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Hutchinson-Guilford progeria syndrome
P K Sarkar and R A Shinton
Postgrad. Med. J. 2001;77;312-317
doi:10.1136/pmj.77.907.312
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312 Postgrad Med J 2001;77:312 317
Hutchinson-Guilford progeria syndrome
P K Sarkar, R A Shinton
Progeria is a human disease model of acceler- The exact inheritance of HGPS is not
ated ageing.1 3 The progeria syndrome is a rare known. In the past, it was thought to be an
genetic disorder, first reported in 1886 by autosomal recessive. DeBusk reviewed only
Hutchinson and Guilford in England.4 The three families where more than one member
inheritance pattern, paternal age eVect, and was aVected, consanguinity was uncommon,
lack of consanguinity argue that it is due to a and advanced paternal age was noted.5 These
sporadic dominant mutation. Hutchinson- observations made an autosomal recessive
Guilford progeria syndrome (HGPS) is associ- inheritance very unlikely and favour a sporadic,
ated with several features of premature dominant mutation. Since most cases are due
ageing for example, growth retardation, char- to isolated mutations of a gamete, the familial
acteristic facies, loss of hair, and subcutaneous occurrence is rare.9 11 Some cases may be due
fat, restricted joint mobility, prominent eyes, to germ line mutations, and therefore, parents
and severe premature atherosclerosis.5 The of one aVected child should be counselled that
exact pathophysiology of this syndrome is not the risk of a subsequent aVected child is one in
known. Recent findings in several laboratories 500 for each pregnancy.11
indicate that progeria patients excrete an In Europe, 26 cases of premature ageing
excessive amount of glycosaminoglycan, hy- syndromes (for example, progeria, Werner s
aluronic acid.6 7 syndrome) were reported between 1995 and
1996 by the Eurostat (social and regional
In 1886, Jonathan Hutchinson reported a
case of a 3.5 year old boy who had the appear- statistics and geographical information system
of Europe), Luxembourg-Kirchberg. Progeria
ance of an old man.4 Later, Hastings Guilford
syndrome is coded under  other endocrine
reported a second case with similar features.8
disorders which also include Werner s syn-
The term,  progeria was taken from the Greek
word for old age,  geras ,8 9 originally pro- drome and pineal gland dysfunction according
to the International Classification of Diseases,
posed by Guilford in 1904.
ninth revision (ICD-9) 259.8.12 Life spans of
The interesting clinical features consist of
various premature ageing syndromes are diVer-
craniofacial disproportion, micrognathia,
prominent scalp veins, scalp alopecia, promi- ent, as for example, fifth/sixth decades for
Werner s syndrome, second/third decades for
nent eyes, wrinkled skin, protruding ears, nail
dystrophy, midfacial cyanosis, growth retarda- progeria syndromes and so on.5 13 In Europe,
out of 26 cases of premature ageing syndromes,
tion, and a sculpted nose at birth. DeBusk
eight patients died before the age of 25 years.
observed that patients with progeria syndrome
The authors contacted the OYce for Na-
are typically considered normal infants.5 The
tional Statistics (ONS), UK and Eurostat,
characteristic facies, posture, stiVness of joints,
Luxembourg-Kirchberg regarding progeria
and bone, teeth, and skin changes become
syndrome. Causes of death recorded on the
apparent during the second year of life. The
death certificate were coded by ONS and
necropsies on patients with HGPS revealed
prominent abnormalities in the skin, cardiovas- Eurostat according to the ICD-9.12 There were
only a handful of deaths between 1993 and
cular tissues, and bone.9
1998 in the UK and Europe where ICD-9
In 1972, DeBusk presented case reports of
259.8 was given as the underlying cause of
four patients and reviewed the world literature
death or was mentioned as a contributory
on HGPS. Although these patients develop
cause of death. Progeria syndrome was specifi-
premature atherosclerosis and die of cardiac or
cally mentioned on the death certificate in only
cerebral vascular disease between 7 and 27
five of these cases in the UK.
years of age, many other features associated
with pathological ageing are absent.5
Clinical features
Epidemiology Patients with this condition generally appear
City Hospital NHS
The estimated incidence of HGPS in the USA normal at birth, but by the age 1 or 2 years
Trust, Birmingham,
is one in eight million births, based on the severe growth retardation is usually observed.
