Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study

Abstract

Background: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ).

Objective: We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort.

Methods: We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS.

Results: Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS.

Conclusion: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.

Keywords: Activated phosphoinositide 3-kinase δ syndrome; PIK3CD gene; bronchiectasis; hematopoietic stem cell transplantation; immunodeficiency; p110δ-activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency; phosphoinositide 3-kinase inhibitor; phosphoinositide 3-kinase δ.

Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Fig E1

EBV-positive diffuse large B-cell lymphoma in patients with APDS. 1, A diffuse infiltrate of large atypical lymphoid cells and some atypical plasmacytoid cells was present in the cerebellum. 2, Immunohistochemical staining showed large B cells expressing CD20, CD79a, Pax5, and interferon regulatory factor 4 but not Bcl6 or CD10. 3, Most neoplastic cells showed positive in situ hybridization for EBV EBER. 4, Plasmacytoid cells expressed CD138 and showed λ restricted immunoglobulin light chain in situ hybridization. H&E, Hematoxylin and eosin.

Fig E2

Primary cutaneous anaplastic large cell lymphoma in patients with APDS. 1 and 2, A multinodular cutaneous tumor on the chest of an 11-year-old boy (Fig E2, 1), which regressed to a flat plaque (Fig E2, 2) on 6 weeks of treatment with rapamycin. 3 and 4, The dermis and subcutis contained a diffuse infiltrate of large atypical lymphoid cells. 5 and 6, Immunohistochemical staining showed large T cells expressing CD3 (Fig E2, 5), CD30 (Fig E2, 6), CD2, interferon regulatory factor 4, T-cell receptor β, and perforin but not CD4, CD8, or ALK. H&E, Hematoxylin and eosin.

Fig 1

BCG-induced granulomatous inflammation in patients with APDS. 1, Granulomatous skin lesion in a 4-year-old at the site of BCG vaccination administered at 4 months of age. 2, Skin biopsy specimen showing granulomatous inflammation.

Fig 2

Lymphoid hyperplasia. 1 and 2, Lymph node showing atypical follicular hyperplasia with disrupted follicles (arrows) and monocytoid B cells (arrowheads). 3-5, Disrupted germinal centers were highlighted by staining for CD20 (Fig 2, 3 and 4) and Bcl6 (Fig 2, 5). 6 and 7, Follicles were infiltrated by T cells (Fig 2, 6), many of which expressed PD1, CD57, or both (Fig 2, 7). 8, IgM-positive plasma cells were present, but IgG-positive plasma cells were reduced or absent. 9, Several lymph nodes contained CMV or EBV (EBER). 10, Tracheal endoscopy showing mucosal nodules. 11 and 12, Lung showing peribronchiolar lymphoid hyperplasia (Fig 2, 11) with disrupted follicles (Fig 2, 12). H&E, Hematoxylin and eosin.

Fig 3

p110δ expression in the mouse brain. Brain sections of adult wild-type (−lacZ cassette) mice (1) and p110 d kinase dead (+lacZ cassette) β-gal reporter mice16 (2) stained with the neuronal stain cresyl violet (purple) and X-gal (blue) representing p110δ expression. Strong expression of p110δ was observed in areas of the hippocampus, cerebral cortex, and thalamus.

Fig 4

Radiology of patients with APDS. 1, CT scan of the chest (2-year-old boy), demonstrating right paratracheal lymphadenopathy (A), right upper lobe consolidation, and centrilobular nodules (B), progressing 2 years later to severe right upper lobe bronchiectasis (C). 2, CT scan of the chest (A-C) in a 7-year-old boy reveals widespread mosaic attenuation (indicative of small airways disease), mild right upper lobe bronchiectasis (A) and atelectasis (B, black arrows). 3, CT scan of the chest (A), abdomen (B), and pelvis (C) of an 8-year-old boy showing axillary, paratracheal, para-aortic (black arrow), mesenteric and inguinal lymphadenopathy (white arrows), and splenomegaly.

Fig 5

Age-related changes in B-cell counts in patients with APDS. Age-related median B-cell count (white dots), B-cell count 5th to 95th percentile normal range (checked area), and less than 5th percentile normal B-cell count (spotted area) were plotted.

Fig 6

Variation in clinical phenotypes of APDS. Each column represents a patient with APDS. Each row represents a frequent or serious complication of APDS. White boxes and gray boxes depict the absence or presence of a complication, respectively.