2011 Group Project 9

From Embryology
Note - This page is an undergraduate science embryology student group project 2011.
2011 Projects: Turner Syndrome | DiGeorge Syndrome | Klinefelter's Syndrome | Huntington's Disease | Fragile X Syndrome | Tetralogy of Fallot | Angelman Syndrome | Friedreich's Ataxia | Williams-Beuren Syndrome | Duchenne Muscular Dystrolphy | Cleft Palate and Lip

2011 Projects: Turner Syndrome | DiGeorge Syndrome | Klinefelter's Syndrome | Huntington's Disease | Fragile X Syndrome | Tetralogy of Fallot | Angelman Syndrome | Friedreich's Ataxia | Williams-Beuren Syndrome | Duchenne Muscular Dystrolphy | Cleft Palate and Lip

Williams-Beuren Syndrome

--Mark Hill 13:09, 8 September 2011 (EST) This is a good start in the way of sub-heading structure. The current problem is that many of these sub-headings contain no content. A previous individual assessment was to insert your text on the project page, someone has either not added their text or their are unallocated sections. Either way it makes the project look very unfinished in places. More importantly at this stage is the lack of any related images or student illustration.

  • Introduction - should be more a brief text intro rather than bullet points here.
  • History of the disease - "William-Beuren Syndrome is named after John C.P. Williams," perhaps you should start with this. Timeline, this sub-sub heading has no text.
  • Genetic factors and Etiology - could indicate the region deleted in an image.
  • Diagnosis - there is a list of descriptions that should be illustrated. seems to be an overlap with the following section (Physical Characteristics).
  • Physical Characteristics - there is no text in this section.
  • Epidemiology - shod be linked earlier to diagnosis.
  • Glossary - no descriptions. Should include all acronyms used (FISH, STR etc).
  • Referencing - formatting seems to be applied well, I have not checked at this stage that all content is correctly cited.


Williams-Beuren Syndrome, more commonly known as Williams Syndrome, is a congenital anomaly caused by the deletion of 28 neighbouring genes on chromosome 7q11.23.[1] [2]

This multisystem developmental genetic disorder implicates psychological, behavioural and medical defects, including diverse phenotypic characteristics such as distinctive facial deformities, cardiovascular abnormalities,intellectual disabilities/mental retardation, growth abnormalities, endocrine abnormalities and a unique personality and cognitive profile. [1] [3] Some or all of these features may be present in varying degrees, with the condition becoming apparent at the onset of birth or in early infancy. [4]

Ever since it was discovered that the cause of this genetic abnormality was a microdeletion in chromosome 7, one of the main focuses of research has been attempting to identify the different responsibilities each gene of the deletion has for the function and development of the brain as well as their role in physical characteristics. These research efforts have the common aim to provide knowledge of how cognitive, behavioural and physical features arise as a result of the gene absence and their interplay with the environment. Current research into the links between genes absent in Williams Syndrome and the brain, behaviour and structural and functional abnormalities have been confirmed and are continuously being investigated through the use of mouse models. [5]

File:Distinctive Facial Features of Williams-Beuren Syndrome.jpg
Figure 1: The distinctive facial features such as periorbital fullness, full cheeks with prominent naso-labial folds, thick lips, and widely spaced permanent dentition suggestive of Williams syndrome in the patient

History of the disease

William-Beuren Syndrome is named after John C.P. Williams, a cardiologist from New Zealand, and Alois J Beuren, a German physician and cardiac researcher.

Initial investigation into Williams-Beuren Syndrome came from two apparently different disorders, idiopathic infantry hypercalcemia and Supravalvular Aortic Stenosis (SVAS). With further research, these abnormalities were identified as being aspects of this same syndrome. [6]

The first cases related to Williams Syndrome were in relation to Infantile Hypercalcemia. In 1957 Stapleton and colleagues studied the effects of hypercalcemia in a number of infants and noted several consistencies between them including abnormal facial features, failure to thrive, developmental delay, and systolic murmurs of the heart, all of which have now been associated with Williams Syndrome. [7] [1]

