Hutchinson-Guilford Progeria Syndrome Postgrad Med J: First Published As 10.1136/Pmj.77.907.312 on 1 May 2001

312 Postgrad Med J 2001;77:312–317

Hutchinson-Guilford progeria syndrome Postgrad Med J: first published as 10.1136/pmj.77.907.312 on 1 May 2001. Downloaded from

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.911 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.67 syndrome) were reported between 1995 and In 1886, Jonathan Hutchinson reported a 1996 by the Eurostat (social and regional case of a 3.5 year old boy who had the appear- statistics and geographical information system ance of an old man.4 Later, Hastings Guilford of Europe), Luxembourg-Kirchberg. Progeria reported a second case with similar features.8 syndrome is coded under “other endocrine The term, “progeria” was taken from the Greek disorders” which also include Werner’s syn- word for old age, “geras”,89 originally pro- drome and pineal gland dysfunction according posed by Guilford in 1904. to the International Classification of Diseases, The interesting clinical features consist of ninth revision (ICD-9) 259.8.12 Life spans of craniofacial disproportion, micrognathia, various premature ageing syndromes are diVer- prominent scalp veins, scalp alopecia, promi- ent, as for example, fifth/sixth decades for nent eyes, wrinkled skin, protruding ears, nail Werner’s syndrome, second/third decades for dystrophy, midfacial cyanosis, growth retarda- progeria syndromes and so on.513 In Europe,

tion, and a sculpted nose at birth. DeBusk out of 26 cases of premature ageing syndromes, http://pmj.bmj.com/ observed that patients with progeria syndrome eight patients died before the age of 25 years. are typically considered normal infants.5 The The authors contacted the OYce for Na- characteristic facies, posture, stiVness of joints, tional Statistics (ONS), UK and Eurostat, and bone, teeth, and skin changes become Luxembourg-Kirchberg regarding progeria apparent during the second year of life. The syndrome. Causes of death recorded on the necropsies on patients with HGPS revealed death certificate were coded by ONS and prominent abnormalities in the skin, cardiovas- Eurostat according to the ICD-9.12 There were cular tissues, and bone.9 only a handful of deaths between 1993 and on September 30, 2021 by guest. Protected copyright. In 1972, DeBusk presented case reports of 1998 in the UK and Europe where ICD-9 four patients and reviewed the world literature 259.8 was given as the underlying cause of on HGPS. Although these patients develop death or was mentioned as a contributory premature atherosclerosis and die of cardiac or cause of death. Progeria syndrome was specifi- cerebral vascular disease between 7 and 27 cally mentioned on the death certificate in only years of age, many other features associated five of these cases in the UK. 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 Birmingham thereby the estimated incidence of one in four absent sexual maturation. Balding occurs due 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.59 Several rare conditions widespread loss of subcutaneous fat. There is Correspondence to: Dr P K Sarkar, Selly Oak exist in human beings that exhibit certain phe- also circumoral cyanosis (table 1). 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- Submitted 19 June 2000 eroid syndromes”, the most important and nent scalp veins, prominent eyes, a beaked Accepted 29 August 2000 widely studied condition was HGPS.10 nose, and a “plucked bird” appearance. The

www.postgradmedj.com Hutchinson-Guilford progeria syndrome 313

19 large bald head and a small jaw give them an inactivity of telomerase. Reintroduction of Postgrad Med J: first published as 10.1136/pmj.77.907.312 on 1 May 2001. Downloaded from 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.621Hyaluronic 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 http://pmj.bmj.com/ 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 on September 30, 2021 by guest. Protected copyright. 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

www.postgradmedj.com 314 Sarkar, Shinton

Table 2 Theories of ageing (modiﬁed from ref 22, 27, 36) Postgrad Med J: first published as 10.1136/pmj.77.907.312 on 1 May 2001. Downloaded from

