What is Williams syndrome?

Risk Factors

There are no known risk factors. The incidence of Williams syndrome is estimated to be less than 1 in 10,000 people. The disease almost always occurs sporadically. In the few reported examples of familial transmission, the deletion acts as an autosomal dominant mutation. Williams syndrome affects males and females equally.

Etiology and Genetics

Williams syndrome is caused by a loss of DNA from band 7q11.23 of chromosome 7. Therefore while the normal number of chromosomes is maintained, approximately twenty-five genes are lost because of the deletion. This region is referred to as the Williams-Bueren syndrome critical region (WBSCR). The deletion of the WBSCR in chromosome 7 is believed to be the result of unequal crossover events during meiosis. This region is flanked by low copy repeats that increase the likelihood of nonallelic homologous recombination. The deletion arises with equal frequency on the maternally or the paternally inherited chromosome 7. The size of the deletion can vary from 1.5 to 1.8 Mb pairs of DNA. Amongst the deleted genes is the elastin (ELN) gene. Loss of this gene is associated with the connective tissue abnormalities, cardiovascular disease (specifically supravalvular aortic stenosis), and facial dysmorphology found in people with this disease.

Other genes contained in this region include LIMK1 (lim kinase 1), GTF2IRD1 (part of the TFII-1 transcription family), and GTF2I (general transcription factor II, I). Their deletion may be responsible for the characteristic difficulties with visual-spatial tasks. Evidence also exists that the loss of the CLIP2 gene, among others, may contribute to the learning disabilities and other cognitive difficulties seen in Williams syndrome.

Most cases of Williams syndrome occur as random events during the formation of reproductive cells in a parent of an affected individual. These cases occur in people with no history of the disorder in their family. Williams syndrome is an autosomal dominant mutation. Williams syndrome should be distinguished from other syndromes that include developmental delay, short stature, distinctive facies, and congenital heart disease, such as Noonan syndrome
(deletion in chromosome 22q11) and Smith-Magenis syndrome (deletion in chromosome 17p11.2).

Symptoms

The onset of symptoms usually occurs just after birth or during infancy and begins with physical characteristics, irritability, colic, and feeding problems. Almost all cases of Williams syndrome have typical facial features that can be recognized even at birth. Williams patients usually have problems with spatial-visual tasks but have strong abilities in the area of music and spoken language. They often have outgoing and engaging personalities. Children often have delays in walking and speaking; however, the latter improves with age. Motor difficulties persist at all ages. Symptoms progress to abdominal pain in adolescents, diabetes, high blood pressure, heart failure (specifically supravalvular aortic stenosis, SVAS, and supravalvular pulmonary stenosis, SVPS), and hearing loss in adults.

Elastin arteriopathy is present in about 75 percent of Williams individuals, with the most common being SVAS. In most cases, morbidity is due to this aortic narrowing, which can lead to elevated left heart pressure, cardiac hypertrophy, and eventually cardiac failure.

Screening and Diagnosis

The clinical manifestations include a distinct facial appearance, which can be observed early after birth. Other characteristics such as cardiovascular anomalies and hypocalcemia, can be detected via electroencephalogram and routine blood examinations. The deletion in chromosome 7 is not detected through standard karyotyping but rather through fluorescence in situ hybridization (FISH). Testing is routinely performed on peripheral blood leukocytes. FISH testing and karyotype are performed in cytogenetics laboratories.

Prenatal testing is clinically available but is rarely used because most cases occur in a single family member only and no prenatal indicators exist for low-risk pregnancies.

Treatment and Therapy

There is currently no cure for Williams syndrome. Williams syndrome is a complex multisystem medical condition that requires the attention of multiple health care professionals. Initial care often centers on failure to thrive, hypocalcemia, or repair of the cardiac lesion. Physical therapy is helpful to patients with joint stiffness. Developmental and speech therapy can also help affected children; for example, verbal strengths can help make up for other weaknesses. Other treatments are based on a patient’s symptoms.

Prevention and Outcomes

There is no known way to prevent the genetic problem that causes Williams syndrome. Prenatal testing is available for couples with a family history of Williams syndrome who wish to conceive. About 75 percent of those with Williams syndrome have some intellectual disability. Most patients will not live as long as normal, due to complications. Most patients require full-time caregivers and often live in supervised group homes.

Bibliography

Bayes, M., et al. “Mutational Mechanisms of Williams-Beuren Syndrome Deletions.” American Journal of Human Genetics 73 (2003): 131–51. Print.

Cassidy, Suzanne B., and Judith E. Allanson. Management of Genetic Syndromes. 3rd ed. Hoboken: Wiley, 2010. Print.

Farran, Emily K., and Annette Karmiloff-Smith. Neurodevelopmental Disorders Across the Lifespan: A Neuroconstructivist Approach. Oxford: Oxford UP, 2012. Print.

Martens, Marilee. “Developmental and Cognitive Troubles in Williams Syndrome.” Pediatric Neurology. Ed. Olivier Dulac, Maryse Lassonde, and Harvey B. Sarnat. Edinburgh: Elsevier, 2013. 291–93. Print.

Morris, C., H. Lenhoff, and P. Wang. Williams-Beuren Syndrome: Research, Evaluation, and Treatment. Baltimore: Johns Hopkins UP, 2006. Print.

Morris, C. A., et al. “Natural History of Williams Syndrome: Physical Characteristics.” Journal of Pediatrics 113 (1988): 318–26. Print.