Williams-Beuren syndrome is a multisystem disorder caused by hemizygous deletion of 1.5 to 1.8 Mb on chromosome 7q11.23, which contains approximately 28 genes. Pober (2010) reviewed the clinical features of Williams-Beuren syndrome as well as the genomic and ... Williams-Beuren syndrome is a multisystem disorder caused by hemizygous deletion of 1.5 to 1.8 Mb on chromosome 7q11.23, which contains approximately 28 genes. Pober (2010) reviewed the clinical features of Williams-Beuren syndrome as well as the genomic and genetic basis and clinical management. See also the distal chromosome 7q11.23 deletion syndrome (613729), which occurs between the WBS region and the MAGI2 gene (606382).
Del Rio et al. (1998) reported a gene-dosage octaplex PCR assay using DNA from buccal smears for the rapid detection of elastin gene deletions in Williams syndrome patients. A domain within the promoter region of the elastin gene ... Del Rio et al. (1998) reported a gene-dosage octaplex PCR assay using DNA from buccal smears for the rapid detection of elastin gene deletions in Williams syndrome patients. A domain within the promoter region of the elastin gene spanning exons 20-21, and part of exon 36, were amplified. The disomic reference gene chosen was the lysyl oxidase gene (LOX; 153455), and a domain of LOX was used in preparation of the internal standard.
Williams et al. (1961) described a syndrome characterized by supravalvular aortic stenosis (SVAS), mental retardation, and distinctive facial features. Beuren et al. (1962) described a similar syndrome with the additional features of dental anomalies and peripheral pulmonary artery ... Williams et al. (1961) described a syndrome characterized by supravalvular aortic stenosis (SVAS), mental retardation, and distinctive facial features. Beuren et al. (1962) described a similar syndrome with the additional features of dental anomalies and peripheral pulmonary artery stenosis. Two features of the syndrome had been described as distinct entities: supravalvular aortic stenosis (Sissman et al., 1959) and infantile hypercalcemia (Fanconi et al., 1952). Black and Bonham-Carter (1963) pointed out the similarity of the facial features described in these reports to those described by Williams et al. (1961) and Beuren et al. (1962). Grimm and Wesselhoeft (1980) suggested that full-blown Williams syndrome includes supravalvular aortic stenosis, multiple peripheral pulmonary arterial stenoses, 'elfin face,' mental and statural deficiency, characteristic dental malformation, and infantile hypercalcemia. In a series of cases ascertained through supravalvular aortic stenosis, they found patients with mental retardation without 'elfin facies' and patients with 'elfin facies' who were mentally normal. Beuren (1972) presented compelling evidence that supravalvular aortic stenosis and idiopathic infantile hypercalcemia are part of the same disorder. Among 19 patients with the Williams syndrome not ascertained through a cardiologic hospital, Jones and Smith (1975) found 6 without supravalvular aortic stenosis, peripheral pulmonary stenosis, or hypoplastic aorta. Oppenheimer (1938) reported a 17-month-old child with pulmonary artery stenosis and calcification of the aorta and pulmonary artery; this may have been an early case. White et al. (1977) described second cousins with the characteristic facies and mental retardation but no documented hypercalcemia and no cardiovascular abnormality. Preus (1984), in 2 companion articles, used numerical taxonomy (Preus, 1980) to sharpen the definition of the Williams syndrome and used the diagnostic index so derived in the differential diagnosis of the Williams and Noonan syndromes. Burn (1986) reviewed the features of Williams syndrome and suggested that the term 'elfin facies' be dropped. He described the characteristic facial features as broad forehead, medial eyebrow flare, periorbital fullness, strabismus, stellate iris pattern, flat nasal bridge, malar flattening, full cheeks and lips, a long smooth philtrum, a pointed chin, and a wide mouth. The face becomes more coarse with age. Preus (1975) pointed out that the iris pattern, described by her as 'lacey' and by others as 'stellate,' can be a useful diagnostic clue in infants. Holmstrom et al. (1990) had 3 ophthalmologists and 4 geneticists examine eye photographs from 43 children with Williams syndrome and 124 control subjects. A stellate pattern was noted in the irides of 51% of the Williams syndrome patients and in 12% of the control subjects. The pattern was more difficult to detect or was absent in heavily pigmented irides. Hotta et al. (1990) reported on the iris pattern in 3 cases. Winter et al. (1996) assessed the frequency and severity of ophthalmologic features in 152 patients with Williams-Beuren syndrome. Eighty-two (54%) had strabismus, while 149 had esotropia. Blue irides were present in 117 (77%), green irides in 10 (7%), and brown irides in 25 (16%). A typical stellate iris pattern of the anterior stroma was found in 112 (74%). Whitish anomalies were also detected in brown irides. Retinal vascular tortuosity was found in 22% of patients with funduscopy. Two 9-year-old patients and a 46-year-old patient had initial cataract. No ocular manifestations of hypercalcemia were noted. Pankau et al. (1992) analyzed the statural growth in 165 patients (75 girls and 90 boys). Intrauterine growth retardation was present in 35% of the girls and 22% of the boys. Poor growth was noted during the first 2 years of life. Until age 9 years in girls and 11 years in boys, mean growth followed the third percentile. A pubertal growth spurt with normal growth rate was seen at age 10 years in girls and 13 years in boys, i.e., 1 to 2 years earlier than normal. Menarche also occurred earlier than normal. Mean adult height was 153.9 +/- 6.9 cm in 17 girls and 168.2 +/- 6.9 cm in 27 boys, approximately corresponding to the third percentile in both sexes. The mean deficit of adult height compared to target height was 10.2 cm in girls and 9.1 cm in boys. Skeletal development progressed at an approximately normal rate in both sexes. Pankau et al. (1993) conducted a retrospective study of 119 patients with Williams syndrome. Results showed limitation of supination at the elbow with radioulnar synostosis in 9 patients. One patient had bilateral radioulnar synostosis. Pankau et al. (1993) suggested that radioulnar synostosis should be considered a common manifestation of the syndrome. Patients with Williams syndrome are often described as having a harsh, brassy, or hoarse voice (Gosch et al., 1994). Stewart et al. (1993) described a patient with bilateral vocal cord paralysis, developing at the age of 9 years, which required tracheostomy. Takamatsu (1996) studied 18 cases of bilateral vocal cord paralysis in children, including 1 patient with WS. Vaux et al. (2003) described 2 WS patients who had bilateral vocal cord abnormalities (1 of whom required tracheostomy because of bilateral vocal cord paralysis), bringing to 4 the number of children with WS in whom such defects had been documented. They suggested that vocal cord abnormalities may be a far more common feature of WS than previously suspected, and that mild vocal cord dysfunction caused by abnormal vocal cord elastin may be the cause of the hoarse voice in this condition. Narin et al. (1993) reported an 8-year-old boy with Williams syndrome who had subvalvular aortic stenosis--seemingly the first report of subvalvular location of obstruction in this disorder. Wollack et al. (1996) described a 19-year-old girl with Williams syndrome who developed an ischemic stroke of the internal capsule and putamen but who was not found to have stenotic lesion on angiography. They reviewed 5 other cases of stroke in Williams syndrome. Cortada et al. (1980) reported the disorder in mother and both twin daughters, presumably dizygotic. One twin had supravalvular and valvular aortic stenosis. The other twin had mild peripheral pulmonary stenosis and mild coarctation of the left pulmonary artery. One twin, who died during cardiac surgery, and the mother had mitral valve prolapse. Intelligence was normal. A stellate pattern of the irides was present in both twins. All 3 had pectus excavatum, hypoplastic nails, and hallux valgus. Murphy et al. (1990) added 2 sets of concordantly affected monozygotic twins to the 2 previously reported sets. To the 5 sets of monozygotic twins with WMS previously reported, Pankau et al. (1993) added a pair concordant for the disorder but showing variable expression. Both had typical facial appearance, developmental delay, mild supravalvular aortic stenosis, hypoplasia of both pulmonary arteries, multiple peripheral pulmonary stenoses, and inguinal hernia. One twin had unilateral renal agenesis. A presumably separate disorder was cleft palate in both twins; the father, grandfather, and great-grandfather all had cleft lip with or without cleft palate. To the 6 pairs of previously reported monozygotic twins with Williams syndrome, Castorina et al. (1997) added 2 further sets. Monozygosity was confirmed by DNA microsatellite analysis and the clinical diagnosis was confirmed by FISH using a WS-specific probe. Analysis of concordance was assisted by a long follow-up. Most clinical signs were concordant in the twins of each pair, with differences present at younger ages, mainly minor facial anomalies, being attenuated with time. Developmental delay was substantially concordant. Inguinal hernia was present in a single twin in 1 pair. Facial anomalies and other signs attributable to connective tissue abnormalities were also displayed by only 1 twin in both sets, suggesting that the WS genotype has only a predisposing role in the development of these signs. Biesecker et al. (1987) described a 19-year-old patient with Williams syndrome who had renal cystic dysplasia and gradual deterioration of renal function, with recurrent episodes of dehydration secondary to a concentrating defect. They suggested that this is a more frequent complication than previously realized. In studies of 40 persons with Williams syndrome who were assessed at an average age of about 7 years, Pober et al. (1993) found renal abnormalities in 7: nephrocalcinosis in 