Autoimmune Lymphoproliferative Syndrome

A number sign (#) is used with this entry because autoimmune lymphoproliferative syndrome (ALPS) type IA is caused by heterozygous mutation in the FAS gene (TNFRSF6, or CD95; 134637); ALPS type IB is caused by heterozygous mutation in the FAS ligand (FASL) gene (TNFSF6 or CD95L; 134638). Both germline and somatic mutations in the FAS gene have been identified in patients with ALPS type IA. A subset of patients may have a heterozygous germline mutation combined with a somatic mutation, resulting in a '2-hit' disease mechanism.

Description

Autoimmune lymphoproliferative syndrome is a heritable disorder of apoptosis, resulting in the accumulation of autoreactive lymphocytes. It manifests in early childhood as nonmalignant lymphadenopathy with hepatosplenomegaly and autoimmune cytopenias (summary by Dowdell et al., 2010).

For a review of the autoimmune lymphoproliferative syndromes, see Teachey et al. (2009).

Genetic Heterogeneity of Autoimmune Lymphoproliferative Syndrome

Type IIA ALPS (ALPS2A; 603909) is caused by mutation in the caspase-10 gene (CASP10; 601762). Puck and Straus (2004) designated caspase-8 deficiency (607271), caused by mutations in the CASP8 gene (601763), as type IIB ALPS. ALPS3 (615559) is caused by mutation in the PRKCD gene (176977). RAS-associated ALPS (RALD, or ALPS4; 614470) is caused by mutation in the NRAS gene (164790). ALPS5 (616100) is caused by mutation in the CTLA4 gene (123890).

Clinical Features

Canale and Smith (1967) described a childhood syndrome of lymphadenopathy and splenomegaly associated with autoimmune hemolytic anemia and thrombocytopenia.

Sneller et al. (1992) reported 2 unrelated girls with a lymphoproliferative/autoimmune syndrome. The first patient developed cervical lymphadenopathy at age 18 months and anemia associated with splenomegaly at age 24 months. Over the next months, she developed renal insufficiency, and a renal biopsy showed mesangiopathic glomerulonephritis with crescent formation. Serologic studies for infectious etiology, including EBV, CMV, toxoplasmosis, HIV, brucella, and hepatitis were all negative. The second patient was diagnosed with autoimmune hemolytic anemia at age 9 months with a positive direct Coomb's test. At age 4 years, she developed peripheral lymphadenopathy, and CT scan at age 8 years showed hepatomegaly and mediastinal, mesenteric, and retroperitoneal adenopathy. Peripheral blood analysis showed that both patients had increased numbers of B lymphocytes and increased numbers of mature CD3+, CD4-, CD8- T lymphocytes expressing alpha/beta T-cell receptors; these T cells accounted for 40 to 60% of all T cells. Neither lymphocyte population was monoclonal. Lymph node biopsy showed paracortical infiltration of the CD4-, CD8- T cells. Sneller et al. (1992) noted that the phenotype in these girls was similar to that of lpr (see 134637) and gld (see 134638) mice.

Fisher et al. (1995) reported 4 unrelated children with ALPS who presented with nonmalignant lymphadenopathy or splenomegaly between 2 months and 5 years of age. All patients had autoimmune hemolytic anemia, thrombocytopenia, and recurrent urticarial rashes consistent with immune vasculitis. Peripheral blood analysis showed hypergammaglobulinemia and expanded populations of CD3+, CD4-, CD8- T lymphocytes in all patients. In vitro studies showed that the expanded T lymphocyte population had impaired TCR-induced apoptosis. Fisher et al. (1995) concluded that the disorder was caused by impaired control of mature lymphocyte homeostasis.

Drappa et al. (1996) provided follow-up on 2 patients reported by Canale and Smith (1967). One patient was a 43-year-old woman who had continued lymphadenopathy and hypergammaglobulinemia throughout her life. She also had several neoplastic lesions, including a breast adenoma, 3 thyroid adenomas, and 2 basal cell carcinomas. Another patient was a 43-year-old man whose lymphadenopathy had gradually diminished during adolescence and was mild during adulthood. He died of hepatocellular carcinoma associated with hepatitis C infection. The patient's son had lymphadenopathy with T-cell hyperplasia and autoimmune hemolytic anemia and thrombocytopenia. Activated T cells from the patients were almost completely resistant to apoptosis induced by ligating the Fas receptor with an anti-Fas antibody. The findings indicated that ALPS is compatible with long-term survival. Sneller et al. (1997) reported 9 unrelated patients with ALPS characterized by moderate to massive splenomegaly and lymphadenopathy, hypergammaglobulinemia, autoimmunity, B-cell lymphocytosis, and the expansion of an unusual population of CD3+, CD4-, CD8- T cells. Hemolytic anemia was the most frequent form of autoimmune disease, occurring in 6 patients with or without idiopathic thrombocytopenic purpura. All patients showed defective lymphocyte apoptosis in vitro. Heterozygous mutations of the FAS gene were detected in 8 patients, and 7 of 8 kindreds had healthy relatives with FAS mutations. These relatives also showed in vitro abnormalities of FAS-mediated lymphocyte apoptosis, but clinical features of ALPS were not present. In 1 ALPS patient, no FAS or FASL gene mutations were identified, and Sneller et al. (1997) proposed the designation ALPS type II to refer to the syndrome in the absence of mutations in these genes.

