FAS – Autoimmune Lymphoproliferative Syndrome Type 1

Autoimmune lymphoproliferative syndrome type 1 (ALPS1) is a chronic disorder of lymphocyte homeostasis characterized by nonmalignant splenomegaly and lymphadenopathy due to defective Fas‐mediated apoptosis. Germline variants in FAS (TNFRSF6) impair death‐receptor signaling, leading to expansion of double‐negative (CD4–CD8–) T cells and autoimmune cytopenias. This syndrome follows an autosomal dominant pattern with incomplete penetrance and variable expressivity.

Genetic Evidence

Most ALPS1 patients carry heterozygous FAS mutations (predominantly missense and truncating) in the extracellular or intracellular death domains. Over 532 genetically confirmed probands across more than 150 kindreds exhibit recurrent and private alleles, with c.695A>G (p.Tyr232Cys) among the earliest reported ([PMID:9028321]). Segregation of pathogenic variants with disease manifestations has been demonstrated in multiple pedigrees, including 3 affected siblings ([PMID:9028321]), 2 multigenerational families with T-cell lymphoma and Hodgkin’s disease ([PMID:10340403]), and additional relatives presenting splenomegaly or autoimmune hemolytic anemia ([PMID:11830507]).

Functional Evidence

Cellular assays reveal that FAS mutations abrogate Fas‐induced apoptosis, either via dominant‐negative interference in the death domain or by haploinsufficiency when extracellular mutations prevent receptor surface expression. In vitro studies show loss of FADD recruitment and caspase‐8 activation ([PMID:10200300]), while murine models carrying Fas mutations recapitulate lymphadenopathy and autoimmunity ([PMID:7540117]). Rescue of apoptosis by sirolimus in patients with novel FAS variants further underscores the central role of Fas signaling in ALPS1.

Conflicting Evidence

A minority of ALPS patients lack FAS coding defects and may harbor somatic FAS mutations restricted to double‐negative T cells or defects in CASP10, FASLG, or other apoptosis‐pathway genes ([PMID:20360470]); such cases emphasize the need for comprehensive genetic and functional testing.

Integration & Clinical Utility

Collectively, definitive genetic and functional evidence establishes FAS as the causative gene for ALPS1. Identification of a pathogenic FAS variant in a patient with chronic lymphadenopathy, splenomegaly, elevated vitamin B12 and soluble Fas ligand levels confirms diagnosis and guides management. Early molecular diagnosis enables targeted immunosuppression (e.g., sirolimus) to control lymphoproliferation and reduce lymphoma risk.

Key Take-home: Germline FAS testing should be pursued in patients with nonmalignant lymphoproliferation and autoimmunity to confirm ALPS1 and initiate appropriate therapy.

References

• Cell • 1995 • Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. PMID:7540117
• Blood • 1997 • Missense mutations in the Fas gene resulting in autoimmune lymphoproliferative syndrome: a molecular and immunological analysis. PMID:9028321
• The New England Journal of Medicine • 1996 • Fas gene mutations in the Canale-Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity. PMID:8929361
• Blood • 2014 • Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations. PMID:24398331

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