Work

Novel HCK-associated mutation causing autoinflammatory disorder with pulmonary manifestations in a pediatric patient

Year: 2025

Type: article

Abstract: Autoinflammatory diseases, characterized by recurrent systemic inflammation due to innate immune dysregulation, often present with fever, arthritis, abdominal pain, and cutaneous involvement, with elevated acute-phase reactants during flare-ups. These rare conditions, arising from monogenic mutations or environmental triggers, can be challenging to diagnose, yet accurate identification is critical for effective targeted therapy. In 2022, Kanderova et al. reported a heterozygous c.1545C>A (p.Tyr515Ter) HCK gene mutation causing early-onset cutaneous pulmonary vasculitis due to increased kinase activity from a truncated HCK protein, leading to chronic inflammation and fatal progression despite partial suppression with ruxolitinib. HCK, a SRC family tyrosine kinase predominantly expressed in granulocytic and monocytic cells, regulates immune functions like phagocytosis and cytokine production. We report a 6-year-old female patient with recurrent fevers, cutaneous petechial rashes, chronic cough, exertional dyspnea, and persistent symptoms despite multiple antibiotic treatments for suspected recurrent lower respiratory tract infections since age 1.5 years, treated for presumed recurrent lower respiratory tract infections with multiple antibiotic courses, though symptoms persisted. No cutaneous manifestations were observed during the current admission, but elevated acute-phase reactants and pulmonary findings were noted. Based on clinical and laboratory features, a rare autoinflammatory condition was suspected. No pathogenic variants were identified in an autoinflammatory disease gene panel. Whole-exome sequencing (WES) using next-generation sequencing (NGS) revealed a novel splice site mutation (c.1016-5T>C) in the HCK gene, absent from existing genomic databases. Anti-IL1B targeted therapy achieved complete clinical and laboratory remission. This study identifies a novel HCK gene mutation as the cause of a hereditary autoinflammatory disease with early-onset pulmonary and cutaneous manifestations, consistent with classical autoinflammatory syndromes.

Source: Pediatric Rheumatology

DOI: 10.1186/s12969-025-01170-8

Authors: Afig Berdeli, Shams Ismayilova, Nida Gürbüz

Institution: Ege University

Language: English

Topic: Inflammasome and immune disorders

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,090