UK
number of cases. Brown suggested that only Generally, these children have short stature
P K Sarkar
one half of the aVected patients were reported, and lower weight for height, and usually have
thereby the estimated incidence of one in four absent sexual maturation. Balding occurs due
Birmingham
Heartlands Hospital, million live births.3 Males are aVected one and to the receding hair line and loss of eye brows
Birmingham, UK
a half times more often than females (M : and eye lashes is common in the early
R A Shinton
F = 1.5 : 1). Ninety seven per cent of aVected childhood. Skin is lax and wrinkled due to
patients are white.5 9 Several rare conditions widespread loss of subcutaneous fat. There is
Correspondence to:
exist in human beings that exhibit certain phe- also circumoral cyanosis (table 1).
Dr P K Sarkar, Selly Oak
Hospital, Raddlebarn Road,
notypic characteristics associated with senes- Features in the head consist of craniofacial
Birmingham B29 6JD, UK
cence. Often referred to as  segmental prog- disproportion, micrognathia, alopecia, promi-
eroid syndromes , the most important and nent scalp veins, prominent eyes, a beaked
Submitted 19 June 2000
Accepted 29 August 2000 widely studied condition was HGPS.10 nose, and a  plucked bird appearance. The
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Hutchinson-Guilford progeria syndrome 313
large bald head and a small jaw give them an inactivity of telomerase.19 Reintroduction of
extremely aged appearance. They are usually telomerase prevents the onset of senescence.
short and thin with an average height of 100 cm This has led to the proposition that telomerase
or so and average weight of 12 15 kg or even activity is an important determinant in human
less. Other clinical features include abnormal ageing. Human cells that do not proliferate fre-
and delayed dentition, thin and high pitched quently have now been shown to have active
voice, pyriform thorax, and short dystrophic telomerase and therefore will not lose telomere
clavicles. length.
The limbs are usually thin and may be asso- Studies of telomerase knock-out mice have
ciated with stiV joints, coxa valga, and dys- demonstrated some aspects of accelerated age-
trophic nails. They also demonstrate  horse ing after three generations, but the relevance of
riding stance and wide based shuZing gait. these observations to normal ageing remains
The bones might show distinctive changes for unconvincing.19 It raises the possibility that tel-
example, resorption of clavicles and replace- omere length and telomerase activity may be
ment by fibrous tissue, resorption of terminal important factors for the pathogenesis of
phallanges (acro-osteolysis), etc. Aseptic premature ageing in HGPS. The observation
necrosis of the head of the femur and hip dislo- that telomere length of somatic chromosomes
cation are also common.14 15 They have a progressively declines with increasing age and
normal IQ and mentation. The median age of that progeria cells have short telomeres lends
death is 12 years.3 support to the idea of a cellular  clock ,
preventing further replication at a critically
Laboratory, biochemical, and cellular reduced length and therefore allowing DNA
abnormalities damage to occur unrepaired.18 20
There are various studies that demonstrated In HGPS, the most important biochemical
the fundamental biochemical and cellular changes occur within the connective tissue,
abnormalities in this syndrome. Normal mainly of mesodermal origin. The most useful
human cells will not divide forever, even in cul- finding in this syndrome appears to be the uri-
ture. After a defined number of cell divisioins, nary excretion of hyaluronic acid. There are at
every culture enters a viable non-dividing state least two studies that demonstrated 10 20
termed senescence.16 This led to the proposal times greater urinary excretion of hyaluronic
that the progressive accumulation of senescent acid in patients with HGPS than with con-
cells contributes to (but does not exclusively trols.6 21 Hyaluronic acid is an unsulphated gly-
cause) the ageing process, as described by cosaminoglycan that maintains the integrity
Faragher and Kipling.16 17 The eventual cessa- and texture of the skeletal, muscular, cutane-
tion of cell division is accompanied by a ous, and vascular systems. These hyaluronic
specific set of changes in cell physiology, acid abnormalities might explain scleroderma-
morphology, and gene expression. Such like skin changes, collagen hardening, and cal-
changes in phenotype have the potential to cification of arterial walls.22 There was experi-
contribute to human ageing and age related mental evidence that hyaluronic acid
diseases. Recent data have demonstrated the containing implants were shown to cause avas-
presence of senescent cells in the aged human cularity when implanted into normal vascular
tissues.17 Substantial progress has been made in wing mesoderm.23
the last few years towards identifying the cell Hyaluronic acid, therefore, appears to be
cycle regulatory mechanisms and the telomere very crucial in the morphogenesis of the blood
ageing clock theory, executing senescence.18 vessels in the embryo and may play an impor-
The telomeres (the sections of DNA occur- tant part as an antiangiogenesis factor during
ring at the end of chromosomes) consist of maturation and ageing. West and colleagues
repeated groups of the base sequence demonstrated that partial degradation prod-
TTAGGG, where T, A, and G represent the ucts of hyaluronic acid have the opposite eVect,
bases thymine, adenine, and guanine, respec- that is, angiogenesis.24 Mutations of hyaluronic
tively. These telomeres lengths are maintained acid metabolism may have pervasive eVects on
by the activity of the enzyme, telomerase, and angiogenesis, which would explain the failure
are thought to be important protective factors to thrive in patients with HGPS.
