Prader-Willi Syndrome: Development and Manifestations available in Hardcover, Paperback
Prader-Willi Syndrome: Development and Manifestations
- ISBN-10:
- 052117337X
- ISBN-13:
- 9780521173377
- Pub. Date:
- 07/21/2011
- Publisher:
- Cambridge University Press
- ISBN-10:
- 052117337X
- ISBN-13:
- 9780521173377
- Pub. Date:
- 07/21/2011
- Publisher:
- Cambridge University Press
Prader-Willi Syndrome: Development and Manifestations
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Product Details
| ISBN-13: | 9780521173377 |
|---|---|
| Publisher: | Cambridge University Press |
| Publication date: | 07/21/2011 |
| Edition description: | Reissue |
| Pages: | 232 |
| Product dimensions: | 6.69(w) x 9.61(h) x 0.47(d) |
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Cambridge University Press
0521840295 - Prader-Willi Syndrome - Development and Manifestations - by Joyce Whittington and Tony Holland
Excerpt
Part I
Background: PraderWilli syndrome, why, what, and how to investigate
1 Background and historical overview
Why study Prader-Willi syndrome?
Prader-Willi Syndrome (PWS) is a genetically determined neurodevelopmental disorder due to one of four presently identified genetic abnormalities that result in the absence of expression of one or more genes at the locus q11-q13 on chromosome 15. Under normal circumstances, these particular genes are expressed when inherited from the father but when of maternal origin they are imprinted (switched off) and therefore in specific tissues are not expressed. The genetic abnormalities associated with PWS result in the alleles of paternal origin being absent and, because the maternal copy is normally imprinted, neither of the alleles of the putative PWS gene(s) are expressed, leading to significant consequences for the developing baby in utero and subsequently throughout the person's lifespan. As described in detail later, PWS is characterised by extreme floppiness (neonatal hypotonia) at birth with failure to thrive and a range of physical, behavioural and cognitive abnormalities that become apparent during development and give rise to often complex health and social needs.
In PWS three significant areas of concern come together. First, there is the developmental delay and the intellectual and functional impairments characteristic of those with an 'intellectual disability'. Second, there is a marked tendency to over-eat and the life-threatening obesity that can arise. Third, there is a propensity to particular behaviour patterns and to psychiatric illness that can have a negative impact on the person's quality of life and that of his or her family. Research in these and others areas is required from both theoretical and practical perspectives. With respect to the former, it is necessary to understand the phenomenon, that is, to add to the body of knowledge from a range of perspectives. With respect to the latter, the knowledge gained needs to be used to improve the lives of people with the syndrome, and also to be generalised to similar or related problems, such as obesity, in the general population. The challenge for research is to identify the precise nature of the genetic abnormality (genotype), to identify those physical and behavioural features that are particularly characteristic of the syndrome (phenotype) and to establish the biological and other mechanisms that link genotype to phenotype.
Whilst much has been learnt, the exact nature of the genetic abnormality, and specifically whether one or more genes are involved, is still unknown, as are the underlying brain abnormalities that underpin the behavioural and psychiatric disorders. From the practical perspective, research directed towards identifying and managing the complex medical, nutritional, psychological, educational, social and therapeutic needs of people with PWS is obviously desirable. The fact that many of the physical, cognitive and behavioural manifestations of PWS are present in all, or almost all, people with PWS, and are certainly more prevalent in PWS than in other groups of people with intellectual disabilities, implies a significant involvement of a certain gene or genes located on chromosome 15. The nature and extent of these maladaptive behaviours are likely also to be influenced by factors in the environment and may be ameliorated by suitable interventions. For example, with respect to the physical phenotype, administration of growth hormone from childhood has been shown to have several beneficial effects, as does a controlled diet. Research can contribute to improving the lives of people with PWS through investigating the relative importance of genetic and environmental influences and how then to engineer biological or environmental interventions to bring about beneficial change. In the future, our hope is that research will enable the development of interventions that can significantly reduce some of the most significant physical and behavioural problems associated with the syndrome.
From the point of view of understanding genetic influences on human development, there are features of the syndrome that make it an important field of scientific research. First, the genes, whose absences of expression are thought to be responsible for the syndrome, are imprinted. As PWS is one of the most striking examples of the role of imprinted genes in human development, this discovery has in itself generated a volume of research into imprinted genes, their aetiology and the processes involved. Second, there are two main distinct genotypes for PWS, which lead to subtly different phenotypes. This fact can be exploited so as to localise the genes and eventually the underlying mechanisms responsible for these phenotypic differences, to identify the genes and gene products, and to establish whether they are imprinted or not. Third, there are certain behaviours that are characteristic of all people with the syndrome, that is, common to both the main PWS genotypes, so that PWS is said to have a distinct 'behavioural phenotype'. These observations have only recently begun to be considered in depth, but it is likely that the mechanisms linking individual genes with particular characteristics or behaviours, the associated gene products and their sites of action in the brain will be identified bringing together genetic and behavioural research.
