Activated phosphoinositide 3-kinase delta syndrome 1 and 2 (APDS 1 and APDS 2): similarities and differences based on clinical presentation in two boys

Abstract

Background: Activated PI3K delta syndrome (APDS) belongs to the heterogeneous group of primary immunodeficiency disorders (PIDs). Progress in next-generation sequencing (NGS) enabled identification of gain-of-function mutations in phosphoinositide 3-kinase (PI3K) genes. Depending on the type of causative mutation, APDS is classified into two types: APDS 1 and APDS 2. To date, less than 100 cases of APDS have been reported. Clinical symptoms of APDS result from impaired immune regulation and are clinically manifested by recurrent infections, allergies, lymphoproliferation and autoimmunity. They show similarity to other PIDs. Therefore, many patients were diagnosed incorrectly. The availability of genetic testing has allowed establishing the correct diagnosis in increasing number of patients suffering from APDS.

Case presentations: The first male patient presented in infancy with recurrent infections. Subsequently he was found to suffer from hepatosplenomegaly, early portal hypertension, massive lymphoproliferation and hypogammaglobulinemia. The common E1021K mutation in the PI3KCD gene was identified. The patient underwent successful hematopoietic stem cell transplantation with resolution of most symptoms. The second patient suffered from persistent growth retardation since early life, facial dysmorphism and recurrent respiratory infections from early childhood. He was found to have systemic lympho-proliferation, panhypoglobulinemia and impaired antibody responses to vaccines. The introduction of NGS in Poland enabled rapid identification of a mutation in the PI3KR1 gene. Growth hormone administration seemed to have worsened the lymphoproliferation.

Conclusions: Patients with suspected common variable immunodeficiency (CVID) and additional symptoms, such as allergy, facial dysmorphia, short stature, enhanced lymphoproliferation and lack of adequate response to human immunoglobulin replacement therapy, should be considered for NGS-based genetic testing. It may substantially shorten the time needed to establish the correct diagnosis, direct appropriate treatment and avoid potentially harmful therapies. To date, few cases of APDS have been described. It is important to report each of them to establish clinical indices and laboratory biomarkers of APDS 1 and APDS 2, to develop the standards of care in these conditions.

Keywords: APDS; Genetic testing; Growth hormone; Hyper IgM; PI3Kδ; Primary immunodeficiency.

Fig. 1

High-resolution computed tomography scan documenting severe lymphoproliferation within mediastinal lymph nodes of the 8-years-old boy with APDS 1