About hutchinson-gilford progeria syndrome (hgps)
What is hutchinson-gilford progeria syndrome (hgps)?
Progeria, or Hutchinson-Gilford progeria syndrome (HGPS), is a rare, fatal, genetic condition of childhood with striking features resembling premature aging. Children with progeria usually have a normal appearance in early infancy. At approximately nine to 24 months of age, affected children begin to experience profound growth delays, resulting in short stature and low weight. They also develop a distinctive facial appearance characterized by a disproportionately small face in comparison to the head; an underdeveloped jaw (micrognathia); malformation and crowding of the teeth; abnormally prominent eyes; a small nose; prominent eyes and a subtle blueness around the mouth. In addition, by the second year of life, the scalp hair, eyebrows, and eyelashes are lost (alopecia), and the scalp hair may be replaced by small, downy, white or blond hairs. Additional characteristic features include generalized atherosclerosis, cardiovascular disease and stroke, hip dislocations, unusually prominent veins of the scalp, loss of the layer of fat beneath the skin (subcutaneous adipose tissue), defects of the nails, joint stiffness, skeletal defects, and/or other abnormalities. According to reports in the medical literature, individuals with HGPS develop premature, widespread thickening and loss of elasticity of artery walls (arteriosclerosis), which result in life-threatening complications during childhood, adolescence, or early adulthood. Children with progeria die of heart disease (atherosclerosis) at an average age of 13 years, with a range of about eight to 21 years. As with any person suffering from heart disease, the common events as heart disease advances for children with progeria can include high blood pressure, strokes, angina (chest pain due to poor blood flow to the heart itself), enlarged heart, and heart failure, all conditions associated with aging.
Progeria is caused by a mutation of the gene LMNA, or lamin A. The lamin A protein, is the scaffolding that holds the nucleus of a cell together. Researchers now believe that the defective lamin A protein, makes the nucleus unstable. That cellular instability appears to lead to the process of premature aging in progeria.
What are the symptoms for hutchinson-gilford progeria syndrome (hgps)?
Newborns with HGPS may have certain suspicious findings present at birth, such as unusually taut, shiny, hardened (i.e., “scleroderma-like”) skin over the buttocks, upper legs, and lower abdomen; bluish discoloration of the skin and mucous membranes within the mid-portion of the face (midfacial cyanosis); and/or a “sculptured” nose. Profound, progressive growth delay usually becomes evident by approximately 24 months of age, resulting in Short stature and weight that remains extremely low for height. Affected children who are 10 years of age typically have a height approximating that of an average three-year-old child.
By the second year of life, there is also underdevelopment (hypoplasia) of the facial bones and the lower jaw (micrognathia). The face appears disproportionately small in comparison to the head, and bones of the front and the sides of the skull (cranium) are unusually prominent (frontal and parietal bossing). Affected children typically have additional, characteristic facial features, including a small, thin, potentially pointed nose; unusually prominent eyes; Small ears with absent lobes; and thin lips. Dental abnormalities may also be present, such as delayed eruption of the primary (deciduous) and secondary (permanent) teeth; irregularly formed, small, discolored, and/or absent teeth; and/or an unusually increased incidence of tooth decay (dental caries). In addition, abnormal smallness of the jaw may result in dental crowding.
The scalp hair becomes sparse and is typically lost (alopecia) by approximately two years of age. Scalp hair may be replaced by fine, downy, white or blond hairs that, in some children, may persist throughout life. In addition, the eyebrows and eyelashes may also be lost during early childhood.
HGPS is also characterized by distinctive skin abnormalities. As discussed above, newborns with the disorder may have “scleroderma-like” skin changes over the buttocks, thighs, and lower abdomen. In addition, beginning in infancy, there is a gradual, almost complete loss of the layer of fat beneath the skin (subcutaneous adipose tissue), and veins in certain areas of the body, particularly over the scalp and thighs, become abnormally prominent. The skin acquires an abnormally aged appearance with areas that are unusually thin, dry, and wrinkled and/or unusually shiny and taut. In addition, brownish skin blotches may tend to develop with increasing age over sun-exposed areas of the skin. Affected children also typically have defects of the nails, such as fingernails and toenails that are yellowish, thin, brittle, curved, and/or absent.
