Anna Giulia Cattaneo, M.D.
Human aging is a multifaceted physiopathological process difficult
to define and stage. Even about the age for its beginning
concordance is poor: in recent years it seems to be delayed,
principally because of better management of associated diseases
and of a number of social changes, but true early aging is
out of discussion when it is present before age of 50 years.
In particular, a number of well known syndromes are characterized
by its early and even very early development: when aging is
the predominant manifestation, the syndrome is called progeria.
These diseases are more often seen in very young people, even
in the newborne. For this reason they are often managed by
pediatricians or internal physicians. However, because of
their strict similarities with common aging processes, they
represent for the gerontologist an interesting source of basic
knowledges, and have been regarded as natural models useful
to study pathophysiological mechanisms of aging in humans
and eventually to prevent its development.
Progeria syndromes differ from each other for a number of
characters, both clinical and genetical, that are of interest
for differential diagnosis. In addition, they share a large
number of manifestations very similar to aging associated
diseases or alterations. These two groups of abnormalities
should be separately described.
1. Human progeria syndromes: common symptoms and signs.
Clinical and instrumental diagnostic.
In all syndromes of human premature aging common features
are, in addition to premature, progressive and accelerated
aging with failure to thrive, severe growth failure and even
dwarfism, with immaturity in the childhood, in addition to
early aged appearance of skin and hair that give to patients
affected by any of human progeria syndromes their characteristic
senescent aspect. Clinical phenomena consequent to aging are
present at dermal, skeletal, cardiovascular, renal and cerebral
levels. Death age is anticipated of decades in comparison
with normal population, cerebral or cardiac accidents being
major causes of death. In recent years better care improved
survival in defined cases, but true prevention of early morbidity
and mortality is usually frustrating.
The skin of these subjects is usually very thin, inelastic,
wrinkled and atrophic with sclerodermal or hyperpigmented
areas and prominent veins with thin walls. Appendages like
hair are often atrophic; scalp hair is usually absent in syndromes
developing during childhood, graying in adult progeria. Loss
of subcutaneous fat is a common finding. Abnormal subdermal
collagen deposition or glycosilation and fragmentation of
elastic fibers, in addition to atrophy of follicles have been
described in different cases.
Skeletal abormalities are only partially degenerative in nature,
and in these cases are usually considered as a consequence
of early aging: stiffened joints, pathological fractures and
arthrosis are often seen. However, disorders of bone and joints
not degenerative in nature are also typical features of diverse
progeria syndromes, between others asymmetrical hypoplasia
of arms and legs, expecially in very early presenting progerias,
pronounced scoliosis associated to coxa valga and vertebral
anomalies, prominent joints and osteolysis of the clavicle.
The voice of many of these patients, both in progeria infantum
and in the Werner syndrome, but even in Cockayne disease,
is high pithced because larynx is anatomically abnormal.
However, most important abnormalities for the welfare and
survival of these young but aged people appear to be linked
to the diffuse atherosclerosis affecting their arteries, expecially
those of coronary and cerebral districts, with associated
illnesses that do not differ greatly from that usually seen
in older subjects. Vascular alterations could be present in
the pulmonary arteries and in renal district, in which they
are more similar to a microangiopathy. Mortality is frequently
a consequence of atherosclerosis-linked events .
Findings from biopsies or autoptic examinations reveal the
presence of uncommon alterations in the arterial intima. True
atherosclerotic plaque formation is an unusual finding in
progeria syndromes, out of adult progeria: cholesterol infarction
in cells and endothelial disruption with subsequent altered
repairing, leading to proliferation of abnormal collagen fibers
and cells are not described in progerias developing in the
neonatal age, childhood or adolescent life. With the only
exclusion of the adult progeria syndrome, the plaque formation
process appears to evolve only partially, with abnormal and
thin collagen fiber deposition, in addition to fibroblasts
and smooth muscle proliferation and contraction into the arterial
wall, involving both the intima and the media. Elastic fibers
have been described as anomaluos, but even normal while rare
and very small, at the electron microscopy. Extensive thrombosis
At cerebral level, gliosis, cerebral atrophy with intracranial
calcifications have been described.
Sporadic renal alterations with glomerulosclerosis and multiple
mesangial alterations, involving collagen deposition and expansion
of mesangial matrix, have been observed.
