Williams Syndrome – 10 Interesting Facts, Symptoms, Prognosis and Treatment

Synopsis

Key Points

  1. Williams syndrome is the result of a sporadic genetic defect most often diagnosed in infancy, based on physical examination findings and failure to thrive
  2. Patients with Williams syndrome are characterized by intellectual difficulties, elastin arteriopathy, cardiovascular disease, endocrinopathies, and facial dysmorphology
  3. Characteristically patients have dysmorphic facies and hypersociable personalities
  4. Primary neonatal cardiovascular abnormalities are supravalvular aortic stenosis and peripheral pulmonary stenosis 1
  5. Hypertension and diffuse elastin arteriopathy are the main issues for adults with Williams syndrome
  6. Endocrine abnormalities include hypercalcemia, hypercalciuria, hypothyroidism, and early puberty
  7. Diagnosis is established by fluorescence in situ hybridization analysis
  8. Treatment entails monitoring for and managing associated complications
  9. Medical treatment for hypertension and constipation most often requires pharmacotherapy over time
  10. Life expectancy is significantly reduced, with a high cardiovascular mortality risk 2

Pitfalls of Williams Syndrome

  • Use of multivitamins and vitamin D can precipitate or worsen hypercalcemia; use sunscreen to avoid excess autologous vitamin D production 3
  • Procedural sedation outside of the operating room (or without anesthesia staff present) imparts a high rate of death
  • Myocardial failure risk is elevated with surgical procedures
  • Patients with supravalvular aortic stenosis are at high risk for coexistent coronary artery abnormalities and sudden death 4
  • ACE inhibitors can precipitate kidney failure if used in renal artery stenosis; if used for treatment of hypertension, rule out renal artery stenosis 4
  • Medications that may prolong QT interval can exacerbate the predisposition to arrhythmia
  • The diagnosis of autism spectrum disorder can easily be missed in children with Williams syndrome due to their superficially social nature 3 5

Terminology

Clinical Clarification

  • Williams syndrome is a multisystem microdeletion disorder associated with intellectual disability (75%), dysmorphic facies (100%), systemic elastin arteriopathy with supravalvular aortic stenosis (75%), and infantile hypercalcemia (15%) 3 7 6
  • Also referred to as Williams-Beuren syndrome (OMIM #194050)
  • Occurs in about 1/10,000 births
  • Progressive multisystemic complications arise in adults and include urologic, gastrointestinal, endocrine, and cardiovascular problems

Diagnosis of Williams Syndrome

Clinical Presentation

  • From Ferrero GB et al: Presenting phenotype and clinical evaluation in a cohort of 22 Williams–Beuren syndrome patients. Eur J Med Genet. 50(5):327-37, 2007, Figure 1.A 1.7-year-old child with Williams syndrome. – Broad forehead with bitemporal narrowing, low nasal root, bulbous nasal tip, periorbital fullness, stellate iris pattern, malar flattening, full lips.
  • From Alizad A et al: Echocardiographic features of genetic diseases: part 6-complex cardiovascular defects. J Am Soc Echocardiogr. 13(6):637-43, 2000, Figure 7.The typical appearance of Williams syndrome is elfin fascies. – Prominent forehead, epicanthal folds, underdeveloped bridge of the nose and mandible, overhanging upper lip, strabismus, and abnormal dentition (widely spaced teeth).
  • From Amenta S et al: Non-Hodgkin lymphoma in a child with Williams syndrome. Cancer Genetics and Cytogenetics. 154(1):86-8, 2004, Figure 2.An 8-year-old child with typical dysmorphic features of Williams syndrome.
  • From Ferrero GB et al: Presenting phenotype and clinical evaluation in a cohort of 22 Williams–Beuren syndrome patients. Eur J Med Genet. 50(5):327-37, 2007, Figure 2.A 14-year-old child with Williams syndrome. – Broad forehead, sparse eyelashes, bilateral megalocornea, stellate iris pattern, bulbous nasal tip, long philtrum, full lips, wide mouth.
  • From Ferrero GB et al: Presenting phenotype and clinical evaluation in a cohort of 22 Williams–Beuren syndrome patients. Eur J Med Genet. 50(5):327-37, 2007, Figure 3.A 39-year-old man with Williams syndrome. – Facial asymmetries, prominent supraorbital ridge, low nasal root, bulbous nasal tip, dental malocclusion.