Children with HGPS also have distinctive skeletal defects. These may include delayed closure of the “soft spot” at the front of the skull (anterior fontanelle), an abnormally thin “dome-like” portion of the skull (calvaria), and/or absence of certain air-filled cavities within the skull that open into the nose (paranasal or frontal sinuses). Affected children may also have short, thin collarbones (clavicles); narrow shoulders; thin ribs; and a narrow or “pear-shaped” chest (pyriform thorax) with a prominent abdomen. In addition, the long bones of the arms and legs may appear unusually thin and fragile and be prone to fractures, particularly the bones of the upper arms (humeri).
In many children with HGPS, Skeletal abnormalities include degenerative changes (osteolysis) that may affect the collarbones (clavicles); bones of the ends of the fingers (terminal phalanges), causing the fingers to appear unusually Short and “tapered”; and/or the hip socket (acetabulum). Degenerative changes of the hip socket may result in a hip deformity in which there is an abnormal increase in the angle of the thigh bone (coxa valga), hip Pain and hip dislocation. Many affected children have abnormal fibrous tissue that forms progressively around certain joints (periarticular fibrosis), such as those of the hands, feet, knees, elbows, and spine, causing unusual prominence, stiffness, and limited movement of affected joints. Due to stiffness of the knees, progressive hip deformity (coxa valga), and other associated musculoskeletal abnormalities, children with the disorder tend to have a characteristic, widely based, “horse-riding stance” and a shuffling manner of walking (gait). The disorder is also associated with generalized loss of bone density (osteoporosis), a condition that may cause or contribute to repeated fractures following minor trauma.
Additional symptoms and findings may also be associated with HGPS. These may include a distinctive, high-pitched voice; absence of the breast or nipple; absence of sexual maturation; hearing impairment; and/or other abnormalities.
Affected children as young as five years of age may develop widespread thickening and loss of elasticity of artery walls (arteriosclerosis). Such changes may be most evident in particular blood vessels, such as the arteries that transport oxygen-rich blood to heart muscle (coronary arteries) and the major artery of the body (aorta).
Additional findings may include enlargement of the heart (cardiomegaly) and abnormal heart sounds (i.e., as heard during a physician’s examination with a stethoscope) due to altered blood flow through valves or chambers of the heart (cardiac murmurs). During childhood or adolescence, progressive arteriosclerosis may lead to episodes of Chest Pain due to deficient oxygen supply to heart muscle (anginal attacks); obstructed blood flow within blood vessels of the brain (cerebrovascular occlusion); progressive inability of the heart to effectively pump blood to the lungs and the rest of the body (heart failure); and/or localized loss of heart muscle caused by interruption of its blood supply (myocardial infarction or heart attack). Progressive arteriosclerosis and associated cardiovascular abnormalities may result in potentially life-threatening complications during childhood, adolescence, or young adulthood.
What are the causes for hutchinson-gilford progeria syndrome (hgps)?
HGPS is caused by a single-letter misspelling in a gene on chromosome 1 that codes for lamin A, a protein that is a key component of the membrane surrounding the cell’s nucleus. The abnormal lamin A protein produced in HGPS is called progerin.
HGPS is not usually passed down in families. The gene change is almost always a chance occurrence that is extremely rare. Children with other types of progeroid syndromes which are not HGPS may have diseases that are passed down in families. However, HGPS is due to a sporadic autosomal dominant mutation – sporadic because it is a new change in that family, and dominant because only one copy of the gene needs to be changed in order to have the syndrome. For parents who have never had a child with progeria, the chance of having a child with progeria is 1 in 4 – 8 million. For parents who have already had a child with progeria, the chance of having another affected child is much higher – about 2-3%. This is due to a condition called mosaicism, where a parent has the genetic mutation for progeria in a small proportion of their cells, but does not have progeria.