in maintaining the integrity of chromosomes.19 Cytogenetic analysis of the postmortem skin
It now appears that in vitro replicative biopsy specimens from identical twins showed
senescence, which has been observed in an inverted insertion of chromosome 1,
cultured somatic cells, is caused by a loss of described as 46XY, inv ins (1;1)(q32;q44q23)
telomere length in those cells, caused by in 70% of the cells. It raises the possibility that
Table 1 Clinical manifestations of HGPS
Incidence: USA 1 in 8 million live births
Male : female 1.5 : 1
General features Short stature, weight low for height, absent sexual maturation
Cutaneous features Loss of subcutaneous fat, wrinkled skin, circumoral cyanosis
Head Craniofacial disproportion, micrognathia, alopecia, prominent scalp veins, prominent eyes,
 plucked bird appearance
Teeth Abnormal and delayed dentition
Trunk Pyriform thorax, short dystrophic clavicles
Limbs  Horse riding stance, wide based shuZing gait, coxa valga, thin limbs, stiV joints,
dystrophic nails, etc
Mentation Normal IQ
Voice Thin and high pitched
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314 Sarkar, Shinton
Table 2 Theories of ageing (modified from ref 22, 27, 36)
Type of theory Explanation
Genetic-molecular Codon restriction: accuracy of DNA-mRNA impaired
Error theories: accuracy of mRNA-proteins impaired
Gene regulation: postreproductive changes in gene expression
Somatic mutation: radiation damage to DNA
Cellular Wear and tear: with use the body wears out and dies
Age pigments: lipofuscin deposit as a primary cause of ageing
Free radicals: lead to cell damage and thus ageing
Cross linking: increased cross linkage of DNA leading to irreversible damage to DNA and
enzymes
Evolutionary Wide range of species-species variation in lifespan
Disposable soma Balance between energy investment in reproduction and maintenance
System level Neuroendocrine control: a  biological clock controls development through neural and
hormonal mechanisms
Immune control: thymus gland as an  immunological clock leading to cell destruction due to
failure to recognise self
Age changes Changes occurring throughout the whole lifespan, often involving deterioration of an
anatomical/physiological nature
a gene for progeria may be located at the break One theory of ageing holds that tissues age as
point site of the inserted chromosome seg- a result of random mutations in the DNA of
ment.21 Subsequent study by Abdenur et al somatic cells, with consequent cumulative
demonstrated the endogenous growth hor- abnormalities.28 29 Others hold that cumulative
mone resistance and malnutrition in children abnormalities are produced by increased cross
with HGPS.25 Ted Brown demonstrated that linkage of collagen and other proteins, possibly
overnight growth hormone concentrations due to the non-enzymatic combination of glu-
were within the normal range (8 12 µg/l), but cose with amino groups on these molecules. A
their insulin-like growth factor I concentrations third theory envisions ageing as the cumulative
in the plasma were very low (0.1 0.2 µU/l).21 A result of damage to the tissues by free radicals
trial of growth hormone treatment resulted in a formed in them. Species with longer life
marked increase in linear growth and a produce more superoxide dismutase, an en-
paradoxical drop in basal metabolic rates. zyme that inactivates oxygen-free radicals.
