Summary Statement: What is Williams Syndrome?

Toddler With Elfin Face, Cardiovascular Abnormalities, Hypercalcemia, and Developmental Delays

Here is one doctor's summary analysis of Williams Syndrome.

JAMES S. LEUNG, MD
Hospital for Sick Children, Toronto C. PION KAO, MD

Classically, Williams syndrome presents with transient infantile hypercalcemia that usually resolves by childhood, congenital cardiovascular defects, dysmorphic craniofacial features, a characteristic cognitive and personality profile, growth retardation, and developmental delays.1,2 This multisystem neurodevelopmental disorder was first described by Williams in 1961 and shortly afterward by Beuren (in 1962).3,4 Hence, it is also known as Williams-Beuren syndrome.

INCIDENCE AND ETIOLOGY

The incidence is about 1 in 7500 live births.5 Boys and girls are equally affected.5

Williams syndrome is caused by a hemizygous microdeletion of the ELN gene and contiguous genes on chromosome 7 at band 7q11.23.6,7 This microdeletion results from an unequal meiotic crossover event in one of the parents.8 Deletions of the ELN gene, which encodes for the protein elastin, are found in virtually all patients with Williams syndrome and are directly implicated in the pathogenesis of cardiovascular disease in these patients.6,9,10 However, because ELN is not expressed in significant levels in the brain, ELN deletions are not thought to be responsible for the visuospatial cognition problems, mental retardation, and facial dysmorphology associated with Williams syndrome.11 Instead, these features have been attributed to the combined effects of LIM-K, CYLN2, GTF2IRD1, and GTF2I gene deletions.9,12

Although most cases appear sporadically from de novo mutations, occasional cases of autosomal dominant transmission—occurring when adults with Williams syndrome have children—have been reported.13

CLINICAL MANIFESTATIONS

About 75% of patients have congenital cardiovascular defects, notably supravalvular aortic stenosis (at least 65% of all patients), followed by peripheral pulmonary stenosis (24%) and ventricular septal defects (12%).1 Renal, coronary, mesenteric, cerebral, and carotid artery stenosis may also occur but usually develop in older children and adults.2,10 Renal disease, in particular, needs to be evaluated early because it can lead to renal failure.

The craniofacial phenotype is characterized by mild microcephaly, upturned nostrils, a flat nasal bridge, full lips, wide mouth, long philtrum, bitemporal depressions, periorbital fullness, stellate irides, micrognathia, epicanthal folds, microdontia, malocclusion, enamel hypoplasia, dental aplasia, and fan-shaped orientation of the front teeth (elfin face).1,2

Children with Williams syndrome consistently exhibit a personality profile characterized by highly sociable and overly friendly behaviors accompanied by seemingly paradoxical anxieties, phobias, and poor daily living skills (“cocktail party” personality).14-17 These children have a happy affect—they cheer you up if you are having a bad day in clinic—and remarkable musical ability, which is one of their paradoxical strengths and gives parents hope. Affected children often have mild to moderate mental retardation, extremely severe visuospatial construction problems, and delayed vocabulary acquisition but have normal grammatical, facial recognition, and auditory rote memory skills.14,17 These children tend to be hyperactive (63% to 87% of children) and are 4 times more likely to have attention-deficit/hyperactivity disorder.1,18

Children with Williams syndrome typically exhibit global growth delays during the first few years of life, followed by a period of childhood catch-up growth; however, they ultimately have short stature in adulthood. Many have precocious puberty.1,19

COMPLICATIONS

Cardiovascular disease continues to be a chief concern as persons with Williams syndrome progress into adulthood.20 Many adults report worsening of preexisting supravalvular aortic stenosis.21 Hypertension may develop secondary to renal artery stenosis.20 Myocardial infarction, congestive heart failure, and stroke have also been reported with increased frequency.2 Affected persons are at increased risk for sudden death attributed mainly to coronary artery stenosis or severe biventricular outflow tract obstruction.22,23