Van der Burg et al. (2000) reported a girl, born of consanguineous parents, who presented immediately after birth with petechiae, generalized edema, and hepatosplenomegaly. During the first month of life, autoantibodies against red blood cells and platelets were demonstrated. A liver biopsy showed extensive extramedullary hematopoiesis, and she had massive generalized adenopathy of the cervical, mesenteric, and paraaortic lymph nodes. Hypergammaglobulinemia persisted for several years; a cutaneous lupus-like disease appeared at a later stage. The patient had histologically malignant lymph nodes, although monoclonal or oligoclonal rearrangements could not be detected on analysis of the gene encoding the T-cell antigen receptor beta subunit (TCRB; see 186930). There was no detectable FAS expression on freshly isolated blood leukocytes.

Other Features

Straus et al. (1997) stated that their experience with over 20 patients with ALPS from 13 kindreds indicated a wider clinical spectrum than that described by Canale and Smith (1967) or by Drappa et al. (1996), including Guillain-Barre syndrome (139393) and panniculitis. In addition, Straus et al. (1997) noted that B-lymphomas developed in early adulthood in 2 brothers with FAS mutations. Four different patients with ALPS had normal FAS and FASL genes, but impaired apoptosis caused by an abnormality in the FAS pathway, suggesting that abnormalities of other proteins in the FAS-signaling cascade or in parallel apoptotic pathways may also cause ALPS.

Straus et al. (2001) found that 130 individuals in 39 families segregating ALPS had heterozygous germline FAS mutations. Eleven B-cell and T-cell lymphomas of diverse types developed in 10 individuals with mutations in 8 families, up to 48 years after lymphoproliferation was first documented. Their risk of non-Hodgkin and Hodgkin lymphomas, respectively, was 14 and 51 times greater than expected. All 10 patients with FAS mutations had defective lymphocyte apoptosis and most had other features of ALPS. The average age of ALPS onset was 5 years, whereas the average age of lymphoma diagnosis was 28 years. The cases in which somatic alterations in FAS were described in lymphomas (e.g., Gronbaek et al., 1998) more typically arose later in life. Straus et al. (2001) stated that the mechanism by which FAS defects in ALPS predispose to lymphomas might involve several components. They suggested that the most obvious possibility is that a general expansion of the lymphoid pool provides a larger target cell population for other transforming events.

Lim et al. (2005) reported a case of bilateral uveitis in an 8-year old child with ALPS1A. The authors concluded that despite a Th2 immune predominance in ALPS, uveitis, a Th1-mediated disease, might still manifest in these patients. They hypothesized that the pathogenesis of uveitis in ALPS might differ from that of the systemic disease overall.

Inheritance

ALPS is most often transmitted in an autosomal dominant manner. However, autosomal recessive inheritance of ALPS1A due to homozygous or compound heterozygous mutations in the FAS gene has been described. In addition, Dowdell et al. (2010) noted that one-third of patients may have somatic mutations in the FAS gene.

In a girl with severe ALPS1A, born of consanguineous parents, van der Burg et al. (2000) identified a homozygous 20-bp duplication in the FAS gene (134637.0013). The findings indicated that autosomal recessive inheritance. Van der Burg et al. (2000) noted that Rieux-Laucat et al. (1995) and Bettinardi et al. (1997) had reported similar patients with 2 FAS gene mutations (see 134637.0006 and 134637.0007).

Molecular Genetics

ALPS1A Due to Heterozygous Mutations in the FAS Gene

In 5 unrelated patients with ALPS1A, 1 of whom was reported by Sneller et al. (1992), Fisher et al. (1995) identified heterozygous mutations in the FAS gene (134637.0001-134637.0005).

In 2 patients with ALPS1A first reported by Canale and Smith (1967), Drappa et al. (1996) identified heterozygous mutations in the FAS gene (134637.0019; 134637.0020).

