# E1021K mutation in PIK3CD gene: clinical heterogeneity and therapeutic implications in three pediatric APDS cases

## TL;DR

This study examines three children with APDS caused by the same E1021K mutation in the PIK3CD gene, highlighting varied symptoms and treatment responses.

## Contribution

The study demonstrates clinical heterogeneity in APDS patients with the same mutation and evaluates therapeutic responses including rapamycin.

## Key findings

- Bronchoscopic nodular lymphoid hyperplasia is a key diagnostic feature of APDS.
- Progressive T-cell exhaustion and immunoglobulin dysregulation correlate with disease severity.
- Rapamycin treatment improved hepatosplenomegaly in one patient.

## Abstract

The aim of this study was to characterize the clinical manifestations, treatment responses, and prognostic indicators of activated PI3K-δ syndrome (APDS) in pediatric patients. Clinical data from three patients diagnosed with APDS in our department were retrospectively analyzed. All patients carried the same heterozygous E1021K (c.3061G > A) gain-of-function mutation in the PIK3CD gene. Immunoglobulin levels varied: IgM was normal or elevated, while IgG and IgA were normal or decreased, with the extent of change correlating with disease severity. All three children received anti-infective therapy, resulting in significant improvement in clinical symptoms and chest imaging findings. Bronchoscopic re-evaluation in Cases 1 and 2 showed marked regression of airway mucosal hyperplasia. Following diagnosis, Cases 1 and 2 received regular immunoglobulin replacement therapy, which reduced the frequency of infections. Case 2 was treated with rapamycin as targeted therapy, leading to significant improvement in hepatosplenomegaly. In conclusion, bronchoscopic detection of nodular lymphoid hyperplasia is a diagnostic hallmark of APDS. Progressive T-cell exhaustion and immunoglobulin dysregulation may serve as biomarkers of disease severity. Targeted therapy, such as rapamycin, demonstrates clinical efficacy. This case series underscores the variable expressivity of APDS even among individuals sharing the same pathogenic variant, emphasizing the need for personalized management.