2, marked asymmetry in kidney size in 2, small kidneys in 1, solitary kidney in 1, and pelvic kidney in 1. Renal artery stenosis was sought in 9 persons who underwent abdominal angiography during cardiac catheterization. Unilateral or bilateral mild renal artery narrowing was found in 4 persons and normal renal arteries in the remaining 5. Persistent hypertension was found in only 2 individuals and did not correlate with renal artery status. Knudtzon et al. (1987) described 2 brothers with Williams syndrome who did not have hypercalcemia. One boy died during the first month of life. His brother developed severe microcephaly and cataract and died at the age of 9 years. The skeleton was osteosclerotic at birth and became osteoporotic by the age of 2 years. This brother had persistently elevated 1,25-dihydroxyvitamin D levels during the first 2 years of life, in spite of normocalcemia. At autopsy, microcalcifications were found in the brain and kidneys. Maisuls et al. (1987) described 2 patients with Williams syndrome and severe mitral regurgitation requiring surgical treatment at ages 8 and 11. Another patient had coarctation of the abdominal aorta. Hallidie-Smith and Karas (1988) described the cardiologic findings in 66 patients with the Williams-Beuren syndrome; systemic hypertension was present in 7.8% of the patients, mitral valve prolapse by clinical and echocardiographic criteria in 15%, and bicuspid aortic valve in 11.6%. Morris et al. (1988) reviewed the natural history of Williams syndrome. After delayed growth in the first 4 years of life, catch-up growth occurred with the ultimate attainment of low-normal adult height. Older children developed progressive joint limitation and hypertonia. Hypertension was frequent in adulthood, being present in 8 of 17 adults. Morris et al. (1988) referred to the Williams Syndrome National Association, which was a source of patients for review. Morris et al. (1990) evaluated 13 adults with Williams syndrome and reviewed the case reports of 16 patients older than 16 years. Hypercalcemia may persist into adulthood. Hypertension was common. Recurrent urinary tract infections led to studies that showed urethral stenosis in some patients and bladder diverticula and vesicoureteral reflux in others. Gastrointestinal problems included chronic constipation and diverticulosis. In 10 adults with Williams syndrome, Lopez-Rangel et al. (1992) found supravalvular aortic stenosis in 4, mitral valve prolapse in 3, bicuspid aortic valve in 1, valvular aortic stenosis in 1, and pulmonary stenosis with right ventricular hypertrophy in 1. Mental retardation was seen in all patients. Verbal skills were better developed than motor skills. All patients led active lives and most were involved in sports. Some held supervised jobs. Conway et al. (1990) reported 3 children, aged 8 years, 16 years, and 59 months, who died suddenly with myocardial ischemia following cardiac catheterization. In addition to supravalvular aortic stenosis, all showed stenosis of the left coronary artery and its branches and regions of recent and/or remote myocardial infarction. Voit et al. (1991) pointed to clinical and morphologic evidence of myopathy in this syndrome giving rise to hypotonia in infancy, delayed walking, joint contractures, scoliosis, and increased exhaustion on exertion. Wessel et al. (1994) reported results of follow-up cardiologic examination of 59 patients with Williams syndrome. Supravalvular aortic stenosis was found in 57 patients, 17 of whom underwent surgery because of severe stenosis. Aortic hypoplasia was diagnosed in 24 patients, peripheral pulmonary stenosis in 49, and coarctation of the aorta in 4. If patients with SVAS had a pressure gradient of less than 20 mm Hg in infancy, their gradient remained unchanged for the next 20 years. If patients with SVAS had a pressure gradient of more than 20 mm Hg in infancy, their gradient increased in later life. Four of 6 patients with aortic hypoplasia and surgery for SVAS developed restenosis, whereas patients without aortic hypoplasia remained free of restenosis. Greenberg (1990) expressed the opinion that no well-documented cases of parent-to-child transmission of classic Williams syndrome have been reported. In 3 unrelated families, Morris et al. (1993) described Williams syndrome in parent and child: father and son in 1 family and mother and daughter in the other 2. None of the patients had supravalvular aortic stenosis or chromosomal abnormalities. In all 3 families, the parent was diagnosed after identification of the syndrome in the affected child. Sadler et al. (1993) reported Williams syndrome in mother and son. Ounap et al. (1998) reported WBS in mother and son. The diagnosis was confirmed in the son by molecular cytogenetic analysis using FISH; the mother was deceased and was thus not studied by FISH. Two traits uncommon in WBS were unilateral renal hypoplasia in the mother and a hemivertebra at L5 in the son. Kaplan et al. (1995) pointed out that stenoses in the cerebral arteries can cause strokes with brain damage and chronic hemiparesis in children with Williams syndrome. Increased irritability, loss of consciousness, and seizures were initial signs in 2 patients. One patient, aged 22 years, had episodes of cerebral vascular insufficiency beginning at the age of 3 years at which time moyamoya was diagnosed. Scothorn and Butler (1997) reported the case of a girl with Williams syndrome who had onset of puberty at 7.5 years of age and menarche at 8.5 years of age. They suggested that because intellectual and emotional development of children with this disorder are delayed, pharmacologic and hormonal intervention to delay puberty may be warranted to allow for intellectual and emotional maturation. Partsch et al. (2002) reported a mean age of menarche of 11.5 +/- 1.7 years in 86 females with Williams syndrome compared with 12.9 +/- 1.1 years in a contemporary cohort of 759 girls. They estimated the prevalence of precocious puberty in Williams syndrome as 1 in 5 to 6 girls (18.3%). Broder et al. (1999) confirmed previous findings of hypertension in Williams syndrome. They studied blood pressure using 24-hour ambulatory BP monitoring in 20 WS subjects and found that they had significantly higher ambulatory blood pressures than controls. The diagnosis of WS added approximately 10 mm Hg to mean daytime and nighttime BPs. Hypertension, defined by elevated mean daytime BP, was present in 40% of WS patients versus 14% of controls; among the children studied, this difference was even more dramatic, with 46% of WS children versus 6% of control children classified as hypertensive. Parental reporting of a history of infantile hypercalcemia was strongly associated with the presence of hypertension. Since the elastin protein is a major component of elastic fibers in the dermis of the skin, Dridi et al. (1999) evaluated elastic fibers in the dermis of 10 Williams syndrome patients, all of whom were shown by FISH to have 7q11.23 deletions. Patients with Williams syndrome showed disorganized pre-elastic and mature elastic fibers when compared with 5 healthy children and 1 patient with isolated supravalvular aortic stenosis. The authors concluded that skin biopsies may provide a simple means to elucidate the extracellular matrix anomalies associated with Williams syndrome. Sadler et al. (2001) did a retrospective analysis of the incidence and severity of cardiovascular disease in Williams syndrome in 127 patients. The prevalence of SVAS was 44 of 127 (35%). Statistical analysis revealed that the severity of both SVAS and total cardiovascular disease was significantly greater in male than female patients. Sadler et al. (2001) also observed that the clinical diagnosis of WS was made at a significantly younger age in male patients and that this was partly because of increased incidence and severity of cardiovascular disease. Rose et al. (2001) followed 112 patients with WS since 1975 and studied 25 of them by aortography. Twenty of 25 patients had vascular stenosis, of whom 19 were affected by segmental narrowing either of the thoracic aorta (9) or the abdominal aorta (7) or both (3). Hypoplasia of the abdominal aorta was characterized by the smallest diameters at the renal artery level and an increased diameter of the infrarenal abdominal aorta. Eleven patients had renal artery stenosis associated with narrowing of other aortic segments in 10 cases. Of 17 patients with hypertension, 2 had no vascular lesions; and in the remaining 15 patients, stenosis was present in more than 1 segment. Rose et al. (2001) concluded that hypertension is a common symptom and must be regarded as a manifestation of generalized arteriopathy rather than renal hypoperfusion. Giannotti et al. (2001) reported a study of celiac disease (212750) in 63 Italian WS patients. The dosage of antigliadin antibodies and antiendomisium antibodies was analyzed, and 6 patients positive for these antibodies underwent small bowel biopsy. Celiac disease was present in 6 (9.5%) WS patients, compared with 1 of 184 (0.54%) Italian children (p less than 0.001). Giannotti et al. (2001) suggested screening for celiac disease in patients with WS. In a retrospective study of 75 patients with WS, Eronen et al. (2002) found that cardiovascular symptoms were evident in 35 patients (47%) at birth. The most common abnormalities were SVAS (73%) and pulmonary artery stenosis (41%). Arterial hypertension was found in 55% of adults. In a study of the natural history of Williams syndrome, Cherniske et al. (2004) performed multisystem assessment of 20 affected adults over 30 years of age and documented a high frequency of problems in multiple organ systems. The most consistent and striking findings were: abnormal body habitus; mild to moderate high-frequency sensorineural hearing loss; cardiovascular disease and hypertension; gastrointestinal symptoms, including diverticular disease; diabetes and abnormal glucose tolerance on standard oral glucose tolerance testing; subclinical hypothyroidism; decreased bone mineral density on dual energy x-ray absorptiometry (DEXA) scanning; and a high frequency of psychiatric symptoms, most notably anxiety, often requiring multimodal therapy. Brain MRI