Background The Canale–Smith syndrome is a childhood disordercharacterized by lymphadenopathy and autoimmunity. The similaritybetween this syndrome and that in mice with the lymphoproliferation(lpr ) phenotype or the generalized-lymphoproliferative-disease(gld) phenotype led us to investigate whether it too is causedby mutations of the Fas gene (lpr mice) or the Fas ligand (gldmice), which regulate apoptosis in lymphocytes.
Methods We studied four patients with the syndrome and theirfamilies. T-lymphocyte phenotypes were analyzed, and the susceptibilityof activated T cells to Fas-mediated apoptosis in vitro wasdetermined. Mutations of Fas were sought by nucleotide-sequenceanalysis.
Results Patients with the Canale–Smith syndrome had increasednumbers of circulating double-negative T cells (>20 percent)and profoundly impaired apoptosis of activated T cells incubatedwith an anti-Fas antibody. Three novel Fas mutations were identified,all of which were heterozygous and predicted to impair signaltransduction by Fas. Autoimmune manifestations of the disease,such as hemolytic anemia and thrombocytopenia, persisted intoadolescence. Two patients followed into adulthood had intermittentlymphadenopathy, which diminished over time. Neoplasms developedin both, and one died of hepatocellular carcinoma at the ageof 43.
Conclusions Patients with the Canale–Smith syndrome havemutations in Fas — a fact that implicates this gene inthe accumulation of lymphocytes and the autoimmunity characteristicof the syndrome.
The Canale–Smith syndrome, first described in 1967,1 isan uncommon cause of lymphadenopathy in children.2,3,4 Patientswith the syndrome present within the first two years of lifewith lymphadenopathy, hepatosplenomegaly, hemolytic anemia,and thrombocytopenia. Lymph-node biopsy reveals nonspecifichyperplasia with increased numbers of lymphocytes, plasma cells,and histiocytes.1 The response to corticosteroids and immunosuppressivedrugs varies, and the long-term prognosis is not known; onlyone patient has been followed into adolescence.
The presence of hypergammaglobulinemia and autoantibodies againsterythrocytes and platelets led Canale and Smith1 to postulatethat the syndrome had a primary immunologic basis. We studiedfour patients with the disorder, and all four had mutationsin the "death domain" of the Fas receptor (also called APO-1and CD95). The death domain is the cytoplasmic region of theFas protein that transduces the intracellular signals requiredto initiate programmed cell death (apoptosis). Fas is particularlyimportant in the apoptosis of activated lymphocytes5 and macrophages.6In mice, mutations in the Fas receptor (lpr, lymphoproliferationphenotype) or its ligand (gld, generalized-lymphoproliferative-diseasephenotype) are associated with massive lymphadenopathy and lupus-likeautoimmunity.5 These animals also have large numbers of T cellswith down-regulated CD4 and CD8 surface molecules ("double-negative"T cells). Normally, the Fas pathway triggers apoptosis in thecells. We found increased numbers of these unusual T cells inpatients with the Canale–Smith syndrome.
Case Reports
Patient 1
Patient 1 is a 43-year-old woman whose presentation and earlyhistory have been described previously.1 At the age of 15, aleft suborbital mass developed, which consisted of chronic inflammatorytissue with numerous foreign-body-type multinucleated giantcells. Two years later, thrombocytopenia resulted in severemenometrorrhagia. At the age of 21, pelvic masses were detectedand a lymphangiogram revealed extensive bilateral iliac andpara-aortic lymphadenopathy. Ten years later, the patient underwentlaparotomy for an enlarging abdominal mass, which was foundto be a lymph-node aggregate weighing 234 g and measuring 9.5by 7 by 5 cm. Immunophenotyping of the cells revealed 87 percentCD3+ T cells (pan-T cells; normal range, 48 to 67 percent),20 percent CD4+ T cells (normal range, 29 to 48 percent); 15percent CD8+ T cells (normal range, 15 to 27 percent), and 67percent HLA-DR+ cells (normal range, 6 to 25 percent). Theseresults are consistent with an excess of activated, double-negativeT cells (CD3+, CD4-, CD8-). The patient continues to have mildcervical, axillary, and intraabdominal lymphadenopathy. Shealso has chronic hepatitis B and hepatitis C infections andpersistent hypergammaglobulinemia: IgA, 488 mg per deciliter(upper limit of normal, 382); IgM, 239 mg per deciliter (upperlimit of normal, 277); and IgG, 4240 mg per deciliter (upperlimit of normal, 1685). She has had multiple neoplastic lesions:a breast adenoma (at the age of 22), three thyroid adenomas(at 15, 32, and 36 years of age), and two basal-cell carcinomas(at 22 and 41 years of age). No autoimmunity or lymphadenopathyhas occurred in her parents, her six siblings, or her son.
