Hutchinson-Gilford Progeria Syndrome: A Comprehensive Review of Pathogenesis, Clinical features, Diagnosis and Management

Abstract

Hutchinson–Gilford Progeria Syndrome (HGPS) is an extremely rare, fatal genetic disorder characterized by accelerated aging during early childhood. The condition is primarily caused by a de novo mutation in the LMNA gene (c.1824C>T), resulting in the production of progeria, an abnormal lamin A protein that disrupts nuclear architecture, genomic stability, and cellular function. Children with HGPS present with growth retardation, alopecia, lipodystrophy, osteoporosis, joint contractures, scleroderma-like skin changes, and characteristic facial features while maintaining normal cognitive development. Progressive cardiovascular disease, including atherosclerosis, myocardial infarction, heart failure, and stroke, remains the leading cause of mortality. Diagnosis is established through clinical evaluation and confirmation of LMNA mutations using molecular genetic techniques such as DNA sequencing and whole-exome sequencing. Current management is primarily supportive and focuses on symptom control and prevention of complications. The farnesyltransferase inhibitor lonafarnib is the only FDA-approved treatment and has demonstrated improved survival and cardiovascular outcomes. Emerging therapeutic approaches, including CRISPR/Cas9 gene editing, antisense oligonucleotides, RNA interference, mTOR inhibitors, and base-editing technologies, offer promising strategies for reducing progerin accumulation and correcting the underlying genetic defect. Continued research into targeted molecular therapies may improve survival, quality of life, and provide potential curative options for patients with HGPS.