J.C.P Williams was one of the first to recognise some of the clinical factors associated with this syndrome. In a study conducted in 1961 of SVAS, an obstruction occurring in the left ventricular outflow tract (LVOT), Williams and his colleagues made the observation that patients suffering from this heart condition had strikingly similar unusual facial features that included broad foreheads, eyes set wider apart than normal, wide mouths with pouting lips and malocclusion of teeth, pointy chin and prominent pointed ears. As well as this they discovered their subjects also presented with mental retardation and a low IQ. Williams and his colleagues suggested that their findings might be indicative of a previously unrecognised syndrome. [6] [8]

In 1962 AJ Beuren and associates also studied the correlations between SVAS, mental retardation and distinctive facial features of a number of subjects and made similar observations to Williams, particularly pointing out the characteristic “elfin” features of Williams syndrome patients. [9] [10] Beuren also noted the behavioural traits of his subjects suffering from SVAS, describing them as all having a “friendly nature”, something which would later be recognised as one of the unique personality traits of people diagnosed with Williams-Beuren Syndrome. [9] [6]

In further studies conducted in 1964, Beuren and his colleagues detailed the possible association of Peripheral Pulmonary Stenosis and complex dental malformations with SVAS, mental retardation and certain facial appearance which they examined previously. They too came to the conclusion that these complications were representative of a new syndrome. [11] [6]


--Mark Hill 13:16, 8 September 2011 (EST) No content here?

1950s: increasing awareness and research into infantile idiopathic hypercalcemia [6]

1952-1957: Studies conducted by several researchers on infantile hypercalcemia revealed correlations between it and several defects known to be characteristic of Williams Syndrome today. These included abnormal facies, developmental delay, mental retardation and heart palpitations [6] [12] [7]

Genetic factors and Etiology

Figure 1. Distribution of quantitative transcription of genes deleted in WS. a: Map of genes commonly deleted in WS. b: Z-scores (relative to the WS mean) of STX1A expression levels.

Williams Syndrome is a multi-system genomic disorder that occurs due to a hemizygous deletion/nonallelic homologous recombination (NAHR). The sizes of deletion commonly range from 1.55 to 1.84 mega base pairs (Mb) on chromosome 7q11.23 which encompasses 28 genes.[1] [3]

The region associated with Williams syndrome contains a single copy gene region with repetitive sequences or Low Copy Repeats (LCR).The deletions that cause Williams syndrome are due to a misalignment of these repetitive sequences or gametes within the Williams-Beuren syndrome critical region. [13] This occurs during the process of meiosis and follows an unequal crossing over that is due to a high similarity of LCRs.

A genotype-phenotype correlation has been found for some of the genes within the deletion region. The most well known of these being elastin gene (ELN), whereby elastin haploinsufficiency is responsible for a number of abnormalities characteristic of Williams Syndrome, particularly connective tissue abnormalities and cardiovascular disease including arterial stenosis. [14] CLIP2, GTF2I, GTF2IRD1 and LIMK1 are some of the other genes that are most commonly deleted in individuals with Williams syndrome. Researchers have suggested that the deletion of these genes could help in the explanation of some of the characteristic signs of Williams syndrome including the unique behavioural characteristics and also some of the related cognitive difficulties.

In most cases, Williams syndrome occurs sporadically and the deletions can occur with no reference to the parental origin of the chromosome that transmits the disease. There have been, however, a very small number of cases where autosomal dominant inheritance of Williams syndrome has been reported.

Gene Normal Function Relation to Williams Syndrome
Elastin (ELN) Elastin is a main component of elastic fibres. It also contributes to the structure of connective tissue, particularly its flexibility and strength. The loss of one copy of this gene reduces the normal production of elastin by half.

Elastin haploinsufficiency is responsible for a number of abnormalities characteristic of Williams Syndrome, particularly connective tissue abnormalities and cardiovascular disease including arterial stenosis. [14]

LIM domain kinase 1 (LIMK1) Studies, such as Wang et al in 1998 [15] suggest that LIMK1 is involved in the area of the brain that is in control of the visualisation of an object as a set of parts.

It has also been implicated in other visual tasks such as drawing, making models and writing.

Studies differ in regards to the contribution of LIMK1 deletions to the phenotype expressed in Williams syndrome. Some studies have suggested that the loss of this gene leads to the problems with visuo-spatial tasks that are common in Williams syndrome. Other studies suggest that it is involved with the characteristic progressive loss of hearing, [16] while other studies have not found these connections.
General transcription factor IIi (GTF2I) This gene is involved in the production of the following two proteins:

• BAP-135: involved in the normal function of the immune system

• TFII-I: helps in the regulation of other genes activity and is therefore active in many tissues of the body, particularly in the brain.

