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AUTHOR AND EDITOR INFORMATION

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Author: Kara N Shah, MD, PhD, Fellow, Department of Pediatrics, Section of Dermatology, Children's Hospital of Philadelphia

Kara N Shah is a member of the following medical societies: American Academy of Dermatology and American Academy of Pediatrics

Coauthor(s): Hans-Wilhelm Kaiser, MD, Professor, Department of Dermatology, University of Bonn, Germany; Julia Hanfland, MD, Consulting Staff, Department of Dermatology, University of Bonn, Germany

Editors: Mark A Crowe, MD, Assistant Clinical Instructor, Department of Medicine, Division of Dermatology, University of Washington School of Medicine; David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Director, Division of Dermatology, Scott and White Clinic; Director Dermatology Residency Training Program, Scott and White Clinic; Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School; Glen H Crawford, MD, Assistant Clinical Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, The Pennsylvania Hospital; Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center

Author and Editor Disclosure

Synonyms and related keywords: Hutchinson-Gilford progeria syndrome, HGPS, HGP syndrome, premature senility syndrome, progeria of childhood, progeria, aging syndrome, premature aging, progeria syndrome, progeria

INTRODUCTION

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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 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 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. 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 male predilection; the male-to-female ratio is 1.5:1.

Age

Clinical manifestations of HGPS may not be apparent at birth. 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

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History

  • Evidence of 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
    • Incomplete sexual maturation
    • Generalized osteoporosis and pathologic fractures
    • Feeding difficulties
    • Delayed dentition, anodontia, hypodontia, or crowding of teeth
  • 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 include abnormalities of the skin and hair in conjunction with characteristic facial features and skeletal abnormalities. The composite appearance of the characteristic facies and parieto-occipital alopecia create a "plucked-bird" appearance. Evidence of growth failure manifests within the first year of life. 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
    • 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
    • Hyperplastic scars
    • Hypoplastic nipples

Causes

  • The syndrome 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.
    • 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.
      • 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.
    • Recently, 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.5 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.6, 7, 8 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 changes observed in cultured fibroblasts from patients with progeria that remained unchallenged include reduced mitotic activity, DNA-synthesis, and cloning efficiency and a reduced capacity for DNA repair in cultured progeria fibroblasts after gamma irradiation.


DIFFERENTIALS

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Eosinophilic Fasciitis
Sclerema Neonatorum
Systemic Sclerosis

Other Problems to be Considered

Werner syndrome (pangeria)

Onset age of 15-30 years
Prematurely aged appearance
High-pitched voice
Beak-shaped nose
Sclerodermatous skin
Immature sexual development
Cataracts
Hypogonadism
Arteriosclerosis: Complications of arteriosclerosis reduce life expectancy to the fifth decade.
RECQL2 (a DNA helicase gene) mutations

Acrogeria (Gottron type)

Onset occurring up to age 6 years
Premature aging of extremities
Cutaneous atrophy and subcutaneous wasting of the face and extremities
Hair unaffected
No atherosclerosis or systemic disease

Rothmund-Thomson syndrome

Onset age of 3-6 months
Cataracts
Poikilodermatous skin changes
Premature graying of the hair and/or alopecia
Increased photosensitivity
Short stature
Microcephaly
Hypogonadism
RECQL4 (a DNA helicase) mutations

Cockayne syndrome

Onset during second year of life
Marked loss of subcutaneous fat
Growth failure
Increased photosensitivity
Ocular abnormalities (eg, optic atrophy, pigmentary retinopathy)
Microcephaly
Ataxia and progressive mental deterioration
Disproportionally large hands and feet
Protruding ears
Sensorineural hearing loss

Seckel syndrome

"Bird-head" facies
Dwarfism
Trident hands
Skeletal defects
Hypodontia
Hypersplenism
Premature graying

Stiff skin syndrome

Diffuse progressive hardening of the skin, usually starting in the gluteal region, beginning at birth or early infancy
Joint contractures
Hypertrichosis
Hyperpigmentation
Increased cutaneous (but not systemic) mucopolysaccharide levels
In the autosomal recessive Paraná type, severe growth retardation and respiratory insufficiency leading to early death

Congenital fascial dystrophy

Diffuse, progressive hardening of the skin, usually starting in the gluteal region, beginning at birth or early infancy
Joint contractures
No systemic disease
Histologically, abnormally thickened fascia along with giant amianthoidlike fibrils and myofibroblasts

