Alternative titles; symbols
ORPHA: 3261; DO: 0110115;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q33.1 | Autoimmune lymphoproliferative syndrome, type II | 603909 | Autosomal dominant | 3 | CASP10 | 601762 |
A number sign (#) is used with this entry because autoimmune lymphoproliferative syndrome type IIA (ALPS2A) is caused by mutation in the CASP10 gene (601762).
For a phenotypic description and a discussion of genetic heterogeneity of ALPS, see 601859.
Wang et al. (1999) reported 2 unrelated patients with ALPS2A. An 11-year-old African American female presented with prominent nonmalignant adenopathy, hepatosplenomegaly, and Coombs-positive hemolytic anemia at 1 year of age. She exhibited a wide-ranging loss of immunologic self-tolerance involving hypergammaglobulinemia with multiple autoantibodies, such as anti-erythrocyte, anti-RNP (180740), anti-SM (601061), anti-SSB (109090), and rheumatoid factor as well as anti-factor VIII (300841) antibody, which caused a severe clotting disorder. She had massive accumulation of single-positive T cells and B cells, indicating loss of lymphocyte homeostasis. CD3+, CD4-, CD8- (double-negative) T cells comprised 42% of her peripheral blood lymphocytes. The patient's mother had high levels of autoantibodies to nuclear antigens and defective lymphocyte apoptosis, whereas the proband's father and 2 sisters were healthy. The second patient reported by Wang et al. (1999) was a 10-year-old Ashkenazi Jewish male who developed lymphadenopathy at age 11 months, followed by bouts of prolonged fever, splenomegaly, elevated sedimentation rate, anemia, and reticulocytosis. He was later found to have a mutation in the TNFRSF1A (191190) gene, consistent with a diagnosis of TNF receptor-associated periodic syndrome (TRAPS; 142680) (Zhu et al., 2006).
Zhu et al. (2006) reported a 7-year-old boy with ALPS2A. He had petechiae and gastrointestinal bleeding, thrombocytopenia, and axillary adenopathy. He subsequently developed Coombs-positive hemolytic anemia and acute nephrotic syndrome with membranous glomerulonephropathy. During his teenage years, he developed lupus (SLE; 152700)-like symptoms, including a malar rash, increased serum IgG and IgE, and antinuclear antibodies. In vitro studies showed impaired lymphocyte apoptosis and an increased percentage of double-negative T cells. Zhu et al. (2006) also reported 2 sisters of mixed Jamaican and Guyanese ancestry who had early-onset ALPS2A. They both had onset by age 2 years with adenopathy, thrombocytopenia, and autoimmune hemolytic anemia. Their mother and a third sister were mutation carriers who were asymptomatic at the time of evaluation, but showed defective T cell apoptosis in vitro, increased numbers of double-negative T cells, and positive direct antiglobulin IgG tests and antithyroid antibodies.
Sneller et al. (1997) found that 1 of 9 patients with ALPS did not have a mutation in either the FAS or FASL gene. The authors proposed the designation ALPS type II to refer to the syndrome in the absence of FAS or FASL mutations.
In an African American girl with ALPS2A, Wang et al. (1999) identified a heterozygous mutation in the CASP10 gene (601762.0001).
In 2 sisters and an unrelated boy with ALPS2A, Zhu et al. (2006) identified a heterozygous mutation in the CASP10 gene (601762.0007).
Sneller, M. C., Wang, J., Dale, J. K., Strober, W., Middleton, L. A., Choi, Y., Fleisher, T. A., Lim, M. S., Jaffe, E. S., Puck, J. M., Lenardo, M. J., Straus, S. E. Clinical, immunologic, and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis. Blood 89: 1341-1348, 1997. [PubMed: 9028957]
Wang, J., Zheng, L., Lobito, A., Chan, F. K., Dale, J., Sneller, M., Yao, X., Puck, J. M., Straus, S. E., Lenardo, M. J. Inherited human caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II. Cell 98: 47-58, 1999. [PubMed: 10412980] [Full Text: https://doi.org/10.1016/S0092-8674(00)80605-4]
Zhu, S., Hsu, A. P., Vacek, M. M., Zheng, L., Schaffer, A. A., Dale, J. K., Davis, J., Fischer, R. E., Straus, S. E., Boruchov, D., Saulsbury, F. T., Lenardo, M. J., Puck, J. M. Genetic alterations in caspase-10 may be causative or protective in autoimmune lymphoproliferative syndrome. Hum. Genet. 119: 284-294, 2006. [PubMed: 16446975] [Full Text: https://doi.org/10.1007/s00439-006-0138-9]