Other associated anomalies and complications include gastroesophageal reflux, peptic ulcer disease, diverticulitis, cholelithiasis, bladder calculi, chronic urinary tract infections, premature gray hair, hypothyroidism, esotropia, bilateral inguinal hernias, joint laxity, joint contractures, scoliosis, kyphosis, lordosis, hypotonia, anxiety, and depression.2,18,20,21

DIAGNOSIS

The differential diagnosis of Williams syndrome includes supravalvular aortic stenosis, infantile hypercalcemia, autism, and Down syndrome.13,17,24,25 The unique clinical features of these conditions often allow a straightforward differentiation to be made. However, the diagnosis of Williams syndrome can be delayed because of a lack of significant clinical features during infancy.1

Suspected cases of Williams syndrome can be confirmed cytogenetically. The preferred diagnostic test is fluorescence in situ hybridization.26 In the patient described, results of this test showed a deletion of the ELN gene at 7q11.23.

TREATMENT

Treatment is largely symptomatic and supportive. A multidisciplinary approach is important; the treatment team should include a pediatrician, cardiologist, geneticist, ophthalmologist, neurologist, physiotherapist, psychologist, dentist, schoolteacher, and social worker. Support groups are also available for families (in Canada: the Canadian Association for Williams Syndrome [http://www.caws-can.org]; in the United States: The Williams Syndrome Association [http://www.williamssyndrome. org]).


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REFERENCES:
1. Morris CA, Demsey SA, Leonard CO, et al. Natural history of Williams syndrome: physical characteristics. J Pediatr. 1988;113:318-326.

2. Lashkari A, Smith AK, Graham JM Jr. Williams-Beuren syndrome: an update and review for the primary physician. Clin Pediatr (Phila). 1999;38:189-208.

3. Williams JC, Barratt-Boyes BG, Lowe JB. Supravalvular aortic stenosis. Circulation. 1961;24:1311-1318.

4. Beuren AJ, Apitz J, Harmjanz D. Supravalvular aortic stenosis in association with mental retardation and certain facial appearance. Circulation. 1962;26: 1235-1240.

5. Strømme P, Bjørnstad PG, Ramstad K. Prevalence estimation of Williams syndrome. J Child Neurol. 2002;17:269-271.

6. Ewart AK, Morris CA, Atkinson D, et al. Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nat Genet. 1993;5:11-16.

7. Paterson SJ, Schultz RT. Neurodevelopmental and behavioral issues in Williams syndrome. Curr Psychiatry Rep. 2007;9:165-171.

8. Urbán Z, Helms C, Fekete G, et al. 7q11.23 deletions in Williams syndrome arise as a consequence of unequal meiotic crossover. Am J Hum Genet. 1996;59: 958-962.

9. Osborne L, Pober B. Genetics of childhood disorders, pt 27: genes and cognition in Williams syndrome. J Am Acad Child Adolesc Psychiatry. 2001;40:732-735.

10. Donnai D, Karmiloff-Smith A. Williams syndrome: from genotype through to the cognitive phenotype. Am J Med Genet. 2000;97:164-171.

11. Ashkenas J. Williams syndrome starts making sense. Am J Hum Genet. 1996;59:756-761.

12. Francke U. Williams-Beuren syndrome: genes and mechanisms. Hum Mol Genet. 1999;8:1947-1954.

13. Metcalfe K, Simeonov E, Beckett W, et al. Autosomal dominant inheritance of Williams-Beuren syndrome in a father and son with haploinsufficiency for FKBP6. Clin Dysmorphol. 2005;14:61-65.

14. Mervis CB, Klein-Tasman BP. Williams syndrome: cognition, personality, and adaptive behavior. Ment Retard Dev Disabil Res Rev. 2000;6:148-158.

15. Dykens E. Anxiety, fears and phobias in persons with Williams syndrome. Dev Neuropsychol. 2003;23:291-316.

16. Klein-Tasman BP, Mervis CB. Distinctive personal characteristics of 8-, 9- and 10-year-olds with Williams syndrome. Dev Neuropsychol. 2003;23:269-290.

17. Mervis CB, Becerra AM. Language and communicative development in Williams syndrome. Ment Retard Dev Disabil Res Rev. 2007;13:3-15.

