para>Pediatric multivitamins (which all contain Vitamin D) should be used with caution; may precipitate infantile hypercalcemia
Neurodevelopmental (2)
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 (3).
Dramatic weakness in visuospatial and visuomotor skills (3)
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 " Ł personality is well-described but not fully accurate.
Behavioral and psychiatric difficulties are common: 50 " ô90% of adolescents and adults meet DSM-4 criteria for anxiety disorder, phobic disorder, and/or ADHD.
Enjoyment of music is common; sensitivity to noise is noted in up to 90%.
GI (2): 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 (2): delayed toilet training, voiding frequency, urgency, enuresis, structural renal abnormalities, bladder diverticula, and more rarely, nephrocalcinosis
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DIAGNOSIS
HISTORY
The signs and symptoms are diagnostic in classic WBS, but clinical presentation is variable: é á
- Prenatal growth deficiency
- In very young children (4)[B]: mild growth retardation (occasionally, more marked failure to thrive), mild to moderate global developmental delay, delay in early language acquisition, ADHD. Hypercalcemia can occur. Vascular stenosis can develop or progress.
- In school-aged children (3)[B]: Expressive language skills relatively better developed than other skill areas, hyperacusis (sensitivity to noise), and ADHD. Cognitive-behavioral: weakness in abstract/visual reasoning and short-term memory
- In teenagers and adults (5,6)[B]: daily living skills relatively impaired, social and friendly demeanor, anticipatory anxiety, perseverative tendencies, phobias, occasional depression
PHYSICAL EXAM
- Growth measurements, on average, plot on the lower percentiles of the typical growth curves. WBS-specific growth curves are available (7).
- Craniofacial features (2)
- Infants and young children have full cheeks.
- Young children have pixie-like facial appearance, wide mouth, long flat philtrum, periorbital puffiness, delicate chin, and upturned nose with a flat nasal bridge.
- Older children have a narrow face and long neck.
- Adults have slightly coarse features, full lips, wide smile, and full nasal tip.
- Ophthalmologic: strabismus, altered visual acuity, reduced stereopsis, narrowing of lacrimal duct. Individuals with blue or green eyes have starburst irises.
- Dental: malocclusion, small widely spaced or unusually shaped primary teeth, hypodontia
- Cardiovascular (1,2): increased risk for HTN, supravalvular aortic stenosis, stenosis of other vessels (auscultation, bruits)
- Musculoskeletal (2): joint laxity, contractures of lower extremities, lordosis/scoliosis, mild short stature
- Skin (2): soft skin with mild premature aging, premature graying of hair, hernias
- Neurologic (2): abnormal tone, hyperreflexia, extra-pyramidal signs, cerebellar findings
- ENT/audiologic (2): frequent ear infections when young. Most adults develop mild to moderate high-frequency sensorineural hearing loss.
- Early puberty (2)
- Postpubertal males and females (2)
- Tendency of adults to be overweight; fat distribution pear-shaped
- HTN in as many as 50%
- Lordosis
- Limited joint movement, especially in lower extremities
DIFFERENTIAL DIAGNOSIS
Rule out isolated hypercalcemia and isolated supravalvular aortic stenosis (due to mutations of the elastin gene only). Patients with isolated SVAS do not display many other problems found in WBS. é á
DIAGNOSTIC TESTS & INTERPRETATION
- Molecular-genetic (DNA) evaluation is the diagnostic test of choice (2)[C],(8)[A]
- Fluorescence in situ hybridization (FISH) can detect absence of an elastin gene, whereas chromosomal microarray analysis (CMA) can demonstrate deletion of the entire WBSCR and determine the size of the deletion.
- Microsatellite markers may be an alternative method for molecular diagnosis of WBS.
- Diagnosis by clinical scoring methods without molecular confirmation is not reliable (8)[A].
- Serum calcium: Monitor hypercalcemia; most common in infancy but can occur or recur later (2,7)
- Echocardiogram to evaluate for supravalvular aortic stenosis, peripheral pulmonic stenosis, and other cardiac lesions (2,7,9,10,11)
- Measure blood pressure (2,7,9,10,11).
