Clinical characteristics.

Williams syndrome (WS) is characterized by cardiovascular disease (elastin arteriopathy, peripheral pulmonary stenosis, supravalvar aortic stenosis, hypertension), distinctive facies, connective tissue abnormalities, intellectual disability (usually mild), a specific cognitive profile, unique personality characteristics, growth abnormalities, and endocrine abnormalities (hypercalcemia, hypercalciuria, hypothyroidism, and early puberty). Feeding difficulties often lead to failure to thrive in infancy. Hypotonia and hyperextensible joints can result in delayed attainment of motor milestones.

Diagnosis/testing.

Clinical diagnostic criteria are available for Williams syndrome; however, the mainstay for diagnosis is detection of the contiguous gene deletion of the Williams-Beuren syndrome critical region (WBSCR) that encompasses the elastin gene (ELN). More than 99% of individuals with the clinical diagnosis of WS have this contiguous gene deletion, which can be detected using fluorescent in situ hybridization (FISH) and/or deletion/duplication testing.

Management.

Treatment of manifestations: Early intervention programs, special education programs, and vocational training address developmental disabilities; programs include speech/language, physical, occupational, feeding, and sensory integration therapies. Psychological and psychiatric evaluation and treatment provide individualized behavioral counseling and medications, especially for attention deficit disorder and anxiety. Surgery may be required for supravalvar aortic or pulmonary artery stenosis, mitral valve insufficiency, and/or renal artery stenosis. Treatment of hypercalcemia may include diet modification, oral corticosteroids, and/or intravenous pamidronate. Refer to a nephrologist for management of nephrocalcinosis, persistent hypercalcemia, and/or hypercalciuria. Treatment of hypertension, hyperopia, and recurrent otitis media does not differ from that in the general population. Orothodontic referral should be considered for malocclusion. Infants with feeding problems may benefit from feeding therapy. Constipation should be aggressively managed at all ages. Early puberty may be treated with a gonadotropin-releasing hormone agonist.

Prevention of secondary complications: Range of motion exercises to prevent or ameliorate joint contractures; anesthesia consultation and electrocardiogram to screen for repolarization abnormalities prior to surgical procedures.

Surveillance: Yearly medical evaluation, vision screening, hearing evaluation, measurement of blood pressure in both arms, measurement of calcium/creatinine ratio in a random spot urine, and urinalysis. Children under age two years should have serum calcium studies every four to six months. Additional periodic evaluations during childhood include: measurement of serum concentration of calcium every two years; assessment of thyroid function every three years; cardiology evaluation for elastin arteriopathy and long QT at least yearly for the first five years and every two to three years thereafter; and renal and bladder ultrasound examination every ten years. Periodic evaluations during adulthood include: oral glucose tolerance; cardiac evaluation for mitral valve prolapse, aortic insufficiency, and arterial stenosis; and ophthalmologic evaluation for cataracts.

Agents/circumstances to avoid: Multivitamins for children because all pediatric multivitamin preparations contain vitamin D.

Genetic counseling.

Williams syndrome is transmitted in an autosomal dominant manner. Most cases are de novo occurrences, but occasionally, parent-to-child transmission is observed. Prenatal testing is possible but is rarely used because most cases occur in a single family member only; and no prenatal indicators exist for low-risk pregnancies.

Clinical Diagnosis

Clinical 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.

Figure 1.

Note the stellate iris pattern in an individual with Williams syndrome.

Figure 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 observed at (more...)

Figure 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.

Figure 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 Testing

Gene. Contiguous gene deletions in the Williams-Beuren syndrome critical region (WBSCR) are known to be associated with Williams syndrome.

Clinical testing

Testing Strategy

To 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.

Clinical Description

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].

Other

• The 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].

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].

Penetrance

Penetrance is 100%; expression of the phenotypic features is variable.

Nomenclature

The first descriptions of WS were incomplete in that they reflected the chief complaint of the individual or the medical specialty of the observer. Thus, nephrologists and endocrinologists described "idiopathic infantile hypercalcemia" (IHC), and cardiologists reported "supravalvular aortic stenosis syndrome" (SASS).

Early reports also noted dysmorphic facial features that were thought to resemble elves of legend; and, for a time, the term "Williams elfin facies syndrome" was used.

After the reports of Williams et al [1961] and Beuren et al [1962], the condition was called Williams syndrome in the US and Williams-Beuren syndrome in Europe.

Prevalence

A study of WS in Norway reported a prevalence of 1:7500 [Stromme et al 2002].

