Hutchinson-Gilford Progeria 

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

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.

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.

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.

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.

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.

 

Presentation

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[14] :

  • 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 levels

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 Examination

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.[15] The composite appearance of the characteristic facies and parieto-occipital alopecia creates 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.[16] The skeletal anomalies are best characterized as a skeletal dysplasia and are thought to be related to microvascular insufficiency and extracellular matrix abnormalities.[16]

Skin and hair findings are as follows:

  • Sclerodermatous skin changes involving the trunk and extremities (see the images below) 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 as depicted in the images below.[17]

  • 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.

    Sclerodermatous skin changes in Hutchinson-Gilford 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.
    Sclerodermatous skin changes in Hutchinson-Gilford Sclerodermatous skin changes in Hutchinson-Gilford progeria syndrome. This 12-month-old infant has indurated, shiny skin with dyspigmentation.

Characteristic facies are as follows (see the image shown below):

  • Protruding ears with absent lobes

  • Beaked nose

  • Thin lips with centrofacial cyanosis

  • Prominent eyes

  • Frontal and parietal bossing with pseudohydrocephaly

  • Large anterior fontanel

    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.

Oral and craniofacial anomalies are as follows:

  • Midface hypoplasia with micrognathia

  • Dental anomalies, including hypodontia and delayed dentition[18]

  • Palatal anomalies[18]

  • Stiff auricular cartilage, small or absent lobules, shortened ear canals[19]

Musculoskeletal abnormalities are as follows:

  • 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 as depicted in the image below

  • Pyriform (pear-shaped) thorax with short, dystrophic clavicles

  • Bilateral hip dislocations

  • Avascular necrosis of the femoral head

    Enlarged joints, mild flexion contractures, and sc Enlarged joints, mild flexion contractures, and sclerodermatous skin changes are seen in this 12-month-old infant with Hutchinson-Gilford progeria syndrome.

Other reported anomalies are as follows:

  • 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 a farnesylated, truncated prelamin A (progerin).[20]

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 also play a role in regulating gene expression, DNA synthesis, and DNA repair.[21]

The most common LMNA mutation and the one associated with classical HGPS involves a C-->T transition at nucleotide 1824 (G608G). Note the following:

  • 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.[22, 23]

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.

Somatic mosaicism for two different LMNA mutations, c.1968+2T>A and c.1968+2T>C, has been described in a child with an intermediate phenotype.[24]

A transgenic mouse model for HGPS has been created by introducing a splicing defect into intron 9 of the mouse LMNA gene.[25] 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.[26, 27, 28] 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.[29]

Complications

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

 

DDx

Diagnostic Considerations

Werner syndrome (pangeria) findings are as follows:

  • 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) findings are as follows:

  • 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 findings are as follows:

  • 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 findings are as follows:

  • 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 findings are as follows:

  • "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 ParanĂ¡ 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 findings are as follows[30] :

  • 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 findings are as follows:

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

Berardinelli-Seip syndrome findings are as follows:

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

Donahue syndrome (leprechaunism) findings are as follows:

  • 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 findings are as follows:

  • 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 findings are as follows:

  • 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 findings are as follows:

  • 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

Differential Diagnoses

 

Workup

Laboratory 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 Hutchinson-Gilford progeria syndrome (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 begin to manifest within the first or second year of life and most commonly involve the skull, thorax, long bones, and phalanges.[16, 31] Typical findings are as follows:

  • Generalized osteopenia

  • Acroosteolysis (distal bone resorption) of the phalanges and distal clavicles

  • Pseudoarthrosis of the distal clavicle

  • "Fish-mouth" vertebral bodies

  • Coxa valga and hip dysplasia

  • Attenuated cortical bone

  • Widened metaphyses, epiphyseal overgrowth, and narrow diaphyses

  • Avascular necrosis of the femoral head

  • Focal concave cortical defects at or near to the insertion of a major muscle group

  • Dystrophic calcification, typically distal to the tufts of the fingers

  • Normal bone age

Use of CT and MRI has identified a spectrum of craniofacial structural bone and soft tissue abnormalities.[32] Common craniofacial abnormalities seen in progeria include the following:

