Hutchinson-Gilford Progeria Syndrome: A Rare Disorder that Accelerates Ageing

What is Hutchinson-Gilford Progeria Syndrome??

Hutchinson-Gilford Progeria Syndrome (HGPS), also known as progeria (pronounced pro-JEER-e-uh), is an extremely rare genetic disorder that causes children to age rapidly, leading to a significantly shortened lifespan. The history of HGPS dates back to 1886 when Jonathan Hutchinson provided the first recorded account of patients with HGPS, which was later reaffirmed in 1897 by his colleague, Hastings Gilford. In 1904, Gilford coined the term “progeria” to describe the condition, derived from the Greek words “pro” (meaning premature) and “geras” (meaning old age). HGPS occurs in approximately 1 in 20 million newborns, affecting all genders and races equally. As of 31 December 2023, 144 individuals worldwide are estimated to be living with the disease.?

What causes Hutchinson-Gilford Progeria Syndrome??

HGPS is typically not inherited within families and is caused by a spontaneous mutation in the LMNA gene, which produces a protein called lamin A. The lamin A protein plays a crucial role in maintaining the structure of the cell’s nucleus and promoting cellular health. The mutation produces an abnormal form of lamin A called progerin, which interferes with normal cell function, resulting in the premature ageing process.

Signs and symptoms of Hutchinson-Gilford Progeria Syndrome?

Children with HGPS show signs of accelerated ageing, while motor and mental development remain normal. The characteristics of the disease may include:

• Suspicious findings at birth such as unusually tight, shiny, and hardened skin over the abdominal and thigh area; midfacial bluish discolouration of the skin and mucosa; and/or a “sculptured” (appears beaked or pointed) nose?
• Growth delay resulting in short stature and low weight for height, and underdevelopment of facial bones by 2 years of age?
• Distinctive facial features such as a narrow face for the size of the head, large eyes, and thin nose and lips?
• Dental abnormalities such as delayed eruption of teeth, irregularly formed and discoloured teeth, dental crowding, and increased incidence of dental cavities?
• Hair loss by 2 years of age, and loss of eyebrows and eyelashes during early childhood?
• Gradual loss of body fat, prominent veins, unusually aged appearance of the skin, brownish skin blotches, and nail defects?
• Skeletal defects such as delayed closure of the “soft spot” at the front of the skull, narrow shoulders and chest, and thin long bones of the arms and legs that may be susceptible to fractures?
• Degenerative changes in bones and joints, causing stiffness and limited movement, hip deformity, a horse-riding stance, and a shuffling gait; and generalised loss of bone density leading to recurring fractures from minor injuries?
• Atherosclerosis (build-up of fat in the arteries), enlargement of the heart, and abnormal heart sounds?
• Other symptoms such as a high-pitched voice, absence of the breast or nipple, absence of sexual maturation, and hearing impairment?

What is the prognosis??

Individuals with the disease most often live to their teenage years; the average lifespan is 14.5 years, although some may live longer or shorter lives. The cause of death is often related to atherosclerosis complications, including:

• Heart attack or heart failure?

• Stroke?

How is it diagnosed??

Diagnosing HGPS can be challenging, as the symptoms often mimic those of other progeroid syndromes (e.g. Werner syndrome). Identification of the disease at birth is rare but can occur based on certain suspicious findings (e.g. unusually tight, shiny, and hardened skin over the abdominal and thigh area; midfacial bluish discolouration of the skin and mucosa; “sculptured” nose). HGPS is typically identified when a child is at least 2 years old or older and starts to show physical signs of the disease.

Thorough clinical examination, observation of distinctive physical features, and detailed review of the medical history are taken into consideration. Subsequently, a genetic test for LMNA mutation is conducted to confirm the diagnosis of HGPS; this allows early implementation of treatment programmes during the initial stages of the disease. Specialised imaging tests may confirm skeletal abnormalities possibly related to the disease, and comprehensive cardiac examinations may also assess associated cardiovascular abnormalities for appropriate disease management.

What is the treatment for Hutchison-Gilford Progeria Syndrome??

Treatment of HGPS is primarily focused on managing symptoms and providing supportive care. This may include medications to manage cardiovascular symptoms, physical therapy to improve joint mobility, and dietary and lifestyle modifications to support overall health and well-being. The Progeria Research Foundation offers a comprehensive guide to managing the condition.

Recently, there have been promising developments in the treatment of progeria. A breakthrough treatment, a farnesyltransferase inhibitor initially created to treat cancer, has been developed to treat progeria by inhibiting the activity of the enzyme that is involved in the disease mechanism. Clinical trials showed that this treatment has been effective in helping patients gain weight, improve their cardiovascular and skeletal health, and extend their lifespan. In November 2020, the United States Food and Drug Administration approved this treatment as the first option to reduce the risk of mortality in HGPS, making a significant development in the management of this challenging disease.

What still needs to be done??

While the breakthrough treatment has been proven effective in improving symptoms and increasing the lifespan of children with HGPS, it comes with a significant cost, making it inaccessible for many, with an annual expense reaching up to $1.2 million for some patients. However, there is hope on the horizon, as Progeria Research Foundation has actively funded research projects worldwide, providing over $9.3 million in support. Research is ongoing to develop more affordable and effective treatments that can further enhance their quality of life, extend their longevity, and ultimately lead to a cure for the disease. These research efforts include gene editing to correct the LMNA mutation, the use of RNA therapeutics to inhibit progerin mRNA production, and other innovative approaches.

A sustained commitment to providing continuous funding and resources for research initiatives is vital to effectively address HGPS, as it creates more opportunities for conducting clinical trials and developing evidence-based interventions. Collaborative efforts among researchers, healthcare professionals, patient advocacy groups, and affected families are also crucial in sharing knowledge and accelerating progress. These combined efforts will help toward reaching a cure and improving the quality of life for individuals suffering from the disease.?

Conclusion?

HGPS is a rare and complex genetic disorder that causes premature ageing in children. Despite its severity, there is currently no cure for the disease, but treatments are available to manage symptoms and improve quality of life. It is important to support affected individuals and their families and raise awareness of this often misunderstood condition. With continued research and support, there is hope that one day a cure for HGPS will be found, allowing affected children to live full and healthy lives. Should you need additional information or help regarding HGPS, you can visit https://www.progeriaresearch.org.?