Therefore, the failure to thrive in patients with Some investigators have speculated that in
HGPS may be due to a bioinactive form of mammals there is a biological ageing clock,
growth hormone and a lack of vasculogenesis possibly situated in the hypothalamus, that is
caused by excessive excretion of hyaluronic responsible for ageing via hormonal or other
acid. It now appears that progeria subjects may pathways.29 30
have bioinactive growth hormone or endog-
enous growth hormone resistance, which may Hayflick limit to cell division
benefit from growth hormone treatment along The Hayflick limit is the number of cell
with nutritional supplementation.21 divisions that human fibroblasts in a cell
culture can undergo before stopping.30 32
Pathophysiology of ageing Human cells can only divide about 50 times
Ageing in man results from a complex interac- when cultured outside the body.30 By contrast,
tion of genetic and environmental factors.26 27 many human cancer cells continue to divide
Many overlapping and sometimes conflicting unchecked and are called immortal.28 The
theories of ageing exist and the emergence of a number of divisions is gradually reduced in
unified theory still seems unlikely. Experimen- cells from ageing individuals, including those
tal studies of senescence are diYcult to design of a younger chronological age, who have an
because of the variable eVect of diseases and inherited form of early ageing called Werner s
other extrinsic factors. syndrome, HGPS. This has led to the idea that
What is ageing? Ageing is a developmental ageing is intracellular.30
process, part of the cycle beginning at concep-
tion and ending with death. Ageing (physiol- Premature ageing syndromes (HGPS,
ogy) is not the same as disease (pathology); metageria, Down s syndrome)
diseases do become much more common in the The very rare inherited premature ageing, or
aged population.28 Cells get old and die just progeria, syndromes lead to early death (due to
like the whole organism, but they do it at a cardiovascular or cerebrovascular complica-
more rapid rate. Normal cells that diVerentiate tions) with many of the characteristics of very
stop dividing and eventually die. Cancer cells old people.5 28 33 The fibroblast cells of aVected
continue to divide and apparently escape people demonstrate a reduced ability to
senescence. A fact for which there is currently replicate.28 Studies of people who age early
no definite explanation is that in a variety of suggest that there are genes which promote
diVerent species, a chronically decreased ageing once they are activated, as if  ageing
energy intake prolongs life.29 However, the genes act as a genetic clock.30
cells of the epidermal layer of the skin shed
themselves within a few days. The lifespan of Cross linkage in DNA, collagen, and
the red blood cell is about 120 days. Various proteins
theories have been put forward to accommo- Increased cross linking between collagen fibres
date the following observations about ageing and proteins interferes with connective tissue
(listed in table 2). functions. In DNA, cross links may form that
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Hutchinson-Guilford progeria syndrome 315
are diYcult to break, leading to errors in repli- Programmed ageing theories and damage
cation.28 theories can be brought together. It is postu-
lated that the regulation of DNA repair mecha-
Autoimmune damage and reduction in nisms, of oxidative stress (free radicals), and of
immune response immune mechanisms is under programmed
genetic control. There is evidence that the
The occurrence of autoimmune diseases for
major histocompatability complex in the
example, pernicious anaemia, thyroid disease,
mouse is associated with both immunological
vasculitis (connective tissue diseases) is more
competence and longevity.28 Support for the
common as people get older. Elderly people
genetic variability in longevity comes from the
have impaired protective immune responses
observation that late egg laying drosophila have
and therefore become more prone to infec-
tions, such as pneumonia and tuberculosis.28 a life span that is a mean 20 days more than
early laying flies.37 38
Could the immune system be a  clock that
Progeria syndromes provide further evi-
triggers ageing?30
dence of genetic contribution to ageing,
although the eVects of these disorders are not
Rate of DNA repair linked to life
clearly the same as ageing in all organs.28
expectancy
Rate of DNA repair varies from species to spe-
Evolutionary theories of ageing
cies. DNA gets damaged in the rough and
Evolutionary ageing theories are designed to
tumble of cellular functions, so DNA repair
explain wide range of life spans the from
enzymes spontaneously deal with the prob-
species to species. It was once thought that
lems. Species that are long lived, such as
ageing was an adaptive response to the threat of
humans and elephants, tend to have a better
DNA repair system than short lived species.28 30 overcrowding and that it might be associated
with accelerated evolutionary change that was
Reduced DNA repair ability has also been pro-
essentially  good for the species. This is abso-
posed in cells from progeria patients.34 DNA
lutely wrong. In the wild average life expectan-
helicase uncoils DNA for a variety of replica-
cies are very short compared with survival in a
tive, transcriptional and repair processes, with
protected environment.28 Natural selection
failure resulting in genomic instability.35 The
(the key evolutionary process) does not operate
occurrence of higher rates of malingnancy in
at a species level but at the level of individuals
premature ageing syndromes, for example,
who survive with a greater chance of preserving
Werner s syndrome, is likely to be due to chro-
their germ line (that is, those cells that are
mosomal abnormalities resulting from reduced
involved in reproduction).
