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Letter to the Editor
and to discuss potential strategies to manage internal conflict as a practitioner. Not administering blood products in this case undoubtedly contributed to the death of mother and foetus. This was because maternal autonomy was respected – which reflects broad legal and ethical consensus that competent adults may refuse any form of medical intervention – even where that intervention is lifesaving.3 Refusal of a lifesaving intervention by an informed patient is generally well respected, but the rights of a mother to refuse such interventions on behalf of her foetus is more controversial. A doctor indeed has moral obligations to both the pregnant woman, and perhaps with differing priority to the unborn foetus.4 Circumstances where foetal and maternal autonomy conflict, or where foetal beneficence conflicts with maternal autonomy, create challenges. All decisions should be strictly within the parameters of informed consent – disclosure, comprehension and free consent – and place patient autonomy at the forefront.5 We advocate the use of a multidisciplinary approach, including obstetrics, neonatology, haematology and clinical ethics, with consistent delivery of accurate, comprehensive information over several clinical encounters. Signed patient disclosures and advanced care directives may be useful in facilitating management plans.
References 1 Yang D, Hladnik L. Treatment of acute promyelocytic leukemia during pregnancy. Pharmacotherapy 2009; 29: 709–24. 2 Lin C-P, Huang M-J, Liu H-J, Chang I-Y, Tsai C-H. Successful treatment of acute promyelocytic leukemia in a pregnant Jehovah’s Witness with all-trans retinoic
There is little published information to assist physicians to manage their own anxieties, doubts and potential moral disagreement with the patient, and to help them maintain respect for a patient and continue to deliver good medical care. To improve care, we recommend developing a clear understanding of your own attitudes and beliefs, open communication between staff, identifying alternative practitioners where time permits, and accessing staff counselling. It is helpful to understand the basis of Jehovah’s Witness’ beliefs;5 however, the ethical conflicts and considerations apply more broadly. Indeed, as more foetalspecific treatments become available, conflict between the best interests of mother and foetus will increase.6 Physicians are required to apply ethical principles rationally and respect patients’ decisions irrespective of their own beliefs. Received 8 September 2014; accepted 27 November 2014. doi:10.1111/imj.12711
A. Biscoe and G. Kidson-Gerber Department of Haematology, Prince of Wales Hospital Sydney, New South Wales, Australia
acid, rhG-CSF, and erythropoietin. Am J Hematol 1996; 51: 251–2. 3 DiGiovanni LM. Ethical issues in obstetrics. Obstet Gynecol Clin North Am 2010; 37: 345–57. 4 Levy JK. Jehovah’s Witnesses, pregnancy, and blood transfusions: a paradigm for the autonomy rights of all pregnant women. JLME 1999; 27: 171–89.
Adult onset autoimmune lymphoproliferative syndrome due to somatic FAS mutation A 55-year-old woman whose medical history includes hypertension, hypercholesterolaemia and polyarthrosis consulted for the presence of bilateral painless lymphadenopathy in the cervical, postauricular and axillary areas. The blood count showed pancytopenia: normochromic normocytic anaemia (haemoglobin 110 g/L), leukopenia (3.4 × 109 leukocytes/L) and mild thrombocytopenia (platelets 126 × 109/L). The direct Coombs was negative. The hepatorenal profile was normal, and the lipid profile confirmed her known hypertriglyceridaemia. Immunoglobulin A was high (7.76 g/L) and a serum
5 Mahoney K, Valenti J. Blood refusal & obstetrics. A high-risk case scenario. AWHONN Lifelines 2004; 8: 220–5. 6 Townsend SF. Ethics for the pediatrician: obstetric conflict: when fetal and maternal interests are at odds. Pediatr Rev 2012; 33: 33–8.
