Progeria

Progeria is an extremely rare genetic disorder characterized by advanced aging and severe failure-to-thrive. A child with progeria typically has characteristic facial features such as alopecia (i.e., baldness) and several conditions that can affect multiple organs, including the skeleton, skin, blood vessels, and heart. Those with progeria typically experience early death in the second decade of life. 

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 genetic mutation leads to formation of progerin, a mutative lamin A protein. Moreover, this genetic variant leads to a permanent farnesylation (i.e., a type of post-translational modification) of progerin, anchoring the progerin to the nuclear envelope and disrupting the nuclear membrane; this causes genomic instability. 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).

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 signs and symptoms affecting multiple organ systems that present in the first years of life. The hallmark of the syndrome is premature aging with a severe failure-to-thrive, which leads to further complications and eventual premature death.

Furthermore, HGPS is characterized by typical facial features, including prominent and visible scalp veins; loss of eyebrows; prominent eyes; beak-shaped nose; undersized mandible, which is placed in an abnormally posterior position (i.e., micrognathia and retrognathia); and thin lips that have a bluish discoloration (i.e., circumoral cyanosis). 

Additionally, children with progeria usually develop problems with growth as well as abnormalities in the musculoskeletal, audiologic, ophthalmic, dermatological, cardiovascular, and neurological systems. Cognitive development and intellectual ability, on the other hand, are generally unaffected. 

In terms of growth and development, children with progeria tend to have a hard time thriving due to poor weight gain regardless of adequate nutrition and intake. This results in a short stature and loss of subcutaneous fat. Additionally, those with progeria tend to lack sexual maturation. 

Children with progeria may have delayed closure of the fontanelles. Their limbs tend to be thin and joints are commonly swollen and stiff. Hip dislocations, contractures, dystrophy in the hands, and distal phalangeal osteolysis (i.e., destruction of the bone tissue in the most distal bones of the toes and fingers) are also typical. The thorax of individuals with progeria is commonly thin (described as pear-shaped), and their clavicles are often short and dystrophic as well. Furthermore, children with progeria often stand in a particular manner, referred to as “horse-riding stance.” 

Specific dental findings characterize children with progeria, including delayed tooth eruption, hypodontia (i.e. absence of some teeth), double rows of teeth, dysmorphic teeth, an ogival palatal arch, and ankyloglossia (i.e., tongue-tie). Individuals may also have a high-pitched voice. 

Affected children may also present with otologic abnormalities, such as stiff auricular cartilages, small or absent ear lobes, and shortened ear canals. They may also experience low-frequency conductive hearing loss. Additionally, vision impairments—including hyperopia (i.e., far-sightedness), nocturnal lagophthalmos (i.e., inability to close the eyelids during sleep), and corneal dryness—are also prevalent. 

Dermatological findings are quite common, including dystrophy of fingernails and toenails; alopecia (i.e., partial or complete hair loss); and skin changes, like atrophy, dryness, or wrinkled skin. Interestingly, the skin may exhibit heterogeneity with some areas that appear overly tight or sclerotic, especially over the abdomen or upper thighs; while others may be loose with outpouching. Hypo- or hyperpigmented areas with mottling or dimpling are also common.

Lastly, cardiovascular conditions are usually the underlying cause of the shortened lifespan that signalizes progeria. Children with progeria tend to have severe accelerated atherosclerosis within their blood vessels. This can occur despite typical risk factors for atherosclerosis, such as hypercholesterolemia and chronic inflammation. Myocardial infarctions or, in some cases, stroke can thereby occur and lead to a premature death.

Hutchinson-Gilford Progeria Syndrome 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.

The treatment of progeria is mainly supportive, aiming to provide optimal nutrition, monitor the progression of the disease (e.g., electrocardiography, echocardiography, and carotid duplex to track the atherosclerosis), 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. It is now approved in Europe as well. This medication works as a farnesyltransferase inhibitor (i.e., it inhibits the farnesylation of progerin), aimed at reducing the risk of mortality in genetically confirmed HGPS. The results from clinical trials elucidated varying improvements to lifespan, largely depending on the length of treatment administration. 

Hutchinson-Gilford Progeria Syndrome (HGPS) is an exceedingly rare disorder caused by a genetic mutation in the LMNA gene, leading to an abnormal form of the Lamin A protein called progerin. It is characterized by premature aging, failure-to-thrive, typical skeletal and facial features, and numerous abnormalities in various organ systems. Children with progeria usually develop accelerated atherosclerosis that can result in a heart attack or stroke, leading to untimely death. Progeria diagnosis is based upon the characteristic findings and a genetic confirmation of the presence of the causative gene variant. Management is mainly supportive, including persistent monitoring and physical therapy as needed. Currently, there is a new medication named Lonafarnib that is indicated for the increase in lifespan of genetically confirmed individuals with HGPS.