The specific underlying cause of the accelerated aging associated with HGPS is not yet known. Many researchers suggest that the abnormal aging process is due to cumulative cellular damage resulting from ongoing chemical (metabolic) processes within bodily cells. According to this theory, certain compounds called free radicals are produced during chemical reactions in the body. The increasing accumulation of free radicals within bodily tissues is thought to eventually cause damage to cells and impair functioning of cells, ultimately resulting in aging. Certain enzymes (antioxidant enzymes) are believed to play a role in keeping the aging process “in check” by promoting the elimination of damaging free radicals. Enzymes are proteins produced by cells that accelerate the rate of chemical reactions in the body. Some researchers suspect that reduced activity of certain enzymes may play a role in causing accelerated aging in individuals with HGPS. In one study, skin cells (fibroblasts) obtained from individuals with progeria were compared with skin cells from individuals without the disease. In the fibroblasts of people with progeria, the activity levels of certain primary antioxidant enzymes (e.g., gluthathione peroxidase [GPx], catalase [CAT]) were significantly lower than the levels present in healthy fibroblasts. Further research is necessary to determine the implications of these findings.
Studies have revealed that progerin is produced at much lower levels by healthy individuals, but it builds up in the coronary arteries over a lifetime as people age. This finding supports the theory that progerin is a contributor to the risk of atherosclerosis in the general population, and merits examination as a potential new marker to help predict heart-disease risk. Researchers have confirmed the link between normal aging, heart disease and progeria, so finding a cure for progeria will not only help these special children, but might also help people who suffer from heart attacks, strokes and other aging-related conditions.
What are the treatments for hutchinson-gilford progeria syndrome (hgps)?
In November 2020, the U.S. Food and Drug Administration (FDA) approved Zokinvy (lonafarnib), a type of farnesyltransferase inhibitor (FTI) originally developed to treat cancer, as the first treatment for Hutchinson-Gilford progeria syndrome. Zokinvy is now available by prescription for those with HGPS in the United States. The drug is also available in many other countries through Eiger Biopharmaceutical’s Managed Access Program.
Before this recent approval, children with progeria could receive treatment with Zokinvy only through participation in a clinical trial run through the Progeria Research Foundation at Boston Children’s Hospital in the United States. Zokinvy has been used to treat over 90 progeria patients through four clinical trials since 2007.
In April 2018, analyses of data collected in an observational cohort study supported by the Progeria Research Foundation compared patients treated with Zokinvy to untreated children and young adults. A lower mortality rate was found in the patients who were treated. Previously, in September 2012, the results of the first-ever clinical drug trial for children with progeria showed that Zokinvy was effective for progeria. Every child showed improvement in one or more of four ways: gaining additional weight, better hearing, improved bone structure and/or, most importantly, increased flexibility of blood vessels.
In addition to the use of Zokinvy, the treatment of HGPS is directed toward the specific symptoms that are apparent in each individual. Management may require the coordinated efforts of a team of specialists who may need to systematically and comprehensively plan an affected child’s treatment. Such specialists may include pediatricians; physicians who diagnose and treat disorders of the skeleton, muscles, joints, and other related tissues (orthopedists); physicians who diagnose and treat abnormalities of the heart and its major blood vessels; physical therapists; and/or other health care professionals.
Specific therapies for individuals with HGPS are symptomatic and supportive. For example, in those with episodes of chest pain due to deficient oxygen supply to heart muscle (anginal attacks), treatment may include the use of certain medications that may help to minimize or manage such symptoms.
What are the risk factors for hutchinson-gilford progeria syndrome (hgps)?
HGPS is a rare disorder that appears to affect males and females equally, and all races equally. The disorder was originally described in the medical literature in 1886 (J. Hutchinson) and 1897 (H. Gilford). The prevalence of HGPS is approximately 1 in 20 million, so at any given time, there are approximately 400 children living with progeria worldwide. Two sets of affected identical twins have been reported in the literature.