Williams-Beuren Syndrome

Description

• Williams-Beuren syndrome (WBS), a.k.a. Williams syndrome, is a multisystem neurodevelopmental disorder characterized by subtle, distinctive facial features and intellectual disabilities, including a characteristic cognitive behavioral profile.
• Growth retardation, hoarse voice, connective tissue abnormalities, vascular stenoses (supravalvular aortic, peripheral pulmonary, renal artery), high blood pressure (BP), endocrine abnormalities (hypercalcemia; diabetes; subclinical and, less often, clinical hypothyroidism), early puberty, musculoskeletal abnormalities (limited joint movement, lordosis), bowel and bladder diverticula
• System(s) affected: cardiovascular, GI, endocrine, musculoskeletal, CNS, renal/urologic
• Synonym(s): Williams syndrome; Fanconi-type idiopathic infantile hypercalcemia; elfin facies with hypercalcemia

Epidemiology

Incidence

• ~1/7,500 live births
• Predominant sex: male = female

Prevalence
~1/7,500 individuals

Etiology and Pathophysiology

• Microdeletion of WBS critical region (WBSCR) produced by unequal crossing over chromosome 7 in meiosis due to blocks of low copy repeats
• The deleted interval contains the ELN gene, encoding the elastin protein, an important component of elastic fibers in the connective tissue, particularly medium- and large-sized arteries. 50% of the dry weight of the normal aorta is elastin.
• Some features of WBS have no obvious relationship to elastin but are caused by loss of other genes in the WBSCR.

Genetics

• WBS is a contiguous gene deletion (microdeletion) disorder involving 26 to 28 genes on chromosome 7q11.23, likely leading to underexpression of products of genes in the WBSCR.
• Online Mendelian Inheritance in Man #194050
• Phenotypic expression is variable.
• Nearly always sporadic (de novo deletion in chromosome 7)

Risk Factors

• Individuals with WBS have a 50% chance of transmitting WBS to each of their offspring.
• Inversion of the WBSCR is a benign polymorphism; however, carriers are slightly more likely to produce a gamete with a deleted WBSCR.

Commonly Associated Conditions

• Cardiovascular (1)
  • Supravalvular aortic stenosis (SVAS) (trivial to severe) in 70%; may be present at birth but often develops or progresses during childhood (rare except in WBS), LVH (40%)
  • Pulmonary arterial stenosis (40%), tends to ameliorate with age
  • Middle aortic syndrome in which thoracic and abdominal aorta and branches are narrowed
  • Renal artery stenosis (60%)
  • Hypertension (HTN) (50%) often without surgically repairable renovascular lesions
  • Prolonged QTc interval (14%)
  • Cardiovascular mortality 25 to 100 times that of general population
• Endocrine (1)
  • Calcium: 5–50% have ≥1 hypercalcemic episode.
  • Diabetes: high prevalence of prediabetes or overt diabetes (>60% of adults), especially with high BMI
  • Thyroid: subclinical hypothyroidism (15–30%), often with mild thyroid hypoplasia. Overt hypothyroidism occurs as well but less often.
  • Puberty: Average age at menarche is 10 years; early puberty is the norm.
  • Early adolescent growth spurt in majority, contributing to diminished adult stature
  ALERT
  Pediatric multivitamins (which all contain vitamin D) should be used with caution; may precipitate infantile hypercalcemia
• Neurodevelopmental (1)
  • Development and cognition
    • Delayed early motor skills and achievement of language milestones
    • Strong social and interpersonal skills
    • Average IQ 50 to 60 (mild to moderate disability), range 40 to 100
    • Some verbal abilities are relatively spared. Individuals have better performance on verbal tasks than on visual tasks.
    • Dramatic weakness in visuospatial and visuomotor skills
    • Frequent and significant impairment of attention (attention deficit disorder [ADD] or attention deficit hyperactivity disorder [ADHD]), resulting in distractibility
  • Personality, behavioral, and emotional
    • Most patients are friendly and empathetic.
    • The overly social “cocktail party” personality is well-described but not fully accurate.
    • Behavioral and psychiatric difficulties are common: 50–90% of adolescents and adults meet DSM-IV criteria for anxiety disorder, phobic disorder, and/or ADHD.
    • Enjoyment of music is common; sensitivity to noise is noted in up to 90%.
• GI (1): Colic, difficulty feeding, and intolerance to food textures are common during infancy; at other ages: chronic constipation, gastroesophageal reflux, diverticular disease, abdominal pain of unknown etiology, rectal prolapse, (rarely) celiac disease
• Genitourinary (1): delayed toilet training, voiding frequency, urgency, enuresis, structural renal abnormalities, bladder diverticula, and more rarely, nephrocalcinosis