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 endogenous growth hormone resistance, which may Hayﬂick limit to cell division

benefit from growth hormone treatment along The Hayflick limit is the number of cell http://pmj.bmj.com/ 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 on September 30, 2021 by guest. Protected copyright. 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 conception 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.52833The 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

www.postgradmedj.com Hutchinson-Guilford progeria syndrome 315

are diYcult to break, leading to errors in repli- Programmed ageing theories and damage Postgrad Med J: first published as 10.1136/pmj.77.907.312 on 1 May 2001. Downloaded from 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 The occurrence of autoimmune diseases—for genetic control. There is evidence that the example, pernicious anaemia, thyroid disease, major histocompatability complex in the vasculitis (connective tissue diseases)—is more mouse is associated with both immunological common as people get older. Elderly people competence and longevity.28 Support for the have impaired protective immune responses genetic variability in longevity comes from the and therefore become more prone to infec- observation that late egg laying drosophila have tions, such as pneumonia and tuberculosis.28 a life span that is a mean 20 days more than Could the immune system be a “clock” that early laying ﬂies.37 38 triggers ageing?30 Progeria syndromes provide further evidence of genetic contribution to ageing, Rate of DNA repair linked to life although the eVects of these disorders are not 28 expectancy clearly the same as ageing in all organs. Rate of DNA repair varies from species to species. DNA gets damaged in the rough and Evolutionary theories of ageing tumble of cellular functions, so DNA repair Evolutionary ageing theories are designed to enzymes spontaneously deal with the prob- explain wide range of life spans the from lems. Species that are long lived, such as species to species. It was once thought that humans and elephants, tend to have a better ageing was an adaptive response to the threat of DNA repair system than short lived species.28 30 overcrowding and that it might be associated Reduced DNA repair ability has also been pro- with accelerated evolutionary change that was posed in cells from progeria patients.34 DNA essentially “good” for the species. This is abso- helicase uncoils DNA for a variety of replica- lutely wrong. In the wild average life expectan- cies are very short compared with survival in a tive, transcriptional and repair processes, with 28 failure resulting in genomic instability.35 The protected environment. Natural selection occurrence of higher rates of malingnancy in (the key evolutionary process) does not operate 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 http://pmj.bmj.com/ 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- 28

aldehydes, which increase cross linking in pro- on September 30, 2021 by guest. Protected copyright. 28 mental hazards). By contrast, if the energy teins and DNA. 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

www.postgradmedj.com 316 Sarkar, Shinton

organs and systems that we recognise as x Radiography of the skull: craniofacial dis- Postgrad Med J: first published as 10.1136/pmj.77.907.312 on 1 May 2001. Downloaded from ageing.28 proportion, delayed and abnormal denti- The ageing eye reveals many defects, for tion. example, cataract, presbyopia, entropion, se- x Radiography of the hands: radiolucent ter- nile macular degeneration. Hearing impair- minal phallanges. ment (presbycusis) is extremely common in old x Urine test: excessive excretion of the age. With increasing age renal size and function glycosaminoglycan, hyaluronic acid. decline. More dramatic is the fall in the x Culture of skin fibroblast exhibited 76.1% number of nephrons, half of which are lost DNA repair capacity compared with nor- between the ages of 40 and 70 years. Similarly mal. ageing brain, heart, lungs, bones, joints, x Genetic: sporadic dominant mutation. muscles, and even immune systems have x Arterial biopsy: premature atherosclerosis 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 27 (2) WERNER’S SYNDROME internal and external factors. 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- 28 age life span of a species. ance test, and increased incidence of malignancies. There is increased excretion of macro- Pathophysiology of HGPS molecular acidic glycosaminoglycans.42 Arteriosclerosis, nephrosclerosis, myocardial fibrosis, and vascular calcifications are signifi- 26 (3) METAGERIA cant cardiovascular findings. 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, 9 brovascular tissues, and bones. 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 http://pmj.bmj.com/ demonstrated bilateral occlusion of internal 39 carotid and vertebral artery origins. Patho- 44 (4) COCKAYNE’S SYNDROME logical studies have demonstrated premature 40 Cockayne’s syndrome is an autosomal recessive subintimal fibrosis in the blood vessels. 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, on September 30, 2021 by guest. Protected copyright. 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.

