eMedicine Specialties > Dermatology > Pediatric Diseases

Hutchinson-Gilford Progeria

Author: Kara N Shah, MD, PhD, Assistant Professor, Department of Pediatrics and Dermatology, University of Pennsylvania School of Medicine; Attending Physician, Section of Dermatology, Division of General Pediatrics, Children's Hospital of Philadelphia
Coauthor(s): Hans-Wilhelm Kaiser, MD, Professor, Department of Dermatology, University of Bonn, Germany; Julia Hanfland, MD, Consulting Staff, Department of Dermatology and Allergology, University of Bonn, Germany
Contributor Information and Disclosures

Updated: Feb 27, 2009

Introduction

Background

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. 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.

In 1886, Hutchinson1 described the first patient with HGPS, a 6-year-old boy whose overall appearance was that of an old man. In 1887, Gilford2 described a second patient with similar clinical findings; in 1904,3,4 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.

Pathophysiology

Patients with Hutchinson-Gilford progeria syndrome (HGPS) develop 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.

Patients with HGPS also develop other clinical signs of accelerated aging, including loss of subcutaneous fat and muscle, skin atrophy, osteoporosis, arthritis, poor growth, and alopecia. 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.

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.

Frequency

International

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.

Mortality/Morbidity

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

  • 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.

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.

Clinical

History

  • Evidence of Hutchinson-Gilford progeria syndrome (HGPS) begins within the first 2 years of life. At birth, infants usually appear healthy, although sclerodermatous skin changes have been noted in some patients. Typically, the onset of the disease occurs at age 6-12 months, when skin changes and alopecia are first noted and when the infant fails to gain weight. The following are other suggestive findings:
    • High-pitched voice
    • Short stature and low weight for height, with prenatal onset of growth failure
    • Incomplete sexual maturation
    • Generalized osteoporosis and pathologic fractures
    • Feeding difficulties
    • Delayed dentition, anodontia, hypodontia, or crowding of teeth
    • Low-frequency conductive hearing loss
    • Hypertension
    • Prolonged prothrombin time, elevated platelet counts, and elevated serum phosphorus levels5
  • Emotionally, patients with HGPS share the same feelings as age-matched healthy persons with regard to expressing proper mood and affect. Patients with HGPS are keenly aware of their different appearance and remain reserved in the company of strangers; in the presence of friends, they display affection and good social interaction.
  • Intelligence is normal.

Physical

The characteristic clinical findings of Hutchinson-Gilford progeria syndrome (HGPS) include abnormalities of the skin and hair in conjunction with characteristic facial features and skeletal abnormalities.6 The composite appearance of the characteristic facies and parieto-occipital alopecia create a "plucked-bird" appearance. Evidence of significant growth failure manifests within the first 1-2 years of life and prenatal growth failure is often apparent.7 Delayed, abnormal dentition is also common.

  • Skin and hair
    • Sclerodermatous skin changes involving the trunk and extremities but sparing the face: These are usually present within the first 6-12 months of life, although they may be present at birth. The skin changes manifest as indurated, shiny, inelastic skin.
    • Prominent scalp veins
    • Generalized lipodystrophy with loose, aged-appearing skin: Areas of skin may appear loose, wrinkled, and aged because of the loss of subcutaneous fat, particularly over the hands and feet.
    • Progressive frecklelike hyperpigmentation in sun-exposed areas
    • Hair loss: Scalp hair and eyelashes are progressively lost, resulting in baldness with only a few vellus hairs remaining.
  • Characteristic facies
    • Protruding ears with absent lobes
    • Beaked nose
    • Thin lips with centrofacial cyanosis
    • Prominent eyes
    • Frontal and parietal bossing with pseudohydrocephaly
    • Midface hypoplasia with micrognathia
    • Large anterior fontanel
  • Musculoskeletal abnormalities
    • Thin limbs with prominent joints
    • Joint contractures and coxa valga with mild flexion of the knees resulting in a wide gait and "horse-riding" stance
    • Pyriform (pear-shaped) thorax with short, dystrophic clavicles
    • Bilateral hip dislocations
  • Other reported anomalies
    • Dystrophic nails
    • Hypertrophic scars
    • Hypoplastic nipples