cell cycle regulation.36
Disposable soma theory
Damage theories
An organism has to achieve a balance between
Mitochondrial DNA and the membranes of
the energy spent in reproduction and the
mitochondria are damaged during a person s
energy spent in maintenance. The evolutionary
life time, probably due to free radicals.30 Free
fitness of a species depends upon the energy
radicals are oxidants (electron donor), pro-
investment in maintenance. If the energy
duced as a byproduct of metabolism, and have
investment in maintenance is very high a
an extra electron. They are very unstable, and
species will become immortal, but this is at the
when they combine with cell membranes this
expense of evolutionary fitness (that is, the
leads to damage producing lipid peroxides and
responsiveness to change according to environ-
aldehydes, which increase cross linking in pro-
mental hazards).28 By contrast, if the energy
teins and DNA.28 Antioxidants, for example,
investment in maintenance is very low the spe-
vitamins C and E and selenium are regarded as
cies age rapidly, and have a short life span with
 antiageing drugs. There is no evidence that
a higher reproductive potential. Species like
these drugs work. The damage and toxic accu-
mice have a very high risk of hazards and must
mulation theories have been described as the
complete their reproduction as quickly as pos-
 clinker theory, where toxic metabolites accu-
sible. They invest very little energy in mainte-
mulate and damage cells. Somatic mutation
nance and therefore have a short life span but a
caused by radiation damage to DNA is another
higher reproductive rate.
variant of the error theories, but is now
The disposable soma theory therefore states
discounted as the levels of radiation would have
that, for a given level of environmental hazard,
to be far too high to explain ageing changes.28
the optimal level of maintenance is less than the
minimum required for immortality or non-
Programmed ageing and genetic theories
ageing. In other words, wear and tear are an
Genetic programme theories state that ageing
inevitable part of being alive.28
is developmentally controlled and that the
whole process from conception through diVer- Age changes theory
entiation and growth to senescence is under a
Age related changes occur throughout the
regulatory gene complex.28 However, it is
whole lifespan, often involving deterioration of
possible that longevity genes are linked with
an anatomical/physiological nature.22 27 Many
characteristics that make us more resistant to cellular functions appear to change with
disease. Programmed ageing is linked to the increasing age. Random molecular damage
development and morphogenesis of cells under leading to accumulation of defects, for exam-
genetic control.27 28 ple, lipofuscin, causes age related changes in
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316 Sarkar, Shinton
organs and systems that we recognise as x Radiography of the skull: craniofacial dis-
ageing.28 proportion, delayed and abnormal denti-
tion.
The ageing eye reveals many defects, for
example, cataract, presbyopia, entropion, se- x Radiography of the hands: radiolucent ter-
minal phallanges.
nile macular degeneration. Hearing impair-
x Urine test: excessive excretion of the
ment (presbycusis) is extremely common in old
glycosaminoglycan, hyaluronic acid.
age. With increasing age renal size and function
x Culture of skin fibroblast exhibited 76.1%
decline. More dramatic is the fall in the
DNA repair capacity compared with nor-
number of nephrons, half of which are lost
mal.
between the ages of 40 and 70 years. Similarly
x Genetic: sporadic dominant mutation.
ageing brain, heart, lungs, bones, joints,
x Arterial biopsy: premature atherosclerosis
muscles, and even immune systems have
and subintimal fibrosis.
impaired function and so on.