www.postgradmedj.com Hutchinson-Guilford progeria syndrome 317

12 World Health Organisation. International classification of dis- Postgrad Med J: first published as 10.1136/pmj.77.907.312 on 1 May 2001. Downloaded from Key points: eases ninth revision (ICD9). A manual of the International classification of diseases, injuries and causes of death. Geneva: x HGPS is a very rare genetic disorder. WHO, 1977–78; Vol 1: 154. x Characteristic facies, wrinkled skin, 13 Mills RG, Weiss AS. Does progeria provide the best model of 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 and gait, “sculpted nose”, and stunted [Am] 1982;64:542–6. 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. growth hormone, thyroid stimulating 18 Ishikawa F. Ageing clock: the watchmaker’s masterpiece. Cell Mol Life Sci 2000;57:698–704. hormone, parathyroid hormone, and 19 Goyns MH, Lavery WL. Telomerase and mammalian adrenal hormones. ageing: a critical appraisal. Mech Ageing Dev 2000;114:69– 77. x Increased insulin resistance. 20 Allsopp RC, Vaziri H, Patterson C, et al. Telomere length x Presence of abnormal collagen. predicts replicative capacity of human fibroblasts. Proc Natl 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 arteries in postmortem studies. Ageing Dev 1986;35:39–46. 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. cular or cerebrovascular disease, 23 Feinberg R, Beebe D. Hyaluronate in vasculogenesis. Science 1983;220:1177–9. between 7 and 27 years of age, many 24 West DC, Hampson IN, Arnold F, et al. Angiogenesis other features of ageing are absent.5 induced by degradation products of hyaluronic acid. Science 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). well. There appears to be increased incidence 26 Pesce K, Rothe MJ. The premature ageing syndromes. Clin 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. from premature vascular events, for example, 29 Ganong WF. Review of medical physiology. 18th Ed. 47 48 Stamford, Connecticut: Appleton and Lange, 1997: 43–4. acute myocardial infarction, confirmed by 30 Vellacott J, Side S. Understanding advanced human biology. postmortem studies. The other modes of death 1st Ed. London: Hodder and Stoughton Educational, 1998: 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. 39 32 Hayflick L. The limited in vitro lifespan of human diploid ebral infarction. 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 cause of death, followed by chronic myocardial manifestation in progeria. Report of clinical and pathologic 5 findings in a patient with severe arteriosclerotic heart infarction. The majority of deaths occurred disease and aortic stenosis. Am Heart J 1962;64:334–46. http://pmj.bmj.com/ during the second decade of life.27 The 34 Wang S, Nishigori C, Yagi T, et al. Reduced DNA repair in 532 progeria cells and eVects of gamma-ray irradiation on maximum life span was noted to be 27 years. 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. 1985; :9–18. on September 30, 2021 by guest. Protected copyright. (HGPS). Heredity 55 38 Fukui HH, Pletcher SD, Curtsinger JW. Selection for increased longevity in Drosophila melanogaster: a response 1 Brown WT. Human mutations aVecting ageing: a review. to Baret and Lints. Gerontology 1995;41:65–8. 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). JAm 44 Levinson P, Zimmerman W, Grammet L, . Cockayne 1978; :296–302. et al Geriatr Soc 26 syndrome. 1982; :1172–4. 7 Brown WT, Kieras FJ, Houck GE, et al. A comparison of J Comput Assist Tomogr 6 adult and childhood progerias: Werner syndrome and 45 Vennos EM, Collins M, James WD. Rothmund-Thomson Hutchinson-Guilford progeria syndrome. Adv Exp Med Biol syndrome: review of the world literature. J Am Acad Derma- 1985;190:229–44. tol 1992;27:750–62. 8 Guilford H. Progeria: a form of senilism. Practitioner 46 McFarlin DE, Strober W, Waldmann TA. Ataxia- 1904;73:188–217. telangiectasia. Medicine 1972;51:281–314. 9 Badame AJ. Progeria. Arch Dermatol 1989;125:540–4. 47 Atkins L. Progeria, report of a case with post-mortem ﬁnd- 10 Martin GM. Genetic modulation of the senescent pheno- ings. N Engl J Med 1954;250:1065. type in homosapiens. Genome 1989;31:390–7. 48 Talbot NB, Butler AM, Pratt EL, et al. Progeria; clinical, 11 Balin AD, ed. Contribution of in vitro skin ﬁbroblast studies metabolic and pathologic studies on a patient. Am J Dis from individuals with genetic disease that predispose to Child 1945;69:267. 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.