Progeria, Hutchinson Gilford

Progeria, Hutchinson Gilford

National Organization for Rare Disorders, Inc.

Important

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Synonyms

  • HGPS
  • Hutchinson-Gilford progeria syndrome
  • Hutchinson-Gilford syndrome
  • premature aging syndrome
  • progeria
  • progeria of childhood

Disorder Subdivisions

  • None

General Discussion

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.

Symptoms

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 midportion of the face (midfacial cyanosis); and/or a "sculptured" nose. Profound, progressive growth retardation usually becomes evident by approximately 24 months of age, resulting in short stature and weight that remains extremely low for height. According to reports in the medical literature, 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.



In children with the disorder, 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 cases, 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. In affected children, 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). In many cases, affected children 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 withHGPS 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. In addition, in many affected children, abnormal fibrous tissue progressively forms 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.



According to reports in the medical literature, affected children as young as five years 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). In individuals with HGPS progressive arteriosclerosis and associated cardiovascular abnormalities may result in potentially life-threatening complications during childhood, adolescence, or young adulthood.

Causes

Researchers have determined that the cause of HGPS is 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 abnomal lamin A protein produced in HGPS is called progerin.



Progeria 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 chances of having a child with progeria are 1 in 4 – 8 million. But for parents who have already had a child with progeria, the chances of it happening again to those parents 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 and impaired functioning of cells, ultimately resulting in aging. Certain enzymes (known as 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 indicate that reduced activity of certain enzymes may play a role in causing accelerated aging in individuals withHGPS. 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 those 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 such findings.



Studies have revealed that progerin is produced at much lower levels by healthy individuals, and it builds normally in the coronary arteries over a lifetime as people age. This finding supports the possibility that progerin is a contributor to the risk of atherosclerosis in the general population, and merits examination as a potential new trait to help predict heart-disease risk. Thus researchers have confirmed the link between normal aging, heart disease and progeria, so finding the cure will help not only these special children, but perhaps also those who suffer from heart attacks, strokes and other aging-related conditions.

Affected Populations

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). As of March 2011, approximately 170 cases have been reported. Estimates indicate that HGPS affects one infant in approximately eight million births, thus at any given time, there are approximately 200 children living with progeria worldwide. Two sets of affected identical twins have been reported in the literature.

Standard Therapies

Diagnosis

HGPS is usually diagnosed during the second year of life or later, when progeroid features begin to be noticeable. The diagnosis is based upon a thorough clinical evaluation, characteristic physical findings, a careful patient history, and diagnostic genetic testing, which is available through The Progeria Research Foundation (www.progeriaresearch.org ). More rarely, the disorder may be suspected at birth based upon recognition of certain suspicious findings (e.g., "scleroderma-like" skin over the buttocks, thighs, lower abdomen; midfacial cyanosis; "sculptured" nose).



Specialized imaging tests may be conducted to confirm or characterize certain skeletal abnormalities potentially associated with the disorder, such as degenerative changes (osteolysis) of certain bones of the fingers (terminal phalanges) and/or the hip socket (acetabulum). In addition, thorough cardiac evaluations and ongoing monitoring may also be performed (e.g., clinical examinations, X-ray studies, specialized cardiac tests) to assess associated cardiovascular abnormalities and determine appropriate disease management.



Treatment

The treatment of HGPS is directed toward the specific symptoms that are apparent in each individual. Disorder 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.

Investigational Therapies

Researchers at Children's Hospital Boston are conducting progeria clinical drug trials with farnesyltransferase inhibitor (FTI) and additional drugs (statins and bisphosphinates) to determine if they are effective treatments for progeria.



Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.



For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:



Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com

References

TEXTBOOKS

Gordon, LB. The Premature Aging Syndrome Hutchinson-Gilford Progeria: Insights into Normal Aging in: Brocklehurst's Textbook of Geriatric Medicine and Gerontology (Seventh Edition 2010:66-72).



Brown WT. Progeria. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:724-5.



Jones KL, ed. Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA: W. B. Saunders Co: 1997:138-41.



Behrman RE, ed. Nelson Textbook of Pediatrics, 15th ed. Philadelphia, PA: W.B. Saunders Company; 1996:1996-97.



Gorlin RJ, et al., eds. Syndromes of the Head and Neck, 3rd ed. New York, NY: Oxford University Press; 1990:482-85.



Buyce ML, ed. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications; For: The Center for Birth Defects Information Services Inc; 1990:1411-14.



JOURNAL ARTICLES

Olive M, et al. Cardiovascular pathology in hutchinson-gilford progeria: correlation with the vascular pathology of aging. Arterioscler Thromb Vasc Biol. 2010 Nov;30(11):2301-9.



Capell BC, et al. Inhibiting farnesylation of progerin prevents characteristic nuclear blebbing of Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci USA. 2005;102:12879-84.



Toth JI, et al. Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with progeriod syndromes. Proc Natl Acad Sci USA. 2005;102:12873-8.



Eriksson M, et al. Recurrent de novo mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature. 2003;423:293-98.



Ackerman J, Gilbert-Barness E. Hutchinson-Gilford progeria syndrome: a pathological study. Pediatr Pathol Mol Med. 2002;21:1-13.



Yan T, et al. Altered levels of primary antioxidant enzymes in progeria skin fibroblasts. Biochem Biophys Res Commun. 1999;257:163-7.



Brown WT. Progeria: a human-disease model of accelerated aging. Am J Clin Nutr. 1992;55:1222S-24S.



Sweeney KH, et al. Hyaluronic acid in progeria and the aged phenotype? Gerontology. 1992;38:139-52.



Yu QX, et al. Progeria: report of a case and review of the literature. J Oral Pathol Med. 1991;20:86-88.



Gillar PJ, et al. Progressive early dermatologic changes in Hutchinson-Gilford progeria syndrome. Pediatr Dermatol. 1991;8:199-206.



Brown WT, et al., Hutchinson-Gilford progeria syndrome: clinical, chromosomal and metabolic abnormalities. Am J Hum Genet. 1990;47:A50.



Dyck JG, et al. Management of coronary artery disease in Hutchinson-Gilford syndrome. J Pediat. 1987;111:407-10.



Brown WT. Human mutations affecting aging--a review. Mech Aging Dev. 1979;9:325-36.



DeBusk FL. The Hutchinson-Gilford progeria syndrome. J Pediat. 1972;80:697-724.



Gilford H. Progeria, a form of senilism. Practitioner. 1904;73:188-217.



Gilford H. Ateleiosis and progeria: continuous youth and premature old age. Brit Med J. 1904;2:914-18.



Gilford H. On a condition of a mixed premature and immature development. Trans Med Chir Soc Edinb. 1897;8017-45.



Hutchinson J. Congenital absence of hair and mammary glands with atrophic condition of the skin and its appendages in a boy whose mother had been almost wholly bald from alopecia areata from the age of six. Trans Med Chir Soc Edinb. 1886



FROM THE INTERNET

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Hutchinson-Gilford Progeria Syndrome; HGPS. Entry No: 176670. Last Updated October 19, 2010. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed April19, 2011.



Hutchinson-Gilford Progeria Syndrome?Frequently Asked Questions. The Progeria Research Foundation.Updated December 2010. http://findtheother150.org/assets/files/PRF%20FAQ%20Dec%202010.pdf. Accessed April 19, 2011.

Resources

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