Restrictive dermopathy

Profound intrauterine growth retardation
Severe arthrogryposis (joint contractures)
Diffuse skin hardening
Pulmonary hypoplasia
Characteristic facies
Lethal in neonatal period
LMNA or ZMPSTE24 mutations

Wiedemann-Rautenstrauch syndrome

Onset at birth
Pseudohydrocephalus with wide sutures
Triangular facies
Aged appearance
Growth retardation
Generalized lack of subcutaneous fat
Prominent scalp veins
Sparse hair

DeBarsy syndrome

Onset at birth
Aged appearance
Joint laxity
Loose, wrinkled skin
Hypotonia
Developmental delay
Ocular abnormalities (eg, strabismus, cataracts, myopia)

Berardinelli-Seip syndrome

Onset at birth
Decreased subcutaneous fat/lipodystrophy
Pseudohypertrophy of muscles
Acanthosis nigricans
Hyperinsulinemia
Acromegaloid appearance
Hypertriglyceridemia

Donahue syndrome (leprechaunism)

Onset at birth
Elfin facies
Hyperinsulinemia
Failure to thrive
Hypertrichosis
Acanthosis nigricans
Decreased subcutaneous fat
Loose skin
Prominent nipples
Insulin receptor gene mutation

GAPO (growth retardation, alopecia, pseudoanodontia, optic atrophy) syndrome

Onset age of 1-2 years
Growth retardation
Alopecia
Pseudoanodontia
Optic atrophy
Craniofacial dysmorphism
Coarse facies
Aged appearance
Joint laxity
Loose skin

Hallermann-Streiff syndrome

Onset at birth
Brachycephaly
Mandibular hypoplasia
Beaked nose
Alopecia
Cutaneous atrophy of the face and scalp
Ocular abnormalities (eg, cataracts, nystagmus, microphthalmos)
Dental anomalies

Familial mandibuloacral dysplasia

Onset age of 3-5 years
Alopecia
Beaked nose
Premature loss of teeth
Acroosteolysis
Dysplastic clavicles
Atrophy of extremity skin
Mandibular hypoplasia
Delayed cranial suture closure
LMNA mutations


WORKUP

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Lab Studies

  • Abnormalities in serum lipid levels are limited to low high-density lipoprotein levels, which are associated with atherosclerotic disease. Serum low-density lipoprotein and total cholesterol levels are normal in patients with HGPS.
  • Elevated levels of hyaluronic acid excretion are seen in the urine of patients with HGPS but are not diagnostic. The significance is unknown.

Imaging Studies

  • Radiography findings usually manifest within the first or second year of life and most commonly involve the skull, thorax, long bones, and phalanges.
    • Diffuse osteopenia
    • Acroosteolysis (distal bone resorption) of the phalanges and distal clavicles
    • "Fish-mouth" vertebral bodies
    • Coxa valga
    • Attenuated cortical bone
    • Widened metaphyses
    • Normal bone age
  • Brain magnetic resonance angiography may identify cerebrovascular occlusive disease.

Other Tests

  • Serial ECG and echocardiography should be performed to monitor for coronary artery disease and congestive heart failure.

Histologic Findings

Skin biopsy specimens from firm, sclerotic areas reveal the characteristics of scleroderma.

In the early stages, the epidermis appears moderately acanthotic with some effacement of the rete ridges. Thickened collagen bundles may be seen in the dermis. Progressive deposition of thickened, homogenized collagen that extends into the subcutaneous tissue is observed. In the upper dermis, a mild perivascular infiltrate may be observed. The amount of acid mucopolysaccharides is increased.

At later stages, the subcutaneous fat is greatly reduced, except for some sparse fat lobules surrounded by connective tissue. Hyalinized dermal collagen is prominent. Blood vessels exhibit a moderate thickening of the muscle wall with a narrowing of the vascular lumen. Hair follicles may appear atrophic.


TREATMENT

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Medical Care

To date, no effective therapy is available.

