Williams syndrome (WS) is a rare genetic and neurodevelopmental disorder. WS often presents at birth, when the child is discovered to have supra-vascular aortic stenosis. The child also shows distinctive facies (Elfin-like features), hypercalcemia, connective tissue abnormalities, growth abnormalities, intellectual disability, behavior deficits, and a gregarious personality.
Cardiologist Dr. John Cyprian Phipps Williams discovered the syndrome in 1961. In 1962, Dr. A. J. Beuren found similar findings, resulting in the naming of the syndrome as Williams-Beuren syndrome.
The genetic cause of Williams syndrome was uncovered in 1993. The disorder is due to deletion at the chromosome band 7q11.23 that involves the elastin gene (ELN). The gene is in the Williams-Beuren Syndrome Critical Region (WBSCR). The gene deletion, comprising 26 genes, is detected through dual color fluorescent in situ hybridization (FISH) or deletion/duplication testing. Microarray analysis is another diagnostic test that can identify the size of the elastin deletion. Both FISH and microarray analyses utilize a parenteral blood sample to extract DNA for analysis. From 96 to 98% of patients with WS have a deleted elastin gene. The genetic disorder shows autosomal dominant transmission. The defect in elastin leads to generalized arteriopathy and may affect any artery in the body, but often affects medium to large-sized arteries.
After birth, infants often present with failure to thrive, short stature, and supra-vascular aortic stenosis. Due to the defect in elastin, children may also have other elastin arteriopathies, along with peripheral pulmonary stenosis and hypertension. During childhood, patients may have middle ear infections and visual difficulty. On physical exam, all children with Williams syndrome have characteristic distinctive facies with elfin-like features.
Children with WS commonly have various endocrine abnormalities. The presence of hypercalcemia and hypercalciuria can result in renal calculi. The patient may also have physical signs of hypothyroidism, delayed growth, or early puberty.
Connective tissue abnormalities often result in hyperextensible joints or hypotonia, resulting in delayed motor milestones or toilet training.
The patient may have comorbid psychiatric disorders, including intellectual disability (ID), attention-deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), or generalized anxiety disorder (GAD).
A definitive diagnosis of WS requires FISH genetic testing demonstrating the gene deletion in the WBSCR.
The following laboratory, imaging, and other tests are necessary for patients with suspected Williams syndrome.
Intellectual disability (ID) in WS is assessed using the Kaufman Brief Intelligence Test, Second Edition (KBIT-2). The assessment computes a composite IQ, along with both verbal and non-verbal standard scores (SSs). Studies utilizing KBIT-2 to measure IQ in children with WS found that their IQ ranged from average to severe ID. Children with WS often struggle with visuospatial construction, which the KBIT-2 does not measure. To measure visuospatial construction, the Differential Ability Scale-II (DAS-II) Special Nonverbal Composite assessments and Wechsler IQ tests may be useful diagnostic tools.
Effective treatment and management of children with WS require a multidisciplinary team, including:
It is essential to rule out other neurodevelopmental disorders that can resemble WS, including:
Autosomal dominant supra-valvular aortic stenosis is another condition that should be ruled out, as it is a separate disorder from WS.
Due to the risk of hypercalcemia, supplements with calcium and vitamin D, including multivitamins, should be avoided in children with WS.
The morbidity of WS is largely due to the presence of arteriopathy and congenital heart disease. Eighty percent of WS patients experience cardiovascular abnormalities, such as stenosed large arteries or ventricular outflow tracts that require cardiothoracic surgery. During the perioperative period, there is a risk of sudden cardiovascular collapse that may contribute to morbidity and mortality.
In terms of inheritance, there is a 50% chance of parents with WS passing the microdeletion to their children. If a parent has one child with WS, but the parent is unaffected, the risk of a sibling acquiring WS is low.
Patients with WS can live semi-independently to independently and are often able to work. As each individual with WS has different needs, it is recommended to complete an individualized life transition plan, preferably before the ages of 13 or 14.
When patients with WS have open heart surgery, there is a risk for complications, often exacerbated by or secondary to the elastin deficiency. A multicenter registry followed patients with WS who underwent surgery for right ventricular outflow tract (RVOT), left ventricular outflow tract (LVOT), or supra-valvular aortic stenosis. The registry found that 9% of patients with WS who had open heart surgery had major adverse cardiac events, such as arrhythmia or coronary artery disease. In cases of coronary artery disease after surgical repair of stenosis, revascularization may be necessary.
The treatment of WS requires a multidisciplinary approach. After the birth of a child with WS, the pediatrician should obtain a consultation from cardiology and cardiothoracic surgery. Later, case discussion with endocrinology, gastroenterology, nephrology, and psychiatry may also be warranted. Additional consultations with occupational therapy (OT), physical therapy (PT), speech therapy (ST), sensory integration therapies, orthodontist, dentist, and psychotherapy may be options. The parents of a child with WS may obtain a referral to a couples therapist or family therapist for counseling and support.
Patients and their families should direct questions to their interprofessional team. More information on the disorder is available through the Williams Syndrome Association (WSA), at williams-syndrome.org.
Effective treatment of patients with WS requires interprofessional communication and collaboration to improve patient outcomes. Healthcare providers including physicians, specialists, and pediatric nurses should monitor children with WS for associated endocrine and neurodevelopmental abnormalities by obtaining weight, BMI, calcium, TSH, CMP, hearing screen, and vision screen at baseline and routinely during treatment.
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