Williams syndrome (ORPHA:904)
A rare genetic multisystemic neurodevelopmental disorder characterized by a distinct facial appearance, cardiac anomalies (most frequently supravalvular aortic stenosis), cognitive and developmental abnormalities, and connective tissue abnormalities (e.g., joint laxity). Facial dysmorphism is characterized by a broad forehead, bitemporal narrowing, periorbital fullness, stellate and/or lacy iris pattern, short upturned nose with bulbous tip, long philtrum, wide mouth, full lips and mild micrognathia.
Epidemiology
Prevalence is approximately 1/7,500. There is no difference between the sexes.
Clinical description
All individuals have facial dysmorphism; in addition to the characteristic features, young children have epicanthal folds, full cheeks, a flat profile and small, widely spaced teeth. Older children and adults often have a narrow face and long neck. The majority of patients (80%) suffer from cardiovascular disease, primarily stenosis of the medium and large arteries (supravalvular aortic stenosis (70%), hypertension (50%), and degeneration of aortic and/or mitral-valve leaflets). Developmental milestones are delayed. A relative strength in language and verbal short-term memory, and a significant weakness in visuospatial construction is characteristic. Intellectual disability is common (75%), and a characteristic cognitive profile with an overly friendly and social personality with enjoyment of music but hypersensitivity to sound is characteristic (90%). Emotional dysregulation is common and many patients (50%) require pharmacologic treatment for anxiety and/or attention deficit hyperactivity disorder. Endocrine abnormalities include hypercalcemia (15-45%), impaired glucose tolerance/type 2 diabetes mellitus (DM), obesity in adolescents/adults, subclinical hypothyroidism (15-30%), and osteopenia or osteoporosis (50%). Other problems include axial hypotonia, peripheral hypertonia with increased deep tendon reflexes in the lower extremities, ataxia and tremor. Growth in children is approximately 75% of normal growth rate. Young children have joint laxity; joint contractures occur in older childredults leading to an awkward gait. Lordosis, kyphosis and scoliosis are common. Other common problems include ocular, auditory and dental anomalies, sleep disorders, feeding difficulties, gastrointestinal problems, bladder diverticula, urinary tract malformation, urinary infection and enuresis.
Etiology
Williams syndrome (WS) is caused by a microdeletion on chromosome 7q11.23, a region containing 26 to 28 genes including ELN.
Diagnostic methods
Diagnosis is based on phenotype and genetic testing (fluorescence in situ hybridization (FISH) or chromosome microarray).
Differential diagnosis
The primary differential diagnosis is familial supravalvular aortic stenosis.
Genetic counseling
Genetic counselling should be provided to affected families. Most cases arise de novo, and thus the recurrence risk is low (<1%). Affected individuals have a 50% risk of transmitting the deletion to offspring. A specific inversion polymorphism in the area may increase the risk of having a child with WS.
Management and treatment
A lifelong multidisciplinary approach involving medical monitoring, anticipatory guidance, direct therapies, pharmacotherapy, surgery, and adaptive changes is necessary. Close cardiac follow-up during the first year of life, and close monitoring of serum calcium during the first 2 years of life is recommended, as well as careful pre- and postoperative planning due to increased risk of cardiovascular complications during surgery. Children should be referred to an early intervention program for physical, occupational and speech therapy. Information, education and support groups are recommended for affected patients, families and caregivers.
Prognosis
A formal assessment of life expectancy is lacking. Cardiovascular complications are the major cause of death. Cardiovascular stenoses may progress, especially during the first 5 years of life. Peripheral pulmonary stenoses often resolves spontaneously. Most individuals will require lifelong supervision at both their home and their workplace.

                            Last update: 
                            March 2021


                            - Expert reviewer(s): 
                            Dr Pernille GREGERSEN | ITHACA* - Dr Mette HANDRUP | ITHACA* - Dr Anne LEEGAARD | ITHACA*


                                * European Reference Network