VEXAS syndrome: a comprehensive clinicopathologic and genetic analysis of a predominantly Indian cohort

VEXAS syndrome is a recently recognized, acquired monogenic adult onset hemato-inflammatory syndrome characterized by somatic mutations within the UBA1 gene. The acronym VEXAS stands for vacuoles, E1 enzyme, X-linked inheritance, autoinflammatory tendencies, and somatic mutations. It presents as a severe progressive disease displaying varied characteristics that bridge hematologic and rheumatologic domains. Herein, we describe a series with a detailed evaluation of 11 cases of VEXAS syndrome.

A comprehensive retrospective analysis of patients diagnosed with VEXAS syndrome over the last 5 years (2020-2025) was conducted. Data on clinical presentation, histopathological findings, genetic characteristics, and outcomes were recorded for systematic characterization.

A total of 11 cases of VEXAS syndrome were identified. All the patients were males with an age range from 42 to 77 years. Prominent clinical characteristics included history of fever (11), arthritis/arthralgia (10), inflammatory skin lesions (7), vasculitis (6), ocular inflammatory conditions (6), relapsing polychondritis (6), unprovoked venous thrombosis (5), and auricular chondritis (4). Persistent unexplained cytopenia was present in all the patients, manifesting as anemia (10, 8 of which were macrocytic), thrombocytopenia (4), and neutropenia (2). Bone marrow examination was performed in nine cases, five showed morphologic dysplasia. Furthermore, all nine cases characteristically showed cytoplasmic vacuolations in hematopoietic precursors. UBA1 somatic mutations included p.Met41Thr (c.122 T>C Exon 3) (55%), p.Met41Val (c.121 A>G Exon 3) (27%), p.Met41Leu (c.121 A>C Exon 3) (9%), and a variant in the acceptor splice site of Exon 3 (c.118 G>C) (9%). p.Met41Val is associated with inferior overall survival (OS).

This study characterizes the clinical, morphologic, and laboratory features of VEXAS syndrome and presents the first comprehensive patient cohort from India. With a complex and heterogeneous clinical profile, awareness of the disease is particularly essential among hematologists, rheumatologists, and dermatologists for accurate diagnosis and management.