History 3 6 8 9

  • Prenatal history
    • Often postterm, more than 41 weeks’ gestation 3
    • Small for gestational age
  • Infants are described as fretful and colicky
  • Gastrointestinal symptoms
    • Feeding difficulties
    • Reflux
    • Frequent vomiting
    • Constipation
  • Failure to thrive (70%) 6 and developmental delay (95%) 3
  • Symptoms of supravalvular aortic stenosis (45%-75%): 4
    • Infants: poor feeding, difficulty breathing
    • Older children: exertional dyspnea, syncope, and angina
  • Hoarse cry/voice
  • Hyperacusis
    • Up to 90% hypersensitive to fireworks and thunderstorms 6 10
  • Poor coordination and fine motor skills
  • Personality features:
    • Friendly, loquacious personality, easily approach strangers, strong interest in others, highly social, and empathetic
    • Difficult temperament characterized by inability to adapt, irritability, negative moods, and low threshold for angry outbursts
    • Anxiety, excessive worry/fears, obsessions, distractibility
    • These patients universally exhibit a great enjoyment for music
  • Cognitive profile:
    • Average IQ approximately 50 to 60 (range 40-100) 1 2 9
    • General language ability function greater than cognitive ability
    • Strengths: verbal, short-term memory, language, and reading
    • Weaknesses: visuospatial skills, math, drawing, and writing

Physical examination 6 8 9

  • Growth parameters:
    • Mild microcephaly
    • Growth rate at about 75% of normal 9
    • Short stature in adulthood with mean adult height below third percentile 6
  • Neurologic manifestations
    • Hypotonia more common in infants
    • Heel cord contractures and cerebellar sign more common in older children and adults
  • Signs of supravalvular aortic stenosis (45%-75%):
    • Long, late harsh systolic ejection murmur
    • Delayed and diminished carotid pulses
  • Dysmorphic facies:
    • Common findings in young children 2
      • Flat nasal bridge
      • Short, upturned nose
      • Periorbital puffiness
      • Long philtrum
    • Common findings in older patients (often, coarse facial features)
      • Full lips
      • Wide smile
      • Full nasal tip
    • Additional facial features (variable severity of abnormalities)
      • Short palpebral fissures
      • Medial eyebrow flare
      • Epicanthal folds
      • Depressed nasal bridge
      • Short, anteverted nares with broad nasal tip
      • Long philtrum
      • Prominent lips with open mouth
      • Small jaw
      • Blue eyes with stellate pattern in the iris
      • Periorbital fullness of subcutaneous tissue
      • Enamel hypoplasia
      • Partial anodontia
      • Malar flattening
      • Broad forehead with bitemporal narrowing
  • Musculoskeletal manifestations: 8
    • Mild spasticity with tight Achilles tendons
    • Hyperactive deep tendon reflexes
    • Limited range of joint motions
    • Scoliosis, kyphosis, lordosis
    • Extra sacral crease
    • Fifth-finger clinodactyly (occasional)
    • Radioulnar synostosis (occasional)
    • Pectus excavatum (occasional)
    • Awkward gait
  • Extremities:
    • Hypoplastic nails
    • Hallux valgus
    • Soft, lax skin

ASSOCIATED CONGENITAL ANOMALIES

  • Cardiovascular manifestations: 4
    • Abnormalities present in approximately 50% to 80% at birth; 75% have more than 1 abnormality 3 4 10
      • Supravalvular aortic stenosis (in approximately 75% of patients with varying severity)
        • May worsen over time, specifically in the first 5 years of life 4 6
      • Peripheral pulmonary artery stenosis (50%) 3
        • Common in infancy
        • Often with spontaneous resolution
      • Pulmonary artery stenoses or aortic arch abnormalities (58%) 4
      • Coronary artery abnormalities (45%) 4
        • Ostial stenosis or arterial dilation
      • Elastin arteriopathy (75%-80%) 6
        • May affect any artery
        • Arterial narrowing in other anatomic locations, including:
          • Aortic arch and descending aorta
          • Pulmonary, coronary, renal, mesenteric, and intracranial arteries
        • Discrete hourglass stenotic lesions or diffuse arterial hypoplasia can be present in any arterial vessel in the body
      • Middle aortic syndrome
        • Less commonly the thoracic aorta, abdominal aorta, and branches are narrowed at birth, resulting in progressive end-organ ischemia
      • Other associated, less common cardiac abnormalities
  • Abdominal manifestations:
  • Genitourinary manifestations:
    • Urethral stenosis
    • Small penis (occasional)
    • Urinary tract structural abnormalities such as small bladder or small, solitary, pelvic kidney, asymmetric kidneys in 20% to 50% 3 6
  • Hypercalcemia:
    • 5% to 50% of patients have 1 episode of acute hypercalcemia 2
    • Symptoms: colic or irritability, poor feeding, vomiting, constipation, abdominal pain, polyuria, seizures 11
    • Signs: muscle weakness, hypotonia, mental status changes 11 12
  • Chiari I malformation:
    • Refers to prolapse of the cerebellar tonsils into the spinal canal without elongation of the brainstem
    • Present in up to 10% of patients 2
    • Reduced brain size and gray-matter volume (more prominent in parietal and occipital areas)
    • Increased gyral complexity

