Williams Syndrome

Williams syndrome (WS), also known as Williams-Beuren syndrome (WBS), is a genetic disease caused by a microdeletion on chromosome 7. Affected individuals have a characteristic elfin facies and short stature. Cognitive, developmental, and behavioral issues are common. Additionally, cardiovascular, connective tissue, endocrine, and renal anomalies may be present. Genetic testing confirms the diagnosis. Treatment is based on the clinical manifestations. Cardiovascular involvement needs to be followed closely because it is the main cause of mortality.

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Epidemiology and Genetics

Epidemiology

The incidence of Williams syndrome (WS) is 1 in 10,000–20,000 live births.

Genetics

  • The inheritance pattern is autosomal dominant.
  • The majority of cases result from de novo mutations with no family history of the condition.
  • Results from a microdeletion in the small region of q11.23 on chromosome 7 
  • The deleted region includes approximately 25 genes:
    • Loss of the elastin gene, ELN, causes cardiovascular and connective tissue abnormalities.
    • Loss of the GTF2IRD1 gene may contribute to the distinctive facial features often associated with WS.
    • Loss of CLIP2, LIMK1, GTF2I, and GTF2IRD1 genes may contribute to behavioral abnormalities, cognitive difficulties, and learning disabilities (particularly visuospatial abilities).

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Clinical Presentation

Outer appearance

  • Distinctive facial features described as “elfin facies” (elf-like):
    • Broad forehead
    • Short nose with a flattened nasal bridge
    • Long philtrum
    • Wide mouth with full lips
    • Full cheeks
    • Medial flaring of the eyebrows (hair abnormally distributed more medially)
  • Strabismus (crossed eyes)
  • Short stature
  • Dental abnormalities such as hypodontia (missing 1 or more teeth), diastema (a gap between the teeth), and malocclusion (misalignment of the teeth)
  • Hoarse voice
  • Low muscle tone
  • Failure to thrive (lack of appropriate growth and weight gain) noted in the early years

Facial features of WS
A: distinctive facial appearance of individuals with WS
B and C: a young child with WS at the age of 15 months and 3 years (note the subtle characteristic facial features, including wide mouth, chubby cheeks, long philtrum, small nose, and delicate chin)
The same patient is shown in Figs. B, C, and D (left; at 21 years of age); another individual with WS aged 28 years is shown in Fig. D on the right.

Image: “Distinctive facial appearance of persons with WBS” by Park-media Ltd. License: CC BY 4.0.

Cognitive features

  • Developmental delays
  • Intellectual disability (mild to moderate)
  • Difficulties with writing, math, and spatial visualization ability (e.g., solving puzzles and drawing)
  • Strengths in language and rote memorization

Behavioral features

  • “Cocktail party” type personality: sociable, outgoing, and engaging 
  • High verbal intelligence quotient (IQ), but a low IQ and a lack of depth and understanding 
  • Excessive talkers
  • Attention deficit disorder (ADD)
  • Non-social anxiety and phobias
  • Affinity for music

Cardiovascular features

Congenital heart disease is present in 80%–90% of WS cases and is a major cause of morbidity and mortality in patients with WS. The risk of sudden cardiac death is 25–100 times greater in patients with WS.

  • Supravalvular aortic stenosis (SVAS):
    • Most common cardiac anomaly in WS, present in 35%–65% of cases
    • Narrowing of aorta occurs just above the aortic valve. 
    • Least common type of aortic stenosis
    • Occurs due to the loss of the ELN gene
    • Approximately 25% of children with SVAS have WS.
    • Without treatment, SVAS can cause heart failure.
  • Branch or peripheral pulmonary artery stenosis: typically mild and/or spontaneously improves
  • Supravalvular pulmonary stenosis: spontaneously improves and/or resolves
  • Stenosis in other vascular structures:
    • Thoracic or abdominal aorta
    • Renal arteries
    • Intracranial arteries
    • Vessels in other sites such as the neck and limbs
  • Additional structural cardiac defects:
    • Septal defects
    • Mitral valve prolapse + regurgitation
    • Bicuspid aortic valve
    • Valvular aortic stenosis or aortic insufficiency
  • Congenital long QTc syndrome (LQTS): seen in approximately 15% of cases
  • Hypertension: develops in childhood in almost 50% of those with WS

Endocrine features

  • Transient neonatal hypercalcemia:
    • Typically mild-to-moderate ↑ serum Ca+ 
    • Symptomatic hypercalcemia, if present, typically occurs in the 1st 2 years of life: 
      • Clinically presents with irritability, vomiting, muscle cramps, constipation
      • Mostly resolves spontaneously during childhood
  • Hypothyroidism or subclinical hypothyroidism:
    • 5%–10% with overt hypothyroidism
    • Approximately 33% with subclinical hypothyroidism
  • Early onset of puberty may be seen in up to 20% of girls with WS.
  • ↑ Prevalence of type 2 diabetes in adults with WS

Renal and urinary tract features

  • Congenital renal and urinary tract anomalies are seen in up to 30% of cases:
    • Ectopic or horseshoe kidney
    • Renal aplasia or hypoplasia (missing or smaller than usual)
    • Bladder diverticula (outpouching of the bladder lining through a weakened bladder wall)
  • ↑ Prevalence of dysfunctional voiding such as ↑ urinary frequency and nocturnal enuresis (bed wetting) 
  • ↑ Risk and frequency of urinary tract infections (UTIs)
  • May also have ↑ urinary calcium and nephrocalcinosis (Ca+ deposits in the kidneys)
  • Renal function is typically maintained except in rare cases.