The search for clinical laboratory markers suitable for identification,
early diagnosis and prediction of progeria syndromes has been
frustrating, while greatly attractive in past decades, when
genetical tests were lacking. Only unremarkable or sporadic
routine alterations have been described: even metabolic and
endocrine tests, inclusive of that useful to study lipids
and glycemic control, do not differ greatly from general population,
with only higher blood growth hormone levels and basal metabolic
rate in some cases of progeria infantum, lipid alterations
in progeroid neonatal syndrome and minor glycemic alterations
seen in adult progeria. Diabetes mellitus and hyperlipidemia
are sporadic. Normal endocrine function with disturbed hypothalamic
control are present in several cases of Cockayne syndrome,
in which atherosclerosis is most prominent at cerebral level.
Mental retardation or regression is present in all progeria
syndromes, with the only exclusion of progeria infantum. They
are more often a consequence of severe cerebral atrophy and
insults due to cerebral atherosclerosis.
2. Human progeria syndromes: differential diagnostics.
True progerias are rare or very rare, genetically transmitted
diseases, described worldwide in all racial groups: they differentiates
each other for the onset of aging development and for modalities
of genetic transmission, in addition to a number of phenotypical
characters. The two more frequent and studied between them
are the Hutchinson-Gilford's progeria (which incidence appears
to be only 0.1-0.2 every 10 E6 healthy newborns) and the Werner
disease. These two have been described in 1886. Cockayne disease
was firstly described in 1936, and the Wiedemann-Rautenstrauch
syndrome more recently (in 1977 by Rautenstrauch & Snigula,
in two female subjects, and in 1979 by Wiedemann, in two males).
A number of variants and other genetically transmitted diseases
in which precocious and accelerated aging is common, have
been described, but they seem to be out of focusing of this
Clinical and instrumental diagnosis.
The most useful criterion for differentiation of these four
most important syndromes has been for decades the age at the
onset, in addition to few clinical manifestation. The age
at the onset is so characteristic that it often appears in
the syndrome denomination: Wiedemann-Rautenstrauch syndrome,
which is present at birth or soon after, is also called neonatal
progeroid syndrome; Hutchinson-Gilford's progeria is the progeria
infantum and begins during the first or second year of life
with delayed growth. A neonatal variant of this syndrome,
distinct from other neonatal progeroids syndromes, has been
described, but it is unusual and rapidly fatal. Cockayne syndrome
begins later in life, usually before 2° decade, and symptoms
are preceded by delayed growth, evident from the 4th year.
Werner disease (also called adult progeria) is usually diagnosed
in patient 20 to 40 years old.
Death is proportionally anticipated: it is usually due to
atherosclerotic damage in the cardiac or cerebral district,
and usually occurs during the first year of extrauterine life,
rarely later, in Rautenstrauch-Wiedemann syndrome or in the
second decade in patients suffering from Hutchinson-Gilford's
progeria. Cockayne disease permits survival until the 4th
or 5th decade, while in subjects suffering from Werner disease
death usually occurs in individuals 50 or 60 years old.
Early diagnosis of progeria syndromes is usually based on
clinical criteria: a number of manifestations are evident
that differ in different syndromes, often included into main
criteria for differential diagnostic. Several are craniofacial.
In Rautenstrauch-Wiedemann syndrome prematurity with delayed
intrauterine development is present. The face is triangular;
scalp hair is poor or absent and veins are prominent. Macrocephaly
with open fontanelles, agenesis of corpum callosum (rare)
and mental retardation have been described. The presence of
neonatal teeth and of lateral suprabuttock adipose pads with
generalized lipoatrophia in other districts represent major
criteria for differential diagnosis. Skin is wrinkled, hands
and feet large with long fingers and toes.
The Hutchinson-Gilford's progeria is characterized by sculptured
nose, prominent scalp veins and absent hair, mandibular and
maxillary hypoplasia, prominent eyes and ears, absence of
ear lobes, delayed and abnormal tooth eruption, and facial
cyanosis. Atrophy of nails and nipples and delayed fontanelles
closure have been reported. Osteopenia and osteolysis, expecially
of clavicle and terminal phalanges, with early closure of
distal phalanges growth plate are frequently seen at the x-ray
examination. These infants are unable to complete sexual maturation,
while their endocrine system does not show major anomalies,
out of inapparent adolescent changes. Insulin resistance sometimes
accompanied by insulin dependent diabetes mellitus could be
present in few subjects. An important laboratory finding is
the defective production of a small leucine-rich peptide,
called PRELP for its large amount of arginine and proline,
responsible for binding of collagen I to membranes and of
collagen II to cartilages. It is lacking at birth and could
became detectable soon before development of generalized symptoms
of the syndrome, while defective. Collagen glycosilation could
be disordered. Both these alterations are under genetic control,
and could explain multiple skeletal and arterial abnormalities
present. In skin fibroblasts, shortened telomere lenght -
a degenerative chromosomal aberration - has been observed.
