Progeria · What Is It, Causes, Clinical Presentation, and More

Progeria is an extremely rare genetic disorder that causes rapid aging in children and severe failure-to-thrive. Children with progeria often appear healthy at birth but begin to show signs of accelerated aging within the first 1-2 years of life. They usually have characteristic facial features associated with old age, such as loss of hair and wrinkled skin, as well as several conditions that affect multiple organs, including the skeletal system, skin, blood vessels, and heart. Children with progeria typically experience early death in the second decade of life due to cardiovascular disease.  

The term “progeria” usually refers to the classic progeria syndrome termed Hutchinson Gilford Progeria Syndrome (HGPS); which is different from atypical progeria syndromes that have partial overlapping manifestations but vary in onset, severity, and survival. Several other rare disorders are also characterized by premature aging and are therefore often termed “progeroid syndromes” (e.g., Wiedemann-Rautenstrauch syndrome).  

Hutchinson-Gilford progeria syndrome is caused by an autosomal dominant mutation in a gene known as Lamin A (LMNA) found on chromosome 1. LMNA has a role in the production of the lamin A protein, which is a structural protein important for the stabilization of the nuclear membrane, the envelope around the cell’s nucleus.  

The genetic mutation leads to the formation of progerin, a mutative lamin A protein that builds up in cells and makes the nuclear envelope unstable. In turn, this affects how cells divide and function, leading to premature cellular aging and damage. Since progeria is related to an aberrant lamin A protein, HGPS can also be referred to as a laminopathy, along with at least 12 other diseases (e.g., Charcot-Marie-Tooth disease). HGPS is usually not inherited; it is almost always caused by a random mutation that happens in a sperm or egg before conception. 

The atypical progeria syndromes are also related to pathogenic variants of the LMNA gene. However, these are caused by various mutations in a different part of the gene, rather than the classical variant that is present in HGPS. 

Progeria is characterized by premature aging and severe failure to thrive, which leads to further complications and eventual premature death.  

Children with progeria usually have a characteristic appearance due to progerin's toxic effects on connective tissue and bone growth. They usually have visible scalp veins, a large forehead, prominent eyes and a beak-shaped nose, along with a small jawbone that is positioned further back than usual. The scalp is usually hairless, and skin has an aged-looking appearance. They can have delayed tooth eruption and crowded or misaligned teeth due to the smaller jaw. 

In terms of growth and development, children with progeria tend to have poor weight gain throughout infancy regardless of adequate nutrition and intake. This results in a short stature and little to no subcutaneous fat and reduced muscle mass. Additionally, many children with progeria have hip dysplasia or dislocations, which affect how their legs align. They also develop joint contractures, meaning the joints become stiff and can't fully extend. These changes force them to adopt a compensatory posture to stay balanced and mobile typically referred to as “horse-riding stance.”  

Regardless of the musculoskeletal anomalies, children with progeria typically have normal motor skills and cognitive development during the first years of life, and intelligence is usually not affected. Even though progerin doesn’t directly affect the brain, strokes are common due to cardiovascular disease.  

In fact, the cardiovascular system is the most serious and life-limiting aspect of progeria. The accumulation of damaged cells contributes to chronic inflammation and especially damage to blood vessels, leading to early-onset atherosclerosis. This results in increased risk of hypertension, heart attacks, and stroke. Many children with progeria die from heart disease, usually between the ages of 13 and 15. 

HGPS is diagnosed through medical history and physical examination. If typical manifestations are identified and there is suspicion for HGPS, genetic testing to identify the pathogenic variant in the LMNA gene can be conducted to confirm diagnosis.   

Once progeria is confirmed, additional tests may be performed to assess the child’s overall health and organ function. These may include blood pressure monitoring, an echocardiogram and ECG to check heart function and look for signs of early heart disease, and X-rays or bone scans to evaluate bone density and skeletal abnormalities. 

The treatment of progeria is mainly supportive, aiming to provide optimal nutrition, monitor the progression of the disease, and treat complications as needed. For example, hip dislocations and joint contractures can be conservatively managed with physical and occupational therapy.  

While there is no cure for progeria, a new oral medication called Lonafarnib was approved by the Food and Drug Administration (FDA) in 2020 for use in the United States and it is now approved in Europe as well. Normally, progerin sticks to the nuclear envelope via a farnesyl group. Lonafarnib is a farnesyltransferase inhibitor; it works by blocking this attachment, reducing damage to the nucleus. The results from clinical trials showed varying improvements to lifespan and improved cardiovascular health, largely depending on the length of treatment administration.