HUTCHINSON-GILFORD PROGERIA SYNDROME

A Case Study presented to the Faculty and Staff of

IMMACULATE HEART OF MARY ACADEMY

in partial fulfillment of the requirements in

GENERAL BIOLOGY 2

Yongco, Laurence Neil L.

Penamante, Philip Marlouie
Lariba, Nickryll Julliene
Gamale, Christein Roger
Grade 12 – BENEVOLENCE

September 2018
 ABSTRACT

The Hutchinson-Gilford syndrome or progeria is a rare autosomal dominant syndrome

characterized by premature aging and involvement of internal systems, such as the circulatory
and locomotor. The diagnosis is essentially clinical and the manifestations become more evident
from the first year of life. Long term outcome data from Progeria Research Foundation clinical
trials have demonstrated an increase in survival in recent years. Even though new trials are
ongoing, the recognition of this syndrome is essential to prevent cardiovascular and
cerebrovascular complications. The diagnosis of Hutchinson-Gilford syndrome was suspected
owing to clinical characteristics. The diagnosis was confirmed by genetic testing. A mutation
c.1824C> T in exon 11 of the LMNA gene was detected. Lonafarnib protocol study is a farnesyl
transferase inhibitor that prevents the production of progeria and slows cardiovascular and
neurological complications of the syndrome. Progeria trials and research may also contribute to
new drug developments related to prevention of aging and atherosclerosis in the near future.
 INTRODUCTION

Hutchinson-Gilford progeria syndrome (HGPS) or simply Progeria is an extremely rare

but devastating disorder characterized by dwarfism and premature aging. It occurs sporadically
with a reported incidence of one in eight million and male predominance with M:F ratio of 1.5:1
and a strong racial susceptibility for Caucasians who represent 97% of patients. Those born with
the syndrome typically live up to the teens and maximum up to 20 years.

The pattern of inheritance is uncertain, though both autosomal dominant and autosomal
recessive modes have been proposed. Recent genetic advances have identified LMNA as a
causative gene of HGPS. LMNA encodes laminins A and C which are the main components of
intermediate filamentous lamina, function as a structural support, and are essential for DNA
replication and mRNA transcription. Though the clinical presentation is typical, conventional
radiological and biochemical investigations help in confirming the diagnosis. We present a case
of progeria which showed classic physical and radiological changes of HGPS.

It became popular due to a movie about it acted by famous Indian actor Mr. Amitab
Bachchan. The word Progeria is derived from a Greek word Pro which means premature and
geria which means old age (Carvalho et.al., 2016).

. Children with progeria usually have a normal appearance in early infancy. At

approximately nine to 24 months of age, affected children begin to experience profound growth
delays, resulting in short stature and low weight. They also develop a distinctive facial
appearance characterized by a disproportionately small face in comparison to the head; an
underdeveloped jaw (micrognathia); malformation and crowding of the teeth; abnormally
prominent eyes; a small nose; prominent eyes and a subtle blueness around the mouth. In
addition, by the second year of life, the scalp hair, eyebrows, and eyelashes are lost (alopecia),
and the scalp hair may be replaced by small, downy, white or blond hairs. Additional
characteristic features include generalized atherosclerosis, cardiovascular disease and stroke, hip
dislocations, unusually prominent veins of the scalp, loss of the layer of fat beneath the skin
(subcutaneous adipose tissue), defects of the nails, joint stiffness, skeletal defects, and/or other
abnormalities. According to reports in the medical literature, individuals with HGPS develop
premature, widespread thickening and loss of elasticity of artery walls (arteriosclerosis), which
result in life-threatening complications during childhood, adolescence, or early adulthood.
Children with progeria die of heart disease (atherosclerosis) at an average age of 13 years, with a
range of about eight to 21 years. As with any person suffering from heart disease, the common
events as heart disease advances for children with progeria can include high blood pressure,
strokes, angina (chest pain due to poor blood flow to the heart itself), enlarged heart, and heart
failure, all conditions associated with aging.

OBJECTIVES:

 To discuss and educate the people about the extremely devastating genetic disorder
Hutchinson-Gilford progeria syndrome.

 To know the diseases or conditions Hutchinson-Gilford progeria syndrome will bring to

the patient.

 To identify what specific ways we can address and treat Hutchinson-Gilford progeria
syndrome.

PROBLEMS:

 What is Hutchinson-Gilford progeria syndrome?

 What are the symptoms and signs for Hutchinson-Gilford progeria syndrome?