protein monoclonal peak was not observed. Thyroid hormones were normal, and antinuclear, antithyroid and antiphospholipid antibodies were negative, as was rheumatoid factor. Complement and acute phase reactants were elevated. Vitamin B12 levels were elevated up to twice the upper limit of normal (>2000 ng/L). Computed tomography of the neck, thorax and abdomen showed many enlarged lymphoid nodes in the cervical, supraclavicular and axillary regions, with the spleen showing a globular appearance and normal size. The bone marrow biopsy was normal. Biopsy was performed on the two left cervical lymph nodes, and showed a lymphoid proliferation CD45+ with increased CD57. Cytometry on peripheral blood showed a population of T lymphocytes (15%) CD3+, TCRab+, © 2015 Royal Australasian College of Physicians
462
Letter to the Editor
double negative CD4− and CD8−. As a result of these findings, she was diagnosed with autoimmune lymphoproliferative syndrome (ALPS). The levels of interleukin 10 and Fas ligand soluble were high in the peripheral blood, which is consistent with the syndrome. Genetic studies were negative for mutations in the Fas and Fas ligand gene. A molecular study for Fas gene was performed in a isolated sample of double negative T (DNT) cells and a somatic mutation Fas gene, c.686T>A, was found. No treatment was initiated because the patient was well, except for the presence of the lymphadenopathy previously described. They fluctuated in size and amount, but did not appear in other locations. One year after diagnosis, positron emission tomography was performed, which showed many enlarged lymphoid nodes below the diaphragm, and in the spleen and bone marrow, with intense elevation of glucose metabolism, by lymphoproliferative process. Following this result, a new bone marrow biopsy was carried out. This was normal. We think that the radiographic progression is due to ALPS and not a lymphoma. We decided to delay treatment because the cytopenias were not clinically symptomatic. This is more common in somatic ALPS patients. ALPS, also known as Canale–Smith syndrome, is a genetic disorder characterised by early-onset, chronic, non-malignant lymphoproliferation, autoimmune manifestations and susceptibility to lymphoma.1 It is a syndrome that usually develops in childhood and disappears in adulthood. There are few reported cases of adult onset (around 8%).1 In ALPS, lymphocyte homeostasis is disrupted by defects in apoptosis mediated by Fas, a cell-surface receptor from the tumour necrosis factor (TNF) receptor superfamily.1 High counts of circulating T-cell receptor (TCR), CD4- and CD8- double negative T cells (DNT) lymphocytes and elevated plasma levels of Fas ligand and interleukin 10 are diagnostic hallmarks of the disease.1 These were present in our patient. The majority of ALPS patients carry heterozygous germline mutations in the TNFRSF6 gene coding for Fas. However, in our patient a somatic mutation of the gene TNFRSF6 was found. Somatic TNFRSF6 mutations represent the second most common genetic cause of ALPS.1 Approximately one-third of patients with ALPS have unidentified genetic mutations.2 Lymphoproliferation is the first sign of the disease, and usually occurs early in life and disappears spontaneously.1 In adulthood, autoimmune manifestations appear several years after the lymphadenopathy, usually persist and require long-term immunosuppression. Cytopenias are the most common autoimmune manifestation.1 Our patient presented with extensive lymphadenopathy and
Table 1 Revised diagnostic criteria for autoimmune lymphoproliferative syndrome (ALPS) Revised diagnostic criteria for ALPS Required 1. Chronic (>6 months), non-malignant, non-infectious lymphadenopathy or splenomegaly or both. 2. Elevated CD3+TCR+CD4−CD8− DNT cells (≥1.5% of total lymphocytes or 2.5% of CD3+ lymphocytes) in the setting of normal or elevated lymphocyte counts.
Accessory Primary 1. Defective lymphocyte apoptosis (in two separate assays). 2. Somatic or germline pathogenic mutation in FAS, FASLG or CASP10. Secondary 1. Elevated plasma sFASL levels (>200 pg/mL) OR elevated plasma interleukin-10 levels (>20 pg/mL) OR elevated serum or plasma vitamin B12 levels (>1500 ng/L) OR elevated plasma interleukin-18 levels >500 pg/mL. 2. Typical immunohistological findings as reviewed by an experienced hematopathologist. 3. Autoimmune cytopenias (haemolytic anaemia, thrombocytopenia or neutropenia) AND elevated immunoglobulin G levels (polyclonal hypergammaglobulinemia) 4. Family history of a non-malignant/non-infectious lymphoproliferation with or without autoimmunity.
