Hutchinson–Gilford progeria syndrome

Overview

Hutchinson–Gilford progeria syndrome (HGPS), commonly referred to as progeria, is an extremely rare genetic disorder characterized by rapid aging in children. Although infants with the condition appear normal at birth, they begin to show signs of accelerated aging within the first two years of life. The name derives from the physicians Jonathan Hutchinson and Hastings Gilford, who first described the condition in the late 19th and early 20th centuries. Progeria affects multiple organ systems and leads to early death, typically due to cardiovascular complications.

Causes

HGPS is caused by a mutation in the LMNA gene, which encodes the lamin A protein. Lamin A is an essential structural component of the nuclear envelope in cells. The most common mutation leads to the production of an abnormal form of the protein called progerin, which destabilizes the nuclear envelope, resulting in premature cellular aging. The condition follows an autosomal dominant pattern, but nearly all cases are due to de novo (new) mutations, meaning it is not inherited from parents.

Symptoms

Children with Hutchinson–Gilford progeria syndrome typically begin to display symptoms between 6 months and 2 years of age. Common clinical features include:

• Growth failure and short stature

• Loss of body fat and muscle

• Baldness with prominent scalp veins

• Small face and jaw with a beaked nose

• Stiff joints and hip dislocations

• Thin, wrinkled skin with visible veins

• Delayed or absent tooth eruption

• Cardiovascular disease (atherosclerosis, hypertension)

Despite their physical appearance, cognitive development is typically normal in affected children.

Diagnosis

Diagnosis of HGPS is primarily clinical, based on the characteristic signs and symptoms. Confirmatory tests include:

• Genetic testing: Identification of a mutation in the LMNA gene (commonly c.1824C>T)

• Physical examination: Recognition of growth failure, facial features, and other clinical signs

• Imaging studies: X-rays may reveal skeletal abnormalities such as resorption of clavicles or hip dysplasia

• Cardiac evaluations: Echocardiograms and EKGs to monitor for cardiovascular disease

Early diagnosis is crucial for timely medical and supportive care interventions.

Treatment

There is no cure for Hutchinson–Gilford progeria syndrome, but several treatments aim to reduce complications and improve quality of life. Current treatment strategies include:

• Lonafarnib: A farnesyltransferase inhibitor approved by the FDA that has shown promise in extending lifespan and improving cardiovascular health

• Supportive care: Regular monitoring and treatment of heart disease, blood pressure, and joint stiffness

• Physical and occupational therapy: To maintain mobility and manage joint contractures

• Nutritional support: High-calorie diets to address growth failure

Multidisciplinary care is essential, involving cardiologists, endocrinologists, geneticists, and rehabilitation specialists.

Prognosis

The prognosis for children with HGPS is poor due to progressive cardiovascular disease. Most affected individuals die from heart attacks or strokes, typically between the ages of 8 and 21, with an average lifespan of around 14 years. However, recent advances in therapy, including the use of lonafarnib, have shown promise in improving survival and quality of life. Continued research and clinical trials offer hope for more effective treatments in the future.