Activated PI3Kδ syndrome type 2: Two patients, a novel mutation, and review of the literature.
Autosomal dominant gain-of-function mutations in PIK3R1 encoding for the regulatory subunit (p85α, p55α, and p50α) of Class IA phosphoinositide 3-kinase (PI3K) result in the activated PI3Kδ syndrome (APDS) type 2 characterized by childhood-onset combined immunodeficiency, lymphoproliferation, and immune dysregulation. To improve clinical awareness and understanding of these rare diseases, we reviewed all hitherto published cases with APDS type 1 and type 2 for their clinical and immunologic symptoms and added novel clinical, immunologic, and genetic findings of two patients with APDS type 2.



Clinical, immunologic, and genetic evaluation of two new patients with APDS2 was performed followed by the systematic collection of all available previously published data of patients with APDS1 and APDS2.



Patients with APDS type 1 (n = 49) and type 2 (n = 15) showed an indistinguishable immunologic phenotype. Overlapping clinical features shared by APDS type 1 and type 2 were observed, but our review also revealed previously unnoticed clinical differences such as remarkably high incidence of microcephaly, poor growth/short stature in patients with APDS2. Clinical management and outcome were variable and included prophylactic antibiotics, immunosuppression, immunoglobulin substitution, and hematopoietic stem cell transplantation.



A disease-specific registry collecting prospective and long-term follow-up data of patients with APDS, as currently set up by the European Society for Immunodeficiencies, are needed to better understand the natural history and to optimize treatment concepts and thereby improving the outcome of this heterogenous patient group.
Seccion de Infectología e Inmunopatología, Unidad de Pediatria, Hospital Virgen del Rocío, Sevilla/Instituto de Biomedicina de Sevilla (IBiS), Sevilla, Spain.
Peter
P
Olbrich
The Institute for Transfusion Medicine, University of Ulm, Ulm, Germany.
Myriam
M
Lorenz
Center for Chronic Immunodeficiency (CCI), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
Paola
P
Cura Daball
Unidad de Inmunología, Hospital Universitario Virgen del Rocío, Sevilla, Spain.
José Manuel
JM
Lucena
Center for Chronic Immunodeficiency (CCI), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
Anne
A
Rensing-Ehl
Unidad de Inmunología, Hospital Universitario Virgen del Rocío, Sevilla, Spain.
Berta
B
Sanchez
The Institute for Transfusion Medicine, University of Ulm, Ulm, Germany.
Marita
M
Führer
Seccion de Infectología e Inmunopatología, Unidad de Pediatria, Hospital Virgen del Rocío, Sevilla/Instituto de Biomedicina de Sevilla (IBiS), Sevilla, Spain.
Marisol
M
Camacho-Lovillo
Seccion de Infectología e Inmunopatología, Unidad de Pediatria, Hospital Virgen del Rocío, Sevilla/Instituto de Biomedicina de Sevilla (IBiS), Sevilla, Spain.
Marta
M
Melon
The Institute for Transfusion Medicine, University of Ulm, Ulm, Germany.|Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service, Baden-Württemberg-Hessen, Ulm, Germany.
Klaus
K
Schwarz
Seccion de Infectología e Inmunopatología, Unidad de Pediatria, Hospital Virgen del Rocío, Sevilla/Instituto de Biomedicina de Sevilla (IBiS), Sevilla, Spain.
Olaf
O
Neth
Center for Chronic Immunodeficiency (CCI), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.|Center for Pediatrics, Department of Pediatric Hematology and Oncology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
Carsten
C
Speckmann
D019072:Antibiotic Prophylaxis; D002675:Child, Preschool; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics*; D005260:Female; D005838:Genotype; D048788:Growth and Development; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D007165:Immunosuppression Therapy; D008297:Male; D008831:Microcephaly; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D000081207:Primary Immunodeficiency Diseases; D017422:Sequence Analysis, DNA
D016756:Immunoglobulins, Intravenous; D058534:Class I Phosphatidylinositol 3-Kinases; C486018:PIK3CD protein, human
activated PI3Kd syndrome; children; combined immunodeficiency; immune dysregulation; lymphoproliferation