simultaneous asymptomatic pancytopenia. ALPS patients with somatic FAS mutations, known as ALPS-sFAS are clinically indistinguishable from the patients with germline FAS mutations (ALPS-FAS), and therefore may also have an increased risk of developing Hodgkin and non-Hodgkin lymphoma.3 It has been reported that the initial age of presentation of patients with a somatic FAS mutation was older than that of the ALPS-FAS patients.3 Our patient was diagnosed at 55 years and had not previously shown lymphadenopathy on examination or tests. Chronic, refractory multi-lineage cytopenias due to splenic sequestration and autoimmune destruction are the most frequent cause of morbidity.4 However, splenectomy does not prevent the recurrence of cytopenias and increases susceptibility to severe bacterial infections after splenectomy, especially by pneumococcus.1,4 The aetiology is unknown and is not believed to be related to immunosuppression, thus splenectomy should be avoided whenever possible.1 Our patient also showed elevated immunoglobulin A and vitamin B12. These are common findings in ALPS.5 Haptocorrin (HC) is a protein that binds to vitamin B12,but its function is not known.5 Due to a mutation in the Fas gene, ALPS patients have elevated plasma levels
© 2015 Royal Australasian College of Physicians
463
Letters to the Editor
of Vitamin B12, up to 15 times the upper limit of the reference interval, with high production of haptocorrin by leukocytes, particularly the DNT lymphocytes.5 We think that the increased plasma B12 levels are the result of lymphoproliferation, although the molecular mechanism of this elevation is unknown.3,4 Serum vitamin B12 levels can reliably identify patients with FAS mutations and appear to be a useful marker of disease.3 However, these biomarkers may be elevated in other conditions, including common variable immunodeficiency.4 Dowdell et al.3 noted low total and high-density lipoprotein cholesterol in somatic ALPS patients, and this could be another marker. However, in our case cholesterol was normal and triglycerides were elevated. Therefore, more studies are needed to confirm the value of using cholesterol and triglycerides as markers in these cases. As the differential diagnosis for lymphadenopathy, splenomegaly and cytopenias involves many conditions with overlapping features, diagnostic criteria for ALPS have been developed (Table 1).2 A definitive diagnosis is based on the presence of both required criteria plus one primary accessory criterion, and a probable diagnosis is based on the presence of both required criteria plus one secondary accessory criterion. ALPS is also classified according to the genetic mutation (Table 2).2 Most cases of ALPS require immunosuppressive therapy, especially those with cytopenias and autoimmune manifestations.1 It is unclear whether patients with ALPS and autoimmune involvement should be treated similarly to those without ALPS. Azathioprine, mycophenolate or rapamycin are useful in this condition. However, rituximab, a monoclonal antibody directed against B cells, is not as effective as it is in patients without ALPS.1 We found radiological progression of lymphadenopathy, but no evidence of a neoplastic lymphoproliferative disorder in our patient a year after diagnosis, and decided to delay starting corticosteroids or immunosuppressants due to clinical stability. Furthermore, somatic ALPS patients usually remain stable without any clinical intervention besides treatment of their cytopenias.3 The findings of Dowdell et al.3 show
References 1 Neven B, Magerus-Chatinet A, Florkin B, Gobert D, Lambotte O, De Somer L et al. A survey of 90 patients with autoimmune lymphoproliferative syndrome related to TNFRSF6 mutation. Blood 2011; 118: 4798–807. 2 Oliveira JB, Bleesing JJ, Dianzani U, Fleisher TA, Jaffe ES, Lenardo MJ et al. Revised diagnostic criteria and
Table 2 Revised classification of autoimmune lymphoproliferative syndrome (ALPS) Previous Revised nomenclature nomenclature ALPS type 0
ALPS-FAS
Gene
Definition
FAS
Patients fulfill ALPS diagnostic criteria and have germline homozygous mutations in FAS. ALPS type Ia ALPS-FAS FAS Patients fulfill ALPS diagnostic criteria and have germline heterozygous mutations in FAS. ALPS type Im ALPS-sFAS FAS Patients fulfill ALPS diagnostic criteria and have somatic mutations in FAS. ALPS type Ib ALPS-FASLG FASLG Patients fulfill ALPS diagnostic criteria and have germline mutations in FAS ligand. ALPS type IIa ALPS-CASP10 CASP10 Patients fulfill ALPS diagnostic criteria and have germline mutations in caspase 10. ALPS type III ALPS-U Unknown Patients meet ALPS diagnostic criteria; however, genetic defect is undetermined (no FAS, FASL or CASP10 defect).