Therefore, progeria syndromes do support
DiVerential diagnosis
the hypothesis that at a DNA level, ageing
(1) ACROGERIA
results, in part, from an imbalance between
Acrogeria is probably an autosomal dominant
DNA damage and repair. In some of these syn-
condition. The important clinical features con-
dromes, malignant transformations occur due
sist of cutaneous atrophy of the hands and feet,
to severe chromosomal aberrations. Genetic
prominent trunkal veins, easy bruising, propto-
theories of ageing and damage theories can be
sis and normal life span.41
viewed as not being mutually exclusive, but as
part of a much more complicated interaction of
(2) WERNER S SYNDROME
internal and external factors.27 It is possible
Werner s syndrome is an autosomal recessive
that there is a network of mechanisms under
condition. Clinical features include alopecia
genetic control that all age at diVerent rates,
with fine hair, dermosclerosis, pigmentation,
but probably the mechanisms that have the
telangiectasia,  bird-like facies, stocky trunk,
shortest life are those that determine the aver-
sclerodactyly, cataracts, impaired glucose toler-
age life span of a species.28
ance test, and increased incidence of malig-
nancies. There is increased excretion of macro-
Pathophysiology of HGPS
molecular acidic glycosaminoglycans.42
Arteriosclerosis, nephrosclerosis, myocardial
fibrosis, and vascular calcifications are signifi-
(3) METAGERIA
cant cardiovascular findings.26 Necropsy stud-
Metageria is most probably an autosomal
ies on patients with HGPS revealed gross
recessive condition. The clinical features con-
abnormalities in skin, cardiovascular and cere-
sist of fine and thin fair, cutaneous atrophy,
brovascular tissues, and bones.9 Loss of sub-
wasting, mottled hyperpigmentation of the
cutaneous fat is always a consistent finding.
skin,  bird-like facies, tall stature, and
Recently, magnetic resonance angiography
diabetes in some cases.43
demonstrated bilateral occlusion of internal
carotid and vertebral artery origins.39 Patho- 44
(4) COCKAYNE S SYNDROME
logical studies have demonstrated premature
Cockayne s syndrome is an autosomal recessive
subintimal fibrosis in the blood vessels.40
condition. The patients are cachectic dwarfs.
Skin abnormalities vary according to the site
They are usually deaf and blind due to optic
and age of the patient. The epidermis is usually
atrophy. Other features include dry thin hair,
normal to mildly hyperkeratotic, with increased
wrinkled skin due to loss of subcutaneous fat,
melanin in the basal layer. There is completely
sunken eyes and  beak-like nose. Their gait is
disorganised collagen, which is usually thick-
usually ataxic due to cerebellar involvement.
ened and hyalinised. The elastic tissue is
surprisingly normal. The density of sweat
(5) ROTHMUND-THOMSON SYNDROME
glands, sebaceous glands, blood vessels, and
Rothmund-Thomson syndrome is an auto-
hair follicles may be normal or reduced. Arrec-
somal recessive condition. The clinical features
tor pilorum muscles are usually prominent.
include alopecia with fine hair, poikiloderma
Skeletal changes are also common. They are
(that is, cutaneous atrophy with pigmentation,
short statured. The cranial bones and the
giving it a mottled appearance), juvenile
diaphysis of the long bones are thin.The clavi-
cataracts, hyperkeratotic plaques, and frontal
cles show osteolysis, with replacement by
bossing. There appears to be increased inci-
fibrous tissue. Osteoporosis is common. Avas- dence of malignancies for example, osteo-
cular necrosis of the heads of the femurs and sarcoma, squamous cell carcinoma, etc in this
acro-osteolysis of the terminal phallanges are condition.45
the other dominant bone changes.26 Delayed
46
and abnormal dentition are also common.
(6) ATAXIA TELANGIECTASIA
Ataxia telangiectasia is an autosomal recessive
Diagnosis
condition. The clinical features consist of cuta-
Diagnosis may be established by the following:
neous atrophy, telangiectasis, cerebellar ataxia,
x Characteristic clinical features.
premature canities (loss of pigments in the
x Classical geriatric disorder of the young. hair), and, at times, abnormal involuntary
x Thin, high pitched voice. movements for example, chorea, dystonia,
x Typical gait and coxa valga. etc. The patients are usually immunodeficient.
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Hutchinson-Guilford progeria syndrome 317
12 World Health Organisation. International classification of dis-
eases ninth revision (ICD9). A manual of the International
Key points:
classification of diseases, injuries and causes of death. Geneva:
x HGPS is a very rare genetic disorder.
WHO, 1977 78; Vol 1: 154.
