Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis
- Jack JH Bleesing, MD, PhD
Jack JH Bleesing, MD, PhD
- Professor of Pediatrics
- Cincinnati Children's Hospital Medical Center
Autoimmune lymphoproliferative syndrome (ALPS) is characterized by dysregulation of the immune system, due to an inability to regulate lymphocyte homeostasis through the process of lymphocyte apoptosis (a form of programmed cell death). The consequences of this include lymphoproliferative disease, manifested by lymphadenopathy, hepatomegaly, splenomegaly, and an increased risk of lymphoma, as well as autoimmune disease, typically involving blood cells.
The signature laboratory abnormalities that facilitate diagnosis of ALPS include an expansion of T cells that express the alpha/beta T cell receptor but lack both CD4 and CD8 (alpha/beta double-negative T [DNT] cells) in peripheral blood and tissue specimens, elevated levels of interleukin-10 (IL-10) in blood, increased levels of vitamin B12, and defective Fas-mediated apoptosis in vitro.
This topic reviews the clinical features and diagnosis of ALPS. The epidemiology, genetics, pathogenesis, management, and prognosis of ALPS are discussed separately. (See "Autoimmune lymphoproliferative syndrome (ALPS): Epidemiology and pathogenesis" and "Autoimmune lymphoproliferative syndrome (ALPS): Management and prognosis".)
In the two largest cohorts of patients with ALPS, the French cohort and National Institutes of Health (NIH) cohort, disease onset was most commonly defined by lymphoproliferative disease, with a median age of disease onset of 2.7 to 3 years of age [1,2]. Patients with later disease onset often presented with autoimmune disease rather than lymphoproliferative disease.
Autoimmune lymphoproliferative syndrome due to mutations in the FAS gene that encodes an apoptosis-associated antigen (ALPS-FAS) is the most common and best-characterized type of ALPS. The following are the main consequences of perturbed lymphocyte homeostasis in ALPS-FAS.
- Neven B, Magerus-Chatinet A, Florkin B, et al. A survey of 90 patients with autoimmune lymphoproliferative syndrome related to TNFRSF6 mutation. Blood 2011; 118:4798.
- Price S, Shaw PA, Seitz A, et al. Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations. Blood 2014; 123:1989.
- Bleesing JJ. Autoimmune lymphoproliferative syndrome (ALPS). Curr Pharm Des 2003; 9:265.
- Rieux-Laucat F, Fischer A, Deist FL. Cell-death signaling and human disease. Curr Opin Immunol 2003; 15:325.
- Bleesing JJ, Brown MR, Straus SE, et al. Immunophenotypic profiles in families with autoimmune lymphoproliferative syndrome. Blood 2001; 98:2466.
- Seif AE, Manno CS, Sheen C, et al. Identifying autoimmune lymphoproliferative syndrome in children with Evans syndrome: a multi-institutional study. Blood 2010; 115:2142.
- Iyengar SR, Ebb DH, Yuan Q, et al. Case records of the Massachusetts General Hospital. Case 27-2013. A 6.5-month-old boy with fever, rash, and cytopenias. N Engl J Med 2013; 369:853.
- Rieux-Laucat F, Blachère S, Danielan S, et al. Lymphoproliferative syndrome with autoimmunity: A possible genetic basis for dominant expression of the clinical manifestations. Blood 1999; 94:2575.
- Vaishnaw AK, Toubi E, Ohsako S, et al. The spectrum of apoptotic defects and clinical manifestations, including systemic lupus erythematosus, in humans with CD95 (Fas/APO-1) mutations. Arthritis Rheum 1999; 42:1833.
- Kanegane H, Vilela MM, Wang Y, et al. Autoimmune lymphoproliferative syndrome presenting with glomerulonephritis. Pediatr Nephrol 2003; 18:454.
- Straus SE, Jaffe ES, Puck JM, et al. The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis. Blood 2001; 98:194.
- Rao VK, Carrasquillo JA, Dale JK, et al. Fluorodeoxyglucose positron emission tomography (FDG-PET) for monitoring lymphadenopathy in the autoimmune lymphoproliferative syndrome (ALPS). Am J Hematol 2006; 81:81.
- Müschen M, Rajewsky K, Krönke M, Küppers R. The origin of CD95-gene mutations in B-cell lymphoma. Trends Immunol 2002; 23:75.
- Houston A, O'Connell J. The Fas signalling pathway and its role in the pathogenesis of cancer. Curr Opin Pharmacol 2004; 4:321.
- Poppema S, Maggio E, van den Berg A. Development of lymphoma in Autoimmune Lymphoproliferative Syndrome (ALPS) and its relationship to Fas gene mutations. Leuk Lymphoma 2004; 45:423.
- Peter ME, Legembre P, Barnhart BC. Does CD95 have tumor promoting activities? Biochim Biophys Acta 2005; 1755:25.
- Bleesing JJ. Sorting out the causes of ALPS. J Pediatr 2005; 147:571.
- Lim MS, Straus SE, Dale JK, et al. Pathological findings in human autoimmune lymphoproliferative syndrome. Am J Pathol 1998; 153:1541.
- Carter LB, Procter JL, Dale JK, et al. Description of serologic features in autoimmune lymphoproliferative syndrome. Transfusion 2000; 40:943.