Patient 2
Patient 2, a man who has been described previously,1 presentedat the age of 43 with hepatitis associated with hepatitis Cinfection. A liver biopsy revealed hepatocellular carcinoma,and he died one month later. He had been treated with corticosteroidsand mercaptopurine from the ages of 4 to 12, with substantial,but incomplete, regression of lymphadenopathy. The lymphadenopathygradually diminished during adolescence and was infrequent andmild during adulthood.
Patient 3
Patient 3 is the eight-year-old son of Patient 2. He presentedat seven months with a syndrome identical to that of his father.A lymph-node biopsy revealed atypical T-cell hyperplasia withangioimmunoblastic features; the bone marrow aspirate containedno atypical cells. Ultrasonography demonstrated a mass of lymphnodes in the porta hepatis.3 Worsening thrombocytopenia requiredsplenectomy at the age of two years. Subsequently, autoimmunehemolytic anemia and thrombocytopenia were controlled with methotrexate(2.5 mg per week). At present, the child has massive lymphadenopathy(predominantly cervical) but is otherwise well. Serum immunoglobulinlevels are normal except for IgA, which is slightly elevated(267 mg per deciliter; upper limit of normal, 202).
Apart from his father, no family member has a history of lymphoproliferativeor autoimmune diseases.
Patient 4
Patient 4, an eight-year-old boy, was found to have splenomegalyat 4 months and hemolytic anemia and neutropenia (absolute neutrophilcount, 154 per cubic millimeter [normal, 500 to 8500]) at 10months of age. A bone-marrow biopsy was normal. Because of generalizedlymphadenopathy, a lymph-node biopsy was done. It revealed reactivefollicular hyperplasia with 24 percent CD4+ T cells (controlvalue, 38 percent), 11 percent CD8+ T cells (control value,29 percent), 42 percent CD2+ T cells (control value, 79 percent),and 55 percent CD19+ T cells (control value, 7 percent). Atthree years of age, hypergammaglobulinemia, a positive directCoombs' test, anti–smooth-muscle antibodies, and an antinuclear-antibodytiter of 1:320 with a nucleolar pattern were detected.
At 3 1/2 years of age, profound thrombocytopenia developed;the patient responded to intravenous immune globulin but requiredsplenectomy. At surgery, massive splenomegaly and mesentericlymphadenopathy were found. Currently, the boy has generalizedlymphadenopathy but is otherwise well; serum immunoglobulinlevels are normal. The family history is unremarkable exceptfor a grandmother who had multiple sclerosis and a grandfatherwho had Guillain–Barré syndrome in 1994. The patienthas a healthy dizygotic twin.
Methods
Flow Cytometry
Peripheral-blood mononuclear cells were isolated by density-gradientcentrifugation and analyzed by flow cytometry 6,7 (FACScan,Becton Dickinson, San Jose, Calif.) with the following primaryantibodies: unconjugated rabbit polyclonal antihuman Fas (N18,Santa Cruz Biotechnology, Santa Cruz, Calif.); biotin-conjugatedanti-CD3, anti-CD4, anti-CD8, and anti-CD19 (Caltag, South SanFrancisco, Calif.); biotinylated anti-CD56 (Southern Biotechnologies,Birmingham, Ala.); and phycoerythrin-conjugated anti-CD4, anti-CD8,and anti-CD25 (Becton Dickinson). The secondary reagents usedwere streptavidin conjugated to fluorescein isothiocyanate (JacksonImmunoResearch, West Grove, Pa.) or Tricolor (Caltag); and donkeyantirabbit IgG conjugated to fluorescein isothiocyanate or phycoerythrin(Jackson ImmunoResearch). Double-negative T cells were detectedby three-color staining with anti-CD3, anti-CD8, and anti-CD4monoclonal antibodies.
