Correspondence
The Canale–Smith Syndrome
N Engl J Med 1997; 336:1457-1458May 15, 1997
- Article
To the Editor:
Drappa et al. (Nov. 28 issue)1 discussed four patients with Fas gene mutations and associated findings that we and others have described as autoimmune lymphoproliferative syndrome,2-4 a more informative name than the eponymous Canale–Smith syndrome. Our own experience with over 20 patients with the autoimmune lymphoproliferative syndrome from 13 kindreds indicates that the genetics of this process and its clinical spectrum extend well beyond that described originally by Canale and Smith or by Drappa et al. in their reanalysis of the patients of Canale and Smith.1
The mere presence of a Fas mutation does not imply that lymphocyte apoptosis is defective. One must prove that the mutation is a functional one, as we did 3 but Drappa et al. did not.1 Furthermore, some subjects with functional Fas mutations have no discernible illness or transient lymphadenopathy or splenomegaly. Others have self-limited episodic autoimmune hemolytic anemia or thrombocytopenia in childhood. Still others manifest the full-blown syndrome with marked, chronic lymphoproliferation and antibody-mediated autoimmune disease, urticaria, and reactive airway disease. The spectrum of disease in some kindreds differs somewhat from that of typical autoimmune lymphoproliferative syndrome. Features such as the accumulation of double-negative T cells, hypergammaglobulinemia, and antibody-mediated autoimmunity are more variable, and there is evidence of additional immune-mediated complications, such as Guillain–Barré syndrome, and panniculitis. We have also documented the development of B-cell lymphomas in early adulthood in two brothers with Fas mutations in one kindred with autoimmune lymphoproliferative syndrome and two cases of lymphoma in other kindreds.
What was not evident from either the original reports of autoimmune lymphoproliferative syndrome 2-4 or the study by Drappa et al.1 is that defects in apoptosis-pathway genes other than Fas can lead to a similar and overlapping spectrum of disease. Four of our patients with autoimmune lymphoproliferative syndrome have normal Fas and Fas-ligand genes but impaired apoptosis caused by an abnormality in the Fas pathway in cellular assays. This implies that there are abnormalities in other proteins in the Fas-signaling cascade or in parallel apoptotic pathways, of which two are now recognized, one mediated by the tumor necrosis factor–receptor 1 and the other by DR3, a related protein.5 Intensive efforts are under way to identify the molecular bases of autoimmune lymphoproliferative syndrome in the patients with nonmutant Fas as well as the potential contributions of other inherited defects to the clinical phenotype.
Autoimmune lymphoproliferative syndrome is an experiment of nature that informs us about critical homeostatic mechanisms that regulate the development and death of lymphocytes. Further study will reveal how the failure of these mechanisms may permit the undesired survival of lymphocytes that distend tissues, mediate autoimmune phenomena, and may in some cases possess malignant potential.
5 ReferencesStephen E. Straus, M.D.
Michael Lenardo, M.D.
National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892Jennifer M. Puck, M.D.
National Center for Human Genome Research, Bethesda, MD 208921
Drappa J ,Vaishnaw AK ,Sullivan KE ,Chu J-L ,Elkon KB . Fas gene mutations in the Canale-Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity. N Engl J Med 1996;335:1643-1649
Full Text | Web of Science | Medline2
Sneller MC ,Straus ST ,Jaffe ES , et al. A novel lymphoproliferative/autoimmune syndrome resembling murine lpr/gld disease. J Clin Invest 1992;90:334-341
CrossRef | Web of Science | Medline3
Fisher GH ,Rosenberg FJ ,Straus SE , et al. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 1995;81:935-946
CrossRef | Web of Science | Medline4
Rieux-Laucat F ,Le Deist F ,Hivroz C , et al. Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science 1995;268:1347-1349
CrossRef | Web of Science | Medline5
Chinnaiyan AM ,O'Rourke K ,Yu GL , et al. Signal transduction by DR3, a death domain-containing receptor related to TNFR-1 and CD95. Science 1996;274:990-992
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Author/Editor Response
The authors reply:
To the Editor: We were interested to hear of the additional cases of autoimmune lymphoproliferative syndrome reported by Straus et al., which illustrate the variability of the clinical phenotype associated with Fas mutations. As we discussed in our article with respect to the family of Patient 4 and backcross studies of lpr and gld mice, the clinical expression of an inherited Fas defect depends on the contribution of other genetic factors.
A childhood syndrome of autoimmunity (hemolytic anemia and thrombocytopenia) with massive lymphadenopathy and splenomegaly was originally reported by Canale and Smith in 1967.1 These clinical features are common to almost all the reported cases of autoimmune lymphoproliferative syndrome 2 and human lymphoproliferative syndrome and autoimmunity,3 so that it seems appropriate to give credit to the clinical investigators who first recognized the syndrome. Furthermore, “lymphoproliferative syndrome” is an unfortunate term to apply to this syndrome in children, because of the connotations of malignancy and because the lymphadenopathy associated with Fas mutations appears to be predominantly due to the accumulation of lymphocytes due to failure of Fas-mediated apoptosis. Previous studies have shown that failure of lymphocyte apoptosis in lpr mice leads to the accumulation in lymph nodes of double-negative T cells in the G0 to G1 phase of the cell cycle 4 and that these cells fail to proliferate in vivo after adoptive transfer into syngeneic recipient mice.5
Although we demonstrated reduced Fas-mediated apoptosis in activated T cells obtained from subjects with a Fas mutation, we agree that heterozygous Fas mutations should not be assumed to result in reduced Fas function. Studies of the coexpression of mutant Fas alleles derived from our patients with Canale–Smith syndrome in combination with wild-type Fas have confirmed their functional effect in reducing Fas-mediated apoptosis (unpublished data) and their dominant negative effect.
In addition to defining the molecular basis of a previously described pediatric disorder, our study showed that Fas mutations are compatible with long-term survival in humans. We also highlighted the potential long-term complications (e.g., chronic hepatitis, hepatocellular carcinoma, and other neoplasms), which emphasize the complex interplay between Fas mutations, other genetic factors, and the environment in the Canale–Smith syndrome.
5 ReferencesAkshay K. Vaishnaw, M.D., Ph.D.
Cornell University Medical Center, New York, NY 10021Kathleen E. Sullivan, M.D., Ph.D.
University of Pennsylvania, Philadelphia, PA 19104Keith B. Elkon, M.D.
Cornell University Medical Center, New York, NY 100211
Canale VC ,Smith CH . Chronic lymphadenopathy simulating malignant lymphoma. J Pediatr 1967;70:891-899
CrossRef | Web of Science | Medline2
Fisher GH ,Rosenberg FJ ,Straus SE , et al. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 1995;81:935-946
CrossRef | Web of Science | Medline3
Rieux-Laucat F ,Le Deist F ,Hivroz C , et al. Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science 1995;268:1347-1349
CrossRef | Web of Science | Medline4
Raveche ES ,Steinberg AD ,DeFranco AL ,Tjio J-H . Cell cycle analysis of lymphocyte activation in normal and autoimmune strains of mice. J Immunol 1982;129:1219-1226
Web of Science | Medline5
Sobel ES ,Kakkanaiah VN ,Rapoport RG ,Eisenberg RA ,Cohen PL . The abnormal lpr double-negative T cells fail to proliferate in vivo. Clin Immunol Immunopathol 1995;74:177-184
CrossRef | Medline