ALPS1A Due to Biallelic Mutations in the FAS Gene

In a girl with severe ALPS1A, born of consanguineous parents, van der Burg et al. (2000) identified a homozygous 20-bp duplication in the FAS gene (134637.0013). Van der Burg et al. (2000) noted that Rieux-Laucat et al. (1995) and Bettinardi et al. (1997) had reported similar patients with 2 FAS gene mutations (see 134637.0006 and 134637.0007).

ALPS1A Due to Heterozygous Germline and Additional Somatic Mutations in the FAS Gene

Dowdell et al. (2010) found that 12 (38.7%) of 31 ALPS patients who were negative for germline FAS mutations carried heterozygous somatic FAS mutations in their double-negative T cells. All of the 12 somatic mutations resulted in known or predicted functional loss of normal FAS signaling; 10 mutations led to a premature stop codon. Patients with somatic FAS mutations were clinically similar to those with germline FAS mutations, although they had a slightly lower incidence of splenectomy and lower lymphocyte counts.

Holzelova et al. (2004) reported 6 children with an unusual form of ALPS, characterized by elevated numbers of double-negative T cells and hypergammaglobulinemia, but normal Fas-mediated apoptosis of T cells in vitro. Double-negative T cells from all 6 patients showed heterozygous mutations in the FAS gene (see, e.g., 134637.0018). In 2 affected patients, FAS mutations were found in a fraction of CD4+ and CD8+ T cells, monocytes, and CD34+ hematopoietic precursors, but not in hair or mucosal epithelial cells, demonstrating somatic mosaicism.

Magerus-Chatinet et al. (2011) reported 7 unrelated patients with typical features of ALPS associated with heterozygous germline mutations in the FAS gene. Four of the patients had asymptomatic relatives who were heterozygous for the same mutation, suggesting incomplete penetrance. All 7 patients and the carrier relatives had low FAS-mediated T cell apoptosis in vitro compared to controls. However, only the symptomatic patients also had increased double-negative T cells, increased IL10 (124092), and increased FAS ligand (FASL; 134638). Three of the 7 symptomatic patients were subsequently found to carry a heterozygous somatic FAS mutation within double-negative T cells, whereas the remaining 4 symptomatic patients showed somatic loss of the wildtype allele. These somatic events were not found in any of the asymptomatic heterozygous carriers. The additional somatic event in the 7 patients led to a clear and profound TNFRSF6 expression defect in the majority of double-negative T cells in all patients except 1, who carried 2 missense mutations that were predicted to be nonfunctional. The double-mutant lymphocytes could not be killed by FAS ligand. These findings were similar to those observed in patients with biallelic TNFRS6 mutations, and supported the idea of a '2-hit' mechanism in which loss of both alleles in relevant cells causes symptomatic lymphoproliferation.

ALPS1B Due to Mutations in the FASL Gene

Wu et al. (1996) reported an African American man with systemic lupus erythematosus (SLE; 152700) and lymphadenopathy who had a heterozygous mutation in the FASL gene (134638.0001). Peripheral blood mononuclear cells from this patient showed decreased FASL activity, decreased activation-induced cell death, and increased T-cell proliferation after activation. Although the patient did not have increased numbers of CD4-, CD8- T cells, Wu et al. (1996) suggested that the lymphadenopathy and autoimmune disease were consistent with an adult type of ALPS. Lenardo (1999) noted that although this patient satisfied the rheumatologic criteria for a diagnosis of SLE, the features were more consistent with ALPS.

Associations Pending Confirmation

For discussion of a possible association between ALPS and variation in the RELA gene, see 164014.0002.

Nomenclature

Vaishnaw et al. (1997) urged the use of the eponym 'Canale-Smith syndrome.' They argued that the term 'lymphoproliferative syndrome' connotes malignancy, but that lymphadenopathy associated with FAS mutations results primarily from the accumulation of lymphocytes due to the failure of FAS-mediated apoptosis.

Animal Model

Krammer (2000) and Nagata (1998) pointed out that the recessive lymphoproliferation (lpr) phenotype and the generalized lymphoproliferative disease (gld) phenotype are mouse models of aberrant T-cell accumulation. In lpr mice, a splicing defect in the Fas gene results in greatly decreased expression of Fas. In mice with the lpr/cg (complementing gld) allele, a point mutation in the intracellular death domain of Fas abolishes the transmission of the apoptotic signal. In gld mice, a point mutation in the C terminus of Fasl impairs its ability to interact successfully with its receptor. These mutations lead to a failure of apoptosis and complex immune disorders in lpr and gld mutant mice that are analogous to the human disorders ALPS1A and ALPS1B.