Causes

  • Hutchinson-Gilford progeria syndrome (HGPS) is related to aberrant processing of the nuclear envelope protein lamin A and accumulation of farnesylated prelamin A
  • Autosomal dominant mutations in the LMNA gene, located on band 1q21.1-1q21.3, are responsible for most cases of HGPS. De novo mutations associated with advanced paternal age are responsible for most cases, although maternal transmission of a mutant LMNA gene from an asymptomatic mother who manifested somatic and gonadal mosaicism has also been reported. In addition, autosomal recessive transmission has also been suggested to account for the reported development of HGPS in several sets of siblings born to unaffected parents.
    • The LMNA genes encodes the nuclear A-type lamins, which are type V intermediate filament proteins that localize to the cell nucleus and form the nuclear lamina, a structure that supports the nuclear envelope. They are important in maintaining nuclear stability and organizing nuclear chromatin. The nuclear lamins may also play a role in regulating gene expression, DNA synthesis, and DNA repair.8
    • The most common LMNA mutation involves a C-->T transition at nucleotide 1824 (G608G).
      • This substitution results in the activation of a cryptic splice donor site in exon 11, which results in a 150-base pair deletion and a truncated lamin A protein, called progerin.
      • The abnormal progerin protein acts in a dominant-negative manner to prevent the normal assembly of nuclear lamins into the nuclear lamina.
      • After translation, the mutant preprogerin protein undergoes normal farnesylation of a CAAX tetrapeptide motif located at the carboxyterminus.
      • The farnesylated preprogerin protein is then incorporated into the nuclear membrane. However, the mutant, truncated protein lacks an important posttranslational processing signal required for cleavage of the preprogerin protein at the carboxyterminus. This cleavage is required for the release of prelamin A from the nuclear membrane, thus allowing its incorporation into the nuclear lamina. The abnormal progerin protein forms insoluble cytoplasmic aggregates.
      • As a result of the absence of lamin A in the nuclear lamina, the cell nuclei from HGPS patients display abnormal nuclear blebbing and aberrant nuclear shapes. Abnormal chromosome segregation and delayed onset and progression of mitosis have also been demonstrated.9,10
    • The presence of the homozygous missense mutation G1626C (K542N) in LMNA was demonstrated in 5 siblings born to asymptomatic, consanguineous carrier parents. This study confirms that autosomal recessive inheritance of HGPS can also occur.
  • A transgenic mouse model for HGPS has been created by introducing a splicing defect into intron 9 of the mouse LMNA gene.11 Transgenic mice display many of the features of HGPS, including loss of subcutaneous fat, decreased bone density, growth failure, craniofacial deformities, skeletal abnormalities, and early death.
  • Using microarray analyses, 3 recent studies.12,13,14 compared the gene expression profiles of cultured fibroblasts from patients with progeria with those of healthy people of various ages. In general, changes in gene activity detected in older patients correlated with changes in gene activity in progeria patients.
    • Of the genes expressed differentially in progeria patients, several that help control mitosis were down-regulated. Many genes that control cell division and DNA or RNA synthesis and processing were also shown to be down-regulated in progeria patients; many of these changes are also seen with normal aging. Some of these changes were postulated to lead to genetic instability and a variety of disturbances in gene function.
    • Changes were also seen in the expression of many genes involved in collagen remodeling and the formation of the extracellular matrix. In general, the changes favored excess extracellular matrix deposition, which may lead to the characteristic changes seen in the skin and the vasculature in progeria patients. Expression of transforming growth factor-beta, a factor that regulates tissue homeostasis and whose sustained expression is responsible for tissue fibrosis, is highly up-regulated in patients with progeria.
    • The expression of several transcription factors, including many involved in musculoskeletal development, were also decreased in progeria patients. Expression of MEOX/GAX, a negative regulator of cell proliferation in mesodermal tissue, is elevated almost 30-fold in patients with HGPS, suggesting a contributory role in the development of the musculoskeletal abnormalities seen in HGPS.
  • A characteristic finding in persons with progeria is an increase in hyaluronic acid excretion. In addition to persons with progeria, it is only detected in those with Werner syndrome, a disease characterized by a later onset of premature aging that occurs during the second decade of life.
    • Usually, hyaluronic acid and other glycosaminoglycan production increases during the fifth to seventh decades of life. Possibly, the increase in hyaluronic acid is a normal feature of advancing age. Fibroblasts from patients with progeria show a 3-fold increase in total glycosaminoglycan production and, in particular, hyaluronic acid production, compared with age-matched control groups. This increase results from an abnormality in degradation and is not caused by increased synthesis.
    • Data from embryonic development suggest that changes in the level of hyaluronic acid are extremely important for morphological development. Experiments performed in chick embryos have demonstrated a correlation between cell differentiation and hyaluronic acid degradation. Hyaluronic acid is also necessary for the morphologic development of blood vessels in chick embryos. A reduction or absence of blood vessels is noted in regions of high hyaluronic acid levels. The decreased density of vasculature, sclerodermatous changes in the skin, and the high prevalence of cardiovascular disease present in persons with progeria may be induced by increased hyaluronic acid levels. Increased hyaluronic acid levels may also promote calcification of blood vessels, thus contributing to arteriosclerosis.
  • In the past, studies of the link between progeria and aging (among other topics) have investigated the role of fibroblast life span.
    • Cells from older donors exhibit a reduced number of cell divisions in comparison to younger donor cells. The reduction of life span in cultured fibroblasts derived from patients with progeria has revealed inconsistent results. A significant reduction in fibroblast life span has been claimed in some studies but has been questioned in later investigations. A recent thorough study indicates the life span of fibroblasts in culture is independent of donor age.
    • Further abnormalities observed in cultured fibroblasts from patients with progeria  include reduced mitotic activity, DNA synthesis, and cloning efficiency and a reduced capacity for DNA repair in cultured progeria fibroblasts after gamma irradiation. Mutant fibroblasts have been shown to demonstrate impaired DNA damage checkpoint signaling, which results in increased DNA double-strand breaks.15