- ECG to measure QTc (2,7,9,10,11)
- Abdominal US, serum BUN, creatinine to assess kidney structure and function. If abdominal bruit, obtain Doppler study (2,7).
- MRI is not routinely performed. Most commonly detected abnormality of potential significance is type 1 Chiari malformation, prevalence up to 10%, but is mild in majority (2,7).
- Thyroid function tests to assess for hypothyroidism
TREATMENT
GENERAL MEASURES
- The American Academy of Pediatrics guidelines for health care supervision of children and adolescents specific to this syndrome (2)[C].
- Generally needs lifelong supervision (2)[C],(5)[B]
- Early intensive educational intervention should be implemented and maintained (2)[C],(4)[B].
- Treat mild to moderate hypercalcemia by controlling dietary intake of calcium and vitamin D. Persistent or marked hypercalcemia may require more aggressive treatment (2,7)[C].
- Monitor continually for cardiovascular anomalies and HTN. Pulmonary HTN or systemic HTN may not be manifest in children but may result in complications in adulthood (2,7)[C],(11)[B].
MEDICATION
- Medication for HTN, as needed, after ruling out surgically correctable renovascular lesions (1,2,7)[C].
- Antihypertensive medication could slow progression of vascular stiffness caused by elastin insufficiency (12)[B].
- Marked hypercalcemia and osteopenia may require bisphosphonate therapy (2,7)[C].
- Hypercalcemia without osteopenia may be treated with oral steroids (13).
- About 50% will need anxiety treatment; SSRIs often the drug of choice. Start using a low-dose because disinhibition is a potential side effect (2,7)[C].
ISSUES FOR REFERRAL
- Developmental, cognitive, behavioral, and psychological assessments (4,7). All WBS patients should have cardiology evaluation for congenital heart or vascular disease, or HTN (9).
- Ophthalmologic evaluations for visual acuity (7)
- Physical and occupational therapy for motor skills, especially upper limb dexterity (4,7)
- Speech and language therapy for articulation, vocabulary, language skills (3,7)
- Therapy (occupational or speech/language) for oromotor and feeding difficulties (7)
- Preventive dentistry (caries, gum disease, malocclusion) (2,7)
- Audiology to monitor otitis media and hearing loss (3)
- Educational evaluations: individual education programs and interventions (3,4,7)
SURGERY/OTHER PROCEDURES
Treatment for aortic, pulmonary, or renal artery stenoses, if needed (~20%) (1,2,9)[C] é á
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Full activity unless cardiovascular stenoses are problematic é á
Patient Monitoring
- Annual health maintenance during childhood; increased monitoring, as needed
- BP measurements, both arms
- Annual hearing and vision screen
- Growth evaluation with WBS-specific charts
- Developmental screen, social skills assessment, screen for generalized anxiety disorder
- Orthopedic evaluation for significant joint limitation, kyphosis, lordosis, spasticity
- Pediatric anesthesia evaluation if surgery anticipated
- Yearly cardiology evaluation for the first 5 years and every 2 to 3 years thereafter if no issues (13)
- Recently diagnosed adults should have auxologic examination as well as endocrinologic, cardiovascular, GI, ophthalmologic, audiologic, nephrologic, gynecologic, orthopedic, and orthodontic/dental examination.
- Monitoring guidelines are based on collective expertise, and frequency of monitoring must be determined individually.
- Laboratory
- Yearly urinalysis, spot urinary calcium-to-creatinine ratio
- Thyroid function test every few years
- Serum calcium every 4 to 6 months until 2 years of age and every 2 years thereafter if no issues (13)
- Serum creatinine level every 2 years
- Fasting glucose and HgA1C annually after age 30 years (earlier with family history of diabetes or obesity in adults). Oral glucose tolerance test should be performed once at 30 years of age.
- Anticipatory guidance
- School placement
- Physical, occupational, speech, language therapy
- Discuss sexuality and reproductive issues.