 What causes Hutchinson-Gilford progeria syndrome?

  How rare is Hutchinson-Gilford progeria syndrome?

 What are related disorders that comes with Hutchinson-Gilford progeria syndrome?

 What is the diagnosis and treatment for Hutchinson-Gilford progeria syndrome?

DISCUSSIONS

Hutchinson-Gilford Progeria Syndrome

Hutchinson-Gilford progeria syndrome is a genetic condition which causes the great, fast
process and appearance of aging during childhood. Children with this disorder look normal at
birth and early infancy, but however grows slowly compared to other children and fail to gain
weight at the expected degree. They develop a facial appearance which include prominent eyes,
thin nose with a beaked tip, thin lips, a small chin, and protruding ears. This condition syndrome
also causes hair loss (alopecia), aged-looking skin, joint abnormalities, and a loss of fat under the
skin (subcutaneous fat), but it does not affect the development of motor skills like sitting,
standing and walking

Persons with this disorder may experience hardening of the arteries (arteriosclerosis)
from childhood. With this condition, they are at high risks of having heart attacks and or stroke
early, and may worsen at time goes by. Such case is life-threatening to the affected persons.

Signs & Symptoms

Infants with HGPS may possess unusual findings such as unusually taut, shiny, hardened
skin over the buttocks, upper legs, and lower abdomen; bluish discoloration of the kin and
mucous membranes within the mid-portion of the face (midfacial cyanosis); and or a
“sculptured” nose. By 24 months, deep and increasing slow growth is usually evident which
results in a short height and low weight, inappropriate for the height. Reports say that affected
children at 10 years of age typically possess a height that of a three year old child.
 At 2 years old, the facial bones and the lower becomes underdeveloped. The face is not
proportional and is smaller than the head, and bones of the front and the sides of the skull are
usually noticeable. Affected children usually have additional facial features such as pointed nose,
unusual prominent eyes, small ears, and thin lips. The development anomalies of the dental
features are also present, such as the delayed growth of the primary and secondary teeth;
irregularly formed, discolored, and or absent teeth; and unusual increased incidence of tooth
decay. And, additional abnormal smallness of the jaw may result in dental crowding.

Children who possess the disorder, the scalp hair becomes sparse and typically lost by
two years of age. The hair may be replaced by fine, downy, white or blond hairs that, in some
cases, may remain for the entire life. Also, the eyebrows and eyelashes may be lost early.

HGPS has also skin abnormalities. As discussed above, newborns with the disorder may
have “scleroderma-like” skin changes over the buttocks, thighs, and lower abdomen. During
infancy the fat beneath the skin is almost completely lost, and veins in certain areas of the body
such as the scalp and thighs become abnormally noticeable. Children with the disorder acquires
skin that is aged in appearance with areas that are unusually thin, dry, and wrinkled, unusually
shiny and taut. Brownish skin blotches may tend to develop with increasing age over sun-
exposed areas of the skin. There will be also defects in the finger nails and toe nails that are
yellowish, thin, brittle, curved, and or absent.

Distinctive skeletal defects is evident in HGPS. This brings in the delayed closure of the
“soft spot” at the front of the skull, an abnormally thin “dome-like” portion of the skull, and
absence of certain air-filled cavities within the skull that open into the nose. Many cases also
include that affected children have short, thin collarbones, narrow shoulders, thin ribs, and a
narrow or “pear-shaped” chest with a prominent abdomen. Long bones of the arms and legs may
appear unusually thin and fragile and is prone to fractures.

Children with HGPS skeletal abnormalities include degenerative changes that may affect
the collar bones; bones of the ends of the fingers causing the fingers to appear unusally short and
tapered; and or the hips socket. Worsening changes of the hip socket may result in a hip
deformity in which is characterized by abnormal increase in the angle of the thigh bone, hip pain,
hip discoloration. In many affected children, abnormal fibrous tissue progressively forms around
certain joints, such as those in the hands, feet, knees, elbows, and spine, causing unusual
prominence, stiffness, and limited movement of affected joints. Caused by the stiffness of knees,
progressive hip deformity and other associated musculoskeletal abnormalities, children with the
disorder tend to have a characteristic, widely based, “horse-riding stance” and a shuffling manner
of walking. There is also an association of generalized loss of bone density which may cause to
repeated fractures following minor trauma.

HGPS may also include symptoms such as distinctive, high-pitched voice, absence of
sexual maturation, hearing impairment, and other abnormalities.

