Hutchinson-Gilford Progeria Clinical Presentation

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

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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
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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]

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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.

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