Clinical and immunological phenotype of patients caryying CASP10 variants

ALPS is a congenital disorder secondary to defects of FASmediated apoptosis, usually showing during the first years of life with variable phenotype, mainly characterized by lymphoproliferation and autoimmunity. Most patients carry mutation on FAS gene, more rarely defects on FASL/CASP10 are involved. Very few cases of ALPS-CASP10 have been reported, therefore clinical and immunological characteristics of such patients need to be better defined. Some mutations with a role in the pathogenesis of the disease have been reported over the years (Leu285Phe, Ile406Leu). Although others with conflicting interpretation have been afterwards classified as polymorphisms (Val410Ile, Tyr446Cys), nonetheless they have been associated with a defective apoptosis function. The aim of this study is to describe the phenotype of a cohort of patients carrying CASP10 variants. The clinical and immunological parameters included in the ALPS diagnostic criteria were evaluated as CD3+TCRaβ+CD4-CD8- (DNTs), the biomarkers (IL10,IL-18,sFAS, Vitamin B12), the ALPS panel signature (high DNT, high DNTsB220+, and low CD27+, low CD3+CD25+/CD3+HLADR+ ratio), and the apoptosis test. Thirty-two patients aged 0–53 years (median 10.9) were studied. Six carried the known Ile406Leu mutation, 11 presented some unreported variants as Cys401Leufs* (3), Pro501Leu (4), Ser239Cys (1), Arg104*(2), c684+4G>A (1). The remaining 16 carried polymorphic variants. Overall, only 18 patients (56%) showed lymphoproliferation and/or splenomegaly. Twenty-seven patients (84%) showed autoimmune features including autoimmune cytopenia (65%) in 19 cases. DNTs were raised in 64% of cases and apoptosis test was positive in 74% of patients including all cases with novel mutations. Five (15%) patients showed hypogammaglobulinemia. Twelve (37%) and 10/32 (31%) patients showed an ALPS and ALPS-like phenotype, respectively. The remaining 10 (31%) presented a different immune-dysregulation pattern. Two patient (6%) developed a lymphoma. Table 1 shows details of clinical and immunological characteristics. Median follow-up was 5.9 years (0.5–24). This is the largest reported cohort of patients carrying CASP10 variants showing that most of them have a clinical phenotype other than ALPS, mainly presenting with milder immune dysregulation showing at older age. Due to this different clinical pattern, ALPS diagnostic criteria should be reviewed and patients with CASP10 variants should be considered as having a different disorder.Table 1. Clinical and immunological characteristics of patients carrying CASP10 variants.Empty CellTotal (З2)Casp10 polymorphic variants (16)Casp10 pathogenic variants (16)pALPS phenotype12 (37%)6 (37%)6 (37%)nsALPS-like phenotype10 (31%)6 (37%)4 (25%)nsOther immunedysregulation10 (31%)4 (25%)6 (37%)nsIL-1S >(500 pg/mL)10 (31%)7 (44%)3 (19%)<0.05B12(>663 pg/mL)11 (34%)5 (31%)6 (37%)nsIL-10 (>20 pg/mL)1 (3%)1 (6%)0 (0%)nssFAS ligand (>200 pg/mL)0 (0%)0 (0%)0 (0%)nsDNT cells (%CD3) (>1,5%)21 (65%)10 (62%)11 (69%)nsCD3CD25+/CD3HLADR+ ratio (<1%)21 (65%)10 (62%)11 (69%)nsTCR αβ+ B220+ (>60%)10 (31%)5 (31%)4 (25%)nsLinfoB CD27+ (CD19tot) (<15%)20 (62%)11 (69%)9 (56%)nsALPS Panel positive 4/45 (15%)3 (19%)2 (12%)ns Table 1. Clinical and immunological characteristics of patients carrying CASP10 variants.