A Rare Case of Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS) Presenting With Hemophagocytosis Complicated With Hodgkin Lymphoma

Abstract

Gain of function mutations in the p110δ catalytic subunit of the phosphatidylinositol-3-OH kinase (PIK3CD) classified as activated phosphoinositide 3-kinase delta syndrome (APDS) are the cause of a primary immunodeficiency characterized by recurrent sinopulmonary infections, and lymphoproliferation. Previously, autoimmunity and Epstein-Barr virus–related B-cell lymphoma have been documented for patients with APDS; here, we present a case that extends the picture, as the patient shows the full diagnostic criteria of hemophagocytic lymphohistiocytosis at 6 months of age. He experienced Hodgkin lymphoma as a 2.5-year-old baby. Next-generation sequencing returned a de novo heterozygous missense variant in PIK3CD (LRG_191t1: c.3061G>A; p.Glu1021Lys), confirming the primary immunodeficiency. After 2 courses of ifosfamide, cisplatin, and etoposide combined with brentuximab, the patient successfully underwent allogeneic hematopoietic stem cell transplantation from his HLA full matched sister, and he has been well for 18 months after that. The hematologist treating Hodgkin lymphoma and/or hemophagocytic lymphohistiocytosis should be vigilant about the possible underlying immune deficiency, and they should consider APDS in their differential diagnosis.

Activated Phosphoinositide 3-Kinase Delta Syndrome 1: Clinical and Immunological Data from an Italian Cohort of Patients

“…Functional and genetic analysis for familiar HLH tested negative and other HLH-related triggers were excluded (i.e., malignancy, infections). Another APDS-1 patients has been described with Hodgkin Lymphoma complicated by HLH [ 29 ], underlining a pivotal role of the PI3K axis in terms of oncogenesis and immune regulation. In addition, Chron’s-like enteropathy, a feature shared by many other IEI (i.e., Cytotoxic T-Lymphocyte Antigen 4 ( CTLA-4 ) haploinsufficiency, immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX), Lipopolysaccharide-Responsive, Beige-Like Anchor Protein (LRBA) deficiency) [ 30 , 31 ], was reported in one of our patients and initially responded to first-line treatment [ 32 ].…”

Hemophagocytic Lymphohistiocytosis in Activated PI3K Delta Syndrome: an Illustrative Case Report

“…Especially in the case of persistent EBV, a virus that is already able to trigger HLH, APDS patients are theoretically more prone to develop hyperinflammation and thus HLH [8]. Although chronically active EBV and EBV-associated lymphomas are common in APDS, HLH has only been reported in two APDS patients, who are summarized in Table 3 [9,10]. Both patients were children at the time of APDS diagnosis, which suggests that genetic diagnosis is more often considered in pediatric HLH.…”

Primary Immune Regulatory Disorders With an Autoimmune Lymphoproliferative Syndrome-Like Phenotype: Immunologic Evaluation, Early Diagnosis and Management

“…ALPS-like patients who have developed HLH should undergo HSCT. HLH turned out to be characteristic of patients with X-linked lymphoproliferative syndrome (XIAP and SH2D1A patients) and was also found in ten patients with TNFRSF9 ( 51 ), LRBA ( 67 ), ITK ( 53 , 68 ), RASGRP1 ( 69 ) deficiencies, CTLA4 haploinsufficiency ( 55 , 70 ), CARD11 GOF ( 71 ) and PIK3CD GOF ( 52 ) ( Table 1 ) .…”

“…The lymphoproliferation and the immune dysregulation predispose both ALPS and ALPS-like patients to malignancies, especially lymphoma or leukemia (48,49). In the ALPS-like group with EBV-susceptibility, several patients developed an EBV-driven B-cell lymphoma from uncontrolled EBV infection (23,(50)(51)(52)(53)(54). No ALPS-like patient with a defect in the PRKCD, XIAP, IL2RA, IL2RB, TPP2, STAT1 GOF, IL12RB1, ADA2 and TNFAIP3 genes presented malignancy in the reviewed literature (Table 1).…”