1995-2025: A long journey in the ALPS

The discovery of heterozygous germline mutations in FAS 30 years ago led to an understanding of the pathophysiology associated with familial forms of autoimmune lymphoproliferative syndrome (ALPS). Ten years later, the identification of somatic mutations in FAS was the first description of an acquired mutation in a non-cancerous disease. It was subsequently observed that haploinsufficient germline mutations are accompanied by a somatic mutation in the second FAS allele or by somatic loss of heterozygosity. More recently, germline and combined mutations in FADD have also been described in ALPS. In contrast, mutations in other proteins of the signaling pathway, such as caspases 8 and 10, do not appear to be associated with ALPS. Finally, biallelic mutations in the FAS ligand (FASLG) can also lead to an ALPS phenotype. In all these genetic forms of ALPS, hyperactivation of the mTOR pathway, observed in animal models and subsequently in humans, has demonstrated the efficacy of mTOR inhibitors as a standard treatment for ALPS. Since the discovery of FAS in ALPS, mutations in numerous other genes (CTLA4, LRBA, STAT3) have been described in patients presenting with ALPS symptoms combined with signs of immunodeficiency. It has been proposed to distinguish these monogenic ALPID disorders to avoid confusing them with ALPS, which is specifically associated with a defect in the FASLG/FAS pathway.