Causes and Risk Factors of Williams Syndrome

Causes

  • Sporadic, hemizygous microdeletion of the Williams-Beuren syndrome chromosome region 7q11.23 6 10
    • Hypoexpression of gene products from this region, which spans 1.5 million to 1.8 million base pairs and contains approximately 26 to 28 genes, results in the phenotypic manifestations of the syndrome 2
    • The ELN gene encoding for elastin is located in the region of the microdeletion and its deletion is associated with cardiovascular abnormalities 2

Risk factors and/or associations

Genetics 6
  • The microdeletion of the Williams-Beuren syndrome chromosome region that causes the syndrome is transmitted in an autosomal dominant manner
    • If a parent is clinically affected (shows the Williams syndrome phenotype), risk of transmission is 50%
    • Very low risk for a clinically unaffected parent (absence of phenotype) to transmit disease by typical mendelian genetics
    • Virtually all cases occur sporadically 2
  • About 25% of clinically unaffected transmitting parents in whom the chromosomal deletion originated carry a paracentric inversion of the Williams-Beuren syndrome chromosome region 6
  • This inversion polymorphism is present in approximately 6% of the general population

Diagnosis of Williams Syndrome

Primary diagnostic tools 6

  • History and physical examination findings are suggestive of diagnosis, but confirmation with genetic testing is necessary
  • Diagnosis of a proband:
    • Molecular genetic testing establishes the diagnosis
    • Fluorescence in situ hybridization is the most widely used method to detect the microdeletion
    • A venous blood draw serves as the source of DNA isolated from peripheral blood lymphocytes
  • Prenatal diagnosis:
    • Molecular genetic testing of cellular material from chorionic villus sampling or amniocentesis establishes an in utero diagnosis
    • Prenatal ultrasonography may suggest supravalvular aortic stenosis or prenatal growth deficiency

Laboratory

  • Fluorescence in situ hybridization analysis
    • Technique that uses fluorescently labeled probes to locate the positions of specific DNA sequences on chromosomes
      • The ELN gene within the Williams-Beuren syndrome chromosome region serves as the specific probe
    • For probands, a venous blood draw serves as the source of DNA isolated from peripheral blood lymphocytes
    • For prenatal diagnosis, chorionic villous sampling serves as the source of DNA
    • Diagnosis is established by showing only the presence of a single allele, rather than 2 hybridization signals, in the microdeletion of the Williams-Beuren syndrome chromosome region (7q11.23) 2
    • Fluorescence in situ hybridization has high sensitivity and specificity
  • Array comparative genomic hybridization
    • Technique that uses DNA microarrays in conjunction with comparative genomic hybridization to analyze copy number variants
    • Alternative to fluorescence in situ hybridization test that has the advantage of detecting atypical deletions, microdeletions, microduplications, or chromosomal rearrangements associated with Williams syndrome or alternative genetic disorders on a genome-wide basis
    • Recommended if the clinical impression is not clearly consistent with Williams syndrome or targeted fluorescence in situ hybridization analysis result is negative 2

Procedures

Prenatal genetic testing

Chorionic villus sampling at 10 to 12 weeks, or

Amniocentesis at 15 to 18 weeks 13

General explanation

  • Biopsy of placenta or aspiration of fetal sac fluid to obtain DNA for molecular genetic testing

Indications

  • Parent with Williams syndrome
  • Concerning finding on prenatal ultrasonogram
    • Supravalvular aortic stenosis
  • Unaffected parent of a child with Williams syndrome
    • Possibility of rare germline mosaicism or inversion polymorphism
    • Only offered with extreme parental concern

Contraindications

  • Infection overlying needle insertion site
  • Relative contraindication to fetus given 1.4% and 1.9% risk of miscarriage with amniocentesis and chorionic villus sampling, respectively 14

Interpretation of results

  • Specimen is submitted for fluorescence in situ hybridization analysis
  • A single hybridization signal showing 1 copy of elastin gene (ELN) in the microdeletion region on chromosome 7q11.23 is diagnostic of Williams syndrome

