PTEN Deficiency: a phenocopy phenomenon

Abstract

BackgroundActivated PI3K delta syndrome 1 (APDS1) is caused by mutations in PI3KCD. The phosphatidylinositol 3-kinase (PI3K) signaling pathway is essential to cell survival, proliferation, and metabolism. PI3K plays a crucial role in the regulation of function and differentiation of immune cells. Phosphatase and tensin homolog (PTEN) serves to antagonize the PI3K pathway. Overlapping immune features of PTEN deficiency and APDS include high IgM, low IgG, increased transitional B cells, specific antibody deficiencies, autoimmunity, and lymphoproliferation. Because PTEN antagonizes PI3K activity, patients with PTEN loss-of-function mutations exhibit a similar phenotype to those with gain-of-function mutations of PI3K and can respond to mTOR inhibition like APDS patients. Overactivation of PI3K due to PTEN deficiency can lead to generalized immune dysregulation. Here we describe a patient with PTEN deficiency who presents as a phenocopy of APDS1 patients. MethodsRetrospective chart review was performed to obtain data on clinical labs of the PTEN deficient patient and APDS1 patients who presented with a similar clinical phenotype. An Epstein-barr virus (EBV) transformed B cell line (BLCL) was created from the patient PBMCs for functional studies to evaluate the PBK/AIKT/mTOR pathway. Patients were consented on an IRB approved protocol. ResultsThe patient was referred to immunology clinic for autoimmune cytopenias (Evan’s syndrome) and hypogammaglobulinemia. WES revealed De novo heterozygous c.406T>C (p.C136R) pathogenic variant in PTEN. Immune profiling showed elevated transitional B cells, increased naïve B cells and a decreased amount of class-switched memory B cells along with hyper IgM and low IgG. An abdominal ultrasound revealed significant splenomegaly with peri-splenic lymphadenopathy and hyper-echoic lesions in the spleen. Functional studies on BLCLs were reserved for confirmation of dysregulated PI3k/AKT/pS6 signaling. The patient was treated with sirolimus and IgG replacement therapy. After sirolimus therapy, lymphoproliferation and splenic findings resolved. DiscussionPTEN deficiency is a clinical and mechanistic phenocopy of APDS1 due to loss of negative regulation by PTEN to control over-activation of PI3 K. While Evan’s syndrome is reported in APDS1 more readily, it is not as prominent in PTEN. Treatment strategies employed for APDS1 and 2 are viable options for controlling the disease manifestations seen in PTEN deficiency.