  • Careful monitoring for cardiovascular and cerebrovascular disease is essential. The use of low-dose aspirin is recommended as prophylaxis against cardiovascular and cerebrovascular atherosclerotic disease.
  • Physical and occupational therapy can help to maintain physical activity and an active lifestyle. The use of hydrotherapy may be particularly effective in improving joint mobility and minimizing symptoms of arthritis.
  • Infants with HGPS may exhibit poor feeding. Provision of adequate nutritional intake may require placement of a gastrostomy tube for supplemental enteral feeding. In older children, the daily consumption of high-energy supplements is recommended, along with careful monitoring of growth and nutrition.
  • In vitro studies suggest a possible role for the use of farnesyltransferase inhibitors (FTIs) in HGPS. FTIs appear to promote the release of the mutant prelamin A (preprogerin) from the nuclear membrane, allowing it to be correctly incorporated into the nuclear lamina, thus correcting the structural and functional nuclear defects. FTIs are currently under evaluation in phase 3 clinical trials as anticancer agents.
  • Preliminary in vitro studies using transfection of modified oligonucleotides that target the cryptic splice site that occurs in patients with the common 1824C-->T mutation have produced encouraging results. By eliminating the production of the mutant LMNA mRNA and protein, normal nuclear morphology is restored, with resultant normalization of heterochromatin structure and gene expression. These nascent studies provide early support for the rationalization of genetic therapy for HGPS patients.
  • Patients, families, and physicians may obtain further information, including opportunities for possible enrollment in clinical trials, through the Progeria Research Foundation. In addition, the US National Institutes of Health are currently conducting a clinical trial (NCT00094393) in which the clinical consequences of HGPS are monitored as part of ongoing research to develop new treatments for the disease. Recruitment information is available through ClinicalTrials.gov.

Consultations

Appropriate care for children with HGPS requires coordinated care from several specialists.

  • Pediatric cardiologists provide regular assessment of cardiovascular status, including monitoring and treatment for early atherogenic cardiac disease.
  • Physical and occupational therapists can develop individualized physical therapy programs to help to maintain physical activity, coordination, and flexibility.
  • Dermatologists and/or geneticists may be the first specialists to evaluate an infant with suspected HGPS and can perform diagnostic testing, including genetic mutation analysis and skin biopsies, as needed.
  • Pediatric gastroenterologists, feeding therapists, and nutritionists can aid in diagnosing and treating feeding disorders and failure to thrive.
  • Pediatric dentists with experience in treating children with dental anomalies can be helpful. Routine fluoride supplementation should be provided to minimize the risks of dental caries. Regular, gentle dental care minimizes the development of periodontal disease.

Diet

Infants and children with HGPS may experience feeding difficulties and failure to thrive. The use of age-appropriate nutritional supplements is recommended.

Activity

Children with HGPS do not require activity restrictions. With adequate supervision, most children are able to experience a wide range of physical activities.


MEDICATION

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Medication is only helpful in treating the associated symptoms.


FOLLOW-UP

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Complications

  • Death due to cardiovascular abnormalities occurs in approximately 75% of patients. Other causes of death mentioned in the literature include stroke, marasmus, inanition, seizures, and accidental head trauma.

Prognosis

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


MISCELLANEOUS

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Medical/Legal Pitfalls

  • Failure to make the correct diagnosis and differentiate HGPS from other similar syndromes, including other progeroid syndromes
  • Failure to provide appropriate monitoring for atherosclerotic cardiovascular and cerebrovascular disease


MULTIMEDIA

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Media file 1:  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.
Click to see larger pictureClick to see detailView Full Size Image
Media type:  Photo

Media file 2:  Sclerodermatous skin changes in Hutchinson-Gilford progeria syndrome. This 12-month-old infant with Hutchinson-Gilford progeria syndrome has indurated, shiny skin with dyspigmentation.
Click to see larger pictureClick to see detailView Full Size Image
Media type:  Photo

Media file 3:  Sclerodermatous skin changes in Hutchinson-Gilford progeria syndrome. This 12-month-old infant has indurated, shiny skin with dyspigmentation.
Click to see larger pictureClick to see detailView Full Size Image
Media type:  Photo

Media file 4:  Enlarged joints, mild flexion contractures, and sclerodermatous skin changes are seen in this 12-month-old infant with Hutchinson-Gilford progeria syndrome.
Click to see larger pictureClick to see detailView Full Size Image
Media type:  Photo

Media file 5:  Sclerodermatous skin changes in Hutchinson-Gilford progeria syndrome. This 12-month-old infant with Hutchinson-Gilford progeria syndrome has indurated, shiny skin and mild joint contractures involving the extremities and trunk.
Click to see larger pictureClick to see detailView Full Size Image
Media type:  Photo


REFERENCES

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Hutchinson-Gilford Progeria excerpt

Article Last Updated: Jan 24, 2007