scans did not demonstrate consistent pathology. The adults were not living independently and the great majority were not competitively employed. One of the patients reported by Cherniske et al. (2004) had hypercalcemia, indicating that this feature is not restricted to infancy. Most of the adults had premature graying of the hair starting as early as 16 years of age, a finding that had been reported by Morris et al. (1988). This feature, together with an earlier than expected onset of cataracts and high-frequency sensorineural hearing loss, suggested mild accelerated aging, which may additionally complicate the long-term course of older adults with WS. Marler et al. (2005) studied auditory system function in 27 William syndrome patients aged 6 to 48 years. They found sensorineural hearing loss in 14 of 18 patients aged 21 or younger. The degree of hearing loss was greater in adults than in children, suggesting early-onset, progressive hearing loss. Gothelf et al. (2006) found that 41 (84%) of 49 patients with Williams syndrome had moderate to severe hyperacusis beginning in infancy. The most frequent sounds of daily life to which the children were sensitive included electric machines, thunder, bursting balloons, and fireworks. The children responded with marked fear and exhibited aversive behaviors. Hyperacusis peaked at age 5.7 years and tended to decrease somewhat thereafter. Quantitative testing of 21 of these patients revealed discomfort at sound intensities on average 20 dB lower than control individuals. Pure-tone audiometry and distortion product otoacoustic emission tests revealed high-frequency cochlear hearing loss. An absence of ipsilateral acoustic reflex responses to maximum stimulation was also observed. On brain auditory evoked response (BAER) testing, patients with Williams syndrome had a significant prolongation in wave I latency. Gothelf et al. (2006) noted that hearing loss in Williams syndrome resembled the configuration of noise-induced hearing loss and suggested that hyperacusis and hearing loss in Williams syndrome resulted from a deficiency in the normally protective acoustic reflex as a result of auditory nerve dysfunction. Game et al. (2010) emphasized the urinary abnormalities in patients with WBS, including urinary frequency, urgency, nocturia, bladder diverticula, structural renal anomalies, and recurrent urinary tract infections. The authors noted that urodynamic testing has suggested evidence of detrusor overactivity and detrusor-sphincter dyssynergia in patients with WBS. - Neurodevelopmental Features Ewart et al. (1993) commented that the IQ in patients with Williams syndrome varies from 20 to 106 (mean = 58). Specific cognitive deficits include poor visual-motor integration. As a result, affected individuals have problems visualizing a complete picture but instead see only the parts. Affected individuals also suffer from attention deficit disorder. Language development, by contrast, is relatively spared and some elements of speech may be enhanced, particularly the quantity and quality of vocabulary, auditory memory, and social use of language. Many patients sing or play musical instruments with considerable expertise and they rarely forget a name. Because of their engaging personalities, language skills, and loquaciousness, mental retardation is often underestimated in children with Williams syndrome. Gosch and Pankau (1996) used 2 methods to examine the cognitive abilities of 18 affected children (9 girls and 9 boys) with a mean age of 6.6 years at year one (T1) and approximately 2 years later (T2). The Draw A Person Test showed stable results (mean IQ of 63.5 at T1 and 65 at T2). The Columbia Mental Maturity Scale revealed a significant decrease of IQ (mean IQ of 77 at T1 and 68 at T2). Gosch and Pankau (1996) contended that this change represented a decrease of developmental rate of special abilities such as the application of classifications. Plissart et al. (1994) studied the psychologic and behavioral characteristics of 11 adult Belgian patients, aged 17 to 66 years. Mental retardation in all patients was moderate or severe. Verbal skills were superior to visuospatial and motor abilities. The most frequent behavioral problems were poor concentration, attention-seeking behavior, and restlessness. The behavioral and emotional disturbances typical for children with Williams syndrome persisted into adulthood. Most patients achieved a good level of autonomy, with the majority living at home with parents and attending a day center. Lenhoff et al. (1997) described the remarkable musical and verbal abilities of individuals with Williams syndrome, who perform poorly on standard IQ tests. They usually read and write poorly and struggle with simple arithmetic, but display a facility not only for spoken language but also for recognizing faces. As a group, they tend to be empathetic, loquacious, and sociable. Lenhoff et al. (1997) presented pictures, suggesting that children with Williams syndrome were an inspiration for pixie legends, and pointed out that the 'wee, magical people' of assorted folktales were often musicians and storytellers. Gosch and Pankau (1994) compared behavioral characteristics in 19 children with Williams syndrome, aged 4 to 10 years, to those in a control group matched for age, gender, and nonverbal reasoning abilities. The children with Williams syndrome were more unreserved with and more willing to follow strangers, hypersensitive to sounds, and less socially adjusted than the control children. Mervis et al. (1999) discussed the subject of visuospatial constructive abilities in persons with normal intelligence and in persons with Williams syndrome or small deletions in the Williams syndrome region. They reviewed behavioral genetic studies of visuospatial constructive ability, which suggested that a substantial portion of the individual differences found among people of normal intelligence has a genetic basis. The behavioral phenotype in Williams syndrome suggests a dorsal and/or ventral developmental dissociation, with defects in dorsal but not the ventral hemispheric visual stream. A shortened extent of the dorsal central sulcus had been observed in autopsy specimens. Galaburda et al. (2001) compared gross anatomic features between the dorsal and ventral portions of the cerebral hemispheres by examining the dorsal extent of the central sulcus in MRI images from 21 subjects with WMS and age- and sex-matched control subjects. They found that the dorsal central sulcus was less likely to reach the interhemispheric fissure in subjects with WMS than in controls for both right and left hemispheres. No differences between the groups were found in the ventral extent of the central sulcus. They concluded that early neurodevelopmental problems affect the development of the dorsal forebrain and are probably related to the deficits in visuospatial ability and behavioral timing often observed in Williams syndrome. Schmitt et al. (2001) performed brain MRI on 20 patients with Williams syndrome to determine how cerebral shape differs from that of normal controls. In Williams syndrome, both cerebral hemispheres and the corpus callosum bend to a lesser degree in the sagittal plane, which the authors believed to be due to variation in the parietooccipital region. In addition, the cerebral hemispheres and corpus callosum midline lengths were decreased in Williams syndrome. Schmitt et al. (2001) suggested that the brain findings are consistent with aberrant premature termination of brain development, which proceeds normally in the rostrocaudal direction. Lenhoff et al. (2001) evaluated 5 patients with Williams syndrome for absolute musical pitch (AP; see 159300), which is the ability to recognize, name, and reproduce the pitch of a musical note without reference. The 5 patients had a mean IQ of 58 but were able to read musical notation. They began to play music at ages 5, 7, 8, 10, and 11 years, respectively. As a group, the 5 patients scored 97.5% on 1,084 absolute pitch trials, indicating that they possessed exceptional abilities in absolute pitch. By comparison, cognitively intact musicians who claim to have AP scored 84.3% on similar tests. Lenhoff et al. (2001) suggested that the prevalence of AP in individuals with Williams syndrome is higher than that in the general Western population (1 in 10,000) and noted that the age window of AP acquisition in Williams syndrome appears to be extended compared to the general population. Hickok et al. (1995) reported that brain imaging of patients with Williams syndrome suggested an exaggerated left-right asymmetry of the planum temporale, which had also been found in musicians with absolute pitch (Schlaug et al., 1995), suggesting a neuroanatomical correlate to the ability. Patients with Williams syndrome have relatively good abilities in face recognition and discrimination. Using functional MRI to assess facial recognition, Mobbs et al. (2004) found that 11 patients with WS showed increased activation in the right fusiform gyrus and several frontal and temporal regions, including subcortical structures. By contrast, control individuals showed greater activation in the primary and secondary visual cortices. The findings suggested that patients with WS have impairments in the visual cortical regions and use frontal and temporal regions as a compensatory mechanism. Primate visual cortex is organized into 2 functionally specialized, hierarchically organized processing pathways: a ventral stream for object processing and a dorsal stream for spatial processing. Patients with Williams syndrome show a visuospatial constructive deficit, which is an inability to visualize an object as a set of parts or to construct a replica. Using multimodal neuroimaging techniques, Meyer-Lindenberg et al. (2004) found that 13 high-functioning individuals with WS showed significant hypoactivation in dorsal stream areas during different visual tasks compared to controls. No differences were found in the ventral stream. Structural imaging studies showed that individuals with WS had gray matter volume reduction in the parietooccipital/intraparietal sulcus, immediately adjacent to the region of hypofunction, suggesting a structural-functional