that somatic mutations can arise in non-malignant conditions and induce chronic disease that includes autoimmune cytopenias requiring treatment with immunosuppressive agents when they are clinically significant.3 We conclude that all patients with FAS mutations should be monitored closely for signs of lymphoma. Received 21 November 2013; accepted 29 September 2014. doi:10.1111/imj.12714
G. M. García García,1 J. C. Bureo Dacal,1 S. Suárez-Varela Pineda2 and R. Elduayen Izaguirre2 Departments of 1Internal Medicine and 2Hematology Hospital Infanta Cristina, Badajoz, Spain
classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop. Blood 2010; 116: e35–40. 3 Dowdell KC, Niemela JE, Price S, Davis J, Hornung RL, Oliveira JB et al. Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome. Blood 2010; 115: 5164–9. 4 Price S, Shaw PA, Seitz A, Joshi G, Davis
J, Niemela JE et al. Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations. Blood 2014; 123: 1989–99. 5 Bowen RA, Dowdell KC, Dale JK, Drake SK, Fleisher TA, Hortin GL et al. Elevated vitamin B12 levels in autoimmune lymphoproliferative syndrome attributable to elevated haptocorrin in lymphocytes. Clin Biochem 2012; 45: 490–2.
© 2015 Royal Australasian College of Physicians
464
Letter to the Editor
and to discuss potential strategies to manage internal conflict as a practitioner. Not administering blood products in this case undoubtedly contributed to the death of mother and foetus. This was because maternal autonomy was respected – which reflects broad legal and ethical consensus that competent adults may refuse any form of medical intervention – even where that intervention is lifesaving.3 Refusal of a lifesaving intervention by an informed patient is generally well respected, but the rights of a mother to refuse such interventions on behalf of her foetus is more controversial. A doctor indeed has moral obligations to both the pregnant woman, and perhaps with differing priority to the unborn foetus.4 Circumstances where foetal and maternal autonomy conflict, or where foetal beneficence conflicts with maternal autonomy, create challenges. All decisions should be strictly within the parameters of informed consent – disclosure, comprehension and free consent – and place patient autonomy at the forefront.5 We advocate the use of a multidisciplinary approach, including obstetrics, neonatology, haematology and clinical ethics, with consistent delivery of accurate, comprehensive information over several clinical encounters. Signed patient disclosures and advanced care directives may be useful in facilitating management plans.
References 1 Yang D, Hladnik L. Treatment of acute promyelocytic leukemia during pregnancy. Pharmacotherapy 2009; 29: 709–24. 2 Lin C-P, Huang M-J, Liu H-J, Chang I-Y, Tsai C-H. Successful treatment of acute promyelocytic leukemia in a pregnant Jehovah’s Witness with all-trans retinoic
There is little published information to assist physicians to manage their own anxieties, doubts and potential moral disagreement with the patient, and to help them maintain respect for a patient and continue to deliver good medical care. To improve care, we recommend developing a clear understanding of your own attitudes and beliefs, open communication between staff, identifying alternative practitioners where time permits, and accessing staff counselling. It is helpful to understand the basis of Jehovah’s Witness’ beliefs;5 however, the ethical conflicts and considerations apply more broadly. Indeed, as more foetalspecific treatments become available, conflict between the best interests of mother and foetus will increase.6 Physicians are required to apply ethical principles rationally and respect patients’ decisions irrespective of their own beliefs. Received 8 September 2014; accepted 27 November 2014. doi:10.1111/imj.12711
A. Biscoe and G. Kidson-Gerber Department of Haematology, Prince of Wales Hospital Sydney, New South Wales, Australia
acid, rhG-CSF, and erythropoietin. Am J Hematol 1996; 51: 251–2. 3 DiGiovanni LM. Ethical issues in obstetrics. Obstet Gynecol Clin North Am 2010; 37: 345–57. 4 Levy JK. Jehovah’s Witnesses, pregnancy, and blood transfusions: a paradigm for the autonomy rights of all pregnant women. JLME 1999; 27: 171–89.