Cell Culture and Analysis of Fas and Fas-Ligand Function
T cells were activated with the anti-CD3 monoclonal antibodyOKT3 (ascites fluid, 1:1000 dilution) and interleukin-2 (20U per milliliter) for seven to eight days before the assays.To examine the function of Fas, the activated T cells were incubatedwith IgG3 anti–APO-18 (kindly provided by Peter Krammer,German Cancer Research Institute, Heidelberg, Germany) or controlmonoclonal antibody for 16 hours,7 and cell viability was measuredby the Alamar Blue assay.6 The function of Fas ligand was evaluatedby a chromium-release assay, with activated T cells (>95percent CD3+) and target cells consisting of a mouse L1210 B-celllymphoma cell line, transfected with murine Fas in either thesense or antisense orientations (kindly provided by W. Clarke,UCLA, Los Angeles).9 Effector cells were incubated with targetslabeled with chromium-51 for six hours in the presence of anti-CD3,and the extent of specific lysis was calculated.6 The assaywas also performed in the presence of magnesium ethyleneglycol-bis-(-aminoethylether)-N,N,N',N'-tetraaceticacid to block calcium-dependent, perforin-mediated cytotoxicity,as described elsewhere.10
Nucleotide Sequence of Fas and Fas-Ligand DNA and Analysis of Single-Strand Conformation Polymorphisms
Complementary DNA (cDNA) was prepared from anti-CD3–activatedT cells,11 and Fas and Fas-ligand (FasL) gene sequences wereamplified with the polymerase chain reaction (PCR) by the primers12,13shown in Table 1. For Fas, a 694-bp 5' cDNA fragment, spanningsequences that encode the extracellular and transmembrane domains(primer pair 1 and 14 in Table 1), and a 506-bp 3' cDNA fragment,encoding transmembrane and cytoplasmic domains (primers 11 and4 in Table 1), were generated. The PCR products were clonedinto pGEM-T (Promega, Madison, Wis.), and bidirectional sequencingof inserts was performed with consensus T7 and Sp6 primers.The results were assembled as directed by the Prism Dye TerminatorCycle Sequencing Ready Reaction kit (Perkin Elmer, Foster City,Calif.) and analyzed on an automated sequencer (model 377, ABI,Foster City, Calif.).
Table 1. Oligonucleotide Primers Used in Studies of the Fas and FasL Genes.
To verify mutations, genomic DNA was isolated from peripheral-bloodleukocytes.14 Up to 200 ng of DNA was used as a template ina 100-µl PCR reaction (denaturation at 95°C for oneminute, annealing at 55 to 60°C for one minute, and extensionat 72°C for one to two minutes) for 30 cycles. The PCR productswere sequenced directly with primers end-labeled with [32P]ATP(fmol DNA cycle sequencing system, Promega). In the case ofPatient 2, archival material was available from his liver-biopsysample (kindly provided by Dr. A. Altman, Warren Hospital, Phillipsburg,N.J.), and genomic DNA was isolated as described elsewhere.15
Analysis of single-strand conformation polymorphisms was usedto investigate the frequency of defined mutations in 100 unrelatedsubjects. Primers spanning the 5' end of the death domain (cDNAposition, 871 to 1055) were used to amplify genomic DNA, asdescribed above. The results were analyzed as reported elsewhere.16
Serologic Analysis
Serum samples were tested for antinuclear antibody by indirectimmunofluorescence with Hep2 cells used as the substrate, asdescribed previously.17 Anticardiolipin18 antibodies, antibodiesagainst double-stranded DNA,17 and IgM rheumatoid factors19were detected by an enzyme-linked immunosorbent assay.
Results
T-Cell Phenotypes
Phenotypic analysis of T cells from the three living patientsrevealed that all had higher levels of double-negative (CD3+CD4-CD8-)T cells (>20 percent) than control subjects (<5 percent)(Figure 1A). In patient 1, almost half of all T cells in theblood had this unusual phenotype (Figure 1B). The clinicallynormal twin sister of Patient 4 had intermediate levels of double-negativeT cells (12 percent). Fas was detected on unstimulated T cellsfrom all patients (data not shown).
Figure 1. Analysis of Lymphocyte Subgroups in Patients with the Canale–Smith Syndrome and Their Relatives, and Control Subjects.
