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-offunction 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.

International retrospective study of allogeneic hematopoietic cell transplantation for activated PI3K-delta syndrome

“…Fifty-seven pediatric and adult patients with APDS who received HCT (43 with PIK3CD, 14 with PIK3R1 mutations) were included, all with confirmed pathogenic mutations and 20 with previously detailed HCT courses. 1,2,12,13,[19][20][21][22][23][24][25][26][27][28][29] Patient and disease characteristics are shown in Table I. All patients had clinical indications for HCT, and none were transplanted preemptively based on genetic diagnosis alone (see Table E2 in this article's Online Repository at www.jacionline.org).…”

Case Report: Hodgkin Lymphoma and Refractory Systemic Lupus Erythematosus Unveil Activated Phosphoinositide 3-Kinase-δ Syndrome 2 in an Adult Patient

“…The presence of autoimmunity, systemic lymphoproliferation, hyper inflammation, and increased risk of neoplastic transformation may underly an inborn error of immune regulation ( 5 ). Growth retardation, mild neurodevelopmental delay, facial dysmorphisms, and tonsillar hypertrophy are typically observed in APDS2 patients ( 6 , 7 ). We report a new heterozygous mutation of PIK3R1 associated with APDS2, observed for the first time in a young adult with predominant immune dysregulation manifestations at the diagnosis.…”

Activated phosphoinositide 3-kinase δ syndrome associated with nephromegaly, growth hormone deficiency, bronchiectasis: a case report

“…Children with APDS2 have also been reported to have short stature and poor growth, sometimes even receiving GH replacement [ 15 ]. However, GH has been reported to exacerbate lymphoproliferation as evidenced by increased lymphadenopathy [ 16 ], likely due to the role of GH in signaling via the PI3K pathway [ 17 ]. Our patient’s diagnosis prompted concern that GH therapy could induce further lymphoproliferation and thereby increase risk of malignancy, which is seen in about 12% of patients with this condition [ 3 ].…”