Molecular overlap between primary immune thrombocytopenia and inherited platelet disorders: A pediatric case report with a novel heterozygous ITGB3 variant identified by next-generation sequencing

Abstract

Primary immune thrombocytopenia (ITP) in children is typically self-limited. However, persistent and treatment-resistant cases require evaluation of alternative pathogenic mechanisms. We report a 12-year-old female with persistent ITP unresponsive to corticosteroids and intravenous immunoglobulin, in whom genetic testing identified a rare heterozygous ITGB3 variant (c.1043G>A; p. Ser348Asn) which encodes the β3 subunit of the platelet αIIbβ3 integrin, a receptor essential for platelet aggregation, outside-in signaling, and megakaryocyte maturation. The variant was not found in population databases and was classified as a variant of uncertain significance according to the American College of Medical Genetics and Genomics (ACMG). Integrated silico analyses using AlphaMissense and PolyPhen-2 yielded a suggestive pathogenicity profile. Parental genetic testing confirmed maternal transmission of the variant, with the mother remaining clinically asymptomatic, consistent with autosomal dominant inheritance with incomplete penetrance. Eltrombopag had been initiated before the genetic results became available, in line with standard management of chronic ITP, and produced a sustained platelet response maintained over 26 months of follow-up. This case highlights the value of molecular evaluation in atypical pediatric ITP, while underscoring that the therapeutic response cannot be interpreted as evidence of variant pathogenicity. The reporting of this case conforms to the CARE guidelines.