Adult onset autoimmune lymphoproliferative syndrome due to somatic FAS mutation A 55-year-old woman whose medical history includes hypertension, hypercholesterolaemia and polyarthrosis consulted for the presence of bilateral painless lymphadenopathy in the cervical, postauricular and axillary areas. The blood count showed pancytopenia: normochromic normocytic anaemia (haemoglobin 110 g/L), leukopenia (3.4 × 109 leukocytes/L) and mild thrombocytopenia (platelets 126 × 109/L). The direct Coombs was negative. The hepatorenal profile was normal, and the lipid profile confirmed her known hypertriglyceridaemia. Immunoglobulin A was high (7.76 g/L) and a serum
5 Mahoney K, Valenti J. Blood refusal & obstetrics. A high-risk case scenario. AWHONN Lifelines 2004; 8: 220–5. 6 Townsend SF. Ethics for the pediatrician: obstetric conflict: when fetal and maternal interests are at odds. Pediatr Rev 2012; 33: 33–8.
protein monoclonal peak was not observed. Thyroid hormones were normal, and antinuclear, antithyroid and antiphospholipid antibodies were negative, as was rheumatoid factor. Complement and acute phase reactants were elevated. Vitamin B12 levels were elevated up to twice the upper limit of normal (>2000 ng/L). Computed tomography of the neck, thorax and abdomen showed many enlarged lymphoid nodes in the cervical, supraclavicular and axillary regions, with the spleen showing a globular appearance and normal size. The bone marrow biopsy was normal. Biopsy was performed on the two left cervical lymph nodes, and showed a lymphoid proliferation CD45+ with increased CD57. Cytometry on peripheral blood showed a population of T lymphocytes (15%) CD3+, TCRab+, © 2015 Royal Australasian College of Physicians
462
Letter to the Editor
double negative CD4− and CD8−. As a result of these findings, she was diagnosed with autoimmune lymphoproliferative syndrome (ALPS). The levels of interleukin 10 and Fas ligand soluble were high in the peripheral blood, which is consistent with the syndrome. Genetic studies were negative for mutations in the Fas and Fas ligand gene. A molecular study for Fas gene was performed in a isolated sample of double negative T (DNT) cells and a somatic mutation Fas gene, c.686T>A, was found. No treatment was initiated because the patient was well, except for the presence of the lymphadenopathy previously described. They fluctuated in size and amount, but did not appear in other locations. One year after diagnosis, positron emission tomography was performed, which showed many enlarged lymphoid nodes below the diaphragm, and in the spleen and bone marrow, with intense elevation of glucose metabolism, by lymphoproliferative process. Following this result, a new bone marrow biopsy was carried out. This was normal. We think that the radiographic progression is due to ALPS and not a lymphoma. We decided to delay treatment because the cytopenias were not clinically symptomatic. This is more common in somatic ALPS patients. ALPS, also known as Canale–Smith syndrome, is a genetic disorder characterised by early-onset, chronic, non-malignant lymphoproliferation, autoimmune manifestations and susceptibility to lymphoma.1 It is a syndrome that usually develops in childhood and disappears in adulthood. There are few reported cases of adult onset (around 8%).1 In ALPS, lymphocyte homeostasis is disrupted by defects in apoptosis mediated by Fas, a cell-surface receptor from the tumour necrosis factor (TNF) receptor superfamily.1 High counts of circulating T-cell receptor (TCR), CD4- and CD8- double negative T cells (DNT) lymphocytes and elevated plasma levels of Fas ligand and interleukin 10 are diagnostic hallmarks of the disease.1 These were present in our patient. The majority of ALPS patients carry heterozygous germline mutations in the TNFRSF6 gene coding for Fas. However, in