- Bleesing JJ, Brown MR, Dale JK, et al. TcR-alpha/beta(+) CD4(-)CD8(-) T cells in humans with the autoimmune lymphoproliferative syndrome express a novel CD45 isoform that is analogous to murine B220 and represents a marker of altered O-glycan biosynthesis. Clin Immunol 2001; 100:314.
- Lopatin U, Yao X, Williams RK, et al. Increases in circulating and lymphoid tissue interleukin-10 in autoimmune lymphoproliferative syndrome are associated with disease expression. Blood 2001; 97:3161.
- Bleesing JJ, Brown MR, Novicio C, et al. A composite picture of TcR alpha/beta(+) CD4(-)CD8(-) T Cells (alpha/beta-DNTCs) in humans with autoimmune lymphoproliferative syndrome. Clin Immunol 2002; 104:21.
- Maric I, Pittaluga S, Dale JK, et al. Histologic features of sinus histiocytosis with massive lymphadenopathy in patients with autoimmune lymphoproliferative syndrome. Am J Surg Pathol 2005; 29:903.
- Magerus-Chatinet A, Stolzenberg MC, Loffredo MS, et al. FAS-L, IL-10, and double-negative CD4- CD8- TCR alpha/beta+ T cells are reliable markers of autoimmune lymphoproliferative syndrome (ALPS) associated with FAS loss of function. Blood 2009; 113:3027.
- Caminha I, Fleisher TA, Hornung RL, et al. Using biomarkers to predict the presence of FAS mutations in patients with features of the autoimmune lymphoproliferative syndrome. J Allergy Clin Immunol 2010; 125:946.
- Oliveira JB, Bleesing JJ, Dianzani U, et al. Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop. Blood 2010; 116:e35.
- Bowen RA, Dowdell KC, Dale JK, et al. Elevated vitamin B₁₂ levels in autoimmune lymphoproliferative syndrome attributable to elevated haptocorrin in lymphocytes. Clin Biochem 2012; 45:490.
- Neven B, Bruneau J, Stolzenberg MC, et al. Defective anti-polysaccharide response and splenic marginal zone disorganization in ALPS patients. Blood 2014; 124:1597.
- Rensing-Ehl A, Janda A, Lorenz MR, et al. Sequential decisions on FAS sequencing guided by biomarkers in patients with lymphoproliferation and autoimmune cytopenia. Haematologica 2013; 98:1948.
- Lo B, Ramaswamy M, Davis J, et al. A rapid ex vivo clinical diagnostic assay for fas receptor-induced T lymphocyte apoptosis. J Clin Immunol 2013; 33:479.
- Teachey DT. New advances in the diagnosis and treatment of autoimmune lymphoproliferative syndrome. Curr Opin Pediatr 2012; 24:1.
- Warnatz K, Denz A, Dräger R, et al. Severe deficiency of switched memory B cells (CD27(+)IgM(-)IgD(-)) in subgroups of patients with common variable immunodeficiency: a new approach to classify a heterogeneous disease. Blood 2002; 99:1544.
- Piqueras B, Lavenu-Bombled C, Galicier L, et al. Common variable immunodeficiency patient classification based on impaired B cell memory differentiation correlates with clinical aspects. J Clin Immunol 2003; 23:385.
- Roberts CA, Ayers L, Bateman EA, et al. Investigation of common variable immunodeficiency patients and healthy individuals using autoimmune lymphoproliferative syndrome biomarkers. Hum Immunol 2013; 74:1531.
- Rensing-Ehl A, Warnatz K, Fuchs S, et al. Clinical and immunological overlap between autoimmune lymphoproliferative syndrome and common variable immunodeficiency. Clin Immunol 2010; 137:357.
- Kuehn HS, Ouyang W, Lo B, et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science 2014; 345:1623.
- Lanzarotti N, Bruneau J, Trinquand A, et al. RAS-associated lymphoproliferative disease evolves into severe juvenile myelo-monocytic leukemia. Blood 2014; 123:1960.
- Oliveira JB, Bidère N, Niemela JE, et al. NRAS mutation causes a human autoimmune lymphoproliferative syndrome. Proc Natl Acad Sci U S A 2007; 104:8953.
- Takagi M, Shinoda K, Piao J, et al. Autoimmune lymphoproliferative syndrome-like disease with somatic KRAS mutation. Blood 2011; 117:2887.
- Niemela JE, Lu L, Fleisher TA, et al. Somatic KRAS mutations associated with a human nonmalignant syndrome of autoimmunity and abnormal leukocyte homeostasis. Blood 2011; 117:2883.
- van der Werff ten Bosch J, Delabie J, Böhler T, et al. Revision of the diagnosis of T-zone lymphoma in the father of a patient with autoimmune lymphoproliferative syndrome type II. Br J Haematol 1999; 106:1045.
- CLINICAL MANIFESTATIONS
- Chronic nonmalignant lymphoproliferation
- Other findings
- Other ALPS genotypes
- LABORATORY FINDINGS
- Diagnostic criteria
- - Required criteria
- - Primary accessory criteria
- - Secondary accessory criteria
- Testing and classification strategy
- Prenatal diagnosis
- Additional testing and diagnostic considerations
- DIFFERENTIAL DIAGNOSIS
- Common variable immunodeficiency disease
- Hyperimmunoglobulin M syndrome
- X-linked lymphoproliferative syndrome
- Wiskott-Aldrich syndrome
- CTLA-4 haploinsufficiency with autoimmune infiltration (CHAI) disease
- Other rare disorders