Reports of medicinal literature, affected children as young as five may acquire

widespread thickening and loss of elasticity of artery walls. This changes may be most evident in
particular blood vessels such as arteries that transport oxygen-rich blood to heart muscle and
major artery of the body.

Findings also include enlargement of the heart and abnormal heart sounds due to altered
blood flow through valves or chambers of the heart. Chest pains due to deficient oxygen supply
to the heart, obstructed blood flow within the blood vessels of the brain, increasing failure of the
heart to effectively pump blood, and localized heat muscle loss, is caused by the progressive
arteriosclerosis in childhood or adolescence. Individuals with HGPS progressive arteriosclerosis
and associated cardiovascular abnormalities may result in potentially life-threatening
complications during childhood, adolescence, or young adulthood

Causes

Researchers discovered that HGPS is a single-letter misspelling gene on chromosome 1

that codes for lamin A, a protein that is a key components of the membrane surrounding the
cells’ nucleus. This abnormal lanin is called progerin

Progeria is not hereditary, the gene change is almost always a chance occurrence that is
very rare. Children with other types of progeriod syndromes which are not HGPS may have
diseases that are passed down to their families. In parents who had never had a child with
progeria has a chance of having a child with the disorder 1 in 4-8 million. But those who already
have a child with progeria, chances is much higher – about 2-3%. This case is due to mosaicism,
where a parent has the genetic mutation for progeria in a small proportion of their cells, but does
not have progeria.

The specific underlying cause of the accelerated aging associated with HGPS is not yet known.
Many researchers suggest that the abnormal aging process is due to cumulative cellular damage
resulting from ongoing chemical (metabolic) processes within bodily cells. According to this
theory, certain compounds called free radicals are produced during chemical reactions in the
body. The increasing accumulation of free radicals within bodily tissues is thought to eventually
cause damage to and impaired functioning of cells, ultimately resulting in aging. Certain
enzymes (known as antioxidant enzymes) are believed to play a role in keeping the aging process
“in check” by promoting the elimination of damaging free radicals. Enzymes are proteins
produced by cells that accelerate the rate of chemical reactions in the body. Some researchers
indicate that reduced activity of certain enzymes may play a role in causing accelerated aging in
individuals with HGPS. In one study, skin cells (fibroblasts) obtained from individuals with
progeria were compared with skin cells from individuals without the disease. In the fibroblasts of
those with progeria, the activity levels of certain primary antioxidant enzymes (e.g., gluthathione
peroxidase [GPx], catalase [CAT]) were significantly lower than the levels present in healthy
fibroblasts. Further research is necessary to determine the implications of such findings.

Studies have revealed that progerin is produced at much lower levels by healthy individuals, and
it builds normally in the coronary arteries over a lifetime as people age. This finding supports the
possibility that progerin is a contributor to the risk of atherosclerosis in the general population,
and merits examination as a potential new trait to help predict heart-disease risk. Thus
researchers have confirmed the link between normal aging, heart disease and progeria, so finding
the cure will help not only these special children, but perhaps also those who suffer from heart
attacks, strokes and other aging-related conditions.

Affected Populations

HGPS, a rare disorder, affects males and females equally, and all races equally. This was
originally described in the medicinal literature in 1886 (J. Hutchinson) and 1897 (H. Gilford). In
January 2014, approximately 200 cases was reported. This report indicate the estimates the
prevalence of HGPS is approximately one in eighteen million, thus at any given time, there are
approximately 350 – 400 children throughout the world with progeria. Two sets of identical
twins have been reported in the literature.

Related Disorders

Symptoms of the following disorders can be similar to those of HGPS Comparisons may
be useful for a differential diagnosis:

Hallermann-Streiff syndrome is a rare genetic disorder that is primarily characterized by

distinctive malformations of the skull and facial (craniofacial) region; sparse hair
(hypotrichosis); eye (ocular) abnormalities; dental defects; degenerative skin changes (atrophy),
particularly in the scalp and nasal regions; and/or short stature (i.e., dwarfism). Characteristic
craniofacial features include a short, broad head (brachycephaly) with an unusually prominent
forehead and/or sides of the skull (frontal and/or parietal bossing); a small, underdeveloped
lower jaw (hypoplastic mandible); a narrow, highly arched roof of the mouth (palate); and a thin,
pinched, tapering nose. Many affected individuals also have clouding of the lenses of the eyes at
birth (congenital cataracts); unusually small eyes (microphthalmia); and/or other ocular
abnormalities. Dental defects may include the presence of certain teeth at birth (natal teeth) and
absence (hypodontia or partial adontia), malformation, and/or improper alignment of teeth. In
almost all cases, Hallermann-Streiff syndrome has appeared to occur randomly for unknown
reasons (sporadically) and may be the result of a new change to genetic material (mutation). (For
more information on this disorder, choose “Hallermann-Streiff” as your search term in the Rare
Disease Database.)