our patient a somatic mutation of the gene TNFRSF6 was found. Somatic TNFRSF6 mutations represent the second most common genetic cause of ALPS.1 Approximately one-third of patients with ALPS have unidentified genetic mutations.2 Lymphoproliferation is the first sign of the disease, and usually occurs early in life and disappears spontaneously.1 In adulthood, autoimmune manifestations appear several years after the lymphadenopathy, usually persist and require long-term immunosuppression. Cytopenias are the most common autoimmune manifestation.1 Our patient presented with extensive lymphadenopathy and
Table 1 Revised diagnostic criteria for autoimmune lymphoproliferative syndrome (ALPS) Revised diagnostic criteria for ALPS Required 1. Chronic (>6 months), non-malignant, non-infectious lymphadenopathy or splenomegaly or both. 2. Elevated CD3+TCR+CD4−CD8− DNT cells (≥1.5% of total lymphocytes or 2.5% of CD3+ lymphocytes) in the setting of normal or elevated lymphocyte counts.
Accessory Primary 1. Defective lymphocyte apoptosis (in two separate assays). 2. Somatic or germline pathogenic mutation in FAS, FASLG or CASP10. Secondary 1. Elevated plasma sFASL levels (>200 pg/mL) OR elevated plasma interleukin-10 levels (>20 pg/mL) OR elevated serum or plasma vitamin B12 levels (>1500 ng/L) OR elevated plasma interleukin-18 levels >500 pg/mL. 2. Typical immunohistological findings as reviewed by an experienced hematopathologist. 3. Autoimmune cytopenias (haemolytic anaemia, thrombocytopenia or neutropenia) AND elevated immunoglobulin G levels (polyclonal hypergammaglobulinemia) 4. Family history of a non-malignant/non-infectious lymphoproliferation with or without autoimmunity.
simultaneous asymptomatic pancytopenia. ALPS patients with somatic FAS mutations, known as ALPS-sFAS are clinically indistinguishable from the patients with germline FAS mutations (ALPS-FAS), and therefore may also have an increased risk of developing Hodgkin and non-Hodgkin lymphoma.3 It has been reported that the initial age of presentation of patients with a somatic FAS mutation was older than that of the ALPS-FAS patients.3 Our patient was diagnosed at 55 years and had not previously shown lymphadenopathy on examination or tests. Chronic, refractory multi-lineage cytopenias due to splenic sequestration and autoimmune destruction are the most frequent cause of morbidity.4 However, splenectomy does not prevent the recurrence of cytopenias and increases susceptibility to severe bacterial infections after splenectomy, especially by pneumococcus.1,4 The aetiology is unknown and is not believed to be related to immunosuppression, thus splenectomy should be avoided whenever possible.1 Our patient also showed elevated immunoglobulin A and vitamin B12. These are common findings in ALPS.5 Haptocorrin (HC) is a protein that binds to vitamin B12,but its function is not known.5 Due to a mutation in the Fas gene, ALPS patients have elevated plasma levels
© 2015 Royal Australasian College of Physicians
463
Letters to the Editor
of Vitamin B12, up to 15 times the upper limit of the reference interval, with high production of haptocorrin by leukocytes, particularly the DNT lymphocytes.5 We think that the increased plasma B12 levels are the result of lymphoproliferation, although the molecular mechanism of this elevation is unknown.3,4 Serum vitamin B12 levels can reliably identify patients with FAS mutations and appear to be a useful marker of disease.3 However, these biomarkers may be elevated in other conditions, including common variable immunodeficiency.4 Dowdell et al.3 noted low total and high-density lipoprotein cholesterol in somatic ALPS patients, and this could be another marker. However, in our case cholesterol was normal and triglycerides were elevated. Therefore, more studies are needed to confirm the value