It has been suggested that the loss of one copy of this gene may be responsible for the intellectual disability seen in Williams syndrome. It may also be involved in the social characteristics of those with Williams syndrome.


There are ways to clinically diagnose Williams Syndrome even though the phenotype varies between individuals. There is not a particular clinical feature that is able to ascertain the diagnosis alone, but there are particular features that individuals with Williams Syndrome may present with. These features include conditions and abnormalities discussed in the associated medical conditions sections, but most commonly include:

•Distinctive facial features

•Unique personality

•Intellectual disability

•Growth abnormalities

•Cardiovascular Disease

•Endocrine Abnormalities

Although these clinical criteria for diagnosis are available, the detection of the contiguous gene deletion responsible for Williams Syndrome is the main form of diagnosis. It has been found that over 99% of individuals that meet the clinical diagnosis criteria for Williams Syndrome also have this contiguous gene deletion. This gene deletion is detected through the use of fluorescent in situ hybridisation (FISH) or through targeted mutation analysis. [17]

Fluorescent in situ hybridisation (FISH): FISH uses elastin probes for a specialised form of chromosome analysis. This method is commercially available and commonly used to determine if an individual showing the clinical signs of William’s syndrome does have the deletion of the genes in the Williams-Beuren syndrome critical region. If the individual only has one copy of the elastin gene, then a diagnosis of William’s syndrome is confirmed.

Figure 2. Genotyping of the five microsatellites markers in WBS families. DNA fragments of those affected are always the first column of each gel followed by DNA from the mother and the last column the DNA of the father. Black arrows indicate allelic loss.

Targeted Mutation Analysis: these are non FISH methods that are also used to detect the contiguous gene deletion in order to determine whether or not an individual has Williams Syndrome.

•Real-time quantitative PCR: is used to establish the number of copies of three of the genes contained within the Williams-Beuren syndrome critical region. A deletion in this area would mean that only a single copy of one of these genes would be found.

•Genomic microarray analysis: makes use of array genomic hybridisation techniques which involved examining multiple genes simultaneously and comparing them in order to determine whether there are any abnormalities in the amount of chromosomal material.

•Heterozygosity testing: is mostly used to identify the size of the deletions, and involves the testing of short tandem repeats (STRs) from the Williams-Beuren syndrome critical region. If there is no deletion, than the STR sizes should be different at each of the markers determining heterozygosity. But if only one STR size is found at a marker, than this may indicate that there is a deletion, but may also indicate homozygosity. Quantitive PCR is then needed to determine whether or not the single STR size is dur to a deletion in the critical area or a non-abnormal finding of homozygosity.



Currently, there is no cure for Williams-Beuren Syndrome as it is a complex multisystem medical condition. As symptoms of Williams-Beuren Syndrome involve multiple disciplines, treatment of those symptoms requires a large clinical team of doctors and nurses.


Currently, there is no cure for Williams Syndrome as it is a complex multisystem medical condition. The treatment of conditions brought about by Williams-Beuren Syndrome can be difficult depending on the number of recognised conditions. The treatment of specific WS phenotypes such as hypercalcemia involves constant monitoring of the patients’ blood calcium levels and food intake. 15% of patients with Williams-Beuren Syndrome show signs of hypercalcemia and it is important to note as the condition contributes to the presence of extreme irritability, vomiting, constipation, and muscle cramps. Treatment of hypercalcemia may include diet modification, oral corticosteroids, and/or intravenous pamidronate.In any case, the WS patient should be referred to a nephrologist in order to treat renal abnormalities as they arise. [13]

Rate of Incidence

Williams-Beuren Syndrome occurs in less than 1 in 20,000 births. In the U.S, this figure is slightly more accurate with occurences of 1 in 7,500-20,000 births.

Phenotype of Williams Syndrome

Most physical musculoskeletal abnormalities result from the absence of elastin due to the elastin gene deletion.

Growth • Transient hypercalcemia

• Developmental delay in height and weight. Often presenting smaller than others at the same gestational age and grow to have a short stature.

• Poor coordination as well as a low IQ. The average IQ is 55 ranging from 40-90. This starts off with a failure to thrive as infants especially in language and motor development.