Panel A shows the results of a phenotypic analysis of T-cell subgroups. In Panel B, peripheral-blood mononuclear cells from Patient 1 and a normal control were analyzed by three-color flow cytometry with monoclonal antibodies specific for CD3, CD4, and CD8. CD3+ cells were gated; the percentages of double-negative cells are indicated in the lower left quadrants.
Fas-Mediated Apoptosis
Activated T cells from the patients were almost completely resistantto apoptosis induced by ligating the Fas receptor with an anti-Fasantibody (Figure 2). Activated T cells from the mother and twinsister of Patient 4 (both of whom were phenotypically normal)were also highly resistant to the anti-Fas antibody (Figure 2).
Figure 2. Fas-Mediated Apoptosis of Activated T Cells in the Patients, Their Relatives, and Normal Controls.
Peripheral-blood T cells were activated by incubation with anti-CD3 and interleukin-2 for eight days in vitro and then tested for Fas-mediated apoptosis.
To assess the function of the Fas ligand, which mediates oneof the cell-mediated cytolytic pathways, we measured the lysisof Fas-positive target cells by activated T cells. The activityof the patients' T cells in this assay was equivalent to thatof T cells from normal subjects at all effector-to-target ratios(data not shown). These findings suggest that the expressionand function of the Fas ligand are intact in the Canale–Smithsyndrome. Consistent with this conclusion is the finding thatFasL coding sequences, which were amplified from the patients'cDNA, cloned, and sequenced (six clones for each insert), containedno variations from the published sequence of FasL.13
Fas Mutations
Since the phenotype of the patients strongly resembled thatassociated with Fas mutations in mice,20Fas coding sequenceswere amplified from cDNA. The PCR products were cloned, andfour or more clones were sequenced in both directions for eachinsert.
In addition to known Fas gene polymorphisms,21 a single nucleotidechange, affecting the death domain (amino acid residues 231to 298), was demonstrated for each patient in half the sequenced3' cDNA clones. Patient 1 had an insertion of a T at cDNA position887, which would predict a frame shift leading to a prematuretermination at residue 230 (K230•). Patient 3 had a transversionof G to T at position 972, resulting in a nonconservative substitutionof tyrosine for aspartic acid at residue 244 (D244Y). Patient4 had a transversion of C to T at position 942 of the Fas cDNA,resulting in an in-frame premature stop codon and truncationat residue 234 (R 234•).
Mutations identified in cloned DNA were confirmed at the genomiclevel by PCR amplification of a 1.3-kb fragment with primerpair 23 and 4 and direct cycle sequencing of the death domainby primer 17. All four patients were heterozygous with respectto their Fas mutation (Figure 3A, Figure 3B, and Figure 3C).
Figure 3. Pedigrees of the Patients with the Canale–Smith Syndrome and the Mutations Identified in the Families.
Asterisks indicate subjects tested for Fas mutations. Square symbols denote male family members, circles female family members, solid symbols clinically affected patients, shaded symbols clinically unaffected carriers of the mutant Fas allele, and symbols with a slash deceased family members. Where relevant, the age and diagnosis are shown. The nucleotide sequences corresponding to the death domain of the Fas receptor for patients are compared with the wild-type sequences. At the bottom of Panel A, sequence analysis reveals the insertion of a T in a cDNA clone and on one allele in the genomic DNA in Patient 1. At the bottom of Panel B, cycle sequencing of genomic DNA from Patient 3 shows a heterozygous transversion of G to T. The identical mutation was detected in genomic DNA extracted from a liver-biopsy specimen from Patient 2 (the father of Patient 3). At the middle of Panel C, cycle sequencing of genomic DNA from Patient 4 shows a heterozygous transversion of C to T. This mutation leads to the loss of a TaqI site. At the bottom of Panel C, a 1.3-kb genomic PCR product spanning the death domain of Fas (primers 23 and 4 in Table 1) was amplified from Patient 3 and his mother, sister, and father and cut with TaqI. Heterozygous family members (the patient and his sister and mother) have bands at 0.1 and 0.3 kb but retain a 1.3-kb fragment, whereas the wild-type fragment (present in the father) has bands only at 1.0 and 0.3 kb. TB denotes tuberculosis, U uncut DNA, and C cut DNA.