The scientific questions to which answers are sought include: the identities of the PWS gene(s) and the gene products, the normal sites of expression of the genes and their modes of action particularly in the brain, the identities of the genes that are presumed to be responsible for differences between the genetic subtypes; and, from a clinical perspective, why some physical and behavioural characteristics are invariably present and others are not, and what are the underlying causative mechanisms? Possible hypothetical models linking genotype to phenotype and how such hypothetical models might be tested are considered in Chapter 8.
Historical perspective of PWS
People with PWS have no doubt been born throughout history (the 6-year-old girl, Eugenia Martinez Vallejo, whose pictures, painted by Juan Carreno de Miranda in about 1680 are in the Prado museum may well have PWS), but because of the neonatal hypotonia and feeding difficulties common to babies with PWS, few such infants may have survived prior to the advent of better neonatal care. The second, over-eating (hyperphagic) phase, which begins after weaning, would therefore have been rarely observed in those days and then only in isolated individuals. The advent of improved mother and baby care, especially of feeding techniques (such as tube feeding), made it possible for significant numbers of babies with the syndrome to survive and, hence, groups of people with apparent similar characteristics to be noticed and eventually reported in the scientific literature. Such reports describing the characteristics of a small number of people with an apparent syndrome led in turn to further reports and ultimately to more systematic investigation.
In 1956,1 the Swiss paediatricians Prader, Labhart and Willi first described a group of children with what subsequently came to be called PWS. The main features noted at that time were neonatal hypotonia, impaired sexual development, short stature, a propensity to severe obesity, and learning disabilities (mental retardation). In 1963, Prader and Willi2 reported 14 Swiss children with similar characteristics, as did Laurance3 in England who described six children. Reports also followed from other parts of the world, from: Canada (Dunn et al., 1961)4; France (Gabilan, 1962)5; United States (Zellweger et al., 1962)6; Spain (Sanchez Villares et al., 1964)7; Sweden (Forssman & Hagberg, 1964)8; Netherlands (Monnens & Kenis, 1965)9; and Belgium (Hooft et al., 1966)10. In a later paper describing nine children, together with a review of other papers, Laurance listed the main features as: neuromuscular (neonatal hypotonia), 'mental disorders' (i.e. IQs in the lowest 2% of the population), abnormalities in body configuration (obesity and poor growth), skeletal disorders (mainly scoliosis), characteristic facial appearance (almond-shaped eyes, high cranial vault), endocrine abnormalities (risk of diabetes mellitus) and delayed gonadal development.11 Other features now recognised as being common, for example, an apparently high pain threshold, were also noted.
As more people were identified with the syndrome, advances were made in delineating common characteristics and in distinguishing PWS from other conditions with some similar features. Zellweger and Schneider12 described 14 people with the syndrome and reviewed the literature on 79 others. They distinguished the early hypotonic stage of feeding difficulties from the obese, food obsessed second stage. They also reported non-consistency of some of the abnormalities that had been reported associated with the syndrome (for example, diabetes mellitus and daytime sleepiness). Hall & Smith13 tabulated the abnormalities that were found to affect 32 people with PWS. It is of note that they found hypotonia, feeding problems, delayed developmental milestones, male hypogenitalism and obesity in 100% of those they considered to have PWS. Decreased fetal movements, 'mental deficiency' (low IQ), 'personality problems', short stature, delayed bone age, acromicria (small hands and feet) and male cryptorchidism (undescended testes) were found in over half of those with PWS described. This article also drew attention to the temper tantrums and stubbornness that often occur from childhood and reported that by late adolescence and adulthood almost all of the individuals had serious 'personality problems'.
One of the most prominent features of PWS is the abnormal interest in food, the eating behaviour (hyperphagia), and the resultant obesity. In the early years most of the people diagnosed following the identification of the syndrome were already well into the second phase and severely obese. When a young child was diagnosed with PWS, while still in the first phase of the syndrome, his growth was monitored into the second phase. His weight began to increase out of proportion to height and efforts were made to restrict his eating by means of a diet designed for children of that age and build. It was found that such a diet still resulted in rapid weight increase, showing that the caloric requirements of people with PWS were less than expected.14 For some years now, detailed dietary advice and advice on food management has been available to parents and carers of people diagnosed with PWS in many countries but, if the diagnosis of PWS was made later in life after the onset of obesity, it was too late to avoid the formation of problematic eating habits and associated medical problems. Given the problems of over-eating and the need to prevent obesity it is now recognised that early diagnosis is particularly important.