connection. Meyer-Lindenberg et al. (2005) used multimodal neuroimaging to characterize hippocampal structure, function, and metabolic integrity in 12 normal-intelligence patients with Williams syndrome and 12 age-, sex-, and IQ-matched healthy controls. PET and functional MRI studies showed profound reduction in resting blood flow and absent differential response to visual stimuli in the anterior hippocampal formation in patients with Williams syndrome. Spectroscopic measures of N-acetylaspartate, a marker of synaptic activity, were reduced. Hippocampal size was preserved, but subtle alterations in shape were present. Meyer-Lindenberg et al. (2005) suggested that hippocampal dysfunction might contribute to neurocognitive abnormalities in Williams syndrome. Castelo-Branco et al. (2007) presented evidence of a neural defect in the retina of WBS patients. High-resolution imaging techniques found that WBS patients had decreased retinal thickness, abnormal optic disc concavity, and impaired visual responses compared to controls. Low-level magnocellular performance was independent of deficits in the integration of information at higher levels. Marenco et al. (2007) performed brain diffusion tensor MRI to assess white matter integrity in 5 high-functioning WBS patients. Patients showed significant differences in white matter tissue organization compared to controls, particularly with respect to alterations in the main orientation of fibers underlying abnormalities in the gray matter. There appeared to be an increase in anterior-posterior longitudinal fibers and a reduction in right-to-left transverse axis fibers in the patients, consistent with the finding of other midline defects, such as dysgenesis of the corpus callosum. Marenco et al. (2007) hypothesized that there is specific alteration in the development of U fibers in the later stages of neuronal migration in patients with WBS and suggested that these abnormal patterns result from deletions of genes within the critical region. - Atypical Williams-Beuren Syndrome Morimoto et al. (2003) reported a Japanese male with a severe form of WBS associated with craniosynostosis and refractory infantile seizures. At age 5 months, he was diagnosed with peripheral pulmonary stenosis and mild ventricular hypertrophy. The seizures responded to ACTH, which had to be discontinued due to progression of the cardiac hypertrophy. EEG showed a variant of hypsarrhythmia. He also had an elfin face, failure-to-thrive, severe developmental delay, and dental malformation, in addition to congenital heart defects. FISH showed deletion of the elastin gene, and high-resolution chromosome analysis revealed interstitial deletion of 7q11.22-q11.23, consistent with Williams syndrome. At 2 years, his seizures were controlled, but his psychomotor development was severely delayed. Treatment with thyrotropin-releasing hormone (TRH) offered improvement in seizure control. Marshall et al. (2008) noted that seizures are not common in WBS. Using high resolution mapping to reexamine the patient reported by Morimoto et al. (2003), Marshall et al. (2008) found that the deletion was 4.4-Mb in length and extended telomeric to the classic WBS region. The deletion included the YWHAG gene (605356) but did not include the MAGI2 gene (606382); see the distal 7q11.23 deletion syndrome (613729). Tassabehji et al. (2005) identified an atypical Williams-Beuren syndrome individual with a smaller genetic deletion relative to classic Williams-Beuren syndrome cases but including 2 extratelomeric genes, CYLN2 (603432) and GTF2IRD1 (604318). The patient was a 4.5-year-old girl with surgically corrected pulmonary artery stenosis. Her birth weight and growth appeared normal, and at 4.5 years her height was just above the 50th centile. Facial features were suggestive of but not classic for Williams-Beuren syndrome. Early developmental milestones such as sitting and walking were within normal limits; however, by 18 months she had a vocabulary of only a few single words and by age 4 she continued to show a delay in language acquisition as well as serious deficits in spatial cognition, but to a lesser degree than that seen in Williams-Beuren syndrome patients.
Wang et al. (1999) analyzed 85 confirmed cases of 7q11.23 deletion and Williams-Beuren syndrome. Deletion of this region is responsible for 90 to 95% of all clinically typical cases. No statistically significant associations were found between clinical features ... Wang et al. (1999) analyzed 85 confirmed cases of 7q11.23 deletion and Williams-Beuren syndrome. Deletion of this region is responsible for 90 to 95% of all clinically typical cases. No statistically significant associations were found between clinical features and deletion size, inherited ELN and LIMK1 alleles, gender, and parental origin of the deletion. The data did not support the presence of imprinted genes in the WBS common deletion, despite a nonsignificant excess of maternal over paternal deletions. Maternal deletion cases were more likely to have a large head circumference. Pairwise comparisons between individual WBS clinical features showed significant association between (1) low birth weight and poor postnatal weight gain and (2) transient infantile hypercalcemia and a stellate iris pattern. The latter association was thought possibly to indicate a common underlying etiology. Tassabehji (2003) reviewed genotype-phenotype correlations in Williams syndrome. The WBS locus is prone to recurrent chromosomal rearrangements, including the microdeletion that causes WBS. Reciprocal duplications of the WBS interval should also occur, and Somerville et al. (2005) described such a case. The most striking phenotype was a severe delay in expressive speech, in contrast to the normal articulation and fluent expressive language observed in persons with WBS. The results suggested that specific genes at 7q11.23 are exquisitely sensitive to dosage alterations that can influence human language and visuospatial capabilities. See 609757 for a discussion of the WBS duplication syndrome, which is the reciprocal of the microdeletion that underlies the Williams-Beuren syndrome. Dai et al. (2009) provided a detailed genotype/phenotype analysis of a 7-year-old girl with WBS resulting from an atypical 7q11.2 deletion (Jarvinen-Pasley et al., 2008). She had some specific features of the disorder, including growth delay, characteristic facies, cardiovascular involvement with pulmonic stenosis and hypertension, delayed growth, and deficits in visual-spatial construction. However, in contrast to the usual findings in WBS, she had normal developmental milestones, comparatively high cognitive function, and did not have the typical delay in language or overly social behavior. By high-resolution oligonucleotide array CGH analysis, multicolor FISH analysis, and PCR analysis of somatic cell hybrids, they showed that the 1.26- to 1.31-Mb deletion included most of FKBP6, possibly NSUN5 and TRIM50 (612548), and all of the other genes in the interval through GTF2IRD1, but not GTF2I. Neuropsychologic studies showed that the patient had IQ scores 1 to 23 standard deviations above typical WBS children. Dai et al. (2009) postulated that deletion of the GTF2I gene may not play a role in some of the physical aspects of WBS, but may play an important role in some aspects of cognition and social behavior seen in the disorder. Since the patient did demonstrate defects in visual-spatial construction, deletion of GTF2IRD1 may play a role in that specific dysfunction. Dai et al. (2009) also found no correlation between neurocognitive performance and social behavior among 20 patients with typical WBS, suggesting that the normal social behavior in the atypical patient did not result from better cognition. Ferrero et al. (2010) reported an 11-year-old Italian boy with a mild form of WBS with mild facial features, normal IQ, and only some of the neuropsychologic features of the disorder, including visual-spatial defects and performance deficits. Although he demonstrated an extroverted personality in infancy, this disappeared as he got older. FISH analysis and quantitative PCR studies identified a de novo 0.84 to 0.94-Mb deletion in the core of the WBS critical region that partially included the BAZ1B gene (605681), but did not include the GTF2IRD1 or GTF2I genes. The findings were consistent with the hypothesis that hemizygosity of the GTF2IRD1 and GTF2I genes may be involved in the facial dysmorphism and specific motor and cognitive deficits observed in WBS patients, since extremes of these features were not found in the patient. Mervis et al. (2012) found that patients with WBS duplication syndrome (609757) had significantly higher levels of separation anxiety (see 607834) compared to patients with WBS and to the general population. Using a parental assessment form with review by a psychologist, Mervis et al. (2012) determined that 8 (29.6%) of 27 children with WBS duplication syndrome had separation anxiety disorder compared to only 9 (4.2%) of 214 patients with WBS. In addition, the proportion of WBS duplication patients with the disorder was significantly higher than in the general population (2.3%). Similar findings were obtained using a second assessment tool. Compared to mice with 1 or 2 copies of the Gtf2i gene, transgenic mice with 3 or 4 copies of the Gtf2i gene showed significantly increased maternal separation-induced anxiety as measured by ultrasonic vocalizations. The findings implicated a role for the GTF2I gene in separation anxiety. Vandeweyer et al. (2012) reported 2 healthy adult sibs with a heterozygous 83-kb deletion including only the CLIP2 gene (603432). The individuals were ascertained during a study involving a relative with global developmental delay due to another cause. Detailed physical and neurocognitive testing of the sibs with the CLIP2 deletion did not reveal any abnormalities in either individual. The findings suggested that haploinsufficiency for CLIP2 is not critical for the cognitive profile of WBS, which is in contrast to earlier studies that had implicated CLIP2 in some clinical manifestations of the disorder (see, e.g., Tassabehji et al., 2005, Dai et al., 2009, Ferrero et al., 2010).
