- 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
- ~1/7,500 live births
- Predominant sex: male = female
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.
- 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)
- 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
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%.
- Development and cognition
- 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
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