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Early aging in humans: focusing on progeria syndromes Torna agli editoriali

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 is unusual.
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 description.

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 defective.
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.

Syndrome Progeria infantum. Hutchinson-Gilford's progeria. (firstly described in England by Hutchinson and Gilford in 1886)
Age for development First or second year (delayed growth); even neonatal (rapidly fatal and unusual).
Inheritance Unknown (autosomal recessive or sporadic and dominant, epigenetic mosaic proposed)
Known mutations Del(1)(q23), defective B4GALT3 gene.
Chromosomal inversion very near the site of PRELP

Syndrome Neonatal progeroid syndrome, Wiedemann-Rautenstrauch syndrome.
(first description: Rautenstrauch & Snigula (2F),1977; Wiedemann (2M) 1979.
Age for development Present at birth, or soon after.
Inheritance Autosomal recessive.
Known mutations None

Syndrome Cockayne syndrome.
(firstly described by Cockayne, 1936)
Age for development Before 2° decade.
Inheritance Autosomal recessive
Known mutations Defective DNA helicases (pleiotropic)

Syndrome Progeria, adult progeria, Werner's syndrome or disease.
(first description: 1886, subsequently defined by Otto Werner (1904).
Age for development Between 40 and 50 years
Inheritance Autosomal recessive
Known mutations 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 earlier
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 serious cases.

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 death.
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 to it.
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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