Jones (1990) speculated that calcitonin-gene-related peptide (114130) may be implicated in this disorder. Using 5 restriction enzymes in the study of 13 families, each with at least 1 affected member, Hitman et al. (1989) could find no abnormality ... Jones (1990) speculated that calcitonin-gene-related peptide (114130) may be implicated in this disorder. Using 5 restriction enzymes in the study of 13 families, each with at least 1 affected member, Hitman et al. (1989) could find no abnormality of the calcitonin-CGRP gene. Furthermore, no association of the Williams-Beuren syndrome with polymorphism of this gene or of the parathormone (168450) locus was found. Russo et al. (1991) found no abnormality of the calcitonin/CGRP gene on Southern blot analysis of white blood cell DNA in 5 patients. Furthermore, the possibility of small deletions or point mutations within the exon encoding the mature calcitonin hormone was considered unlikely based on the negative findings of ribonuclease protection assays with patient DNA amplified by PCR. Thus the calcitonin deficiency found in these patients may be due either to mutations elsewhere in the gene or to defects in the cellular machinery needed for calcitonin synthesis and/or secretion. As with many other haploinsufficiency diseases, the mechanism underlying the WBS deletion is thought to be unequal meiotic recombination, probably mediated by the highly homologous DNA that flanks the commonly deleted region (Baumer et al., 1998). Osborne et al. (2001) used interphase fluorescence in situ hybridization (FISH) and pulsed field gel electrophoresis to identify a genomic polymorphism in families with WBS, consisting of an inversion of the WBS region. They found that the inversion was hemizygous in 3 of 11 (27%) atypical affected individuals who showed a subset of the WBS phenotypic spectrum but did not carry the typical WBS microdeletion. Two of these individuals also had a parent who carried the inversion. In addition, in 4 of 12 (33%) families with a proband carrying the WBS deletion, they observed the inversion exclusively in the parent transmitting the disease-related chromosome. These results suggested the presence of a genomic variant within the population that may be associated with WBS. The variant may result in predisposition to primarily WBS-causing microdeletions, but may also cause translocations and inversions. Scherer et al. (2005) reported 2 sibs with WBS and demonstrated that the 7q11 deletion was paternally inherited in both cases. Although DNA from the father was not available for study, the authors used site-specific nucleotide analysis and dosage comparisons to determine that the father carried the inverted WBS variant chromosome (WBSinv-1) reported by Osborne et al. (2001). The inversion of 7q11.23 on one chromosome 7 likely caused misalignment of the WBS region between sister chromatids during meiosis, resulting in deletion and/or duplication of the region during recombination. Scherer et al. (2005) concluded that presence of the WBSinv-1 variant, which is estimated to occur in 5% of the population, confers an increased risk of WBS in the offspring of carriers. The findings were significant in identifying a potential genetic risk factor for WBS. Williams-Beuren syndrome represents a model for studying hypertension in a genetically determined disorder. Haploinsufficiency of the elastin gene is known to lead to the vascular stenoses in WBS and is also thought to predispose to hypertension, which is present in approximately 50% of patients. Del Campo et al. (2006) performed detailed clinical and molecular characterization of 96 patients with WBS to explore clinical-molecular correlations. Deletion breakpoints were precisely defined and found to result in variability at 2 genes, NCF1 (608512) and GTF2IRD2 (608899). Hypertension was significantly less prevalent in patients with WBS who had a deletion that included NCF1 (p = 0.02), a gene encoding the p47(phox) subunit of NADPH oxidase. Decreased levels of the p47(phox) protein, decreased superoxide anion production, and lower protein nitrotyrosination were all observed in cell lines from patients hemizygous at NCF1. The results indicated that the loss of a functional copy of NCF1 protects a proportion of patients with WBS against hypertension, likely through a lifelong reduced angiotensin II (see 106150)-mediated oxidative stress. Del Campo et al. (2006) speculated that antioxidant therapy that reduces NADPH oxidase activity might have a benefit in identifiable patients with WBS in whom serious complications related to hypertension have been reported, as well as in forms of essential hypertension mediated by a similar pathogenic mechanism. Merla et al. (2006) measured the relative expression level of genes that map within the microdeletion that causes WBS and within its flanking regions. They found, unexpectedly, that not only hemizygous genes but also normal-copy neighboring genes showed decreased relative levels of expression. The results suggested that not only the aneuploid genes but also the flanking genes that map several megabases away from a genomic rearrangement should be considered possible contributors to the phenotypic variation in genomic disorders. Kaminsky et al. (2011) presented the largest copy number variant case-control study to that time, comprising 15,749 International Standards for Cytogenomic Arrays cases and 10,118 published controls, focusing on recurrent deletions and duplications involving 14 copy number variant regions. Compared with controls, 14 deletions and 7 duplications were significantly overrepresented in cases, providing a clinical diagnosis as pathogenic. The 7q11.23 deletion was identified in 34 cases and no controls for a p value of 8.49 x 10(-8) and a frequency of 1 in 463 cases.
Grimm and Wesselhoeft (1980) estimated the frequency of Williams syndrome to be 1 in 10,000.
Stromme et al. (2002) estimated that the Williams-Beuren syndrome occurs at a frequency of approximately 1 in 7,500 live births, with ... Grimm and Wesselhoeft (1980) estimated the frequency of Williams syndrome to be 1 in 10,000. Stromme et al. (2002) estimated that the Williams-Beuren syndrome occurs at a frequency of approximately 1 in 7,500 live births, with approximately two-thirds of the deletion events being intrachromosomal.
Clinical diagnostic criteria are available for Williams syndrome (WS) [Preus 1984, Committee on Genetics 2001, Committee on Genetics 2002]....
Diagnosis
Clinical DiagnosisClinical diagnostic criteria are available for Williams syndrome (WS) [Preus 1984, Committee on Genetics 2001, Committee on Genetics 2002].The WS phenotype is variable, and no single clinical feature is required to establish the diagnosis. Williams syndrome is suspected in individuals with the following findings:Cardiovascular disease (elastin arteriopathy). Any artery may be narrowed. Supravalvar aortic stenosis (SVAS) is the most clinically significant and most common cardiovascular finding; it occurs in 75% of affected individuals. Peripheral pulmonic stenosis (PPS) is common in infancy.Distinctive facies. Broad forehead, bitemporal narrowing, periorbital fullness, a stellate/lacy iris pattern (Figure 1), strabismus, short nose, broad nasal tip, malar flattening, long philtrum, thick vermilion of the upper and lower lips, wide mouth, malocclusion, small jaw, and large ear lobes are observed at all ages (Figure 2). Young children have epicanthal folds, full cheeks, and small, widely spaced teeth (Figure 3), while adults typically have a long face and neck, accentuated by sloping shoulders, resulting in a more gaunt appearance (Figure 4).Connective tissue abnormalities. Hoarse voice, inguinal/umbilical hernia, bowel/bladder diverticulae, rectal prolapse, joint limitation or laxity, and soft, lax skin are observed.Intellectual disability. Most individuals have some degree of intellectual disability, which can range from severe to mild. Some have average intelligence.Specific cognitive profile. Strengths in verbal short-term memory and language and extreme weakness in visuospatial construction are typical. The Williams syndrome cognitive profile is independent of IQ.Unique personality. Overfriendliness, empathy, generalized anxiety, specific phobias, and attention deficit disorder are commonly observed.Growth abnormalities. The growth pattern is characterized by: prenatal growth deficiency, failure to thrive in infancy (70%), poor weight gain and linear growth in the first four years; a rate of linear growth that is 75% of normal in childhood; and a brief pubertal growth spurt. The mean adult height is below the third centile.Endocrine abnormalities. Findings include: idiopathic hypercalcemia, hypercalciuria, hypothyroidism, and early (but not precocious) puberty. An increased frequency of subclinical hypothyroidism, abnormal oral glucose tolerance tests, and diabetes mellitus is observed in adults with WS.FigureFigure 1. Note the stellate iris pattern in an individual with Williams syndrome. FigureFigure 2. A broad forehead, bitemporal narrowing, periorbital fullness, strabismus, short nose, broad nasal tip, malar flattening, long philtrum, thick vermilion of the upper and lower lips, wide mouth, malocclusion, small jaw, and large earlobes are (more...)FigureFigure 3. Young children with Williams syndrome typically have epicanthal folds, full cheeks, and small, widely spaced teeth as seen in these children at the following ages: A, newborn; B, 10 months; C and D, 21 months. FigureFigure 4. Adults typically have a long face and neck, accentuated by sloping shoulders, resulting in a gaunt appearance, as seen in this 43-year-old affected individual. Molecular Genetic TestingGene. Contiguous gene deletions in the Williams-Beuren syndrome critical region (WBSCR) are known to be associated with Williams syndrome.Clinical testingTable 1. Summary of Molecular Genetic Testing Used in Williams SyndromeView in own windowCritical Region 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3Test AvailabilityWBSCR