13 Mills RG, Weiss AS. Does progeria provide the best model of
x Characteristic facies, wrinkled skin,
accelerated ageing in humans? Gerontology 1990;36:84 98.
prominent scalp veins, typical posture
14 Moen C. Orthopaedic aspects of progeria. J Bone Joint Surg
[Am] 1982;64:542 6.
and gait,  sculpted nose , and stunted
15 Gamble JG. Hip disease in Hutchinson-Guilford progeria
growth will lead to the diagnosis.
syndrome. J Pediatr Orthop 1984;4:585 9.
x Normal motor and mental develop- 16 Faragher RG. Cell senescence and human ageing: where s
the link? Biochem Soc Trans 2000;28:221 6.
ment.
17 Faragher RG, Kipling D. How might replicative senescence
x No demonstrable abnormalities of contribute to human ageing? Bioessays 1998;20:985 91.
18 Ishikawa F. Ageing clock: the watchmaker s masterpiece.
growth hormone, thyroid stimulating
Cell Mol Life Sci 2000;57:698 704.
hormone, parathyroid hormone, and
19 Goyns MH, Lavery WL. Telomerase and mammalian
ageing: a critical appraisal. Mech Ageing Dev 2000;114:69
adrenal hormones.
77.
x Increased insulin resistance.
20 Allsopp RC, Vaziri H, Patterson C, et al. Telomere length
predicts replicative capacity of human fibroblasts. Proc Natl
x Presence of abnormal collagen.
Acad Sci U S A 1992;89:1014 8.
x Varying degrees of generalised athero-
21 Zebrower M, Kieras FJ, Brown WT. Urinary hyaluronic acid
sclerosis involving chiefly the larger elevation in Hutchinson-Guilford progeria syndrome. Mech
Ageing Dev 1986;35:39 46.
arteries in postmortem studies.
22 Sweeney KJ, Weiss AS. Hyaluronic acid in progeria and the
x Although the majority die of cardiovas- aged phenotype. Gerontology 1992;38:139 52.
23 Feinberg R, Beebe D. Hyaluronate in vasculogenesis. Science
cular or cerebrovascular disease,
1983;220:1177 9.
between 7 and 27 years of age, many
24 West DC, Hampson IN, Arnold F, et al. Angiogenesis
induced by degradation products of hyaluronic acid. Science
other features of ageing are absent.5
1985;228:1324 6.
25 Abdenur JE, Brown WT, Freidman S, et al. Endogenous
growth hormone resistance and malnutrition in children
with Hutchinson-Guilford progeria syndrome (HGP). Pedi-
There may be signs of peripheral neuropathy as
atr Res 1991;29:73A(abstract).
26 Pesce K, Rothe MJ. The premature ageing syndromes. Clin
well. There appears to be increased incidence
Dermatol 1996;14:161 70.
of malignancies in this syndrome.
27 Dyer CAE, Sinclair AJ. The premature ageing syndromes:
insights into the ageing process. Age Ageing 1998;27:73 80.
28 Bennett GCJ, Ebrahim S. The essentials of health care in old
Prognosis
age. 2nd Ed. New York: Oxford University Press, 1995:
The prognosis is guarded. These patients suVer 3 10.
29 Ganong WF. Review of medical physiology. 18th Ed.
from premature vascular events, for example,
Stamford, Connecticut: Appleton and Lange, 1997: 43 4.
acute myocardial infarction,47 48 confirmed by
30 Vellacott J, Side S. Understanding advanced human biology.
1st Ed. London: Hodder and Stoughton Educational, 1998:
postmortem studies. The other modes of death
315 9.
are due to congestive cardiac failure caused by
31 Hayflick L. Aspects of cellular ageing. Rev Clin Gerontol
coronary artery disease32 49 and also due to cer- 1993;3:207 22.
32 Hayflick L. The limited in vitro lifespan of human diploid
ebral infarction.39 In a review of 60 cases, acute
cell strains. Exp Cell Res 1965;37:614 36.
myocardial infarction was the most common 33 Makous N, Freidman S, Yakovac W, et al. Cardiovascular
manifestation in progeria. Report of clinical and pathologic
cause of death, followed by chronic myocardial
findings in a patient with severe arteriosclerotic heart
infarction.5 The majority of deaths occurred disease and aortic stenosis. Am Heart J 1962;64:334 46.
34 Wang S, Nishigori C, Yagi T, et al. Reduced DNA repair in
during the second decade of life.27 The
progeria cells and eVects of gamma-ray irradiation on
maximum life span was noted to be 27 years.5 32
UV-induced unscheduled DNA synthesis in normal and
progeria cells. Mutat Res 1991;256:59 61.
