HGPS

HGPS, or Hutchinson-Gilford Progeria Syndrome, is a rare genetic disorder characterized by features of accelerated aging that begin in early childhood. Affected individuals are typically normal at birth but develop growth retardation, loss of body fat and hair, aged-looking skin, joint stiffness, and characteristic facial features. Cardiovascular disease often becomes evident in childhood or adolescence and is a major contributor to mortality.

Cause and genetics: Most cases arise from a de novo mutation in the LMNA gene, most commonly a silent c.1824C>T change (p.G608G) that activates a cryptic splice site and yields progerin, an abnormal form of lamin A. Progerin disrupts the nuclear envelope and cellular aging processes. The condition is usually not inherited in a traditional sense; new mutations account for the majority of cases, with rare familial occurrences.

Pathophysiology: The production of progerin leads to nuclear architecture defects, genomic instability, and impaired cellular function. Progressive loss of vascular smooth muscle cells and abnormal collagen remodeling contribute to premature vascular aging, a hallmark of the disease.

Diagnosis: Diagnosis is based on clinical features and confirmed by genetic testing for LMNA mutations. Additional assessments typically monitor growth, nutrition, and cardiovascular status, including imaging and laboratory tests as indicated.

Treatment and management: There is no cure. Management is multidisciplinary, focusing on supportive care and treatment of complications. Lonafarnib, a farnesyltransferase inhibitor, has been shown to improve growth and survival in some patients. Other measures include nutritional support, physical therapy, and vigilant cardiovascular monitoring and risk management.

Prognosis and epidemiology: Incidence is estimated at about 1 in 4 to 20 million births, with most cases occurring sporadically. Life expectancy is substantially reduced compared with the general population, often with cardiovascular disease as a leading cause of death. The disease was first described in the late 19th century and linked to LMNA mutations in the early 2000s.