Impact of PWS clinics
The complexity of needs of people with PWS led to the recognition that the skills of different professionals were required: dieticians, paediatricians, psychiatrists, and psychologists to help advise on the prevention of obesity and on the other behaviours; occupational and physical therapists for the hypotonia and inactivity; speech and language therapists for speech problems; educational psychologists and educators to assess and ameliorate the consequences of developmental delay and learning disabilities; and family support services for parents. For this reason the first PWS clinic was established in the United States in 1972 at the University of Washington, with professionals available to cover the above areas of need; others subsequently followed.
The results of such clinics were, first, that problems could be recognised early and dealt with immediately. Second, parents were able to meet others facing the same kinds of difficulties, and could exchange experiences and support one another. Third, it enabled research to be undertaken based on people with PWS seen in these clinics. Such research had its strengths and weaknesses. One major concern was the absence at that time of agreed diagnostic criteria and no genetic test was then available. In the absence of established and valid criteria and a sound genetic test, diagnosis was potentially problematic, only improving with the development of proper diagnostic criteria and ultimately the identification of the genetic abnormality.
Impact of PWS associations
The success of PWS clinics in bringing families of people with PWS together and the formation of local groups of such families, along with the growing perception of the need for support and information services, led to the formation of national PWS associations. The first of these was American in 1975, followed by the UK Association in 1981. In 1991 the International Prader-Willi Syndrome Organisation (IPSWO) was established bringing together over 30 national associations. These associations have had important impacts on knowledge about, and support for, people with PWS. They were (and still are) the first resource for most families with a newly diagnosed baby with PWS. The associations provide emotional and practical support when crises arise and information about the syndrome when needed. Whilst those who are directly concerned with the support of a person with PWS may become knowledgeable, local medical, social and educational services tended to remain in ignorance, and even today one can still find attitudes that reflect this ignorance. For example, we found that one local authority agreed to pay for a man with PWS to go to a PWS home for a limited period of six months so that he could 'lose a bit of weight and sort himself out'; and another thought that 'all learning disabled people are alike, we do not distinguish people with PWS from the rest'. The second impact of the establishment of associations has been on research. Access to an association mailing list has meant that larger groups of people with PWS could be contacted for questionnaire and other studies. Although this means of ascertainment raises concern about potential bias, the larger numbers have given more statistical power to the analyses of the data collected.
In 1977, researchers from the Washington PWS clinic undertook a questionnaire survey of parents and professionals who had written to the clinic about the syndrome. Returned questionnaires identified 98 people, out of 106 returns, diagnosed with PWS by other physicians, who also satisfied the clinic's own criteria. These, together with reports in the literature and opinions of physicians attending a PWS Workshop at the University of Washington in 1979, formed the basis of the first set of Consensus Diagnostic Criteria.15 At that time it was agreed that symptoms essential for diagnosis included: infantile central hypotonia; hypogonadism; obesity; cognitive and learning disabilities; short stature for familial background; and dysmorphic facial features. Infantile central hypotonia is often associated with abnormal delivery and almost always associated with poor suck, feeding problems, and delayed motor landmarks. Hypogonadism, or abnormal development of physical sexual characteristics, is difficult to diagnose in infancy in females but less so in males, since undescended testes are common. Later it is often manifested in absent or infrequent menstrual periods in adult females and a small penis in adult males. Following the failure to thrive in infancy, obesity can occur in the absence of intervention to limit access to food. When food intake is controlled, the propensity to obesity is still apparent, in that the person's caloric requirement is low and the distribution of subcutaneous fat tissue is more prolific on the lower trunk, buttocks, and thighs. The cognitive and learning disabilities in PWS are not always associated with a low IQ, but educational attainment, relative to measured IQ, is generally disappointing, with arithmetic being worse than reading. Short-term memory and comprehension of abstract concepts are usually weak compared to visuo-spatial skills. Although most people with PWS are short, some people with PWS are above the 10th centile for height, these tend to be those with very tall parents, for whom one would predict a height above the 95th centile. Such people are therefore of short stature for familial background. Dysmorphic facial features, associated with PWS, include a high narrow forehead, almond-shaped eyes, and a triangular mouth, but these are not so pronounced when obesity is prevented.
All other symptoms reported to occur in people with PWS were not consistently present, each reportedly occurring in less than 100% of those with the syndrome. The prevalence of these symptoms in the questionnaire survey could be affected by response bias and might not be representative of the total PWS population. However, based on this survey, the desirability of the adoption of diagnostic criteria for PWS was first recognised, in order to improve the ability of clinicians to accurately diagnose the syndrome.
