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

Abstract

Activated phosphoinositide 3-kinase delta syndrome 1 (APDS-1) is a recently described inborn error of immunity caused by monoallelic gain-of-function mutations in the PIK3CD gene. We reviewed for the first time medical records and laboratory data of eight Italian APDS-1 patients. Recurrent sinopulmonary infections were the most common clinical feature at onset of disease. Seven patients presented lymphoproliferative disease, at onset or during follow-up, one of which resembled hemophagocytic lymphohistiocytosis (HLH). Genetic analysis of the PIK3CD gene revealed three novel mutations: functional testing confirmed their activating nature. In the remaining patients, the previously reported variants p.E1021K (n = 4) and p.E525A (n = 1) were identified. Six patients were started on immunoglobulin replacement treatment (IgRT). One patient successfully underwent hematopoietic stem cell transplantation (HSCT), with good chimerism and no GVHD at 21 months post-HSCT. APDS-1 is a combined immune deficiency with a wide variety of clinical manifestations and a complex immunological presentation. Besides IgRT, specific therapies targeting the PI3Kδ pathway will most likely become a valid aid for the amelioration of patients' clinical management and their quality of life.

Keywords: PI3K; PIK3CD; activated phosphoinositide 3-kinase delta syndrome 1; lymphoproliferation; p110δ; primary combined immune deficiency.

Figure 1

P2′s thoraco-abdominal computed tomography (CT) scans. On post contrast axial CT scans at the level of the axillary regions (a) numerous lymph nodes (white arrows) with homogeneous density are evident. On the scan just below the tracheal carina (b); solid mediastinal adenopathic conglomerate and bilateral hilar lymph nodes (yellow arrow) are clearly visible. In the abdomen, multiple adenopathies are evident in the hepatic hilum (c) (blue arrow) and in the mesentery (d) (green arrow).

Figure 2

P5′s whole-body magnetic resonance imaging (MRI). On coronal fat suppressed T2 weighted sequences, numerous homogeneously hyperintense lymph nodes are detectable at the level of the neck (a) (white arrows), the axillary regions (b) (yellow arrows) and in the inguinal area bilaterally (c) (blue arrows). The spleen has a homogeneous signal intensity and increased size (d) (green arrow).

Figure 3

phospo-S6 kinase (pS6K) levels in peripheral T cells from Activated Phosphoinositide 3-Kinase Delta Syndrome-1 (APDS-1) patients (Pts). Summarized data for pS6K levels from patients harbouring the Y524D, P658L and R108L PIK3CD mutations are shown for CD4⁺ T cells (a) and CD8⁺ T cells (b) after anti-CD3 stimulation and/or CAL-101 treatment. (Data were summarized from n = 3 experiments from the index patients and four different healthy controls (HCs); statistical analysis was performed using the Student’s t-test (* p < 0.05). Abbreviations: a-CD3: anti-CD3, CAL-101: Idelalisib, GS-1101, MFI: mean fluorescence intensity.