of using cholesterol and triglycerides as markers in these cases. As the differential diagnosis for lymphadenopathy, splenomegaly and cytopenias involves many conditions with overlapping features, diagnostic criteria for ALPS have been developed (Table 1).2 A definitive diagnosis is based on the presence of both required criteria plus one primary accessory criterion, and a probable diagnosis is based on the presence of both required criteria plus one secondary accessory criterion. ALPS is also classified according to the genetic mutation (Table 2).2 Most cases of ALPS require immunosuppressive therapy, especially those with cytopenias and autoimmune manifestations.1 It is unclear whether patients with ALPS and autoimmune involvement should be treated similarly to those without ALPS. Azathioprine, mycophenolate or rapamycin are useful in this condition. However, rituximab, a monoclonal antibody directed against B cells, is not as effective as it is in patients without ALPS.1 We found radiological progression of lymphadenopathy, but no evidence of a neoplastic lymphoproliferative disorder in our patient a year after diagnosis, and decided to delay starting corticosteroids or immunosuppressants due to clinical stability. Furthermore, somatic ALPS patients usually remain stable without any clinical intervention besides treatment of their cytopenias.3 The findings of Dowdell et al.3 show
References 1 Neven B, Magerus-Chatinet A, Florkin B, Gobert D, Lambotte O, De Somer L et al. A survey of 90 patients with autoimmune lymphoproliferative syndrome related to TNFRSF6 mutation. Blood 2011; 118: 4798–807. 2 Oliveira JB, Bleesing JJ, Dianzani U, Fleisher TA, Jaffe ES, Lenardo MJ et al. Revised diagnostic criteria and
Table 2 Revised classification of autoimmune lymphoproliferative syndrome (ALPS) Previous Revised nomenclature nomenclature ALPS type 0
ALPS-FAS
Gene
Definition
FAS
Patients fulfill ALPS diagnostic criteria and have germline homozygous mutations in FAS. ALPS type Ia ALPS-FAS FAS Patients fulfill ALPS diagnostic criteria and have germline heterozygous mutations in FAS. ALPS type Im ALPS-sFAS FAS Patients fulfill ALPS diagnostic criteria and have somatic mutations in FAS. ALPS type Ib ALPS-FASLG FASLG Patients fulfill ALPS diagnostic criteria and have germline mutations in FAS ligand. ALPS type IIa ALPS-CASP10 CASP10 Patients fulfill ALPS diagnostic criteria and have germline mutations in caspase 10. ALPS type III ALPS-U Unknown Patients meet ALPS diagnostic criteria; however, genetic defect is undetermined (no FAS, FASL or CASP10 defect).
that somatic mutations can arise in non-malignant conditions and induce chronic disease that includes autoimmune cytopenias requiring treatment with immunosuppressive agents when they are clinically significant.3 We conclude that all patients with FAS mutations should be monitored closely for signs of lymphoma. Received 21 November 2013; accepted 29 September 2014. doi:10.1111/imj.12714
G. M. García García,1 J. C. Bureo Dacal,1 S. Suárez-Varela Pineda2 and R. Elduayen Izaguirre2 Departments of 1Internal Medicine and 2Hematology Hospital Infanta Cristina, Badajoz, Spain
classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop. Blood 2010; 116: e35–40. 3 Dowdell KC, Niemela JE, Price S, Davis J, Hornung RL, Oliveira JB et al. Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome. Blood 2010; 115: 5164–9. 4 Price S, Shaw PA, Seitz A, Joshi G, Davis
J, Niemela JE et al. Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations. Blood 2014; 123: 1989–99. 5 Bowen RA, Dowdell KC, Dale JK, Drake SK, Fleisher TA, Hortin GL et al. Elevated vitamin B12 levels in autoimmune lymphoproliferative syndrome attributable to elevated haptocorrin in lymphocytes. Clin Biochem 2012; 45: 490–2.
© 2015 Royal Australasian College of Physicians
464