FISH 4Deletion of WBSCR 100%ClinicalDeletion/duplication testing 5, 61. See Table A. Genes and Databases for chromosome locus and protein name.2. See Molecular Genetics for information on allelic variants and genes within the WBSCR.3. The ability of the test method used to detect a deletion in the indicated critical region4. A commonly used commercially available FISH probe covers approximately 180 kb of the WBSCR deleted in WS including the genes ELN and LIMK1 and the D7S613 locus [Ewart et al 1993a, Lowery et al 1995, Mari et al 1995, Nickerson et al 1995].5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. 6. Some laboratories may analyze only three genes within the WBSCR: ELN, LIMK1, and GTF2I [Somerville et al 2002].Testing StrategyTo confirm/establish the diagnosis in a proband, molecular genetic testing (FISH or deletion/duplication analysis) that detects deletion of the WBSCR is necessary.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require molecular genetic testing that detects deletion of the WBSCR. Genetically Related (Allelic) DisordersAutosomal dominant cutis laxa is caused by frameshift ELN mutations that have a dominant-negative effect on elastic fiber structure [Tassabehji et al 1998, Zhang et al 1999, Sugitani et al 2012].Autosomal rececssive cutis laxa has been reported in a Syrian family with a homozygous recessive mutation in ELN exon 12 [Mégarbané et al 2009]. Autosomal dominant supravalvar aortic stenosis (SVAS) is caused by mutation or intragenic deletion of ELN [Ewart et al 1993b, Olson et al 1993, Morris & Mervis 2000, Micale et al 2010]. Individuals with autosomal dominant SVAS typically have only connective tissue abnormalities, and thus do not have WS. Autosomal dominant "SVAS plus" is caused by deletion of contiguous genes in the WBSCR that includes ELN and other contiguous genes. Members of families with these short deletions have SVAS rather than classic WS; however, they share some phenotypic features with WS, including difficulty with visuospatial construction [Morris & Mervis 2000, Morris et al 2003].Duplication 7q11.23 syndrome (Williams syndrome region duplication syndrome) is caused by duplication of the contiguous genes in the WBSCR. Typical facial features include prominent and/or broad forehead, long eyelashes, low-hanging columnella of nose, short philtrum, high-arched palate, mild facial asymmetry, thin vermilion of the upper and lower lips, and retrognathia. The most significant clinical finding is severe impairment in expressive language including a phonologic disorder, in contrast to the relative strength in language exhibited by individuals with WS. Many have ADHD and/or anxiety, typically separation or social anxiety. Many children have difficulty with unipedal stance and tandem gait [Somerville et al 2005, Berg et al 2007, Van der Aa et al 2009, Dixit et al 2013].
Infancy. The infant with WS is often born post-term and is small for the family background. Feeding difficulties leading to failure to thrive are common, including gastroesophageal (G-E) reflux, disordered suck and swallow, textural aversion, and vomiting. Prolonged colic (>4 months) may be related to G-E reflux, chronic constipation, and/or idiopathic hypercalcemia. Other medical problems that often occur in the first year include strabismus, chronic otitis media, rectal prolapse, umbilical and/or inguinal hernia, and cardiovascular disease [Morris et al 1988]. Infants with WS are hypotonic and typically have hyperextensible joints, resulting in delayed attainment of motor milestones. Walking usually occurs by age 24 months. Speech is also delayed but later becomes a relative strength. Fine motor difficulties are present at all ages....
Natural History
Infancy. The infant with WS is often born post-term and is small for the family background. Feeding difficulties leading to failure to thrive are common, including gastroesophageal (G-E) reflux, disordered suck and swallow, textural aversion, and vomiting. Prolonged colic (>4 months) may be related to G-E reflux, chronic constipation, and/or idiopathic hypercalcemia. Other medical problems that often occur in the first year include strabismus, chronic otitis media, rectal prolapse, umbilical and/or inguinal hernia, and cardiovascular disease [Morris et al 1988]. Infants with WS are hypotonic and typically have hyperextensible joints, resulting in delayed attainment of motor milestones. Walking usually occurs by age 24 months. Speech is also delayed but later becomes a relative strength. Fine motor difficulties are present at all ages.Cognitive abilities. Intellectual disability, usually mild, occurs in 75% of individuals with WS. The cognitive profile is distinctive, consisting of strengths in verbal short-term memory and language but extreme weakness in visuospatial constructive cognition. As a result, children with WS usually score higher on verbal subtests than on tests measuring visuospatial construction [Greer et al 1997, Mervis et al 1998]. No gender difference in IQ is reported and the IQ is stable over time in children [Mervis et al 2012b]. Academically, individuals with WS perform relatively well in reading, and adults may read at the high school level, though the range of achievement is wide. Reading skills correlate with cognitive ability rather than language-related skills [Levy et al 2003]. Difficulty with writing, drawing, and mathematics is significant; however, many adults with WS are able to perform simple addition.Adaptive behavior is commensurate with IQ in children [Mervis et al 2001], but adaptive behavior is less than expected for IQ in adults [Davies et al 1997], adversely affecting the ability of adults with WS to function independently.Unique personality. The characteristic personality profile of WS includes overfriendliness, social disinhibition, excessive empathy, attention problems, and non-social anxiety [Einfeld et al 2001, Doyle et al 2004, Morris 2010, Munoz et al 2010]. Other common behavior problems include difficulty with sensory modulation/sensory processing, perseveration, unusual or restricted interests, sleep difficulties, and specific phobias (80%) [Dykens 2003, Laws & Bishop 2004, John & Mervis 2010]. Compared to other children with disabilities, children with WS rate high on measures of the following: empathy, gregariousness, people-orientation, tenseness, sensitivity, and "visibility" (easily noticed) [Klein-Tasman & Mervis 2003]. In children, attention deficit disorder occurs in 65% and anxiety disorder in 57% (usually specific phobias) [Leyfer et al 2006]. Anxiety is common across the life span; longitudinal studies of anxiety indicate a prevalence of 80% [Woodruff-Borden et al 2010].Cardiovascular disease. Elastin arteriopathy is present in 75%-80% of affected individuals and may affect any artery [Morris et al 1988, Pober et al 2008, Del Pasqua et al 2009, Collins et al 2010b]. Males are more likely to have severe cardiovascular disease than females [Sadler et al 2001].Peripheral pulmonic stenosis (PPS) is common in infancy but usually improves over time.The most common arteriopathy is supravalvar aortic stenosis (SVAS), which may worsen over time, especially in the first five years of life [Collins et al 2010b]. The greatest morbidity results from this aortic narrowing, which can be either a discrete hourglass stenosis or diffuse aortic hypoplasia. If untreated, the resultant increase in arterial resistance leads to elevated left heart pressure, cardiac hypertrophy, and cardiac failure. Middle aortic syndrome, including diffuse narrowing of the thoracic and abdominal aorta, occurs rarely but can be difficult to treat and may require reintervention [Radford & Pohlner 2000]. Individuals with