Fas Mutations and Defective Fas-Mediated Apoptosis
The mutated Fas allele in Patient 3 was assumed to be derivedfrom his father, Patient 2.1 A Fas mutation in Patient 2 wasdetected in DNA that was extracted from an antemortem liverbiopsy and amplified by PCR (primers 17 and 47). Sequencingof the cloned PCR product revealed the D244Y mutation (datanot shown). No Fas mutations were detected in genomic DNA fromthe son of Patient 1 or the mother of Patient 3.
Analysis of genomic DNA from relatives of Patient 4 revealedthat his mother and sister, but not his father, were heterozygousfor the R 234• mutation (Figure 3C). The mutations in thisfamily therefore segregated with the in vitro resistance toFas-mediated apoptosis but not with the expression of disease.
The likelihood that the Fas mutations we found were causallyrelated to the Canale–Smith syndrome was supported byour failure to detect any of the mutations in 100 unrelatedsubjects by analysis with PCR and single-strand conformationpolymorphisms (not shown).
Serologic Analysis
Serum samples from all three patients and the relatives studiedin Figure 1A and Figure 1B were negative for antinuclear, anti–double-strandedDNA, and anticardiolipin autoantibodies. Patient 1 had a hightiter (positive at a dilution of 1:1000) of IgM rheumatoid factor.
Discussion
We found that, like lpr and gld mice,22 patients with the Canale–Smithsyndrome have increased numbers of double-negative (CD3+CD4-CD8-)T cells in the circulation and lymph nodes and profoundly impairedFas-mediated apoptosis of activated T cells. It is thought thatnormally activated T cells down-regulate CD4 and CD8 moleculesand are disposed of by Fas-mediated apoptosis. But in mice witha mutant Fas gene, they accumulate in vast numbers. Canale andSmith1 commented that the syndrome of chronic lymphadenopathy,hepatosplenomegaly, and autoimmunity named after them did nothave a genetic basis, but, prompted by the family history ofPatient 3 and the striking features of the murine lpr phenotypepresent in these patients, we tested the hypothesis that a mutationof the Fas or FasL gene causes the syndrome. The four patientswe studied had novel Fas mutations predicted to cause eithertruncation (K 230• and R 234•) or a nonconservativeamino-acid substitution (D244Y) in a highly conserved regionof the Fas death domain.23,24
Fas is a member of the superfamily of tumor necrosis factorand nerve growth factor receptors. Binding to its cognate ligandcauses clustering of the Fas receptor,25 which recruits signal-transductionmolecules to its intracytoplasmic death domain, thereby initiatingprogrammed cell death.24,25,26 Fas is expressed on thymocytesand activated T and B cells and is thought to be primarily responsiblefor the apoptosis of antigen-primed, activated lymphocytes.5Defective Fas function could therefore cause an accumulationof lymphocytes, including potentially autoreactive cells. Thesemolecular abnormalities can account, at least in part, for thelymphadenopathy and autoimmunity characteristic of the Canale–Smithsyndrome.
Resistance to Fas-mediated apoptosis in vitro was found in allpatients who were heterozygous for a Fas mutation, suggestingthat the mutant alleles act in a dominant negative manner. Inlprcg mice a heterozygous amino-acid substitution at position225 in the Fas death domain results in lymphadenopathy and autoimmunity,27and in vitro cotransfection of wild-type and mutant Fas genesimpairs Fas-mediated apoptosis.28 However, the genotype–phenotyperelation is complex. Three members of the family of Patient4 had the R 234• mutation, as well as defective Fas-mediatedapoptosis, but only the proband had autoimmunity and lymphadenopathy.We conclude that a single mutant Fas allele can affect Fas-mediatedapoptosis in vitro, but by itself is insufficient to cause disease;additional factors modulate Fas deficiency, as observed in micebearing the lpr mutation that have different genetic backgrounds.29,30
Our findings are similar to those in the original reports ofFas dysfunction in humans, which also documented inherited,heterozygous Fas mutations with variable penetrance.28,31,32Comparison of these five cases of a "human autoimmune lymphoproliferativesyndrome"28 and three cases of "human lymphoproliferative syndromeand autoimmunity"32 with the Canale–Smith syndrome suggeststhat all three syndromes are the same.