18. Leyfer OT, Woodruff-Borden J, Klein-Tasman BP, et al. Prevalence of psychiatric disorders in 4 to 16-year-olds with Williams syndrome. Am J Med Genet B Neuropsychiatr Genet. 2006;141B:615-622.

19. Partsch CJ, Dreyer G, Gosch A, et al. Longitudinal evaluation of growth, puberty, and bone maturation in children with Williams syndrome. J Pediatr. 1999;134:82-89.

20. Howlin P, Udwin O. Outcome in adult life for people with Williams syndrome— results from a survey of 239 families. J Intellect Disabil Res. 2006; 50(pt 2):151-160.

21. Lopez-Rangel E, Maurice M, McGillivray B, Friedman JM. Williams syndrome in adults. Am J Med Genet. 1992;44:720-729.

22. Bird LM, Billman GF, Lacro RV, et al. Sudden death in Williams syndrome: report of ten cases. J Pediatr. 1996;129:926-931.

23. Wessel A, Gravenhorst V, Buchhorn R, et al. Risk of sudden death in the Williams-Beuren syndrome. Am J Med Genet. 2004;127A:234-237.

24. Morris CA, Mervis CB. Williams syndrome and related disorders. Annu Rev Genomics Hum Genet. 2000;1:461-484.

25. Mervis CB, Robinson BF. Expressive vocabulary ability of toddlers with Williams syndrome or Down syndrome: a comparison. Dev Neuropsychol. 2000; 17:111-126.

26. Cagle AP, Waguespack SG, Buckingham BA, et al. Severe infantile hypercalcemia associated with Williams syndrome successfully treated with intravenously administered pamidronate. Pediatrics. 2004;114:1091-1095.

Clarity on Williams Syndrome Causes

What Causes Williams Syndrome?

There are 20,000-25,000 genes in the human genome and Williams syndrome is caused by a deletion of about 25 of them from a specific region on chromosome 7. It is likely that the absence of a few of these genes (not all) causes the problems associated with Williams syndrome. Amongst the genes that are usually missing from affected individuals are CLIP2, ELN, and GTF21.
CLIP2 - codes for a protein called CAP-GLY domain containing linker protein 2; it is believed to play a role in the structure and function of nerve cells.
ELN - codes for a protein called elastin which is a major component of elastin fibres that provide strength and flexibility to connective tissue. Researchers have discovered that absence of ELN is associated with connective tissue problems and cardiovascular abnormalities.
GTF1 - codes for two proteins called BAP-135 and TFII-I. BAP-135 has a role in the immune system and contributes to the activation of B cells in response to foreign invaders. TFII-I is a transcription factor that is active in the brain and other parts of the body. Some scientists think that it is involved in the regulation of calcium into cells. It has also been postulated that loss of the GTF1 gene is associated with the learning disabilities observed in Williams syndrome.
At the time of writing (December 2009) the relationship between many of the deleted genes and Williams syndrome symptoms is unknown.

Raising awareness, funds - Greenwich Times

Raising awareness, funds - Greenwich Time:

"Still, the Conrods know people with Williams syndrome typically require multiple therapies, such as speech and physical, since they often have delayed verbal skills and joint stiffness as they grow. They also can require surgery, sometimes multiple procedures. The Conrods said George will need open heart surgery to fix the narrowing of his aortic valve.
Dr. Barbara Pober, who has been treating George since he was a newborn, is a geneticist based at Massachusetts General Hospital. For the past 20 years, she has been treating hundreds of people with the syndrome, which is caused by random genetic mutation. She also has conducted research, looking into genetic influence on social and cognitive skills.
In effect, anyone is at risk for the disorder, no matter what gender, ethnicity or hereditary influences. The odds go up, to 50/50, for someone whose parent has the disorder.
Prior to the early 1990s, when a blood test became available to test for elastin, a diagnosis was determined by looking for physical and developmental characteristics, Pober said.
She said some of the latest research is focused on studying the missing genes to determine function, as well as therapies or other treatments that could compensate for the omission.
'Every parent dreams the developmental delays can be lessened, but that is a tough nut to crack,' she said. 'But that doesn't mean you can't ask the question or design research. Are there therapies ... that can ameliorate or minimize some of the complications.'
Those kinds of questions are what drew Westport resident Marshall Kiev to the board of the Williams Syndrome Association. As the father of a young daughter with the disorder, who has had multiple heart operations, he is working to raise funds for research work.
'I remember asking, 'Can anything be done?' ' he said of a conversation he had with several friends who were doctors.
The answer? More money was needed for research.
His first project focused on cardiovascular issues, particularly the narrowing of arteries, which affects about 75 percent of those with the disorder, some more severely than others.
'We know what causes it, but we don't know how to fix it,' he said.
That effort led to a symposium last year at Yale University and the $320,000 grant.
'We've seen the mountains, now we have to figure out how to start climbing them,' he said."