- Career counseling; foster independence; transition to adulthood
- Daily exercise, attention to range of motion
- Prompt medical attention for urinary tract or GI symptoms
- Mental health issues
DIET
- For hypercalcemia, control intake of calcium and vitamin D for a short period (weeks or months).
- Supplementation with vitamin D for deficient or insufficient vitamin D levels has not been systematically studied in WBS.
PATIENT EDUCATION
Genetic evaluation and counseling: Williams Syndrome Association, Box 297, Clawson, MI 48017; 800-806-1871; http://www.williams-syndrome.org/ é á
PROGNOSIS
- May need lifelong supervision. Few live independently.
- Slightly decreased life expectancy, primarily due to cardiovascular or GI complications
COMPLICATIONS
- Behavioral problems: inattention to personal safety, social difficulties, postpubescent anxiety, emotional lability, and, less frequently, depression
- Risk of cardiovascular disease, especially supravalvular aortic stenosis and HTN
- Structural cardiovascular abnormalities in 80%
- Cardiovascular defects most common cause of death
- Sudden cardiac death: Increased risk is not well understood.
- Endocrine pathologies (diabetes, hypothyroidism, hypercalcemia in 50%); obesity
REFERENCES
11 Pober é áBR, Johnson é áM, Urban é áZ. Mechanisms and treatment of cardiovascular disease in Williams-Beuren syndrome. J Clin Invest. 2008;118(5):1606 " ô1615.22 Pober é áBR. Williams-Beuren syndrome. N Engl J Med. 2010;362(3):239 " ô252.33 Santos é áA, Deruelle é áC. Verbal peaks and visual valleys in theory of mind ability in Williams syndrome. J Autism Dev Disord. 2009;39(4):651 " ô659.44 Tsai é áSW, Wu é áSK, Liou é áYM, et al. Early development in Williams syndrome. Pediatr Int. 2008;50(2):221 " ô224.55 Cherniske é áEM, Carpenter é áTO, Klaiman é áC, et al. Multisystem study of 20 older adults with Williams syndrome. Am J Med Genet A. 2004;131(3):255 " ô264.66 Bedeschi é áMF, Bianchi é áV, Colli é áAM, et al. Clinical follow-up of young adults affected by Williams syndrome: experience of 45 Italian patients. Am J Med Genet A. 2011;155A(2):353 " ô359.77 Committee on Genetics. American Academy of Pediatrics: health care supervision for children with Williams syndrome. Pediatrics. 2001;107(5):1192 " ô1204.88 Leme é áDE, Souza é áDH, Mercado é áG, et al. Assessment of clinical scoring systems for the diagnosis of Williams-Beuren syndrome. Genet Mol Res. 2013;12(3):3407 " ô3411.99 Collins é áRTII. Cardiovascular disease in Williams syndrome. Circulation. 2013;127(21):2125 " ô2134.1010 Collins é áRTII. Clinical significance of prolonged QTc interval in Williams syndrome. Am J Cardiol. 2011;108(3):471 " ô473.1111 De Rubens Figueroa é áJ, Rodr â şguez é áLM, Hach é áJL, et al. Cardiovascular spectrum in Williams-Beuren syndrome: the Mexican experience in 40 patients. Tex Heart Inst J. 2008;35(3):279 " ô285.1212 Kozel é áBA, Danback é áJR, Waxler é áJL, et al. Williams syndrome predisposes to vascular stiffness modified by antihypertensive use and copy number changes in NCF1. Hypertension. 2014;63(1):74 " ô79.1313 Morris é áCA. Williams syndrome. http://www.ncbi.nlm.nih.gov/books/NBK1249/
CODES
ICD10
Q89.8 Other specified congenital malformations é á
ICD9
759.89 Other specified congenital anomalies é á
SNOMED
Williams syndrome é á
CLINICAL PEARLS
- WBS is a multisystem neurodevelopmental disorder characterized by distinctive facial features and intellectual disabilities.
- These include a characteristic cognitive-behavioral profile (growth failure, characteristic facial appearance, overly friendly personality, supravalvular aortic stenosis, endocrine abnormalities, and an array of neurodevelopmental abnormalities).