Subjects affected by Cockayne disease are characterized by
a triangular face, dwarfism and marked scoliosis due to multiple
skeletrical abnormalities. Unlike other syndromes of premature
aging in humans, in Cockayne disease atherosclerosis seems
to be limited to the cerebral district: cerebral atrophy has
been diagnosed by means of Magnetic Resonance and Computerized
Thomography Imaging, with mental decline and ataxia. Normotensive
hydrocephalus has been described. Cataract development and
pygmental retinal degeneration, in addition to neural deafness
which is often present at birth, considerably reduce the sensorial
acuity of these patients. Loss of mural smooth muscle cells
has been described in the aorta. Overlapping of clinical manifestations
of Cockayne syndrome with those of xeroderma pigmentosum are
possible, and could be due to a fragility of common chromosomal
regions in both diseases, that share hypersensitivity to sunlight.
Werner disease appears to be the most similar between progeria
syndromes to the decline seen in aged individuals. Skin and
appendages are prematurely aged, with scleroderma-like skin
and graying hair. In in vitro studies carried on fibroblasts,
cells appear poorly proliferating, with altered responsiveness
to growth factors and with high level of chromosome aberrations.
Cytoskeletal abnormalities, often degenerative (arthrosis)
and osteopenic, and spindly ankles are frequently seen. Antibody
titres are usually normal, elevation of urinary hyaluronic
acid has been seen. Cataract develops often, and it is frequently
complicated after surgical treatment. Hypogonadism, with early
menopausa or primary amenorrea, is evident in women. Diffuse
atherosclerosis leads to the developement of peripheral vascular
disease, with leg ulcers and macro- as well as microangiopatic
manifestations, in additon to hearth failure, coronary disease
and other cardiovascular abnormalities. Diabetes mellitus
and type II hyperlipidemia are sporadic. Dementia, slowly
evolving or subsequent to an ictus, can be observed. Predisposition
to malignant degenerations, expecially rare tumors is present
: as an exemple, osteosarcoma in unusual anatomic sites and
with peculiar genetic markers, or early bladder carcinoma
have been described.
Distinct patterns of genetic transmission differentiates
progeria syndromes from each other and from the common aging
process. Great advancement in knowledges about human genes
have been reached by medical researches in recent years, helping
to better characterize a number of genetically transmitted
diseases. Human progeria syndromes here discussed have been
only partially studied, however a number of new knowledges
permit to give a new description of this class of disease.
The Hutchinson-Gilford's progeria seems to be more a syndrome
that a disease. Its modalities of inheritance are unknown:
parental transmission is often inapparent, but affected twins
have been described. Both autosomal recessive and sporadic,
autosomal dominant mutation have been proposed. The manifestations
of the syndrome are typically multisystemic, but clinical
cases in which one or more apparatus are preserved from anomalies
have suggested the possible existence of an epigenetic mosaic.
In addition, a number of mutations and abnormalities have
been described, the most important being the presence of a
gene for defective galactosyltransferase, the B4GALT3, mapped
in the interval 1q21-23 and possibly explaining the altered
glycosilation of collagen fibers seen in this disease. Chromosomal
inversion very near to the site of proline/arginine rich end
leucine-rich repeat protein (PRELP) could be responsible for
the lack of collagen binding to the basement membranes. In
skin fibroblasts, shortened telomere lenght - a degenerative
chromosomal aberration - has been observed.
The autosomal recessive Werner disease appears to be the most
well characterized between progeria syndromes. It has been
described in almost 44% of relatives, and linked to the presence
of a defective gene, called Werner gene (WRN), that has been
localized: in people not affected by the syndrome, it codifies
for a product in which helicase and exonuclease domains are
present, and acts as a transcriptional activator. All these
functions are defective in people affected by the Werner syndrome.
Due to the rarity of the syndrome, diagnostic screening test
for the WRN are lacking, at the present. Its mRNA is expressed
in vitro in fibroblasts, neurons, neurites and glia with different
patterns in homozygous and heterozygous patients. In cells
from homozygous donors mRNA is mutant, and its amount is reduced
by 70%; while in cells from their heterozygous relatives mutant
and normal mRNA cohexist, this last in very limited amounts.
