What is Williams syndrome?

Williams Syndrome

Williams syndrome is a rare genetic disorder caused by a deletion of part of chromosome 7q11.23, characterized by distinctive facial features, cardiovascular abnormalities (particularly supravalvular aortic stenosis), intellectual disability, and a unique cognitive and behavioral profile that significantly impacts morbidity, mortality, and quality of life. 1

Genetic Basis and Prevalence

Williams syndrome (WS), also known as Williams-Beuren syndrome, is:

• Present at birth with a prevalence of approximately 1 in 7,500 individuals 1, 2
• Affects males and females equally 1
• Caused by a deletion of 1.5-1.8 Mb on chromosome 7q11.23 containing 26-28 genes 1
• The deletion includes the ELN gene that codes for elastin, explaining many physical features 1
• Most deletions occur de novo, with affected individuals having a 50% chance of transmitting the deletion to offspring 1

Key Clinical Features

Physical Characteristics

• Distinctive facial features (100%) 1:

  • Broad forehead
  • Bitemporal narrowness
  • Periorbital fullness
  • Stellate/lacy iris pattern
  • Short nose with bulbous tip
  • Wide mouth with full lips
  • Mild micrognathia

• Growth abnormalities:

  • Mild prenatal growth deficiency
  • Postnatal growth rate ~75% of normal
  • Microcephaly in one-third of patients
  • Decreased fat stores in childhood; potential obesity in adolescence/adulthood

Cardiovascular Abnormalities (80%) 1

• Supravalvular aortic stenosis (SVAS) (75%)
• Supravalvular pulmonic stenosis (25%)
• Peripheral pulmonary artery stenosis (50%)
• Other arterial stenosis (20%)
• Ventricular septal defects (10%)
• Hypertension (50%)
• Prolonged QTc (13%)

Important: Patients with WS are at increased risk for myocardial ischemia, acute hemodynamic deterioration, and sudden death due to cardiovascular anomalies, especially during sedation and anesthesia 1.

Neurological and Developmental Features

• Intellectual disability (75%) 1
• Normal intelligence (5%) 1
• Developmental delay (95%) 1
• Impaired visuospatial constructive cognition (95%) 1
• Hypotonia (central) (80%) 1
• Hypertonia (peripheral) (50%) 1
• Hyperactive deep tendon reflexes (75%) 1
• Chiari I malformation (10%) 1

Behavioral Profile

• Hypersociability 3
• Attention deficit hyperactivity disorder (65%) 1
• Anxiety disorders (70%) 1
• Sleep disorders (65%) 1

Other System Involvement

• Endocrine/Metabolic:

  • Hypercalcemia (15-45%, more common in children <2 years) 1
  • Hypercalciuria (30%) 1
  • Hypothyroidism (5-10%) 1
  • Diabetes mellitus (15% in adults) 1

• Gastrointestinal:

  • Feeding difficulties (70%) 1
  • Constipation (50%) 1
  • Colon diverticula (30%) 1
  • Rectal prolapse (15%) 1

• Genitourinary:

  • Structural anomalies (5%) 1
  • Enuresis (50%) 1
  • Bladder diverticula (50%) 1
  • Nephrocalcinosis (5%) 1

• Musculoskeletal:

  • Joint hypermobility (90%) 1
  • Joint contractures (50%) 1
  • Radioulnar synostosis (20%) 1
  • Scoliosis (18%) 1
  • Lordosis (40%) 1
  • Kyphosis (20% in adults) 1
  • Awkward gait (60%) 1

Diagnosis

Diagnosis of Williams syndrome is based on:

1. Clinical features and distinctive facial appearance
2. Confirmation by genetic testing showing the characteristic deletion on chromosome 7q11.23 using:
   • Fluorescence in situ hybridization (FISH)
   • Chromosomal microarray
   • Multiplex ligation-dependent probe amplification 1

While typically diagnosed in infancy or childhood, diagnosis may be delayed in the absence of classical findings such as cardiovascular anomalies, hypercalcemia, and obvious cognitive impairment 2.

Clinical Implications and Management

Due to the multisystemic and progressive nature of Williams syndrome, accurate diagnosis is critical for appropriate care and screening for associated morbidities 2. Management should focus on:

1. Cardiovascular monitoring and intervention - particularly for SVAS and other arterial stenoses
2. Developmental and educational support - addressing intellectual disability and specific learning challenges
3. Behavioral management - for anxiety, ADHD, and social difficulties
4. Endocrine monitoring - particularly calcium levels in young children
5. Regular screening for other system involvement (musculoskeletal, gastrointestinal, etc.)

Prognosis

The prognosis for individuals with Williams syndrome varies depending on the severity of cardiovascular involvement and other medical complications. The risk of sudden death (1 per 1,000 patient-years) is primarily related to cardiovascular abnormalities, particularly those affecting the coronary arteries 1. With appropriate medical management and supportive care, many individuals with Williams syndrome can have good quality of life despite their challenges.