Synonyms

Williams-Beuren syndrome

Short Description or Definition

Williams syndrome (WS) is a neurodevelopmental disorder that is caused by a hemizygous microdeletion of chromosome 7q11.23, with an incidence of 1 in 7,500 live births. (Note that a duplication of the same region results in Duplication 7 syndrome, with a differing phenotype.) A characteristic physical, cognitive, and personality phenotype is present, with some variability. Physical features of WS include dysmorphic facial features, stunted growth, and musculoskeletal problems, as well as connective tissue abnormalities including congenital heart abnormalities. Cognitive features include delayed development, intellectual functioning typically in the range of mild intellectual disability (ID), a marked relative weakness in visuospatial constructive skills, with general language functioning at the level of overall functioning. Personality features include overfriendliness and sociability coupled with social skills difficulties, attention problems, and anxiety.

Categorization

Classification of WS is based on results of FISH testing for the hemizygous microdeletion of the Elastin (ELN) gene. More detailed molecular genetic testing can reveal the breakpoints of the deletion. The genes in the classic WS deletion are illustrated in Fig. 1. There is some variability in the breakpoints, with evidence that people with deletions smaller than the entire WS region often exhibit a partial phenotype, while individuals with longer deletions that include greater telomeric effect, including gene GTF2I, have greater deficits in cognitive functioning (Morris et al. 2003). Examinations of the role of specific genes in the WS region also point to a role of ELN in connective tissue abnormalities, including cardiovascular symptoms (Ewart et al. 1993) and LIMK1 (Lim kinase 1) in visuospatial construction difficulties (Frangiskakis et al. 1996). While the facial gestalt associated with WS is universally found, the specific facial features show some variability, as do the medical, cognitive, and behavioral symptoms (for a review, see Mervis and Morris 2007).

Williams Syndrome, Fig. 1
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Genetic material on the long arm of chromosome 7 deleted in Williams syndrome

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Epidemiology

The incidence of WS is 1 in 7,500 live births (Stromme et al. 2002). The vast majority of cases are spontaneous mutations. The syndrome follows an autosomal dominant pattern of inheritance in that the child of a person with WS has a 50% chance of having WS. The deletions are presumed to occur because of uneven crossover during meiosis.

Natural History, Prognostic Factors, and Outcomes

WS was first identified in 1961 by the cardiologist Williams of New Zealand who identified a group of patients presenting with similar symptoms indicative of a heart defect, a unique facial appearance, and below-average cognitive functioning (Williams et al. 1961) (Fig. 2). Soon after, a second group, in Germany, described patients with similar symptoms (Beuren et al. 1962). The syndrome was subsequently named in honor of the two physicians leading the teams, Williams and Beuren. The genetic etiology of WS was identified because of the high rate of supravalvular aortic stenosis (SVAS), which was shown to result from a mutation of the ELN gene on chromosome 7q (Ewart et al. 1993).

Williams Syndrome, Fig. 2
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Unique facial appearance of patients with Williams syndrome

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The facial features associated with WS, identifiable beginning in infancy, are the cardinal feature of the disorder. All children with WS show at least 9 of 17 facial features, which include broad brow, bitemporal narrowing, periorbital fullness, epicanthal folds, stellate or lacy iris pattern, strabismus, short upturned nose, full or bulbous nasal tip, malar hypoplasia, long philtrum, full prominent lips, full cheeks, wide mouth, small jaw, small and widely spaced teeth, dental malocclusion, and prominent earlobes (Morris 2006a). (Note that these features can be seen in other children with developmental delays, but only WS is associated with many of these features together.)

WS is associated with a number of medical difficulties (Morris 2006b). About half of neonates are small based on standard growth curves, and adult stature is generally short. Eighty percent of children with WS have cardiovascular disease of some kind, with 75% with SVAS and 50% showing peripheral pulmonary stenosis (PPS). Hypotonia is commonly observed beginning in infancy and is associated with feeding difficulties and motor development delays. Older children are typically hypertonic. Fine motor difficulties and balance difficulties are commonly seen. Gastrointestinal difficulties such as gastroesophageal reflux, constipation, and colic are common, as are inguinal hernias. These features result in a 70% rate of failure to thrive in infancy. Hypercalcemia is present in approximately 15% of children and is thought to be underdiagnosed; therefore, Vitamin D supplements are not recommended, and calcium monitoring is recommended for those who have a history of hypercalcemia. Urinary tract malformation is present in about 35% of children with WS, and bladder capacity is typically reduced. There is also an increased rate of endocrine difficulties such as hypothyroidism, early puberty, and diabetes mellitus. Vision difficulties are also common, particularly strabismus. Chronic otitis media is present in about 50% of children with WS. Recent studies indicate an increased incidence of progressive sensorineural hearing loss beginning in the school-age years. Hypersensitivity to sound is commonly seen. The life expectancy in WS is normal unless there is a serious cardiovascular condition.

Neuropsychology and Psychology of WS

Intellectual disability is present for the vast majority of individuals with WS, with functioning typically in the mild to moderate intellectual disability range, and about 25% of individuals with functioning in the borderline to average range (Mervis et al. 2000). A distinctive cognitive profile is characteristically found across development, with a relative strength in auditory short-term memory, language abilities at or above general cognitive ability levels, and a significant relative weakness in visuospatial constructive skills and fine motor dexterity (Mervis et al. 2000). While language development is typically delayed, fluid spontaneous language is usually ultimately present (Bellugi et al. 1990). Some have pointed to language abilities as preserved; however, general consensus is that impairments in grammatical abilities, vocabulary, and pragmatics are indeed present in comparison to same-aged peers (Mervis and Morris 2007). Particular difficulties with relational vocabulary are noted. There is evidence of a strong reliance on phonological memory skills in language development (Robinson et al. 2003). In terms of adaptive functioning, personal care and domestic responsibility skills are typically areas of significant relative weakness, with milder delays also found in communication and socialization (Mervis et al. 2001). Executive functioning impairments have also been noted in the areas of set shifting, verbal and spatial working memory, and planning (Hocking et al. 2015; Lanfranchi et al. 2015; Rhodes et al. 2010, 2011a).

