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FAS-related Autoimmune Lymphoproliferative Syndrome

FAS-related Autoimmune Lymphoproliferative Syndrome: Mechanistic Summary

2026-04-16
Manual MONDO:1060194 Model: n/a 10 citations

FAS-related Autoimmune Lymphoproliferative Syndrome: Mechanistic Summary

Disease scope and terminology

FAS-related autoimmune lymphoproliferative syndrome corresponds to the classical FAS-driven ALPS spectrum and aligns with the newer MONDO label MONDO:1060194 FAS-related autoimmune lymphoproliferative syndrome. In historical literature, the dominant form is usually called ALPS-Ia or autoimmune lymphoproliferative syndrome type 1A.

Genetics and inheritance

The dominant clinical form is usually caused by heterozygous germline FAS variants, especially lesions affecting the intracellular death domain. Published family studies support autosomal dominant inheritance with incomplete penetrance. Reviews consistently describe FAS as the most frequent molecular cause of ALPS.

Core pathophysiology

FAS-related ALPS is fundamentally a disorder of defective Fas-mediated apoptosis. Failure of activation-induced lymphocyte deletion disrupts lymphocyte homeostasis, allowing survival of autoreactive lymphocytes and expansion of the characteristic alpha-beta double-negative T-cell population. This mechanistically explains the triad of:

  • chronic benign lymphoproliferation
  • autoimmune cytopenias
  • lymphoma predisposition

Hallmark clinical phenotype

The core phenotype includes:

  • chronic non-malignant lymphadenopathy
  • hepatosplenomegaly
  • autoimmune cytopenias, especially autoimmune hemolytic anemia, autoimmune thrombocytopenia, and autoimmune neutropenia
  • elevated circulating alpha-beta double-negative T cells
  • increased lifetime risk of Hodgkin and non-Hodgkin lymphoma

Diagnosis

Diagnosis is supported by:

  • flow-cytometric quantification of CD3+TCR-alpha-beta+CD4-CD8- cells
  • serum biomarker assessment including vitamin B12, soluble Fas ligand, and IL-10
  • functional apoptosis assays demonstrating impaired Fas-mediated apoptosis
  • confirmatory FAS molecular genetic testing

Treatment

The strongest treatment evidence identified here supports sirolimus as a highly effective steroid-sparing therapy for refractory autoimmune cytopenias and benign lymphoproliferation in ALPS. Reviews also describe mycophenolate mofetil as active, but sirolimus has the clearest direct response data.

References