35 Hoehn H, Bryant EM, Au K, et al. Variegated transloca-
We are very grateful to Pamela Sarkar for her help in typing the
tional mosaicism in human skin fibroblast cultures.
manuscript. We are also indebted to Olivia Christophersen,
Cytogenet Cell Genet 1975;15:282 98.
Research OYcer, Census, Population and Health Statistics,
36 Tlsty TD, Briot A, Gualberto A, et al. Genomic instability
ONS, UK and Dr Marleen De Smedt, Head of Sector  Health
and cancer. Mutat Res 1995;337:1 7.
and Safety Statistics , Eurostat, L-2920 Luxembourg-
37 Luckinbill LS, Clare MJ. Selection for lifespan in Dro-
Kirchberg, for providing statistical data on progeria syndrome
sophila melanogaster. Heredity 1985;55:9 18.
(HGPS).
38 Fukui HH, Pletcher SD, Curtsinger JW. Selection for
increased longevity in Drosophila melanogaster: a response
to Baret and Lints. Gerontology 1995;41:65 8.
1 Brown WT. Human mutations aVecting ageing: a review.
Mech Ageing Dev 1979;9:325 6. 39 Smith AS, Wiznitzer M, Karaman BA, et al. MRA detection
2 Hamilton WJ. The biology of the smokey shrew (Sorex of vascular occlusion in a child with progeria. Am J Neurora-
fumeus fumeus miller). Zoologica (NY) 1940;23:473 91. diol 1993;14:441 3.
3 Brown WT. Progeria: a human disease model of accelerated 40 Gabr M, Hashem N, Hashem M, et al. Progeria: a
ageing. Am J Clin Nutr 1992;55:1222S 4S.
pathologic study. J Pediatr 1960;57:70 7.
4 Hutchinson J. Congenital absence of hair and mammary
41 Matsumura Y, Hamanaka H, Okuwa T. A case of acrogeria.
glands with atrophic condition of the skin and its
J Dermatol 1993;20:572 6.
appendages in a boy whose mother had been almost totally
42 Goto M, Murata K. Urinary excretion of macromolecular
bald from alopecia areata from the age of six. Medicochir-
acidic glycosaminoglycans in Werner s syndrome. Clin Chem
urgical Transactions 1886;69:473 7.
Acta 1978;85:101 6.
5 DeBusk FL. The Hutchinson-Guilford progeria syndrome.
43 Greally JM, Boone LY, Lenkey SL, et al. Acrometageria: a
J Pediatr 1972;90:697 724.
spectrum of premature ageing syndromes. Am J Med Genet
6 Tonunaga M, Wakamatsu E, Soto K, et al. Hyaluronuria in
1992;44:334 9.
a case of progeria (Hutchinson-Guilford syndrome). J Am
44 Levinson P, Zimmerman W, Grammet L, et al. Cockayne
Geriatr Soc 1978;26:296 302.
syndrome. J Comput Assist Tomogr 1982;6:1172 4.
7 Brown WT, Kieras FJ, Houck GE, et al. A comparison of
45 Vennos EM, Collins M, James WD. Rothmund-Thomson
adult and childhood progerias: Werner syndrome and
syndrome: review of the world literature. J Am Acad Derma-
Hutchinson-Guilford progeria syndrome. Adv Exp Med Biol
tol 1992;27:750 62.
1985;190:229 44.
46 McFarlin DE, Strober W, Waldmann TA. Ataxia-
8 Guilford H. Progeria: a form of senilism. Practitioner
telangiectasia. Medicine 1972;51:281 314.
1904;73:188 217.
47 Atkins L. Progeria, report of a case with post-mortem find-
9 Badame AJ. Progeria. Arch Dermatol 1989;125:540 4.
ings. N Engl J Med 1954;250:1065.
10 Martin GM. Genetic modulation of the senescent pheno-
48 Talbot NB, Butler AM, Pratt EL, et al. Progeria; clinical,
type in homosapiens. Genome 1989;31:390 7.
metabolic and pathologic studies on a patient. Am J Dis
11 Balin AD, ed. Contribution of in vitro skin fibroblast studies
Child 1945;69:267.
from individuals with genetic disease that predispose to
accelerated ageing phenomena to our understanding of the ageing 49 Album MM, Hope JW. Progeria, report of a case. Oral Surg
process. New York: Raven Press, 1989: 93 119. 1958;11:985.
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