A distinctive personality profile is also typically present, characterized by high sociability coupled with anxiety (Klein-Tasman and Mervis 2003). The intense interest in interaction with others is observable even in infancy (Mervis et al. 2003) and continues throughout development (Ng et al. 2014). Despite this sociability, people with WS typically have difficulty establishing sustained friendships with peers (Davies et al. 1997, 1998) and social-communicative deficits are usually present and can overlap with the autism spectrum (Klein-Tasman et al. 2007, 2009; Laws and Bishop 2004). Elevated levels of anxiety, fear, or worry are commonly reported, with specific phobia rates upward of 50%. Anticipatory anxiety is particularly common. Recent research suggests that more anxiety is associated with greater social difficulty (Riby et al. 2014). Significant attention problems are present in up to 65% of people with WS (Dykens 2003; Leyfer et al. 2006). The attention and inhibitory difficulties noted (Greer et al. 2013; Rhodes et al. 2011b) are suggested to be related to difficulty inhibiting social approach (Little et al. 2013). High levels of sound sensitivity have been observed (Jarvinen et al. 2012; Zarchi et al. 2015), with accompanying problem behaviors in response to this sensory sensitivity (Gallo et al. 2008; Janes et al. 2014; Levitin et al. 2005; Riby et al. 2013).

Studies have had mixed findings regarding face-processing abilities and theory of mind development. Performance on tasks of face recognition is similar to mental age-matched controls (Deruelle et al. 1999), though there seems to be a distinctive pattern of activation when processing facial expressions (Doherty-Sneddon et al. 2009; Mills et al. 2000). Findings are mixed about whether facial processing is holistic (Tager-Flusberg et al. 2003) or piecemeal (Gagliardi et al. 2003) and whether those with WS have difficulty with disengaging from faces (Doherty-Sneddon et al. 2009, 2013; Hanley et al. 2013; Riby et al. 2011). Attention bias to emotional or threatening faces is frequently studied (Kirk et al. 2013; McGrath et al. 2016). While early research suggested theory of mind might be stronger than that of children with some other developmental disabilities, more detailed studies have found some difficulties when compared to typically developing peers (Hanley et al. 2013; Tager-Flusberg and Sullivan 2000).

Results of neuroimaging investigations have indicated overall reduction in brain size, significant reductions in cerebral and brainstem volumes, no differences in cerebellar volume, and significant reductions in occipital cortex and thalamic gray matter after controlling for brain size (Reiss et al. 2004). Increased cortical thickness in WS, as well as reduced surface area, suggested to be related to reduced brain volume overall, have also been observed (Green et al. 2016). Significantly larger amygdala, superior temporal gyrus, orbital prefrontal cortex, and dorsal anterior cingulate have also been identified. Reduced levels of functional connectivity in the WS brain have been found (Vega et al. 2015). fMRI investigation found consistent hypoactivation of an area of the parietal cortex commonly associated with visuospatial construction tasks (Meyer-Lindenberg et al. 2004), with structural MRI showing gray matter reduction in the parietooccipital/intraparietal sulcus (Kippenhan et al. 2005). Significantly diminished amygdala activity in response to viewing threatening faces and, conversely, increased activity while viewing threatening scenes, relative to age, sex, and IQ-matched controls, were observed (Meyer-Lindenberg et al. 2005). Reduced activation in the dorsolateral prefrontal cortex, dorsal anterior cingulate cortex, and striatum in the WS group during a Go/NoGo task has also been found (Mobbs et al. 2007).

Evaluation

FISH test is typically conducted when WS is suspected and is the accepted method of diagnosis.

Treatment

There is no cure for WS. Optimal treatment consists of multidisciplinary involvement to address the medical, psychiatric, and neuropsychological sequelae of the disorder. As there is variability in the phenotype, the need for health-care services also varies considerably across individuals. Guidelines regarding medical management are available from the American Academy of Pediatrics ( 2001) and Morris (2006a, b) and are updated regularly on the Williams Syndrome Association website (For more information, see the Williams Syndrome Association website: www.williams-syndrome.org.). Special education services are generally necessary, with many children educated in mainstream classrooms with support. Phonetic approaches to reading instruction are more beneficial than whole word approaches. Speech, occupational, and physical therapy are typically needed. Psychotropic medication is often used, including stimulants and nonstimulant medication for attention problems, and selective serotonin reuptake inhibitors (SSRIs) for anxiety and mood difficulty. Careful monitoring and consultation with cardiology is strongly recommended, especially for children with a history of cardiovascular involvement. Psychotherapeutic techniques such as cognitive behavioral therapy (CBT) for anxiety and social skills training may prove beneficial to address fears and improve coping skills (Phillips and Klein-Tasman 2009).

Psychoeducational and/or neuropsychological assessment can play an important role in the development of academic intervention strategies for children and adolescents with WS (see Klein-Tasman et al. 2008 for an example). At the very least, administration of intellectual, adaptive behavior, and academic achievement measures designed to assess for the presence of ID, learning disability, and relative strengths and weaknesses is recommended. Examination of receptive and expressive language, visual-spatial skills, and attentional resources may also prove helpful in the development of an Individualized Education Plan. Occupational and speech therapy are often needed. Educating teachers and other service providers about the difficulties commonly experienced in WS may help them to anticipate needs that may arise as the child progresses through school.

Cross-References