The major medical complications in infancy and childhood areautoimmune hemolytic anemia, thrombocytopenia, and infectiondue to splenectomy or neutropenia. Treatment with corticosteroids,immunosuppressive drugs, or both can reduce the degree of lymphadenopathyand improve the cytopenias. However, most of our patients underwentsplenectomy during childhood to alleviate the cytopenias.1 Thewaxing and waning of the lymph nodes suggests that alternativepathways of lymphocyte apoptosis can compensate for impairedFas function for extended periods. Exacerbations of lymphadenopathycould have been precipitated by viral infections, since certainDNA viruses can inhibit apoptosis.33 Canale and Smith1 observedthat bacterial infections frequently cause a reduction in thesize of the lymph nodes; bacterial infections induce the releaseof cytokines such as tumor necrosis factor that promote lymphocyteapoptosis through alternative pathways.34,35
Our results show that defective Fas function is compatible withlong-term survival; two of our patients have been or were undermedical care for 29 years. However, lymphadenopathy, autoimmunethrombocytopenia, and complications of blood transfusion (hepatitisvirus infection) have continued into adolescence and adulthood.In two patients (Patient 1 and Patient 2) neoplasms developedin adulthood. These tumors could have been related to cytotoxicdrugs or hepatitis virus, but a role for Fas mutations requiresconsideration. Fas is expressed at multiple sites throughoutthe body, including skin, liver, and gastrointestinal tract.36Its role in nonlymphoid tissue is not known, but Fas is functionalin hepatocytes37,38 and is up-regulated in hepatitis B and Cinfection.38,39 The failure of cytotoxic T cells to eliminatehepatitis virus through the Fas pathway could therefore havecontributed to the persistence of hepatitis virus in Patients1 and 2. Furthermore, Fas-knockout mice, in which the Fas geneis disabled, have liver hyperplasia, suggesting a role for Fasin controlling the growth of hepatocytes.40 Cells bearing mutantFas receptors at other sites may also have a growth advantageresulting from the failure of CD8 or natural killer cells toperform tumor surveillance through the Fas effector pathway.41,42,43Preliminary studies suggest that some families with Fas mutationshave an increased frequency of lymphomas.44
Twelve cases of lymphadenopathy and autoimmunity associatedwith Fas mutations have now been reported. The characterizationof factors that modulate the clinical outcome of Fas mutationsmay lead to the identification of important susceptibility genesor environmental agents that participate in other autoimmuneand lymphoproliferative disorders.
Supported in part by a Specialized Center of Research grantfrom the National Institutes of Health (SLE P50-AR42588) andby a grant from the Histiocytosis Association of America. Dr.Vaishnaw is a recipient of the Copeman Travelling Fellowshipfrom the Arthritis and Rheumatism Council, United Kingdom.
We are indebted to Drs. M. Hilgartner (New York Hospital, NewYork), D. Douglas (Children's Hospital of Philadelphia), A.Altman (Warren Hospital, Phillipsburg, N.J.), Steven Halpern(Overlook Hospital, Summit, N.J.), and R. McMillan (ScrippsClinic, La Jolla, Calif.) for patient information; and to Dr.Michael Lenardo (National Institutes of Health, Bethesda, Md.)and our colleagues at the Hospital for Special Surgery for helpfuldiscussions.
Source Information
From the Division of Rheumatology, Hospital for Special Surgery, Cornell University Medical Center, New York (J.D., A.K.V., J.-L.C., K.B.E.), and the Division of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia (K.E.S.).
Address reprint requests to Dr. Elkon at the Hospital for Special Surgery, 535 E. 70th St., New York, NY 10021.
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The Canale–Smith Syndrome
Straus S. E., Lenardo M., Puck J. M., Vaishnaw A. K., Sullivan K. E., Elkon K. B.
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Full Text
N Engl J Med 1997;
336:1457-1458, May 15, 1997.
Correspondence
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-aminoethylether)-N,N,N',N'-tetraacetic acid to block calcium-dependent, perforin-mediated cytotoxicity, as described elsewhere.10 
32P]ATP (fmol DNA cycle sequencing system, Promega). In the case of Patient 2, archival material was available from his liver-biopsy sample (kindly provided by Dr. A. Altman, Warren Hospital, Phillipsburg, N.J.), and genomic DNA was isolated as described elsewhere.15 
that promote lymphocyte apoptosis through alternative pathways.34,35 
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