Consensus Diagnostic Criteria (CDC)
Ten years after the first proposal for the adoption of diagnostic criteria for PWS, the need for clinical diagnostic criteria was seen to be threefold: (a) for use by practicing clinicians in diagnosis; (b) as a screening instrument to identify the advisability of genetic testing, ideally in early childhood; and (c) to ensure more uniformity and reliability in those taking part in research studies. Seven professionals, each with many years of clinical experience with PWS, developed lists of diagnostic criteria for PWS. These were then assessed by five of these professionals on 113 people previously diagnosed with PWS. Minor alterations were made in the criteria following discussion at several scientific meetings. The final criteria were published as the Consensus Diagnostic Criteria in 1993.16 They were divided into three groups: eight major criteria; eleven minor criteria; and eight supportive findings. Major criteria scored one point, minor criteria scored half a point and supportive findings were not scored but were said to increase the certainty of diagnosis. The two distinct phases of PWS were acknowledged, in that the requirements for diagnosis were distinct for ages 0-3 years (five or more points at least four of which are major) and 3 years to adulthood (eight or more points at least five of which are major). It is to be noted that no specific criterion was required to be present, merely that the total numbers present reached the minimum specified. The relationship between these criteria and PWS genetics will be considered further in Chapter 5.
Prevalence of PWS
The physicians consulted in the first Consensus Diagnostic Criteria debate also reached agreement on the birth incidence of PWS as roughly 1:10 000. Other estimates followed, mainly based on surveys of physicians with experience of diagnosing PWS, and the agreed prevalence was generally quoted as between 1:15 000 and 1:25 000. Prior to our Cambridge study, only two estimates appear to be based on epidemiological data, those of Akefeldt et al., published in 1991,17 and Burd et al., published in 1990.18 In the latter North Dakota study, the authors surveyed paediatricians, neurologists, and clinical geneticists, and also contacted the state's comprehensive evaluation centre, the state hospital, the state institution for the 'mentally retarded', and group homes for the developmentally disabled, including one for people with PWS. In most communities, at least four of these sources of information were consulted. Each was sent a one-page questionnaire pictorially demonstrating the signs of PWS to aid identification. The response rate was 99%. These procedures resulted in the identification of eight males, eight females, and one person whose gender was not given, with an age range from 9 to 30 years. At that time the population of North Dakota for that age range was 263 444, giving a prevalence rate of 1:16 062, equivalent to 1:38 395 in the entire population. No figures were given for the number of people with an established genetic diagnosis.
In the Akefeldt study, the authors estimated the prevalence of PWS in the age range 0 to 25 years in the rural Swedish county of Skaraborg, by surveying paediatricians, neuropaediatricians, child psychiatrists, school health visitors, general practitioners and doctors working in the fields of general medicine, rehabilitation and mental disabilities. The authors circulated diagnostic criteria for PWS to these professionals and also invited all school nurses in the county to seminars where the features of PWS were described. Requests were made that they should be informed about all people with possible PWS. All people with possible PWS were examined by a neuropaediatrician, a child psychiatrist, a child psychologist and a speech pathologist. Clinical diagnoses were made on the basis of their findings. Eleven people (seven male and four female) were considered to definitely have PWS and a further five (two male and three female) were considered probable. These numbers gave a population prevalence of 'clear PWS' up to age 25 years of 1:8500 and between 7 to 25 years, 1:8000. If the people with suspected PWS were also included, these prevalence rates became 1: 6700 and 1:5000, respectively. As discussed in a later chapter, it is likely that these were significant over-estimates of the prevalence rates.
Mortality in PWS
The North Dakota study, mentioned above, found no people with PWS over the age of 30. In the PWS literature, very few older people have been described with genetically confirmed PWS. An exception is the report19 of a woman who died aged 71 years, who was found to have a chromosomal deletion characteristic of PWS. There is a report of two older women (aged 54 and 69) in 1988,20 but the diagnoses had only been made on clinical grounds. The Cambridge study found several older adults who may have PWS on clinical grounds, but all those genetically tested over the age of 47 years were subsequently found not to have the PWS genotype. The observation of an apparent lack of older people with the syndrome suggests that there is a significant mortality rate in later life, but such studies cannot rule out the unlikely possibility that older people with PWS are living in the community but have never been recognised as having the syndrome.
Anecdotally, the probable increased mortality of older people with PWS has been attributed to obesity-related deaths that have been thought to be most prevalent in early adulthood, when parental control over access to food has had to be relaxed or relinquished. More recently, this latter view has been challenged. At the 2001 International PWS Organisation conference, one speaker described sudden deaths in PWS occurring at all ages. Moreover, findings from our study were interpreted as showing a linear increased mortality rate across the age range (not just in later life) compared to the general population (see Chapter 4).
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