Williams Syndrome
Williams syndrome (WS) is caused by a microdeletion on the long arm of chromosome 7 (7q11.23). This deletion, which includes approximately 25-28 genes, is most often a de novo (spontaneous) event and is rarely inherited.
The most significant gene within this deleted region is the elastin gene (ELN), which accounts for the characteristic cardiovascular and connective tissue abnormalities. The deletion also includes other genes that contribute to the neurodevelopmental and cognitive profile.
Key Features
Distinctive Facial Features: “Elfin-like” facies are classic, including a broad forehead, short nose with a broad nasal bridge, full cheeks, and a wide mouth with full lips. These features may become more pronounced with age.
Cardiovascular: This is a major concern and often leads to early diagnosis. The most common finding is supravalvular aortic stenosis (SVAS), a progressive narrowing of the aorta above the valve. Peripheral pulmonary artery stenosis (PPS) is also common, especially in infancy, but often improves spontaneously. Hypertension is a frequent finding, often related to renovascular disease.
Growth & Feeding: Infants may present with failure to thrive, feeding difficulties, and a low birth weight. Growth may be delayed, and final adult height is typically shorter than average.
Endocrine: Infantile hypercalcaemia is a well-known feature, though it usually resolves. Other endocrine issues can include a higher risk of hypothyroidism and premature puberty.
Neurocognitive & Behavioural: A characteristic neurocognitive profile includes a mild to moderate intellectual disability, but with a striking discrepancy between verbal and non-verbal skills. Verbal language is often a relative strength, and individuals may have a love of music and be highly sociable. However, these abilities can mask significant difficulties with visuospatial skills, attention deficits (often presenting as ADHD-like symptoms), and executive function. Anxiety, phobias, and social disinhibition are common and increase in prevalence with age, presenting a significant management challenge.
Clinical Monitoring & Recent Developments
A multidisciplinary team approach is essential for the long-term management of Williams syndrome.
Diagnosis: Diagnosis is confirmed by genetic testing, such as Fluorescence In Situ Hybridization (FISH) or chromosomal microarray, which detects the 7q11.23 microdeletion.
Cardiovascular: Annual cardiology review is recommended in childhood, including echocardiogram and blood pressure measurement in all four limbs. The frequency of imaging can be reduced in patients with no or stable cardiovascular findings. Close monitoring and early intervention are crucial for SVAS and other vascular abnormalities. The risk of sudden death is a serious consideration, especially during anaesthesia.
Endocrine: Serum calcium should be monitored, particularly in infancy, and diet should be modified to manage hypercalcaemia if present. Thyroid function tests should be performed if symptoms suggest hypothyroidism.
Renal: An initial renal ultrasound is recommended to screen for renal and bladder abnormalities.
Neurodevelopmental: Regular developmental assessments are crucial for early identification of learning difficulties. Educational support, occupational therapy for fine motor and visuospatial challenges, and speech and language therapy are often required. Counselling and psychological support are vital for managing anxiety and behavioural issues.
Other: Audiology assessments are important due to a high prevalence of hyperacusis (hypersensitivity to sound) and an increased risk of sensorineural hearing loss. Dental care is also vital due to enamel hypoplasia and other dental anomalies.
Recent developments in research are exploring the underlying genetic mechanisms to inform targeted therapies, for example, a clinical trial investigating the use of an FDA-approved drug (clemastine) to improve myelination and cognitive function is currently underway.