combined SVAS and PPS (biventricular outflow tract obstruction) may develop biventricular hypertrophy and hypertension, increasing the risk for myocardial ischemia, dysrhythmias, and sudden death [Pham et al 2009]. Coronary artery stenosis has been implicated in some cases of sudden death in WS [Bird et al 1996]. The incidence of sudden death in one cohort of 293 individuals with WS was 1/1000 patient years, which is 25 to 100 times higher than the age-matched population [Wessel et al 2004]. Corrected QT prolongation has been reported in 13.6% of individuals with WS; screening for repolarization abnormalities is recommended [Collins et al 2010a].The prevalence of hypertension in individuals with WS is 40%-50%. Hypertension may present at any age [Broder et al 1999, Giordano et al 2001, Eronen et al 2002, Bouchireb et al 2010] and may be secondary to renal artery stenosis in some cases [Deal et al 1992].Mitral valve prolapse and aortic insufficiency have been reported in adults [Morris et al 1990, Kececioglu et al 1993, Collins et al 2010a].Stenosis of the mesenteric arteries may contribute to abdominal pain.Neurovascular abnormalities are rarely reported but may result in stroke [Ardinger et al 1994, Soper et al 1995, Cherniske et al 2004].Eye, ear, nose, and throat. Hyperopia and strabismus are found in 50% of individuals with WS [Kapp et al 1995]. Cataracts have been reported in adults [Cherniske et al 2004].Chronic otitis media is seen in 50% of affected individuals. Increased sensitivity to sound is common (90%), and individuals with WS report discomfort at 20 decibels (db) lower than controls [Gothelf et al 2006]. Many report specific phobias for certain sounds [Levitin et al 2005].Progressive sensorineural hearing loss has been observed; mild to moderate hearing loss is detected in 63% of children and 92% of adults [Gothelf et al 2006, Marler et al 2010]. Mild to moderate high-frequency sensorineural hearing loss is common in adults, as is excessive build-up of ear wax [Cherniske et al 2004].Most individuals have a hoarse or low-pitched voice; vocal cord abnormalities secondary to elastin deficiency are likely causative [Vaux et al 2003].Dental problems include microdontia, enamel hypoplasia, and malocclusion [Hertzberg et al 1994]. One or more permanent teeth are missing in 40% of individuals with WS [Axelsson et al 2003].Gastrointestinal difficulties. Individuals with WS have sensory defensiveness, both auditory [Van Borsel et al 1997] and tactile. The difficulty with food textures leads to problems in transitioning from breast milk or formula to solid foods in infancy.Chronic abdominal pain is a common complaint of children and adults with WS; possible causes include G-E reflux, hiatal hernia, peptic ulcer disease, cholelithiasis, diverticulitis, ischemic bowel disease, chronic constipation, and somatization of anxiety. The prevalence of diverticulitis is increased in adolescents [Stagi et al 2010] and adults with WS [Partsch et al 2005].Hypercalcemia may contribute to irritability, vomiting, constipation, and muscle cramps; it is more common in infancy but may recur in adults [Morris et al 1990, Pober et al 1993].In one study, the incidence of celiac disease was increased in children with WS (9.6% vs 0.5% in the general population) [Giannotti et al 2001] (see Celiac Disease).Urinary tract abnormalities. Urinary frequency and enuresis (50%) are common in children with WS. Renal artery stenosis is found in 50% of individuals with WS, structural abnormalities of the urinary tract in 35%-50%, bladder diverticulae in 40%, chronic urinary tract infections in 30% of adults, and nephrocalcinosis in fewer than 5% [Pober et al 1993, Pankau et al 1996, Sforzini et al 2002, Sammour et al 2006]. Bladder capacity is reduced, and detrusor overactivity is observed in 60% [Sammour et al 2006]. Average daytime urinary continence is at age four years, nocturnal continence occurs in 50% by age ten years.Musculoskeletal/neurologic problems. The hypotonia and lax joints of the young child lead to abnormal compensatory postures to achieve stability. Older children and adults with WS typically have hypertonia and hyperactive deep-tendon reflexes. Gradual tightening of the heel cords and hamstrings occurs, resulting in a stiff and awkward gait, kyphosis, and lordosis by adolescence [Morris et al 1988, Kaplan et al 1989]. Fine motor function is impaired, leading to difficulty with tool use and handwriting at all ages.Cerebellar signs in adults include ataxia, dysmetria, and tremor [Pober & Morris 2007].Neuroimaging. Reduced brain size, reduced gray matter volume especially in the parietal and occipital regions, and increased gyral complexity are seen on brain MRI [Jackowski et al 2009, Eisenberg et al 2010]. Reduced posterior fossa size coupled with preserved cerebellar size may contribute to Chiari 1 malformation found in some affected individuals [Pober & Filiano 1995, Mercuri et al 1997].Growth. Individuals with WS are short for their family background. Specific growth curves for WS are available [Morris et al 1988, Saul et al 1988, Martin et al 2007]. Failure to thrive is observed in 70% of infants. The growth pattern is characterized by prenatal growth deficiency, poor weight gain, and poor linear growth in the first four years, a rate of linear growth that is 75% of normal in childhood, and a brief pubertal growth spurt. The mean adult height is below the third centile.Puberty usually occurs early [Partsch et al 2002], but true precocious puberty is rare.Endocrine problems. Endocrine abnormalities include hypercalciuria (30%), idiopathic hypercalcemia (15%-50%), hypothyroidism (10%), and early (though not precocious) puberty (50%). An increased frequency of subclinical hypothyroidism, abnormal oral glucose tolerance tests, and diabetes mellitus is observed in adults with WS [Cherniske et al 2004].OtherThe hair grays prematurely [Morris et al 1988].Sleep problems are common in WS, including increased sleep latency and decreased sleep efficiency [Goldman et al 2009, Mason et al 2011].
The WBSCR deletion comprises 1.55 megabases (Mb) in 95% of individuals with WS and 1.84 Mb in 5% [Bayes et al 2003]....
Genotype-Phenotype Correlations
The WBSCR deletion comprises 1.55 megabases (Mb) in 95% of individuals with WS and 1.84 Mb in 5% [Bayes et al 2003].Hypertension is less prevalent in those individuals with WS who are hemizygous for NCF1, located in one of the blocks of low copy repeats that flank the WBSCR [Del Campo et al 2006].A more severe phenotype with lower cognitive ability is observed in individuals with very large deletions (> 2-4 Mb) that include the WBSCR than in individuals with the typical WBSCR deletion [Stock et al 2003, Marshall et al 2008].Shorter deletions within the WBSCR have a variable phenotype depending on the extent of the deletion.Individuals with WBSCR deletions that include the usual telomeric breakpoint (including GTF2I) have classic WS features, including intellectual disability [Botta et al 1999, Heller et al 2003].Those with short WBSCR deletions that do not include deletion of GTF2I, – including some individuals with de novo short deletions and families with "SVAS plus" – do not have intellectual disability but often demonstrate the WS cognitive profile [Morris et al 2003]. In two families, deletion of ELN and an additional gene, LIMK1, was associated with the WS cognitive profile but not with intellectual disability or other characteristics of WS [Frangiskakis et al 1996]. Another family with a similar deletion did not have the WS cognitive profile [Tassabehji et al 1998].The WBSCR deletion may be of maternal or paternal origin [Ewart et al 1993a, Dutly & Schinzel 1996, Urban et al 1996]. No phenotypic differences have been related to the parent of origin in some series [Wu et al 1998], while microcephaly has been correlated with maternal origin of the WBSCR deletion in others [Del Campo et al 2006].
WS should be distinguished from other syndromes that include developmental delay, short stature, distinctive facies, and congenital heart disease. These include: Noonan syndrome, deletion 22q11 (DiGeorge syndrome), Smith-Magenis syndrome, Kabuki syndrome, and fetal alcohol syndrome (FAS)....
Differential Diagnosis
WS should be distinguished from other syndromes that include developmental delay, short stature, distinctive facies, and congenital heart disease. These include: Noonan syndrome, deletion 22q11 (DiGeorge syndrome), Smith-Magenis syndrome, Kabuki syndrome, and fetal alcohol syndrome (FAS).Individuals with SVAS should be evaluated to determine if WS or autosomal dominant SVAS is the appropriate diagnosis.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with Williams syndrome, and to guide medical management, the following evaluations are recommended [Morris et al 1999, Committee on Genetics 2001, Committee on Genetics 2002]:...