• Some degree of mental retardation ranging from moderate to mild in the majority of cases.

• Hypercacusis, an abnormal sensitivity to everyday sounds.

Facial Characteristics • Lips are full and prominent. Often wide and help open.

• Teeth are often missing and/or hypoplastic, has thin enamel.

• Long philltrum also present in the majority of cases.

• Flat nasal bridge with a shorter, upturned nose and anterverted nares.

• Eyes often have a stellate arrangement of the iris.

• Eyebrows flare medially

• Ears are lower than the normal height on the face and have prominent ear lobes.

Musculoskeletal Abnormalities • Joint limitation

• Kyphoscoliosis, an abnormal corving of the spine in both the sagittal and coronal planes.

• Hallux Vagus, a projection of the metatarsophalangeal joint inward to the innerfoot

• hypoplastic nails, undergrown or incomplete nails.

• Horse voice

Cardiac Conditions


Other problems

Genitourinary Conditions

Renal Tract Abnormalities

In a study of 40 patients with Williams Syndrome, some form of renal abnormality was detected in 7 of the patients from the study group. This study provided the foundation for the statistic stating that 18% of people with Williams Syndrome have some form of renal tract abnormality.[18] Some of these abnormalities include:

Renal Agenesis

Renal agenesis is a disorder involving the absence of one or both of the kidneys, categorised into unilateral or bilateral respectively. In this case, renal agenesis is a secondary condition to the developmental genetic disorder that is Williams Syndrome.

Bilateral renal agenesis is fatal and most infants die within the first four hours following birth. This is due to the noticeable deficiency of amniotic fluid (oligohydramnios) after 12-13 weeks causing pulmonary hypoplasia.

It is diagnosed firstly by the absence of amniotic fluid followed by the absence of the bladder and kidneys. [19]

Following diagnostic tests such as CT scans and ultrasonography, Colour Doppler has been found to be useful in detecting and identifying vascular anomalies related to renal agenesis. [20]

Unilateral renal agenesis results in mostly normal development. Patients must be examined periodically as there is an increased incidence of urinary tract infections amongst those affected. Elevated blood pressure may result in kidney damage. Patients are advised to not participate in contact sports in order to protect the sole remaining kidney. Unilateral/Bilateral renal agenesis results from a lack of induction of the metanephric blastema by the ureteral bud [21]

Duplicated kidneys

Vesicourinary reflux

Vesicourinary (vesicoureteral) reflux is the reverse flow of urine from the bladder to the ureters or even the kidneys. It results as a failure of the ureteric openings which store and void urine.


Nephrocalcinosis occurs in less than 5% of patients with WS, but is one symptom which presents in infant, child and adult life. It is the deposition of excess calcium in the kidneys which may lead to kidney failure, kidney stones or obstructive uropathy. Nephrocalcinosis may be diagnosed by abdominal CT scans, ultrasounds of the kidney and urinalysis.

Other Abnormalities

There are a number of other abnormalities associated with Williams Syndrome including a hoarse voice, inguinal hernias and joint abnormalities. These abnormalities vary in severity between different individuals and elastin haploinsufficiency is responsible for a number of these abnormalities characteristic of Williams Syndrome.[14]



Hypercalcemia refers to elevated levels of calcium in the bloodstream. It is not always observed in individuals with Williams syndrome but it is more common among children with infantile hypercalcemia being reported in approximately 15% of infants diagnosed with Williams syndrome. Most of these cases are reported within the first four years of age, but cases of recurrence in puberty have also been reported. Typically, the infantile hypercalcemia is transient and found only in mind forms, but in rare cases it can also be life-threateningly severe. [PMID: 15466114]

Diabetes Mellitus

It is reported that approximately 75% of adult individuals with Williams syndrome suffer from a form of pre-diabetes, such as impaired glucose tolerance, or diabetes mellitus. [PMID: 20425788] In the Williams-Beuren syndrome critical region, one of the genes is syntaxin-1A (STX-1A). This gene codes for a protein that is involved in exocytosis of insulin granules in pancreatic beta-cells. Lam et al in 2005 [PMID: 16123365] used a mouse model and an intraperitoneal glucose challenge to show that an overproduction of this syntaxin-1A gene resulted in hyperglycemia (described above) as well as a lower secretary level of insulin.


