High incidence of lymphomas in a subgroup of wiskott–aldrich syndrome patients

We read with interest the report of Inoue et al (2002) describing Wiskott–Aldrich syndrome (WAS) caused by the intron 6 (+ 5), g → a mutation of the WASP gene in several members of one family, including a girl. In the Wiskott–Aldrich syndrome, the course of disease varies from the full-blown disorder, characterized by profound thrombocytopenia, immunodeficiency, eczema, autoimmune pathology and tumours, especially B-cell lymphomas (Sullivan et al, 1994), to thrombocytopenia with or without mild immunodeficiency (also called X-linked thrombocytopenia or XLT) (Ochs, 1998) as found in the family described by Inoue et al (2002). We wish to comment on additional kindred who have this splice site mutation (Kwan et al, 1995; Zhu et al, 1997; Lemahieu et al, 1999; Shcherbina et al, 1999), and call attention to the unusual effect of the mutation at the cell level and the surprising and worrisome phenotype. The unfortunate feature of the intron 6 (+ 5), g → a mutation compared with other WASP mutations associated with mild disease seems to be the high frequency of B-cell lymphomas that develop when the patients are young adults (Shcherbina et al, 1999). To test our initial observations on lymphoma frequency, we assembled data for WAS patients with known mutations. Table I includes information from published reports as well as responses to questionnaires distributed to clinician researchers known to care for WAS patients (18 responses to 33 inquiries). Although there is not strict correlation between the nature of the mutation and disease severity, missense mutations, especially the frequent mutations in exons 1–3, generally lead to mild disease, whereas nonsense and frameshift mutations, expected to lead to WASP-negative cells, are associated with more severe disease. (A) Detailed distribution. (B) Summary of distribution. For the 158 kindred with known missense mutations, cases of lymphoma were reported for five kindred (3·2%) (Table I). Among the 163 kindred with nonsense and frameshift mutations, lymphoma cases were reported for 15 kindred (9·2%). For this group, the observed lymphoma frequency probably underestimates the true susceptibility because many severe phenotype patients undergo early bone marrow transplantation or do not survive to adulthood. The patients with splice site mutations had the highest incidence of lymphomas (seven of 58 kindred or 12·1%). For intron 6 splice site mutations, the incidence was four of nine kindred (44%, statistically different from the incidence for all mutations, χ2 test, P < 0·0002). For the single mutation intron 6 (+ 5), g → a, the incidence was three cases in seven kindred. We previously demonstrated the discordant expression of WASP in blood cells of five patients with two intron 6 mutations (Shcherbina et al, 1999). Whereas T cells of these patients had low but readily detectable levels of WASP (∼10–20% of normal levels), the patients' peripheral B cells, as well as their Epstein–Barr virus-transformed B-cell lines, did not express the protein. Similar discordance between T and B cells was also demonstrated for a patient with an exon 1 nonsense mutation, who died of lymphoma, and two members of a family with an intron 7 splice site mutation, who have mild disease. We propose that discordant expression of WASP in T and B cells is an indication of increased risk of lymphomas in patients, even for those with an otherwise mild course of the disease. Bone marrow transplantation may be indicated for this subgroup of mild WAS patients. We thank K. K. Marino, The Immunodeficiency Foundation and the Registry of U.S. Residents Affected by WAS (supported by NIH NO1-AI-75328) for information on patients with lymphoma. We are grateful to WAS researchers Drs Genevieve de Sainte Basile, Michael Blaese, Luigi Notarangelo, Hans Ochs, Klaus Schwarz, Richard Stiehm, Adrian Thrasher, Jerry Winkelstein and many others who provided information on individual patients. This work was supported by National Institute of Health grants HL59561 and AI39574, and contract NO1-AI-75328 awarded to the Immune Deficiency Foundation.