Management
Evaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Williams syndrome, and to guide medical management, the following evaluations are recommended [Morris et al 1999, Committee on Genetics 2001, Committee on Genetics 2002]:Complete physical and neurologic examinationPlotting of growth parameters on Williams syndrome growth chartsCardiology evaluationFull clinical evaluation by a cardiologist, with measurement of blood pressure in all four limbsEchocardiogram, including Doppler flow studiesElectrocardiogram to evaluate for repolarization abnormalities (prolonged cQT)Urinary system evaluationUltrasound examination of the bladder and kidneysSerum concentration of BUN and creatinineUrinalysisCalcium determinationsSerum concentration of calcium or ionized calciumCalcium/creatinine determination on a spot urine sample (see Sargent et al [1993] for normal values).Thyroid function testsOphthalmologic evaluationBaseline audiologic evaluationGenetics evaluation/consultation for individualized assessment/recommendations and discussion of clinical manifestations, natural history, and recurrence risksMultidisciplinary developmental evaluation, including assessment of motor, speech, language, personal-social, general cognitive, and vocational skillsAssessment of behavior including attention, anxiety, and adaptive skillsTreatment of ManifestationsDevelopmental disabilities should be addressed by early intervention programs, special education programs, and vocational training. Recommended therapies include speech/language, physical, and occupational, especially sensory integration.Verbal strengths can be used to assist in learning spatial tasks.Phonics methods are recommended to teach reading [John & Mervis 2010].Mastery of daily living skills contributes to adult well-being and should be encouraged.Psychological evaluation, polysomnography, and psychiatric evaluation should guide therapy for the individual. Behavior in young children may be addressed using techniques based on applied behavior analysis.Behavioral counseling and psychotropic medication are often used to manage behavior problems, especially attention deficit disorder and anxiety, which require pharmacologic treatment in approximately 50% [Cherniske et al 2004]. Self-calming techniques can help manage anxiety.Surgical correction of SVAS is required in 20-30% [Kececioglu et al 1993, Bruno et al 2003, Collins et al 2010b]. Surgical treatment of mitral valve insufficiency or renal artery stenosis may be required.Hypertension is usually treated medically. In one series, calcium channel blockers were used successfully [Bouchireb et al 2010].Management of hypercalcemia involves the following:The diet should be adjusted with the help of a nutritionist so that the calcium intake is not higher than 100% of the recommended daily allowance (RDA). If the serum concentration of calcium remains elevated, dietary calcium should be reduced; but the serum concentration of calcium must be monitored.Refractory hypercalcemia may be treated with oral steroids.Intravenous pamidronate has been used successfully to treat infants with severe symptomatic hypercalcemia [Cagle et al 2004, Oliveri et al 2004].Referral to a nephrologist is recommended for treatment of nephrocalcinosis or persistent hypercalcemia and/or hypercalciuria.Hyperopia is treated with corrective lenses; strabismus is treated with patching of one eye or surgery.Recurrent otitis media may be treated with tympanotomy tubes.Hypersensitivity to sounds may be treated with ear protection when increased noise levels can be predicted.Dental care may require assistance with daily brushing and flossing. Dental cleanings should be done every three months. Orthodontic referral should be considered for treatment of malocclusion.The treatment of feeding problems in infancy and abdominal pain in children and adults depends upon the cause (e.g., G-E reflux, hypercalcemia, hiatal hernia, and/or diverticulitis). Infants often benefit from feeding therapy. Constipation should be aggressively managed at all ages to prevent early onset diverticulosis/diverticulitis. Severe abdominal pain may indicate diverticulitis, which may occur at a young age in WS.Early puberty may be treated with a gonadotropin-releasing hormone agonist [Partsch et al 2002, Pober 2010].Prevention of Secondary ComplicationsThe following are indicated:Exercise and a balanced diet to avoid insulin resistance/diabetes mellitusRange of motion exercises to prevent or ameliorate joint contracturesBecause of the increased risk for myocardial insufficiency in individuals with biventricular outflow tract obstruction, especially during induction of anesthesia [Horowitz et al 2002], anesthesia consultation for surgical procedures. Electrocardiogram to screen for repolarization abnormalities prior to surgery.Awareness of the risk of myocardial insufficiency; for surgical procedures, use of a center equipped for cardiopulmonary resuscitationSurveillanceTable 2. Surveillance for Williams SyndromeView in own windowInterval/AgeTest/MeasurementInfancy
• Serum calcium determination every 4-6 months until age 2 yearsAnnual• Medical evaluation • Vision screening to monitor for refractive errors and strabismus • Hearing evaluation • Monitoring of blood pressure in both arms • Measurement of calcium/creatinine ratio in a random spot urine and urinalysis • Cardiology evaluation at least yearly for the first 5 years, every 2-3 years thereafterEvery 2 years• Serum concentration of calciumEvery 3 years• Thyroid function and TSH levelEvery 10 years• Renal and bladder ultrasound examinationIn adults• Oral glucose tolerance test (OGTT) starting at age 30 years to evaluate for diabetes mellitus 1• Evaluation for mitral valve prolapse, aortic insufficiency, and arterial stenoses • Evaluation for cataracts1. If normal, OGTT should be repeated every five years.Agents/Circumstances to AvoidChildren with WS should not be given multivitamins because all pediatric multivitamin preparations contain vitamin D.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Williams Syndrome: Genes and DatabasesView in own windowCritical RegionGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDELN7q11.23
ElastinELN homepage - Mendelian genesELNWBSCRUnknown7q11.2Unknown Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Williams Syndrome (View All in OMIM) View in own window 130160ELASTIN; ELN 194050WILLIAMS-BEUREN SYNDROME; WBS 605678MLX-INTERACTING PROTEIN-LIKE; MLXIPLMolecular Genetic PathogenesisBoth the deletion of the WBSCR that causes WS and the duplication of the WBSCR are mediated by the genomic structure of the region. The WBSCR is flanked by low copy repeats that predispose to nonallelic homologous recombination. In 95% of individuals with WS the deletion comprises 1.55 Mb; in 5% it comprises 1.84 Mb [Bayes et al 2003]; the deletion is mediated by nonallelic homologous recombination between blocks of low copy repeats (LCRs), and the size of deletion reflects which blocks are involved. Inversion of the WS region is present in 25% of WS progenitors and 6% of the general population; individuals with an inversion have a 1/1750 chance to have a child with WS [Hobart et al 2010]. The inversion does not cause clinical symptoms [Tam et al 2008]. Three genes, GTF2I, GTF2IRD1, and GTF2IRD2, have been identified in the telomeric region of the WBSCR and adjacent LCR. These members of the TFII-I gene family are likely to play an important role in the WS phenotype because they can bind at both basal and upstream regulatory sites in various promoters. These transcription factor proteins are involved in complex protein interactions and have a role in signal transduction. Each of the proteins in the family has isoforms that have different expression patterns in different tissues, raising the possibility that hemizygosity of these genes could contribute to many different aspects of the WS phenotype [Hinsley et al 2004, Jackson et al 2005]. Normal allelic variants. A number of genes have been mapped within the WBSCR region:ELN (elastin). Deletion of ELN is responsible for the connective tissue abnormalities, including the cardiovascular disease in WS [Ewart et al 1993a].LIMK1 (lim kinase 1), expressed in the brain. Deletion of LIMK1 has been implicated in the abnormality of visuospatial constructive cognition in WS [Frangiskakis et al 1996, Morris et al 2003, Hoogenraad et al 2004].GTF2I (general transcription factor II, I) [OMIM 601679]. GTF2I encodes transcription factor TFII-I [Perez Jurado et al 1998, Danoff et al 2004]. Deletion mapping of "SVAS plus" families has suggested that deletion of this gene has a negative effect on IQ [Morris et al 2003]. Duplication of the gene is associated with separation anxiety [Mervis et al 2012a]STX1A (syntaxin 1A) [OMIM 186590], involved in neurotransmitter release and insulin secretion. STX1A may have a role in diabetes in WS [Osborne et al 1997, Lam et al 2005].BAZ1B (bromodomain adjacent to a leucine zipper 1B). The BAZ1B protein is part of a chromatin remodeling complex. Because it binds the vitamin D receptor, it has been theorized that it may have a role in hypercalcemia in WS [Meng et al 1998a].CLIP2 (cytoplasmic linker 2). Strongly expressed in the brain, the CLIP2 protein interacts with membrane microtubules and is postulated to be involved in cerebellar abnormalities in WS [Hoogenraad et al 1998, Hoogenraad et al 2004] [OMIM 603432].GTF2IRD1. Part of the TFII-1 transcription family, GTF2IRD1 has been implicated in the craniofacial features of WS [Osborne et al 1999, Tassabehji et al 2005].NCF1 (neutrophil cytosolic factor 1). NCF1 encodes a component of the NADPH oxidase system. Hemizygosity for NCF1 is associated with a decreased risk for hypertension in WS. It is deleted in approximately 40% of individuals with WS [Del Campo et al 2006].For the remaining genes in the WBSCR, the relationship to the WS phenotype is unknown:RFC2 (replication factor C, subunit 2) [OMIM 600404], involved in DNA elongation [Peoples et al 1996]FZD9 (frizzled 9) [OMIM 601766], homologous to Drosophila frizzled gene [Wang et al 1997]; encodes transmembrane cell surface receptor that binds to Wnt proteins to alter the beta catenin pathway.FKBP6, homologous to FK-506 binding protein class of immunophilins [Meng et al 1998b]TBL2 [Meng et al 1998a]MLXIPL (WS-basic helix-loop-helix leucine zipper) [Meng et al 1998a, Cairo et al 2001]VPS37D [Schubert 2009]DNAJC30 encoding a heat shock protein [Merla et al 2002].BCL7B, [Meng et al 1998a]ABHD11 [Merla et al 2002]CLDN4 [Paperna et al 1998] [OMIM 602909]CLDN3 [Paperna et al 1998] [OMIM 602910]EIF4H [Osborne et al 1996, Richter-Cook et al 1998] [OMIM 603431]LAT2 [Brdicka et al 2002]WBSCR11 [Osborne et al 1999]WBSCR22 [Merla et al 2002]WBSCR23, WBSCR27 and WBSCR28 [Schubert 2009]GTF2IRD2, sometimes deleted in WS [Makeyev et al 2004, Tipney et al 2004]Pathologic allelic variants. Mutations of ELN typically result in autosomal dominant SVAS [Li et al 1997]. ELN mutations have also been reported in congenital cutis laxa [Tassabehji et al 1998, Zhang et al 1999].Normal gene productThe ELN gene product is the structural protein elastin, a major component of elastic fibers found in many tissues.Lim kinase 1 has two LIM motifs and a protein kinase domain that may be involved in intracellular signaling.RFC 2 is a primer recognition protein involved in DNA elongation.Syntaxin 1A mediates neurotransmitter release through protein-protein interactions.Frizzled is a member of a family of domain receptors.GTF2I encodes a transcription factor, TFII-I.CYLN2 encodes CLIP-115, a cytoplasmic linker protein.Abnormal gene product. Unknown