CVID and dysregulation syndrome in three members of a same family with a new variant of CTLA4 gene

MOREIRA, I.; REGAIRAZ, LORENA; SEMINARIO, GISELA; CALDIROLA, MARÍA SOLEDAD; GAILLARD, MARÍA ISABEL; LLARENS, AGOSTINA; AZCOITI, MARÍA ESNAOLA; BEZRODNIK, LILIANA

Simposio; 2020 CIS Annual meeting; 2020

Introduction: CTLA4 is a negative immune regulator that inhibits Tcell activation by various suppressive functions. Haploinsufficiency in CTLA4 presents with a diverse clinical phenotype and laboratory results. Objective: Report a family with diverse clinical presentation due to CTLA genevariant.Results: Three members of a family presented a CTLA4 gene variant. The index case (IC) is a girl 15 years old (yo), with a background of severe varicella and mononucleosis syndrome during her childhood. Since 11yo suffered from recurrent oral thrush and Evans Syndrome. She was treated with IVIG, steroids and rituximab, without improvement. Luckily, cytopenias were controlled by Eltrombopag and Sirolimus. Laboratory showed: low IgM, IgG and antibody responses could not be evaluated because of IVIG; T/NK lymphopenia, with an expansion of central memory T cells. Her sister (18yo) has recurrent respiratory infections (RRI), since she was 1yo and has been sufferingfrom chronic diarrhea. A bowel biopsy (BB) demonstrated follicular lymphoid hyperplasia (FLH) and focal active colitis. IBD showed partial response to steroids (discontinued) and azathioprine. Vedolizumab was added. She was diagnosed with CVID due to hypogammaglobulinemia and impaired antibody responses. Moreover, she showed T/NK lymphopenia, low counts of PostswitchB cells and an increase of TCR αβ double negative T cells. Actually she is under SCIG. Their father (47yo), has been suffering from RRI since his childhood and oral/genital thrush. He developed asevere goiter at 18yo. For the past 10 years, he has been switching between diarrhea and constipation. FLH was found in BB, therefore oral Budesonide was started. He only showed mild T-Lymphopenia. All of them present low levels of regulatory T cells (Treg) and high levels of circulating T follicular helper cells (cTfh) with a variable cTfh1/cTfh17 profile. NGS showed an heterozygous CTLA4 gene variant (p.Leu141Pro). This is not reported in ExAC or GenomAD.Futhermore, the three patients had low expression of CTLA4 in Tregs. We believe that this finding could explain the different phenotypes. Both siblings received a Hematopoietic stem cell transplantation (HSCT): IC with match unrelated donor, and her older sister with match related donor. Both received a reduced-intensity conditioning (RIC) regimen based on melphalan and fludarabine associated with antithymocyte globulin (ATG). Good neutrophils engraftment.Currently, they are in day + 19 IC and in day + 27 awaiting immune reconstitution. Discussion: The 3 patients presented symptoms in second childhood and adolescence. Their clinical manifestationswere different. Both daughters with CVID profile due to hematological and intestinal involvement and endocrinological involvement in their father, All with low CTLA4 expression in Treg. Thisdemonstrates the complexity of these patients that lead us to face different therapeutic paths from the modulation of the treatment to a BMT. HSCT for severe presentation can be a therapeutic option. However, there are few published reports in the literature. The great risk in patients who undergo to HSCT is inflammation because of the alloreactivity development.