  • J-shaped sella

  • Increased calvarial vascular markings

  • Abnormal mandibular condyles

  • Hypoplastic articular eminences

  • Small zygomatic arches

  • Prominent parotid glands

  • Optic nerve kinking

Brain magnetic resonance angiography may identify cerebrovascular occlusive disease. Features of a distinct vasculopathy may be seen, including intracranial steno-occlusive arterial lesions, basal cistern collateral vessels, and slow compensatory collateral flow over the cerebral convexities; vertebral artery stenosis with stenosis and calcification of both the cervical internal and common carotid arteries; and high percentage of both early symptomatic and clinically silent infarcts.[33]

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

Approach Considerations

Pharmacologic approaches to the treatment of Hutchinson-Gilford progeria syndrome (HGPS) may involve attempts to reduce the expression or accumulation of progerin and promote autophagy.

Medical Care

To date, there is no approved therapy for HGPS.

In vitro, exposure of cultured HGPS fibroblasts to rapamycin, a macrolide antibiotic that has been shown to regulate aging-related cellular pathways, and its analog temsirolimus, has been demonstrated to prevent or reverse nuclear blebbing, retard cellular senescence, enhance autophagic degradation of progerin, and delay the development of cellular senescence, suggesting that it may be a useful therapy for children with progeria.[34, 35, 36, 37, 38] The addition of all-trans retinoic acid to low-dose rapamycin reduces the expression of progerin and prelamin A in cultured fibroblasts and suggests an additional pharmacologic treatment for progeria.[39]

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.

The use of growth hormone has been used to decrease catabolic demands and augment weight gain and linear growth in a small number of patients with progeria.[40]

Sulforaphane, an antioxidant derived from cruciferous vegetables, has been demonstrated to stimulate proteasome activity and autophagy in cultured HGPS fibroblasts, to enhance progerin clearance by autophagy, and to restore a normal cellular phenotype.[41]

In vitro studies also suggest a possible role for the use of farnesyltransferase inhibitors (FTIs) in HGPS.[42] 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, although it remains to be determined whether use of FTIs also has an effect on the abnormalities seen in HGPS that result from loss of normal lamin A function.

In vivo studies using FTIs in transgenic mouse models have demonstrated encouraging results with regards to prevention of the cardiovascular complications seen in progeria[43] as well as reversal of the cutaneous manifestations[44] and overall improvement in many of the phenotypic features of progeria, including increased longevity.[45, 46]

Treatment of transgenic mice expressing progerin in the epidermis with FTI-276, a farnesyltransferase inhibitor, or a combination of pravastatin, a lipid-lowering agent, and zoledronic acid, an agent used to increase bone mineral density, has been shown to reverse the morphological nuclear abnormalities that are seen in HGPS.[47]

Results from a clinical trial of lonafarnib, an FTI, in progeria have indicated that treatment with lonafarnib may improve weight gain, increase bone mineral density, reduce vascular stiffness, and result in improved sensorineural hearing in patients with progeria.[48] Lonafarnib treatment has also been shown to reduce the frequency of clinical stroke, headaches, and seizures.[49]

Results from a clinical trial that combined use of lonafarnib with two additional protein farnesylation inhibitors, pravastatin and zoledronic acid, demonstrated increased bone mineral density without any additional cardiovascular benefit as compared with lonafarnib monotherapy.[50]

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 also produced encouraging results. Transfection of an exon 11 antisense oligonucleotide reduced lamin A expression in wild-type mice and progerin expression in an HGPS mouse model.[51] 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.

In vitro, use of rapamycin, a macrolide antibiotic, and its analog temsirolimus, has been demonstrated to prevent nuclear blebbing, enhance autophagic degradation of progerin, and delay the development of cellular senescence, suggesting that it may be a useful therapy for children with progeria.[34, 35, 36, 37, 38]

Patients, families, and physicians may obtain further information, including opportunities for possible enrollment in clinical trials, through the Progeria Research Foundation.

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.

 

Guidelines

Guidelines Summary

There are currently no peer-reviewed clinical guidelines for the management of Hutchinson-Gilford progeria.

The Progeria Research Foundation published The Progeria Handbook for parents and clinicians in 2010. It is available through the Progeria Research Foundation.

 

Medication

Medication Summary

Medications may be prescribed to treat the associated complications, including arteriosclerosis, and are beyond the scope of this review.