Other Associated Medical Conditions

Joint Abnormalities : info

Inguinal Hernias : info

Auditory Abnormalities : [22]

Vocal cord paralysis : info

Hoarse Voice : The hoarse voice is present in 98% of people with Williams Syndrome and it is due to a connective tissue abnormality, where the lamina propria in the vocal folds has a decreased amount of elastic fibres.

Cognitive, Behavioural and Neurological Phenotype

Williams syndrome patients have been described as having a cognitive variety of relative strengths and weaknesses. Relative strengths include the social use of language, facial recognition and attraction to music. However there are deficits in visuospatial learning, use of vocabulary, onset of words in infancy and arithmetic. There is also a distinct behavioural characteristic of Williams syndrome, hyper sociability. These individuals are overly enthusiastic and socially interactive to an abnormal extent. Over 90% of Williams Syndrome cases also present with some form of anxiety or an anxiety disorder. Ironically, phobias often present themselves despite the affiliation for other people.

Language Representations

Many studies have been performed on the effects of Williams syndrome on individuals language abilities as it is one of the relative strengths in cognitive functioning. One area of interest is the expressive language used by individuals with Williams syndrome. A key feature of Williams syndrome is the incorrect use of sophisticated words in expressive language. The choice of such erroneous words is the result of selecting the right semantic field however failing to select for the appropriate context. This is possibly due to the presence of a different wiring mechanism of neurons in semantic processing. Adolescents and adults are often articulate and very talkative which prevents other individuals engaged in conversation with them to recognise any cognitive abnormalities.

During infancy, there is a stunted development of language as the onset of the first word is later than normal infants. All aspects of the behavioural phenotype of Williams syndrome is delayed heavily during the earlier years, this includes language. Although the onset of words is delayed, it is followed by a rapid acquisition words. However, the meaning of words may not be fully understood by the developing child saying them. For example, a 4 year old child could repeat long and often complex words such as encyclopaedia, proficiency and accomplishment without understanding the meaning of the word. The development of strong grammar during childhood years is followed by the rapid development of language. It is this rapid development of grammar that allows Williams syndrome to be distinguished from other forms of mental retardation. The acquisition of proper grammar allows adolescents and adults with Williams syndrome to form complex grammatical forms thus having greater language production compared to others with various forms of mental retardation.


Williams Syndroms is a distinct disorder which is characterised by the individuals hypersociability and need for social interactions. Unlike most other disorders, individuals are remarkably social, empathetic and friendly. Williams syndrome individuals perceive others as friends rather than strangers. Across various studies, it has been found that individuals with Williams syndrome rate unfamiliar faces more approachable than most other normal controls. This finding is consistent with their interest in approaching strangers and their social phenotype. An early emergence of this social behaviour is present in infants with Williams syndrome. Whilst conducting tests on infants, an obstacle to retrieving accurate results is the tendency for the child to pay more attention to the people present than the task at hand. One theory is that the social behaviour is a mechanism by which the child can avoid the difficult task at hand.

Individuals with Williams Syndrome use language to effectively communicate with other on a social level. They not only engage in conversation with others, but also maintain the conversation by the extensive use of linguistic devices. There is an over use of lexical evaluative devices and vocal prosody to construct coherent and complex stories. The hypersocial phenotype of Williams syndrome is characterised by the individuals use of expressive devices over various linguistic settings to engage and maintain their audiences attention during conversation. This skill is developed throughout childhood and perfected during adolescents once grammar is established firmly in the individual.


There is relatively less known about the musicality of Williams syndrome, however it has been marked as a relatively spared cognitive function. This could be explained by the multisensory processing which occurs when listening to music. The auditory centres are known to be the thalamus and cortex, however, the visual cortex has been shown to activate in Williams syndrome individuals when stimulated by music. At a cortival level, There seems to be a hyperactivity when a musical stimuli is present. This is the result of a more excitable auditory response formed by hyperexcitable neurons which form irregular neural systems with other functional areas of the brain. Heschl’s gyrus has been sound to be duplicated in William syndrome individuals who present with 2-4 pairs of Heschl’s gyrus. The auditory cortex of these individuals has been shown to be relatively larger than an average human, 2.2 times in the left hemisphere and 1.2 in the right.