The WRN mRNA seems to be present in the brain with a biphasic
pattern through life, highest levels being measured in the
embryonic brain and later in the life.
In Cockayne syndrome pleiotropic gene for a DNA-helicase is
No mutations are known in the autosomal recessive syndrome
of Wiedemann-Rautenstrauch syndrome, which appear to be so
rare that no more than 20 to 30 cases have been reported in
the English litterature from first description up to the present.
The following schemas represent a short summary of knowledges
concerning genetic transmission of progeria syndromes.
||Progeria infantum. Hutchinson-Gilford's
progeria. (firstly described in England by Hutchinson
and Gilford in 1886)
||First or second year (delayed
growth); even neonatal (rapidly fatal and unusual).
||Unknown (autosomal recessive
or sporadic and dominant, epigenetic mosaic proposed)
Chromosomal inversion very near the site of PRELP
||Neonatal progeroid syndrome,
(first description: Rautenstrauch & Snigula (2F),1977;
Wiedemann (2M) 1979.
||Present at birth, or soon
|| Autosomal recessive.
(firstly described by Cockayne, 1936)
||Before 2° decade.
||Defective DNA helicases
||Progeria, adult progeria,
Werner's syndrome or disease.
(first description: 1886, subsequently defined by Otto
||Between 40 and 50 years
||Werner gene (WRN)
Morbidity and mortality in progeria syndromes: therapeutical
problems and prevention.
Morbid processes and fatal event do not differ greatly in
subjects suffering from progeria and in old aged patients.
Prevention of progeria syndromes development and evolution
is even more difficult than that for aging process in common
population. Because genetically determined, these syndromes
present an independent pattern that does not appear sensitive
to the influence of preventive measures. In progeria infantum
tentative therapy with nonaggressive nutritional therapy,
with or without concurrent administration of exogenous GH
enhances growth rate and reduces high metabolic rates and
associated failure to thrive, but could not prevent morbid
evolution of syndrome. In all these diseases the treatment
is palliative or focused on prevention and cure of permanent
disabilities consequent to major pathological events.
Patients suffering from progeria present problems linked to
their multiple alterations at bone, cardiac, cerebral and
pulmonary levels: care and mortality prevention require a
multidisciplinary approach rendered by far more complicated
by the great frailty of these patients.
Craniofacial abnormalities, namely mandibular hypoplasia and
abnormal tooth eruption, as well as dermal inelasticity, pose
serious problems for eventual intubation of children during
major surgery or intensive care and limit the potentiality
of classical modalities of cure for oral abnormalities. When
necessary, dental care should be carried out with skilled
professionality both in choicing anaesthetic agents and in
performing modified and resolutive interventions.
Skeletal abnormalities require qualified orthopedic care,
both for their treatment and for prevention of further degenerative
evolution. To give to a child or to a young patient a painless
possibility to walk even in the presence of important alterations
like scoliosis and coxa valga enhances its welfare and could
even prevent major complications. Sometimes surgery appears
to be unevoidable, however it is hazardous, because of frequent
anaesthetic and infectious complications only recently manged
with good results. The nature of these abnormalities rarely
affects life, so only palliative care is the first choice
in many cases.
Mental decline or retardation, present in different degree
in all syndromes out of progeria infantum, reduces the ability
of affected patients to actively take care of themselves:
as a consequence the taking-care should be intelligent and
skilled, able to balance the active life of patient with a
prudent management of its capacities and to give a correct
and early interpretation of its failure to thrive, possible
expression of major complications of the disease.
Surgical treatment of cataract is possible, even if subjects
with Werner syndrome, most exposed to this evenience, show
a predisposition to a variety of postsurgical complications.
For their treatment the phacoemulsification technique has
been proposed as satisfactorily safe.
Predisposition to develop malignant degenerations, expecially
rare tumors like osteosarcoma in unusual anatomic sites and
early bladder carcinoma, is present in Werner's syndrome.
Care requested does not differ from that usually necessary
in similar cases affecting subjects without progeria, and
the illness is often a terminal event.
However, the most important morbid events in these syndromes
remain those linked to the atherosclerotic lesions described
Renal and pulmonary complications are only partially due to
atherosclerosis; lesions present in subjects suffering from
these alterations are also a consequence of anomaluos collagen
deposition in the glomerular matrix, and do not represent
a very frequent cause of death, even if fatal pulmonary hypertension
has been reported in children suffering from progeria infantum.