Differential Diagnosis of Williams Syndrome

Most common

  • Fetal alcohol syndrome (Related: ) 7Fetal alcohol syndrome and fetal alcohol spectrum disorders
    • Intellectual disability, microcephaly, growth deficiency, behavioral dysfunction, and similar characteristic facial features (smooth philtrum, thin vermilion border, and small palpebral fissures) are features of both Williams and fetal alcohol syndromes
    • Distinguishing features of fetal alcohol syndrome include history of excessive maternal consumption of alcohol and in utero exposure
    • Definitively differentiated from Williams syndrome on the basis of normal results of molecular genetic testing
  • DiGeorge syndrome 915
    • Congenital syndrome characterized by developmental defects in the thymus, parathyroids, and great vessels (fourth branchial arch, third and fourth branchial pouch development)
    • Intellectual disability and dysmorphic facies are features of both Williams and DiGeorge syndromes
    • Distinguishing features of DiGeorge syndrome include hypoparathyroidism, frequent cleft lip/palate, craniofacial defects, hypocalcemia, and immunodeficiency
    • Differentiated from Williams syndrome by detection of the genetic deletion at 22q11 by fluorescence in situ hybridization
  • 916Noonan syndrome
    • Congenital syndrome characterized by short stature, congenital heart defects, and developmental delay; classic facial features include low-set, posteriorly rotated ears; wide-spaced eyes with vivid-blue irises; prominent epicanthal folds; and thick, droopy eyelids
    • Mild intellectual disability and short stature are features of both Williams and Noonan syndromes
    • Distinguishing findings include male Turnerlike features with webbed neck, pectus excavatum, pulmonic stenosis/hypertrophic cardiomyopathy, hemorrhagic diathesis, and cryptorchism
    • Differentiated from Williams syndrome by mutational analysis and detection of alterations in 1 of several causative genes (PTPN11SOS1RAF1, or KRAS)
  • Smith-Magenis syndrome 17
    • Congenital syndrome characterized by:
      • Developmental delay, cognitive impairment, and distinctive neurobehavioral abnormalities
      • Notable dysmorphic facial features, including midface retrusion; short, upturned nose; deep-set, close-spaced eyes with upslanting palpebral fissures; brachycephaly; broad forehead; and down-turned, tent-shaped upper vermilion lip border
    • Dysmorphic facies, mild mental disability, engaging personalities, and short stature are characteristics of both Williams and Smith-Magenis syndromes
    • Distinguishing features include behavioral problems and sleep disturbances
    • Differentiated from Williams syndrome by specific chromosomal deletion found at 17p11.2 by fluorescence in situ hybridization
  • Kabuki syndrome 18
    • Congenital syndrome characterized by growth deficiency, mental disability, and skeletal abnormalities
      • Specific abnormalities include persistent fetal fingertip pads and facial dysmorphology (prominent cupped dysplastic ears; arched, broad eyebrows with sparse lateral third; short columella with depressed nasal tip; elongated palpebral fissures with eversion of the lateral third of the lower eyelid)
      • Variable findings include congenital heart defects, genitourinary anomalies, gastrointestinal abnormalities, ocular anomalies, dental abnormalities, and cleft lip/palate
    • Dysmorphic facies, intellectual disability, short stature, and congenital heart defects are features of both Williams and Kabuki syndromes
    • Distinguishing features include seizures, scoliosis, nystagmus, and autoimmune disorders
    • Differentiated from Williams syndrome by mutational analysis and detection of alterations in the KMT2D/KDM6A gene

Treatment

Goals

  • Achieve and maintain serum calcium levels in a normal or minimally elevated range
  • Achieve and maintain blood pressure below the 95th percentile for age
  • Prevent long-term health complications
  • Promote physical function and long-term quality of life

Disposition

Recommendations for specialist referral

  • Cardiologist 3
    • Refer to cardiologist for evaluation and management of supravalvular aortic stenosis, hypertension, long QT interval, elastin arteriopathy, and other vascular abnormalities
    • Referral for detailed cardiovascular assessment is imperative to identify the variety of arterial anomalies seen in patients with Williams syndrome
  • Pediatric anesthesiologist 3
    • Refer before initiating any anesthesia or conscious sedation
  • Genetic counselor
    • Refer for individualized risk assessment and recommendations on genetic testing of family members
  • Urologist
    • Refer for structural abnormalities in urinary system or kidneys
  • Nephrologist
    • Refer for hypercalcuria, persistent hypercalcemia, or nephrocalcinosis
  • Ophthalmologist
    • Refer for hyperopia, strabismus, or cataracts
  • Gastroenterologist
    • Refer for feeding therapy for infants and children
  • Endocrinologist
    • Refer for early puberty, hypercalcemia, or other endocrinopathy
  • Bariatrician 19
    • Refer for treatment of overweight or obesity
    • Williams syndrome–specific growth charts for height and weight are available on the American Academy of Pediatrics guidelines site for Health Care Supervision for Children with Williams Syndrome 3
  • Orthopedist
    • Refer for joint contractures
  • Pediatrician
    • Refer for coordination of care, regular physical examination, and ongoing laboratory monitoring for complications of disease
  • Adult family practitioner or internist
    • Refer for coordination of care, regular physical examination, and ongoing laboratory monitoring for complications of disease
  • Developmental pediatrician/early intervention program
    • Refer for individualized multidisciplinary evaluation and treatment
  • Psychiatrist/psychologist
    • Refer for behavioral assessment

