Research Information System
PEDIATRIC ALLERGY AND IMMUNOLOGY, vol.35, no.9, 2024 (SCI-Expanded)
Background: Phosphoinositide 3 kinases (PI3K) are lipid kinases expressed in lympho-cytes/myeloid cells. PI3K/AKT/mTOR signaling defects present with recurrent infec -tions, autoimmunity, lymphoproliferation, and agammaglobulinemia.Objective: To characterize the PI3K/AKT/mTOR pathway defects and perform path -way analyses to assess novel variant pathogenicity. Methods: We included 12 patients (heterozygous PIK3CD (n= 9) and PIK3R1 (n= 1) (activated PI3K delta syndrome (APDS) with gain- of- function mutations) and homozy-gous PIK3R1 variant (n= 2)), performed clinical/laboratory/genetic evaluation, and flow cytometric PI3K/AKT/mTOR pathway analyses. Results: Median age at onset of complaints was 17.5 months (3 months to 12 years) and at diagnosis was 15.7 years (2.5-37) in APDS. Median diagnostic delay was 12.9 years (1.6-27). Recurrent respiratory tract infections (90%), lymphoproliferation (70%), autoimmune/inflammatory findings (60%), and allergy (40%) were common in APDS. Recurrent viral infections were present in 4/10 and malignancy (non- Hodgkin lymphoma and testicular yolk sac tumor) was present in 2/10 in APDS. Low CD4+ T cells(5/8) with increased CD4+ effector memory (8/8) and CD4+ TEMRA cells (6/8) were present in the given number of APDS patients. We diagnosed tubulointerstitial nephritis, Langerhans cell histiocytosis, and late- onset congenital adrenal hyperplasia in APDS. Allergic findings, lymphoproliferation/malignancy, and high IgM were pre -sent in the APDS but not in PIK3R1 deficiency. Low IgM/IgG/CD19+ B cell counts were characteristic in patients with PIK3R1 homozygous loss-of function mutations. Conclusion: Differential diagnosis with combined immunodeficiency and diseases of immune dysregulation make molecular genetic analysis crucial for diagnosing mTOR pathway defects. It is easy to differentiate APDS and homozygous PIK3R1 defects with specific laboratory features. Additionally, mTOR pathway functional analysis is a definitive diagnostic and pathogenicity assessment tool for novel APDS mutations.