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References
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Further Reading

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Keywords

Hutchinson-Gilford progeria, Hutchinson-Gilford progeria syndrome, HGPS, HGP syndrome, premature senility syndrome, progeria of childhood, progeria, aging syndrome, premature aging, progeria syndrome, progeria

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Contributor Information and Disclosures

Author

Kara N Shah, MD, PhD, Assistant Professor, Department of Pediatrics and Dermatology, University of Pennsylvania School of Medicine; Attending Physician, Section of Dermatology, Division of General Pediatrics, Children's Hospital of Philadelphia
Kara N Shah, MD, PhD is a member of the following medical societies: American Academy of Dermatology, American Academy of Pediatrics, and Society for Pediatric Dermatology
Disclosure: Nothing to disclose.

Coauthor(s)

Hans-Wilhelm Kaiser, MD, Professor, Department of Dermatology, University of Bonn, Germany
Disclosure: Nothing to disclose.

Julia Hanfland, MD, Consulting Staff, Department of Dermatology and Allergology, University of Bonn, Germany
Disclosure: Nothing to disclose.

Medical Editor

Mark A Crowe, MD, Assistant Clinical Instructor, Department of Medicine, Division of Dermatology, University of Washington School of Medicine
Mark A Crowe, MD is a member of the following medical societies: American Academy of Dermatology and North American Clinical Dermatologic Society
Disclosure: Nothing to disclose.

Pharmacy Editor

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Managing Editor

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

CME Editor

Glen H Crawford, MD, Assistant Clinical Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, The Pennsylvania Hospital
Glen H Crawford, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Phi Beta Kappa, and Society of USAF Flight Surgeons
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

 
 
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