Williams Syndrome

Williams (Williams-Beuren) syndrome is a contiguous gene deletion disorder due to a 1.5 to 1.8 Mb microdeletion at 7q11.23, which includes ELN (elastin), GTF2I, GTF2IRD1, LIMK1 and others. Prevalence is about 1 in 7,500 to 10,000. Most cases are de novo (inheritance is autosomal dominant when a parent carries the deletion). ELN haploinsufficiency causes the vasculopathy and connective tissue features; GTF2I and related genes contribute to the cognitive and behavioural profile.

• Facies: broad forehead, periorbital fullness, stellate (lacy) iris pattern, short nose with bulbous tip, long philtrum, wide mouth with full lips, widely spaced teeth, "elfin" appearance
• Cardiovascular (about 80%): supravalvular aortic stenosis (the commonest, about 70%), peripheral pulmonary artery stenosis (often improves), renal artery stenosis and hypertension, coronary artery stenosis, mid-aortic syndrome; sudden death occurs, especially during anaesthesia and sedation
• Hypercalcaemia in infancy (15 to 50%; infantile colic, irritability, poor feeding, constipation), and hypercalciuria with nephrocalcinosis
• Endocrine: hypothyroidism, early puberty, impaired glucose tolerance and diabetes in adulthood, and short stature
• Neurocognitive: mild to moderate intellectual disability (mean IQ about 55 to 60), with a distinctive profile (relative strength in verbal language and music, marked weakness in visuospatial construction), friendly and over sociable personality, anxiety (80%), ADHD, phobias, and attention problems
• Hyperacusis, chronic otitis media and sensorineural hearing loss, joint contractures or laxity, gastrointestinal problems (constipation, diverticulitis), dental anomalies, hernias, and strabismus and hyperopia

• Fluorescence in situ hybridisation for the ELN deletion has largely been replaced by chromosomal microarray, which defines the deletion size and breakpoints; MLPA is an alternative. Workup after diagnosis: echocardiography with attention to the aortic and pulmonary arteries, blood pressure in four limbs, renal ultrasound with renal artery Doppler, serum calcium (also ionised), phosphate, creatinine and urine calcium-to-creatinine ratio, thyroid function, audiology, ophthalmology, developmental assessment, and anaesthetic risk assessment.

• Cardiovascular: cardiology review at diagnosis and every 6 to 12 months, depending on severity; surgical correction of supravalvular aortic stenosis (patch aortoplasty) when the gradient is above 50 mmHg or there are symptoms; avoid dehydration, and take great care with anaesthesia, with cardiac anaesthesia expertise and avoidance of agents that lower systemic vascular resistance or heart rate, and with MRI sedation. Treat hypertension (ACE inhibitors require caution in renal artery stenosis; calcium channel blockers or beta blockers are used) and evaluate for renovascular disease.
• Hypercalcaemia: low calcium, low vitamin D diet or formula (such as Calcilo), generous fluids, corticosteroids (prednisolone 1 to 2 mg/kg/day) in severe cases, and bisphosphonates (pamidronate 0.5 to 1 mg/kg IV) for refractory hypercalcaemia; monitor for nephrocalcinosis and renal function.
• Feeding and colic: small frequent feeds, reflux therapy, and treatment of constipation.
• Endocrine: annual thyroid screening, glucose tolerance testing in adolescence and adulthood, and management of early puberty with GnRH analogues if rapid.
• Neurodevelopment: early intervention, speech, occupational and physical therapy, and music therapy; SSRIs (sertraline) for anxiety, methylphenidate or guanfacine for ADHD, and melatonin for sleep.
• Surveillance: blood pressure annually, renal ultrasound, hearing, eye examination, scoliosis, and bladder and colon complications (diverticulitis, rectal prolapse).
• Genetic counselling: 50% recurrence risk when a parent carries the deletion; negligible otherwise.