Williams syndrome patients exhibit increased sensitivity towards auditory stimuli. There is known hypercusis, phonophobia and auditory fascination. 80% of Williams syndrome patients shows an aversion toward everyday noises, as the individuals find such stimuli as painfully strong. Phonophobia has been diagnosed in 91% of the Williams syndrome individuals. This fear of normal sounds and aversion to everyday noises have been shown to be the result of an abnormalities in the limbic system aswell as the autonomic system. This avoidance and anxiety towards everyday noises and normal sounds are seen in younger children peaking at about 5-8 years and slowly reduces. This initial fear toward sounds however, is thought to be the start of auditory fascination. William Syndrome individuals are captivated by music and their strong emotional response to it. There is uniform and holistic sound perception found in the majority of Williams syndrome individuals. There is a high rate of rhythmic creativity found and a particular liking for rhythmic and percussion instruments.

Anxiety and Phobias

It has been found that when compared to the general population, children with Williams syndrome have a significantly higher rate of anxiety related disorders. They particularly showed a higher occurrence of generalised anxiety disorder and specific phobia disorder. [23]

Spatial cognition

Individuals with Williams syndrome typically have a deficiency in spacial cognition. An adult with Williams will function at a 5 year olds level of spacial cognition. This is often seen as the result of the attention paid to detail at the expense of the whole. There is often a bias present to carefully note the local aspects of the visual stimuli thus overlooking the global picture. An example of this is the replication of the letter Z constructed by a number of letter z’s. A Williams syndrome individual will draw a number of the smaller, local z as opposed to the complete structure. When asked to draw freehand images of a house, William syndrome adolescents were unable to present a logical arrangement of the building. Compared to a normal control of the same age, Williams syndrome individuals are highly impaired in spacial cognitive functions. Spacial cognition follows a specific path throughout development which remains impaired as the individual matures. These spatial insufficiencies also extend to influence speech negatively. An example of this would be describing the tree relative to the house as behind the house when the tree is in fact next to the house. There is an obstruction of language expressed to the poor spacial skills exhibited in Williams syndrome. Williams Syndrome individuals often have difficulty with spacial representations and this effectively impairs other cognitive functions which require such spacial skills.

Facial processing

Despite deficits in spacial cognition, facial representations are an area of sparing in Williams syndrome. There is a remarkable ability to remember, discriminate between and recognise between both familiar and unfamiliar faces. This strength of facial recognition extends to the perception of faces in various contexts. Changing the lighting, orientation and background does not affect the identification of faces in Williams syndrome. Williams syndrome individuals are just as skilled as normal individuals of the same age in facial perception if not, better. Younger individuals with Williams syndrome are shown to have superior facial recognition abilities compared to age-matched individuals.

Other cognitive functions

William syndrome individuals show moderate to mild forms of mental retardation with an IQ average of 55 for the population. The IQ ranges from 40-90, which means some individuals have the IQ of a normal person. By adulthood, there is a failure to successfully perform piagetian seriation and conservation tasks normally achieved by 8 years of age. The cognitive impairment of Williams syndrome has been shown to be similar to that of Down syndrome. There is little difference shown between the verbal and performance IQ scores of the two groups. Arithmatics is shown to be the greatest challenge for the syndrome and language to be a relative strength. A severe impairment with the use of arithmetics and its implications to daily life has been shown to be expressed in Williams syndrome individuals. This can be shown by their preference for a hundred 5c as opposed to a $5 note. Some individuals however, are known to have adequately learn addition, subtraction and even division. Adults are also shown to have difficulty estimating quantities a normal developing child can do. For example, the length of a bus can be estimated to be as small as 1cm or as large as 100m when a normal child would say about 11m. Reading is a more variable function as some find it difficult to reading whilst others read particular topics of interests. Williams syndrome presents an uneven cognitive profile with specific strengths and various deficits unlike most forms of mental retardation where there is a general deficiency in all aspects of cognitive function.

Specialised Facilities and Supportive Associations

Case studies

Interesting facts

Current research and developments


Congenital anomaly: an abnormality or defect present at birth

FISH: Fluorescence in situ hybridisation; a technique used to detect the presence or absence of targeted DNA sequences on chromosomes

Hemizygous: Only having a single copy of a gene as oppose to the normal two copies

Nonallelic homologous recombination(NAHR):




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