Gottron’s syndrome (acrogeria) is amild and inherited form of premature aging which
include abnormal small hands and feet with thin and delicate skin. Children with this disorder
may appeae older than other children. There is an unusual thin and parchment- like on the hands
and feet, which its smallness appear abnormal into adulthood.

Wiedemann-Rautenstrauch syndrome (WRS), also known as neonatal progeroid

syndrome, is a very rare genetic disorder characterized by an aged appearance at birth (old man
look) growth delays before and after birth (prenatal and postnatal growth retardation); and
deficiency or absence of the layer of fat under the skin (subcutaneous lipoatrophy). It is
anticipated that most individuals with WRS have decreased life expectancy. There are few
individuals who have lived well in to the teens and afew still live in their 20s. WRS is inherited
as an autosomal recessive trait, as several pairs of siblings have been reported in families with
unaffected parents. (For more information on this disorder, choose “Wiedemann-Rautenstrauch”
as your search term in the Rare Disease Database.)

De Barsy syndrome is a rare disorder that is inherited as an autosomal recessive genetic

trait. The main characteristics include degeneration of the elastic tissue in the skin (cutis laxa),
involuntary movements of the arms and legs (athetosis), cloudy corneas of the eyes, large
prominent ears, and loss of muscle tone. Other symptoms may include unusual flexibility of the
small joints, a forehead that protrudes outward (frontal bossing), and/or short stature. The loss of
elasticity of the skin leads to an aged wrinkled appearance. Newborn children with this disorder
may look like newborns withHGPS. (For more information on this disorder, choose “De Barsy”
as your search term in the Rare Disease Database.)

Progeroid syndrome with Ehlers-Danlos features is an extremely rare genetic disorder

characterized in newborns by a “progeria-like” (progeroid) appearance. The skin may be
wrinkled leading to an aged appearance. Other symptoms include sparse eyebrows, scanty
eyelashes, multiple birthmarks, and extremely fragile skin which bruises easily. Some children
with this disorder may have low-set prominent ears, a receding chin, and/or irregular teeth.

Diagnosis

HGPS is usually diagnosed during the second year of life or later, when progeroid features begin
to be noticeable. The diagnosis is based upon a thorough clinical evaluation, characteristic
physical findings, a careful patient history, and diagnostic genetic testing, which is available
through The Progeria Research Foundation. More rarely, the disorder may be suspected at birth
based upon recognition of certain suspicious findings (e.g., "scleroderma-like" skin over the
buttocks, thighs, lower abdomen; midfacial cyanosis; "sculptured" nose).

Specialized imaging tests may be conducted to confirm or characterize certain skeletal

abnormalities potentially associated with the disorder, such as degenerative changes (osteolysis)
of certain bones of the fingers (terminal phalanges) and/or the hip socket (acetabulum). In
addition, thorough cardiac evaluations and ongoing monitoring may also be performed (e.g.,
clinical examinations, X-ray studies, specialized cardiac tests) to assess associated cardiovascular
abnormalities and determine appropriate disease management.

Treatment

In September 2012, results of the first-ever clinical drug trial for children with progeria showed
that LOnafarnib, a typr of farnesyltransferase inhibitor (FTI), which is developed for cancer, is
found to be effective for progeria. Improvements include our ways: gaining weight, better
hearing, improved bone structure and or increased flexibility of blood vessel.

Other than lonafarnib, which is not FDA-approved and thus only available through clinical drug
trials, the treatment of HGPS is directed toward the specific symptoms that are apparent in each
individual. Disorder management may require the coordinated efforts of a team of specialists
who may need to systematically and comprehensively plan an affected child's treatment. Such
specialists may include pediatricians; physicians who diagnose and treat disorders of the
skeleton, muscles, joints, and other related tissues (orthopedists); physicians who diagnose and
treat abnormalities of the heart and its major blood vessels; physical therapists; and/or other
health care professionals.

Special therapies for individuals are indicative and supportive. For example, in people
with chest pain due to deficient oxygen supply to the heart muscle, treatment may include certain
medication that may help to minimize or manage such symptoms.
 RECOMMENDATIONS

Below are the following recommendations that we have formulated in this case study: