UMLS:C0019214 - FACTA Search

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Query: UMLS:C0019214 (hepatosplenomegaly)
4,408 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inherited mutations of the Fas/Apo1/CD95 gene, a cell-surface receptor involved in cell death signaling and in the control of self-reactivity, characterize the recently identified autoimmune lymphoproliferative syndromes. A patient with type 2 autoimmune hepatitis with the immunologic and genetic features of autoimmune lymphoproliferative syndrome is described. The clinical picture was dominated by liver disease with hepatosplenomegaly and positivity for anti-liver-kidney microsome 1 and anti-liver-cytosol 1 antibodies. A marked increase in CD3+CD4-CD8-T lymphocytes and inherited mutations in Fas alleles that led to the expression of a soluble form of the protein were also found. Fas-mediated apoptosis was deficient in the patient as it was in her mother and her sister, who carried the same allele 2 mutation. This observation links type 2 autoimmune hepatitis, an organ-specific disease, with a genetically determined defect in peripheral tolerance control.
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PMID:Fas/Apo1 mutations and autoimmune lymphoproliferative syndrome in a patient with type 2 autoimmune hepatitis. 961 60

The FAS (CD95/APO-1) receptor and its ligand play an important role in the initiation of apoptosis under many physiologic conditions. Loss of function mutations of the FAS gene have been described in lpr mice and in humans with autoimmune phenomena, recurrent lymphadenopathies, and hepatosplenomegaly. This syndrome is now called autoimmune lymphoproliferative syndrome type I (ALPS I). Recently, patients with similar clinical symptoms due to a functional FAS deficiency without FAS gene mutations have been distinguished. This disease has been termed autoimmune lymphoproliferative syndrome type II (ALPS II) or autoimmune lymphoproliferative disease (ALD). This report is the first description of the lymph node pathology and immunohistochemistry in a patient with ALPS II. After recurrent bacterial infections, a 4-year-old child developed cervical giant lymphadenopathy suggesting lymphoma. Lymph node histology resembled the findings in Epstein Barr virus-associated posttransplant atypical lymphoproliferations. Confluent sheets of immunoblasts, however, showed a monoclonal expression of IgG/lambda and a monoclonal rearrangement of the JH chain. The same clone was also present in the peripheral blood. Although high-grade lymphoma could not be excluded, the patient's parents insisted on the patient's leaving the hospital with only antibiotic treatment. Surprisingly, the giant lymphadenopathy completely resolved within 7 weeks, and the clone was no longer detectable in the peripheral blood. Twelve months later the patient was still free from lymphoma and was doing well. Retrospectively, transient monoclonal B-cell populations could be identified in an archival frozen blood sample taken when the patient was 3 years old. Increased FAS-independent spontaneous apoptosis was a feature of the patient's lymphocytes and could be the molecular basis for self-elimination of B-cell clones. We conclude that the diagnosis of a FAS-FAS-L deficiency should be considered in children with an otherwise unexplained atypical lymphoproliferation and that a diagnosis of lymphoma in patients with functional FAS deficiency should be made with considerable reservation.
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PMID:Reversible monoclonal lymphadenopathy in autoimmune lymphoproliferative syndrome with functional FAS (CD95/APO-1) deficiency. 1040 7

Most humans with autoimmune lymphoproliferative syndrome (ALPS) carry heterozygous dominant mutations in one allele of the gene encoding Fas/APO-1/CD95. ALPS patients, like Fas-deficient MRL lpr/lpr mice, have lymphoproliferation, autoimmunity, increased CD4(-)/CD8(-) T lymphocytes, and apoptosis defects. Consistent with the phenotypic variability of lpr/lpr mice of different background strains, human genetic studies indicate that a Fas mutation is insufficient to induce ALPS in all mutation carriers. To investigate the dominant function of human Fas mutations and the additional genetic factor(s) involved in the development of ALPS, we generated transgenic mice expressing, in addition to endogenous Fas, mouse Fas molecules bearing mutations in the intracellular death domain corresponding to mutations identified in ALPS patients. Transgenic mice developed mild features of ALPS, including hepatosplenomegaly, elevated proportions of lymphocytes in spleen and lymph nodes, apoptotic defects, and hepatic lymphocytic infiltrates. Therefore defective murine Fas proteins act in a dominant manner to impair apoptosis of activated lymphocytes and disrupt lymphocyte homeostasis. The influence of genetic background on phenotype was studied by comparing transgenic mice on FVB/N and (FVB/N x MRL) backgrounds with syngenetic control mice and with MRL and MRL lpr/lpr mice. While expression of transgenic mutant Fas contributed mainly to hepatosplenomegaly and accumulation of lymphocytes, MRL background genes played a major role in the production of autoantibodies and elevated serum immunoglobulin levels. Moreover, compared to FVB/N (+/+) mice, a substantial Fas-specific apoptotic defect was found in MRL (+/+) mice, suggesting a mechanism for the known tendency of this strain to develop autoimmunity.
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PMID:Expression in transgenic mice of dominant interfering Fas mutations: a model for human autoimmune lymphoproliferative syndrome. 1049 9

This case provides a complete light microscopic, immunophenotypic, and molecular genetic analysis of autoimmune lymphoproliferative syndrome (ALPS), a rare benign cause of dramatic lymphadenopathy with atypical histology and phenotype that may be mistaken for malignancy. The patient is 3-year-old child who was first clinically evaluated at the age of 16 months because of marked generalized lymphadenopathy and hepatosplenomegaly. Histologic sections of a cervical lymph node demonstrated a marked paracortical proliferation of occasional small and intermediate-sized lymphocytes and numerous large immunoblasts, the majority of which displayed a CD3(+), CD43(+), CD45RO(-) (OPD4, UCHL1) CD4(-), CD8(-) phenotype on paraffin sections, and which had a CD2(+), CD3(+), CD5(+), CD56(-), Tdelta1(-), [CD4(-), CD8(-)] double negative profile on flow cytometric analysis. Southern blot analysis did not identify a clonal T or B cell population, and sequencing of the fas gene identified a mutation that caused a single amino acid substitution in the intracytoplasmic death domain of this protein. An enriched population of CD45RO-negative naive T cells in the paracortex may explain the atypical histologic and immunophenotypic features of this case. Greater awareness of this heritable lymphoproliferative disorder will facilitate its recognition and minimize the possibility of misdiagnosis.
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PMID:Light microscopic, immunophenotypic, and molecular genetic study of autoimmune lymphoproliferative syndrome caused by fas mutation. 1059 39

The importance of Fas in the homeostatic balance between lymphocyte survival and death is underscored by the three main consequences of defective Fas-mediated apoptosis, as experienced by patients with ALPS: (1) abnormal accumulation of lymphocytes results in lymphadenopathy, hepatosplenomegaly, and hypersplenism; (2) failure of removal of potentially autoreactive lymphocytes, a process normally used to eliminate lymphocytes that have escaped negative selection in the thymus and bone marrow (see article by Fleisher and Blessing, p. 1197), is associated with the appearance of autoimmune manifestations; and (3) inappropriate survival of lymphocytes may lead to the development of malignancies. As with other "experiments of nature," the many aspects of ALPS have provided valuable new insights into the immune system and the importance of a proper balance between life and death of lymphocytes. ALPS is an example of how a mouse disease model was applied directly to the identification of the molecular basis and the understanding of a remarkable disease in humans. It is also an example of clinical observations being linked to basic scientific data to unlock the underlying defect(s) causing a disease. Despite the difficulty in fully understanding the complex nature of the clinical course, the immunologic abnormalities, and the genetic aspects of ALPS, the accumulated experience in diagnosis, treatment, and follow-up of patients and relatives has generated a "road map" that can be used as a guide for their care. As examples, the appreciation that manifestations of lymphoproliferation usually subside over time has allowed a "wait-and-see" approach in many patients who might previously have been treated aggressively. The appreciation that these patients are at increased risk for malignancies has mandated the adoption of careful and lifelong follow-up. Future efforts directed at careful clinical follow-up and scientific investigation are required to learn more about the incidence and natural history of ALPS, therapeutic interventions directed at altering the consequences of TNFRSF6 mutations, and the identification of other genetic and environmental factors that may have a role in the pathogenesis of ALPS.
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PMID:Autoimmune lymphoproliferative syndrome. A human disorder of abnormal lymphocyte survival. 1113 Sep 97

A 6-month-old girl presented to the hospital with cervical lymphadenopathy and hepatosplenomegaly. She was known to have an enlarged spleen, anemia, and thrombocytopenia since the age of 1 month. A lymph node biopsy showed a diffuse proliferation of blasts with few remnants of follicles. The blasts were CD3+CD57+CD4-CD8-, consistent with the usual autoimmune lymphoproliferative syndrome phenotype. However, these double negative T cells stained positive for gammadelta T-cell receptors, whereas double negative T cells in patients with autoimmune lymphoproliferative syndrome usually bear alphabeta T-cell receptor. Mutation analysis of the FAS gene revealed a mutation in the death domain of the FAS gene, which is a frequent finding in patients with autoimmune lymphoproliferative syndrome. Based on these results, the diagnosis of autoimmune lymphoproliferative syndrome was established. RT-PCR analysis of the affected lymph node tissue revealed a strong upregulation of interleukin 10 and a moderate upregulation of interferon-gamma expression compared with normal tissue. Our findings indicate that autoimmune lymphoproliferative syndrome can result in a prominent proliferation of gammadelta+ double negative T cells. It is important to distinguish this benign polyclonal proliferation from neoplastic gammadelta+ T-cell proliferations, such as hepatosplenic gammadelta T-cell lymphomas. Factors contributing to the accumulation of these gammadelta+ double negative T cells may be an unidentified infection in combination with the young age of onset in this patient.
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PMID:FAS gene mutation in a case of autoimmune lymphoproliferative syndrome type IA with accumulation of gammadelta+ T cells. 1265 42