Microangiopathy is disturbing: leg ulcers are frequent in
patients with Werner syndrome, but also seen in those affected
by progeria infantum. They may require surgical debridement
and local medication with antibiotics: distal ulcers are fastidious,
but not life threatening.
Instead, macroangiopathy subsequent to diffuse atherosclerosis
may significantly enhance mortality. At cerebral level it
may causes infarctions and predisposition to intracranial
hematoma and hemorrage after minimal trauma: this evenience
has been often described in syndromes affecting younger patients.
Both eveniences are invalidant and serious; if death does
not intervene, sequelae like hemiparesis, dementia and seizures
can permanently affect the patient.
In addition, progeria syndromes cause marked predisposition
to hypertension and heart failure or infarction. Cardiac complication
are the most frequent causes of death in these syndromes,
at any age. Only the Wiedemann-Rautenstrauch syndrome escapes
this rule, mortality for unusual infections and immaturity
or congenital deformity being more frequent.
Emergency care and even surgery are very important to preserve
patients life during the acute phase of cerebral or cardiac
event. Myocardial infarct of ictus cerebri require intensive
care, and aggressive manoeuvres for intubation and chatherization.
Repair of cardiac valve or drenage of an intracranial hematoma
require even more aggressive intervention, with great risk
both for anaesthetic management and for postsurgical care.
Unfortunately, subjects suffering from progeria syndromes
do not tolerate very well surgery, nor even anaesthetic management.
A number of reasons render difficult intubation, not last
the conformation of their mandible or the presence in several
cases of dental abnormalities. Pharmacological sensitivity
to anaesthetic drugs, existing siezures-prone habits and cerebral
lesions, in addition to medical sequelae render hazardous
this kind of care. A number of paper recently published rewiev
the argument and propose new schemas for better management
of anaesthesia in progeria affected people. Infectious postsurgical
complications are frequent, and difficult to manage. However,
enhancement of therapeutics in recent years permits to reach
a percentage of success higher than in the past, even in very
Summary and comments.
Human progeria syndromes are characterized by an early beginning
of aging processes, even in the neonatal age and early in
the childhood, and by a proportionally early death principally
due to atherosclerotic damage of arteries in cardiac and vascular
districts and its complications. Hearth failure and infarct
and cerebral infarctions and hemorrages are by far the most
invalidant events affecting this young people and causing
Progeria syndromes in humans are genetically determined, and
a true prevention of their evolution is limited to palliative
cures for complications.
Pathological changes seen in the Werner syndrome, adult progeria,
intervening in adult 40-50 years aged, appear to be most similar
to aging processes seen in inaffected individuals. ··Progeria
syndromes and human aging process show strong similarities
and a number of processes at cellular levels are shared: this
permits to think that better understanding of progeria could
lead to better understanding of common aging, and viceversa.
This fact renders progeria knowledges interesting for general
practioners and gerontologist, not only for pediatricians
that often take care of youngest patients.
However, due to their relative rarity, no epidemiological
studies have been carried out to check the real diffusion
of genes linked to development of progeria's symptoms in general
population, nor all is understood about genetic transmission
in some of these diseases, in spite of their knowledge dates
from the beginning of this century. Open questions could concern
the relative importance of genetic versus epigentic phenomena,
the stability of genetical mutations linked to different progeria
syndromes (see schemas previously reported), their diffusion
in population not affected by progeria syndromes. As an exemple,
an improvement of knowledges about general aging process and
progeria syndrome evolution and transmission should be carried
out by the possibility to systematically perform wider and
easier testing of mutations altering helicases, collagen deposition
and binding, or routine checking the diffusion of Werner gene,
at the present unknown because of lacking of commercial tests.
Also a more systematic study of "in vitro" tests
for cell aging should be usefull. A well orderd comparison
between alterations present in genetically determined precocious
aging, in precocious aging due to physical and chemical agents
(like ionizing radiation and free radical exposure), and in
common aging should lead to significant results, and even
make some surprising finding if attention should be payed
In concomitance with preventive measures, ameliorations of
surgical and medical cares, and expecially a more skilled
choice of antibiotics and anaesthetics agents permits to successfully
treat these frail patients. To perform minimally invasive,
instead of classical, surgical techniques could reduce the
incidence of mortality, usually severe. From a wide application
of this approach both patients suffering from progeria syndromes,
and commonly aged people could take a significant advantage
for a life expectancy better for quality as for lenght.
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