Williams Syndrome and Social Fearlessness

Williams Syndrome and Social Fearlessness

Using a brain scanner, a team of scientists at Stanford University studied the brain activation as people with and without Williams syndrome looked at pictures of facial expressions: happy, neutral, or afraid.

Like a previous study, the scientists found that the amygdala in Williams syndrome was rather unmoved by the afraid faces. It's as though their brain did not register that those faces were something to feel nervous about, and might explain the hallmark social fearlessness of Williams syndrome.

But—and this was the new finding—the amygdala was highly activated when people with Williams syndrome looked at happy faces.

It was the other way around for the group without the syndrome: The amygdala turned on to fearful faces but not so much to happy ones.

This doesn't mean that people with Williams syndrome are frightened by happy faces, says Brian Haas, Ph.D., first author of the study. Instead, he says it reflects what's emotionally riveting for people.

"Happy facial expressions may be more rewarding for those with Williams syndrome," Haas says. "This may explain their increased drive and motivation to approach others and to socially interact."

This finding also fits with a broader picture of the amygdala that has been emerging recently. Rather than solely devoted to fear, the amygdala seems to deal with other strong emotions too, like sadness and happiness.

Haas says that the amygdala tunes into the things that are very relevant to us now and that can sway our feelings. So if you spot a snake, or watch a friend break into tears, the amygdala leaps to attention and points the brain's resources to these emotionally charged situations.

And for people with Williams syndrome, a happy face tugs powerfully on their attention. Haas hopes that this affinity for happy expressions may somehow be used to motivate or reinforce people with Williams syndrome when they are taught about what is socially appropriate. This could help those with the syndrome form closer social bonds with others, which often suffer due to their overly outgoing ways, he says.

High School Student Wins Science Fair with Williams Syndrome Project

Montgomery News:

"This year’s project, “The Effect of Williams Syndrome on the Symmetry of the Planum Temporal in Musicians” won a second-place award in its category in this year’s Delaware Valley Science Fair, followed up with a first place in the May 17-19 Pennsylvania Junior Academy of Science competition at Penn State University.

The brain’s planum temporale controls language, auditory functions and pitch differentiation. Williams syndrome, which Keppley has been studying for the past few years, is a rare genetic condition that causes medical and developmental problems. People with the syndrome are also more likely to have musical skills."

Williams Syndrome Researcher Named to American Academy of Arts and Sciences

Johns Hopkins Gazette | April 27, 2009:

"Barbara Landau is the Dick and Lydia Todd Professor and chair of the Department of Cognitive Science. Her work focuses on language learning, spatial representation and the relationships between these foundational systems of human knowledge. In particular, Landau investigates these issues in normally developing children and in people who have severe spatial impairments due to a rare genetic condition known as Williams syndrome.

She is a fellow of the Cognitive Science Society, the American Psychological Society, the American Psychological Association and the American Association for the Advancement of Science. Last month, the John Simon Guggenheim Memorial Foundation named her a Guggenheim Fellow. She also serves on the governing board of the Cognitive Science Society and recently completed a term on the board of scientific affairs of the American Psychological Association. She is at work on a book to be titled 'Gene, Brain, Mind and Development: The Puzzle of Williams Syndrome.'"