25, which deletes exon 2 splice donor site, and is predicted to result in the skipping of exon 2, and thus in a truncated, nonfunctional protein. XIAP was also sequenced and no mutation was found. CONCLUSIONS: Final diagnosis: XLP.The patient is currently in the program for hematopoietic stem-cell transplantation.