Autoimmune Lymphoproliferative Syndrome Type IIB (ALPS IIB)

Autoimmune lymphoproliferative syndrome (all types) generally presents in early childhood, and is characterized by chronic, non-malignant lymphadenopathy, usually with autoimmunity. The underlying cause is a defect in lymphocyte apoptosis, or programmed cell death, leading to persistence of mature T and B cells, including the usually rare CD4/CD8-double-negative T (DNT) cell. The formal diagnostic triad for ALPS is elevated DNT cells, hepato/splenomegaly, and defective in vitro lymphocyte apoptosis. Autoimmunity may be present, most often directed against erythrocytes, platelets and neutrophils. In some patients, skin rashes, glomerulonephritis, arthritis, Guillan-Barré syndrome and autoimmune hepatitis may occur. The disorder can vary significantly in severity, even within families. Some individuals have only positive laboratory findings, typically including DNT cells, autoantibodies (such as Coombs positivity), hypergammaglobulinemia (IgG, IgM, IgA), elevated serum IL-10, and elevated serum vitamin B12. The majority of ALPS patients have mutations in the FAS (TNFRSF6) gene and are referred to as Type IA. ALPS cases associated with CASP8 and CASP10 mutations are extremely rare and less well understood. ALPS2B has been called Caspase-8 Deficiency State (CEDS) because the two published siblings have immunodeficiency in addition to ALPS.

Tests Available

Forms and Documents

Test Details

CASP10, CASP8, FASLG, TNFRSF6
  • Confirmation of the clinical diagnosis. Differentiation from malignant forms of lymphoproliferation.
  • Distinguish sub-type of ALPS.
  • Development of an appropriate treatment plan for affected individuals.
  • Development of an appropriate medical surveillance plan for relatives at risk of lymphoma.
  • Next-Gen Sequencing
  • Deletion/Duplication Analysis

Ordering

T990
3 weeks
2-5 mL Blood - Lavender Top Tube
Oral Rinse (30-40 mL) | Buccal Swabs

Billing

81479x1
No
Yes
* For price inquiries please email zebras@genedx.com

References

  1. Su HC and Lenardo MJ. Genetic defects of apoptosis and primary immunodeficiency. Immunology And Allergy Clinics Of North America. 2008 28(2):329-51, ix.18424336
  2. Wang J et al. Inherited human Caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II. Cell. 1999 Jul 9 98(1):47-58.10412980
  3. Zhu S et al. Genetic alterations in caspase-10 may be causative or protective in autoimmune lymphoproliferative syndrome. Human Genetics. 2006 119(3):284-94.16446975
  4. Chun HJ et al. Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature. 2002 419(6905):395-9.12353035
  5. Cerutti E et al. Co-inherited mutations of Fas and caspase-10 in development of the autoimmune lymphoproliferative syndrome. Bmc Immunology. 2007 8:28.17999750
  6. Jackson CE et al. Autoimmune lymphoproliferative syndrome with defective Fas: genotype influences penetrance. American Journal Of Human Genetics. 1999 64(4):1002-14.10090885
  7. Vaishnaw AK et al. The molecular basis for apoptotic defects in patients with CD95 (Fas/Apo-1) mutations. The Journal Of Clinical Investigation. 1999 Feb 103(3):355-63.9927496
  8. Niemela J et al. Caspase-8 Deficiency Presenting as Late-Onset Multi-Organ Lymphocytic Infiltration with Granulomas in two Adult Siblings. Journal Of Clinical Immunology. 2015 May 35(4):348-55.25814141
  9. Shah S et al. Autoimmune lymphoproliferative syndrome: an update and review of the literature. Current Allergy And Asthma Reports. 2014 Sep 14(9):462.25086580
  10. Del-Rey M et al. A homozygous Fas ligand gene mutation in a patient causes a new type of autoimmune lymphoproliferative syndrome. Blood. 2006 Aug 15 108(4):1306-12.16627752
  11. Magerus-Chatinet A et al. Autoimmune lymphoproliferative syndrome caused by a homozygous null FAS ligand (FASLG) mutation. The Journal Of Allergy And Clinical Immunology. 2013 Feb 131(2):486-90.22857792
  12. Ruiz-García R et al. Decreased activation-induced cell death by EBV-transformed B-cells from a patient with autoimmune lymphoproliferative syndrome caused by a novel FASLG mutation. Pediatric Research. 2015 Dec 78(6):603-8.26334989
  13. Nabhani S et al. A novel homozygous Fas ligand mutation leads to early protein truncation, abrogation of death receptor and reverse signaling and a severe form of the autoimmune lymphoproliferative syndrome. Clinical Immunology (Orlando, Fla.). 2014 Dec 1