Makindo Medical Notes

Williams–Beuren syndrome (WS) is a contiguous gene deletion syndrome (incidence ~1 in 7,500–20,000) caused by a recurrent microdeletion at 7q11.23 that includes the ELN (elastin) gene. Most cases are de novo, but inheritance is autosomal dominant if a parent is affected. Hallmarks: distinctive facies, a characteristic neurocognitive–behavioural profile, and vascular stenoses (especially supravalvular aortic stenosis).

🔎 Aetiology & Pathophysiology

• Genetics: 7q11.23 microdeletion (typically 1.5–1.8 Mb) involving ELN and ~25+ genes ➝ elastin haploinsufficiency underpinning vascular disease.
• Inheritance: AD; ~95% de novo. If a parent is affected, recurrence risk ≈50%.
• Calcium metabolism: Infantile hypercalcaemia and/or hypercalciuria may occur; mechanism likely ↑ vitamin D sensitivity and renal handling changes. (A primary calcitonin deficiency is not established.)

🩺 Clinical Presentation

• Cardiovascular: Supravalvular aortic stenosis (SVAS); peripheral pulmonary artery stenosis; possible coronary ostial stenosis; systemic hypertension (consider renal artery stenosis); progressive vascular stiffness with age.
• Facies/ENT/Ocular: “Elfin” facies (broad forehead, periorbital fullness, stellate irides, wide mouth/full lips), hyperacusis, otitis media, strabismus, refractive error.
• Neurodevelopment & Behaviour: Global developmental delay/intellectual disability (often mild–moderate), relative verbal strength with marked visuospatial deficits, social disinhibition/overfriendliness, anxiety/ADHD common; sleep disturbance.
• Growth & Endocrine: Short stature; infantile feeding difficulty/FTT; early puberty variably; hypothyroidism (screen); glucose intolerance/diabetes risk ↑ in adults.
• Renal & Metabolic: Hypercalcaemia/hypercalciuria (infancy>childhood), nephrocalcinosis; constipation/GERD; hernias; musculoskeletal laxity, scoliosis; joint contractures later.

🧪 Investigations

• Genetic confirmation: Chromosomal microarray (CMA) or targeted FISH/MLPA for 7q11.23 deletion.
• Cardiac: ECG & transthoracic echo at diagnosis; repeat per cardiology. Consider coronary imaging if symptoms or severe SVAS.
• Renal/Metabolic: U&E, calcium, phosphate, PTH, 25(OH)D (±1,25(OH)₂D in selected cases); urine Ca/Cr ratio; renal ultrasound for nephrocalcinosis.
• BP: Measure at each visit; evaluate for secondary causes (renal artery Doppler/CTA if refractory HTN).
• Endocrine: TSH/FT4 (baseline and periodic), fasting glucose/HbA1c in older children/adults.
• Developmental/Audiology/Ophthalmology: Formal developmental assessment; hearing & vision screening.

🧰 Management (Multidisciplinary)

• Cardiology: Surveillance of SVAS/branch PA stenosis; manage HTN (ACEi/ARB often first line); timing of intervention (balloon/patch aortoplasty) per specialist team.
• Hypercalcaemia (infancy):
  • Hydration (IV if moderate–severe), avoid thiazides (worsen Ca).
  • Loop diuretic (e.g., furosemide) after rehydration to enhance calciuresis.
  • Short-term dietary Ca/Vit D restriction only if hypercalcaemic; recheck frequently to avoid rickets/osteopenia.
  • Refractory cases: consider calcitonin or IV bisphosphonate (specialist advice).
• Renal: Monitor for hypercalciuria/nephrocalcinosis; manage stones; counsel on fluids.
• Developmental & Mental Health: Early years intervention; SALT/OT/physio; support for learning difficulties; screen/treat anxiety/ADHD; sleep hygiene.
• Endocrine: Treat hypothyroidism; monitor growth/puberty; adult metabolic risk review.
• ENT/Ophthalmology: Manage hyperacusis (sound desensitisation/ear protection) and vision/hearing problems.
• Dentistry/MSK: Dental anomalies common; manage scoliosis/joint laxity; physiotherapy.

⚠️ Peri-operative / Anaesthetic Precautions

• Pre-op cardiology review for SVAS/coronary ostial disease; maintain coronary perfusion (avoid profound hypotension/tachycardia).
• Meticulous BP monitoring; consider arterial line in significant disease.

🧠 Clinical Pearls (exam/ward)

• SVAS + elfin facies + hyperacusis → think Williams syndrome.
• “Friendly, talkative child” with visuospatial deficits is characteristic.
• Hypercalcaemia is usually transient in infancy; long-term blanket vitamin D/Ca restriction is harmful — individualise.
• Unexplained childhood hypertension → check for renal artery stenosis and elastin-related vascular disease.

📚 References & UK Resources

• Williams Syndrome Foundation UK – Clinical Guidelines
• GeneReviews®: Williams–Beuren Syndrome (comprehensive genetics & management)
• Orphanet overview (epidemiology, complications)