Evaluations Following Initial Diagnosis

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]:

• Complete physical and neurologic examination
• Plotting of growth parameters on Williams syndrome growth charts
• Cardiology evaluation
  • Full clinical evaluation by a cardiologist, with measurement of blood pressure in all four limbs
  • Echocardiogram, including Doppler flow studies
  • Electrocardiogram to evaluate for repolarization abnormalities (prolonged cQT)
• Urinary system evaluation
  • Ultrasound examination of the bladder and kidneys
  • Serum concentration of BUN and creatinine
  • Urinalysis
• Calcium determinations
  • Serum concentration of calcium or ionized calcium
  • Calcium/creatinine determination on a spot urine sample (see Sargent et al [1993] for normal values).
• Thyroid function tests
• Ophthalmologic evaluation
• Baseline audiologic evaluation
• Genetics evaluation/consultation for individualized assessment/recommendations and discussion of clinical manifestations, natural history, and recurrence risks
• Multidisciplinary developmental evaluation, including assessment of motor, speech, language, personal-social, general cognitive, and vocational skills
• Assessment of behavior including attention, anxiety, and adaptive skills

Treatment of Manifestations

Developmental 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 on 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 Complications

The following are indicated:

• Exercise and a balanced diet to avoid insulin resistance/diabetes mellitus
• Range of motion exercises to prevent or ameliorate joint contractures
• Because 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 resuscitation

Surveillance

Agents/Circumstances to Avoid

Children with WS should not be given multivitamins because all pediatric multivitamin preparations contain vitamin D.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search 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.

Mode of Inheritance

The microdeletion of the WBSCR critical region that causes WS is transmitted in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• In most instances, the parents of an individual with WS are not affected.
• In the absence of clinical findings of WS in the parents, FISH testing of the parents is not warranted.
• Recent studies have shown that, in approximately 25% of cases, the unaffected parent in whom the chromosome deletion originated has an inversion on chromosome 7 involving the WBSCR [Osborne et al 2001, Bayes et al 2003, Hobart et al 2010]. Approximately 6% of the general population also has this inversion polymorphism [Hobart et al 2010]. There have been two reports of siblings with WS; in one family, the deletions occurred on the paternal chromosome that had an inversion involving the WBSCR; and, in the other, the deletions were likely the result of maternal germline mosaicism because no inversion involving the WBSCR was found [Scherer et al 2005].

Sibs of a proband. The risk to the sibs of the proband depends on the status of the parents:

• If a parent is affected, the risk is 50%.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low because few familial cases have been reported.

Offspring of a proband. Individuals who have the WBSCR critical region deletion have a 50% chance of transmitting the deletion to each child. Parent-to-child transmission has been reported [Morris et al 1993, Sadler et al 1993].

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

For pregnancies at increased risk for WS, FISH testing may be used to detect the microdeletion of the WBSCR critical region in fetal cells obtained by chorionic villus sampling or amniocentesis.

Prenatal testing may also be offered to unaffected parents who have had a child with WS because of the recurrence risk associated with the possibility of germline mosaicism or inversion polymorphism or in cases of parental anxiety.

Prenatal testing for pregnancies not known to be at increased risk for WS is possible but is rarely used because most cases are a single occurrence in a family and no prenatal indicators exist for low-risk pregnancies.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the microdeletion of the WBSCR critical region has been identified.

Molecular Genetic Pathogenesis

Both 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].

Benign 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]

Pathogenic allelic variants. Mutation of ELN typically results in autosomal dominant SVAS [Li et al 1997]. ELN variants have also been reported in congenital cutis laxa [Tassabehji et al 1998, Zhang et al 1999].

Normal gene product

• The 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

Published Guidelines/Consensus Statements

1. American Academy of Pediatrics Committee on Genetics. Health care supervision for children with Williams syndrome. 2001. Available online. Accessed 12-21-15.

Literature Cited

1. Ardinger RH Jr, Goertz KK, Mattioli LF. Cerebrovascular stenoses with cerebral infarction in a child with Williams syndrome. Am J Med Genet. 1994;51:200–2. [PubMed: 8074144]
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Acknowledgments

The author's research was supported by grant NS35102 from the National Institute of Neurological Disorders and Stroke, the Williams Syndrome Association, and the Las Vegas Pediatric Research Fund of the University of Nevada. The research has advanced thanks to the work of multiple talented scientist-collaborators over the past 27 years; current co-investigators include Dr. Carolyn B. Mervis of the University of Louisville, Department of Psychology and Dr. Lucy Osborne of the University of Toronto Department of Molecular Genetics. Also, thanks must be given to the individuals who have participated in Williams syndrome research for their commitment to the research as well as giving generously of their time.

Revision History

• 13 June 2013 (me) Comprehensive update posted live
• 21 April 2006 (me) Comprehensive update posted to live Web site
• 22 August 2003 (me) Comprehensive update posted to live Web site
• 9 April 1999 (me) Review posted to live Web site
• 7 January 1999 (cm) Original submission