The autoimmune lymphoproliferative syndrome (ALPS) or Canale-Smith syndrome is a recently described clinical entity consisting of chronic, non-malignant lymphadenopathy and hepatosplenomegaly together with hypergammaglobulinemia, positive autoantibodies and/or overt autoimmune diseases. It is caused by a genetic defect in the mechanism of programmed cell death (apoptosis) and is characterized by the presence of double-negative (TCR alpha/beta CD4- CD8-) T lymphocytes (DNT). Although well known in pediatric patients, ALPS is an unusual diagnosis in adults. The oldest reported patient was aged 54. We describe another two adult patients in whom a presenting autoimmune disease led to the diagnosis of ALPS.
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PMID:The autoimmune lymphoproliferative syndrome (Canale-Smith) in adulthood. 1474 82

Autoimmune Lymphoproliferative Syndrome (ALPS) is generally the result of a mutation in genes associated with apoptosis, like Fas, Fas ligand, Casp 8 and Casp 10. As a result, the normal homeostasis of T- and B-lymphocytes is disturbed and a proliferation of polyclonal T lymphocytes occurs. This leads to hepatosplenomegaly and lymphadenopathy and in most patients also to autoimmune phenomena like anemia and thrombocytopenia. The proliferating T cells are TCRalphabeta and/or TCRgammadelta positive but lack both CD4 and CD8. Hence they are termed double negative (DN) T cells. In addition, there is an increase of CD5 positive B cells. Individuals with germline mutations in the Fas gene have a high risk to develop non Hodgkin lymphomas (x 14) as well as Hodgkin lymphomas (x 51), in particular NLP Hodgkin lymphoma. Somatic mutations of Fas are frequently acquired during the normal germinal center reaction. Non Hodgkin lymphomas carry somatic mutations of the Fas gene in 11% and of the Casp 10 gene in 14.5% of the patients. In Hodgkin lymphomas, Fas mutations can be demonstrated in Reed-Sternberg cells in 10-20% of the patients. These data implicate a role for Fas-mediated apoptosis in preventing lymphomas. Inherited defects in receptor-mediated lymphocyte apoptosis represent a risk factor for lymphomas and somatic mutations of these genes may also play a role in the development and/or progression of lymphomas.
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PMID:Development of lymphoma in Autoimmune Lymphoproliferative Syndrome (ALPS) and its relationship to Fas gene mutations. 1516 Sep 2

The autoimmune lymphoproliferative syndrome (ALPS) and ALPS-like syndrome are variable clinical conditions characterized by lymphoproliferative disease, autoimmune cytopenias and susceptibility to malignancy. A 59-year-old woman was admitted to the hospital for intractable generalized pain and stiffness with multiple swollen joints for 2 weeks. A low-grade fever, intermittent hypotension and confusion were associated with the pain. The evaluation revealed multiple joint bony erosions with effusion and a ruptured Baker's cyst and positive AFB testing on the joint biopsy of the right wrist. In addition, there were a macular skin rash with telangiectasia and perivascular lymphocyte infiltration, a cytopenia without abnormal cells, a hepatosplenomegaly, a pericardial thickness with effusion and pleural effusion. The patient was treated with anti-mycobacterial drugs, NSAIDs and glucocorticoids for 10 months. But with the symptoms worsening, the patient developed cervical lymph node enlargements and was diagnosed as a diffuse large B cell lymphoma with hemophagocytosis on biopsy.
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PMID:Autoimmune lymphoproliferative syndrome-like syndrome presented as lupus-like syndrome with mycobacterial joint infection evolved into the lymphoma. 1882 Sep 32

Patients with autoimmune lymphoproliferative syndrome (ALPS) have defective lymphocyte apoptosis with increased risk for lymphoid malignancies. Herein, we report a patient with ALPS who developed histiocytic sarcoma in a background of sinus histiocytosis and massive lymphadenopathy or Rosai- Dorfman disease. This patient had documented ALPS type Ia with a germline missense mutation in exon 9 of the TNFRSF6 gene (973 A>T, D244V) encoding Fas (CD95/Apo-1). He presented at 10 months with hepatosplenomegaly and autoimmune hemolytic anemia and was diagnosed with ALPS. At the age of 6 (1/2) years, he developed classic Hodgkin lymphoma which was treated using standard chemotherapy. Two years later, a biopsy of a positron emission tomography-positive axillary node showed features of ALPS and focal involvement by sinus histiocytosis and massive lymphadenopathy. Thereafter, the patient continued to have continued lymphadenopathy and progressive splenomegaly, leading to exploratory surgery at the age of 13 years for suspicion of lymphoma. Para-abdominal nodes revealed sheets of malignant- looking histiocytes with increased mitotic activity and areas of necrosis, indicative of histiocytic sarcoma. Spleen and lymph nodes also showed involvement by Rosai-Dorfman disease. Both components had an identical phenotype of S-100+/CD68+/ CD163+. The occurrence of malignancies involving 2 separate hematopoietic lineages in ALPS has not been reported earlier. Given the central role of defective Fas signaling in ALPS, histiocytes may be yet another lineage at risk for neoplastic transformation secondary to a block in apoptosis.
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PMID:Development of disseminated histiocytic sarcoma in a patient with autoimmune lymphoproliferative syndrome and associated Rosai-Dorfman disease. 2021 76

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