Acute leukemia, HLH, lymphomatosis granulomatosa and disseminated CMV infection in a patient with PIK3R5 mutation

MARIA SOLEDAD CALDIROLA; GUADALUPE RODRIGUEZ BROGGI; MARIA ISABEL GAILLARD; JAVIER CABANA; CECILIA MURRAY; MARA DE MARTINO; ANDREA BERNASCONI; TORRES, NICOLAS; JULIE NIEMELA; JENNIFER STODDARD; SERGIO ROSENZWEIG; LILIANA BEZRODNIK; ZWIRNER, NORBERTO W.; IGNACIO URIARTE

Congreso; Immune Deficiency and Dysregulation North American Conference; 2017

clinical immunology society

Primary immune deficiencies (PIDs) are commonly characterized by an increased susceptibility to specific infections and, in certain instances, a higher incidence of malignancies. Here we present the case of a 17 year old boy with unusual association of acute mielocitic leukemia (AML), Haemophagositosis syndrome (HLH), lymphomatoid granulomatosis and disseminated CMV and EBV susceptibility. He was healthy until the age of 12 years when he presented a first episode of M3 AML. He is the first of 4 boys born from non consanguineous parents. He has no remarkably perinatal history. He has received complete vaccination for age (including BCG) with no complications.After having completed GATLA treatment for his leukemia, he presented an episode of HLH that resolved with HLH 2004 protocol treatment. EBV and CMV infection had been discarded by PCR with positive EBNA antigens.Ten months later he began with adenopathies, hepatomegaly and fever. Axial tomography showed several hypodense images in liver and chest. Biospsy revealed EBV-related lymphomatoid granulomatosis affecting his lungs and skin.During his hospitalization he had episodes of diarrhea and abdominal pain and began with ulcers in his mouth, so a new biopsy was done, showing CMV compatible ulcers which were confirmed by positive CMV PCR in blood and urine sample. Immune evaluation revealed severe hipogammaglobulinemia and lymphopenia with extremely low counts of B cells, NK cells and iNKT cells. T cells showed CD4/CD8 inversion, with the CD8+ compartment skewed to terminal effector phenotype (CD57+). Lymphoproliferation assay (CFSE) showed normal response with different mitogens in the CD4+ subpopulations with minor response in the CD8+ cells.Expression of citoplasmatic SAP, XIAP and perforin proteins were normal with normal degranulation assay (CD107a) in NK cells and CD8+ too. Normal production of IFNg in NK cells after stimulus with rIL12/15/18. A rare heterozygous substitution in PIK3R5 gene (c.523G>A p.V175M) was detected by targeted NGS and confirmed by Sanger sequencing. In order to characterize this mutation, we performed functional assays which revealed absent Akt phosphorylation in the patient?s cells, both at baseline and after stimulation wit anti-CD3, confirming the loss of function of the PI3K signaling pathhway.Nowadays, the patient is waiting for HSCT and under prophylactic antibiotic and IVIG treatment.Therefore, here we report a patient with heterozygous PIK3R5 (V175M) mutation, abnormal PI3K signaling, combined immunodeficiency phenotype affecting T, B, NK and iNKT cells, which was associated with increased susceptibility to AML, HLH and severe/disseminated viral infections.