Gastrointestinal features

  • Constipation
  • Feeding difficulties
  • Umbilical and inguinal hernias
  • Diverticula

Otologic/auditory features

  • Mild-to-moderate sensorineural hearing loss
  • Hyperacusis (intense sensitivity to sounds) 
  • Recurrent otitis media

Ocular features

  • Hyperopia (far-sightedness)
  • Nasolacrimal duct obstruction

Musculoskeletal features

  • Joint laxity/hypermobility in childhood
  • Joint limitations and contractures as an adult
  • Abnormal curvature of the spine (e.g., kyphosis)
  • Gait ataxia (difficulty walking)

Diagnosis

  • History and clinical examination
  • Genetic testing confirms the diagnosis.
  • Labs:
    • Serum and urinary calcium levels: checked at birth (↑) and closely followed during the 1st few months of life
    • Thyroid function tests:
      • ↑ Thyroid-stimulating hormone (TSH), ↓ triiodothyronine (T3) and thyroxine (T4) in hypothyroidism
      • ↑ Thyroid-stimulating hormone (TSH) with normal T3 and T4 levels in subclinical hypothyroidism
    • Renal function tests
    • Urinalysis
  • Additional screening tests once the diagnosis is confirmed:
    • Pediatric cardiology evaluation with electrocardiogram (ECG) and echocardiogram (ECHO) to evaluate for cardiac anomalies
    • Renal and bladder ultrasounds to evaluate for anomalies
    • Thyroid ultrasound to evaluate for possible hypoplasia
    • Nutritional/feeding evaluation
    • Ophthalmology evaluation
    • Auditory exam 
    • Neuropsychologic, developmental, educational, and behavioral assessments/screenings

Management

Treatment is based on the clinical manifestations present and is aimed at improving the quality of life and treating associated conditions.

Cardiovascular

  • Approximately 20% require surgical or catheter-based intervention in the 1st few years of life.
  • Annual cardiology follow-up
  • Pre-operative assessment by a pediatric cardiologist and anesthesiology before any procedures requiring sedation or anesthesia due to ↑ risk of sudden cardiac death
  • Routine blood pressure check in all extremities:
    • Hypertension treated with calcium channel blockers or beta blockers
    • Renal ultrasound with Doppler flow studies to evaluate for renal artery stenosis as a cause for hypertension

Endocrine

  • Hypercalcemia: 
    • Monitor monthly with laboratory tests until resolved.
    • Avoid vitamin D supplementation.
  • Hypothyroidism: treated with levothyroxine
  • Oral glucose tolerance testing starting at 20 years of age
  • Early puberty in girls: treated with a gonadotropin-releasing hormone agonist

Nutritional and gastrointestinal

  • Regular monitoring of caloric intake and any feeding difficulties
  • Feeding tube may be needed.
  • Routine constipation evaluations with aggressive treatment, if needed, to avoid diverticulosis, hemorrhoids, and rectal prolapse

Otologic

  • Hearing aids
  • Tympanostomy tubes for recurrent otitis media

Ocular

  • Strabismus correction
  • Corrective lenses for hyperopia

Other

  • Physical therapy
  • Speech and language therapy
  • Behavioral therapy
  • Educational interventions
  • Genetic counseling

Differential Diagnosis

  • Smith-Magenis syndrome: a non-inherited genetic condition due to a deleted region of genes on chromosome 17. Patients also have short stature, cardiac anomalies, hyperacusis, and intellectual disabilities. Patients with Smith-Magenis syndrome additionally show self-injurious behavior patterns. Genetic testing confirms the diagnosis. Treatment is tailored to the clinical manifestations present. 
  • Noonan’s syndrome: an autosomal dominant genetic condition caused by several potential gene mutations. Men and women can be affected. Clinical presentation includes short stature, developmental delay, and congenital heart defects. Noonan’s syndrome patients also have abnormal bruising and bleeding. Genetic testing confirms the diagnosis. Treatment is tailored to the symptoms present.

References

  1. Waz, W.R., & Lee, T.M. (2020). Williams syndrome. UpToDate. Retrieved December 12, 2020, from https://www.uptodate.com/contents/williams-syndrome?search=williams%20syndrome&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
  2. U.S. National Library of Medicine. (2020). Supravalvular aortic stenosis. MedlinePlus. Retrieved December 14, 2020, from https://medlineplus.gov/genetics/condition/supravalvular-aortic-stenosis/#causes
  3. Collins, R. T., 2nd (2018). Cardiovascular disease in Williams syndrome. Current opinion in pediatrics, 30(5), 609–615. https://doi.org/10.1097/MOP.0000000000000664

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