Hutchinson-Gilford Progeria

Updated: Feb 08, 2017
  • Author: Kara N Shah, MD, PhD; Chief Editor: Dirk M Elston, MD  more...
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Overview

Practice Essentials

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare hereditary disease that affects the skin, musculoskeletal system, and vasculature. HGPS is characterized by signs of premature aging most notable in the skin, cardiovascular system, and musculoskeletal systems. HGPS is caused by mutations in LMNA that result in the production of an abnormal form of lamin A termed progerin.

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Background

The term progeria is derived from the Greek word geras, meaning old age. Significant morbidity and mortality result from accelerated atherosclerosis of the carotid and coronary arteries, leading to premature death during the first or second decade of life. HGPS is considered a segmental aging syndrome, as affected patients do not manifest all of the typical features of aging, such as increased incidence of cancer and neurocognitive decline.

See the image shown below depicting Hutchinson-Gilford progeria syndrome in an infant.

Early Hutchinson-Gilford progeria syndrome. Note t Early Hutchinson-Gilford progeria syndrome. Note the alopecia, prominent scalp veins, and frontal bossing apparent in this 12-month-old infant with Hutchinson-Gilford progeria syndrome. Midface hypoplasia and micrognathia are less apparent.

In 1886, Hutchinson [1] described the first patient with HGPS, a 6-year-old boy whose overall appearance was that of an old man. [2] In 1887, Gilford [3] described a second patient with similar clinical findings; in 1904, [4, 5] he published a series of photographs depicting the clinical manifestations of progeria at different ages. To date, approximately 100 patients with HGPS have been described in the literature.

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Pathophysiology

Patients with Hutchinson-Gilford progeria syndrome (HGPS) develop clinical features of accelerated aging, including accelerated atherosclerosis of the cerebral and coronary arteries. Unlike arteriosclerosis in the general population, however, in progeria, the only lipid abnormality is decreased high-density lipoprotein cholesterol levels. Interestingly, patients with HGPS do not develop other disease processes associated with aging, such as increased tumor formation, cataract development, or senility. In this sense, HGPS is considered a segmental progeroid syndrome in that it does not recapitulate all of the characteristic phenomena of aging.

Patients with HGPS also develop loss of subcutaneous fat and muscle, skin atrophy, osteoporosis, arthritis, poor growth, and alopecia. There is evidence that patients with HGPS also manifest features of skeletal dysplasia with abnormalities in bone structural geometry and skeletal strength. [6] Extensive lipofuscin deposition, a marker for aging, is extensively distributed in patients with HGPS. Affected organs include the kidneys, brain, adrenal glands, liver, testes, and heart.

These clinical manifestations occur as the result of defects in processing and function of lamin A, an intermediate filament protein component of the nuclear membrane that regulates a diverse number of cellular functions, including nuclear morphology and integrity, DNA repair, regulation of gene expression, and telomere stability; the end result of these defects is genomic instability, decreased cell proliferation, and premature cell senescence and death. [7] The abnormal protein, progerin, represents a truncated form of the lamin A precursor prelamin A and results from mutations in LMNA. It is interesting to note that mutations in LMNA are associated not only with premature aging syndromes (HPGS, restrictive dermopathy, and atypical Werner syndrome), but also with several muscular dystrophies, lipodystrophic syndromes, and mandibuloacral dysplasia.

Marked loss of vascular smooth muscle cells within the great vessels, arteries, and arterioles associated with sclerosis and fibrosis is a consistent finding in patients with HGPS. [8] Preferential accumulation of progerin in vascular endothelial and smooth muscle cells has been observed. [9]

Clinically, children with progeria develop atherosclerosis, arteriosclerosis of small vessels, and prominent adventitial fibrosis with increasing deposition of progerin within coronary arteries. [10] The accelerated vascular stiffening and peripheral vascular occlusive disease that develop resemble the cardiovascular features of normal aging and atheroscleroisis. [11] Together with the clinical observations of accelerated and often fatal arteriosclerosis, these findings suggest that the effects of progerin on the cardiovascular system are a major contributor to the pathophysiology of HGPS.

Interestingly, spontaneous accumulation of progerin has been observed in cultured fibroblasts from normally aged individuals in combination with similar nuclear defects, further reinforcing the theory that HGPS results, at least in part, from accelerated production and accumulation of progerin. [12] It is important to note that the pathophysiology of HGPS results from the presence of progerin and a dominant-negative effect on lamin A function and not simply from the absence of normal lamin A.

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Epidemiology

International frequency

HGPS is a rare disease with a reported prevalence of 1 in 8 million births. The true prevalence, however, has been suggested to be closer to 1 in 4 million births because many cases likely go undiagnosed or are misdiagnosed. The incidence in the Netherlands over the last century was 1:4,000,000. Approximately 100 cases of HGPS have been reported in the literature.

Race

White persons represent 97% of reported patients. The reason for this racial disparity is unknown.

Sex

HGPS has a slight male predilection; the male-to-female ratio is 1.5:1.

Age

Clinical manifestations of HGPS may not be recognized or apparent at birth, although many affected children present with sclerodermatous skin changes. Delayed recognition of the characteristic facial features along with the cutaneous and musculoskeletal manifestations may not occur until age 6-12 months or older, when the development of failure to thrive engenders a more thorough evaluation.

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Prognosis

The average life expectancy for a patient with HGPS is 13 years, with an age range of 7-27 years.

Data from the largest cohort of HGPS patients indicated a mean survival of 14.6 years, with an increased mean survival of 1.6 years in patients treated with a protein farnesylation inhibitor after a median follow-up of 5.3 years from treatment initiation. [13]

Morbidity and mortality in persons with HGPS occur primarily as a result of atherosclerosis of the coronary and cerebrovascular arteries, with at least 90% of patient deaths directly related to complications of progressive atherosclerosis. Cardiovascular complications include myocardial infarction and congestive heart failure. Interstitial fibrosis, diffuse myocardial fibrosis, and calcification of the mitral and aortic valves may occur. Cerebrovascular complications occurring as a result of cerebrovascular infarction include hemiplegia, subdural hematoma, and seizures. Other causes of morbidity and mortality include marasmus, loss of mobility, and inanition.

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