Treatment Options 6

Overview

  • Williams syndrome affects multiple systems and therefore treatment entails monitoring and managing associated multisystemic complications

Hypercalcemia

  • Observation/surveillance at mildly elevated calcium levels (under 12 mg/dL) is sufficient in some cases
  • Pharmacotherapy with a bisphosphonate or glucocorticoid becomes necessary when patients are symptomatic, have evidence of hypercalcuria/elevated calcium-creatinine ratios, or have moderately to severely elevated (over 12 mg/dL) serum calcium levels
    • Normal calcium-creatinine ratios for age can be found in American Academy of Pediatrics Health Care Supervision for Children with Williams Syndrome guidelines 3
  • Generally managed in consultation with an endocrinologist or nephrologist
  • Severe hypercalcemia (over 14 mg/dL) or symptomatic moderate hypercalcemia (over 12 mg/dL) requires urgent treatment with fluids and loop diuretics 11

Hypertension

  • Implement dietary and lifestyle approaches to control blood pressure in all children with Williams syndrome
    • Provide advice on the Dietary Approaches to Stop Hypertension (DASH) diet and recommend moderate to vigorous physical activity at least 5 days per week (30-60 minutes per session) to help reduce blood pressure 20
  • Pharmacotherapy often required in adolescent and adult populations with blood pressure elevated above the 95th percentile for age 21
    • There are no clear guidelines for management
    • A variety of antihypertensives can be used, most commonly calcium channel blockers, but also β-blockers, ACE inhibitors, and angiotensin II receptor blockers
      • Avoid ACE inhibitors and angiotensin II receptor blockers in the setting of renal artery stenosis
      • Interventional treatment of renal artery stenosis is not consistently helpful in controlling hypertension

Constipation (pharmacotherapy often required in patients with Williams syndrome)

  • If behavioral interventions are not effective, use a trial of stool softeners
  • Another option is polyethylene glycol, which can be started and titrated to effect
  • Avoid excess calcium and vitamin D, which can exacerbate constipation

Cardiac manifestations

  • Surgical correction of supravalvular aortic stenosis is necessary in 20% to 30% of cases 6
    • Transcatheter balloon angioplasty procedure is ineffective, so surgery is required in most patients
  • Arterioplasty is required for symptomatic or moderate to severe arterial lesions

Physical therapy sessions are recommended to prevent contractures

Mental health

  • Behavioral therapy and possibly pharmacotherapy for comorbid attention deficit/hyperactivity disorder, anxiety, and autism spectrum disorder

Drug therapy 6

  • Hypercalcemia treatment 12
    • Bisphosphonates
      • Pamidronate IV indicated for severe hypercalcemia (over 14 mg/dL)
        • Pamidronate Disodium Solution for injection; Infants and Children: 1 mg/kg IV infusion over 6 hours has been reported. (Max: 90 mg/dose). 22
    • Oral steroids are second line treatment for hypercalcemia refractory to bisphosphonate therapy, or as adjunct therapy for severe symptomatic hypercalcemia
      • Consult with a pediatric endocrinologist for dosing of steroids
  • Antihypertensives 4
    • Calcium channel blockers (dihydropyridine type)
      • Amlodipine
        • Amlodipine Besylate Oral tablet; Children and Adolescents 6 to 17 years: 2.5 to 5 mg PO once daily. Max: 5 mg/day. Some investigators have reported initial doses of 0.05 to 0.3 mg/kg/day PO divided once daily to twice daily (Max: 0.6 mg/kg/day up to 10 to 20 mg/day). Adjust dose every 5 to 7 days. Younger children require higher doses per kg of body weight relative to older children and may benefit from twice daily dosing in some cases.
        • Amlodipine Besylate Oral tablet; Adults: 5 mg PO once daily initially. Max: 10 mg/day.
      • Nifedipine
        • Nifedipine Oral tablet, extended-release; Children† and Adolescents†: Initially, 0.25 to 0.5 mg/kg/day PO, titrated up to maximum of 3 mg/kg/day (not to exceed 180 mg/day), has been suggested. Extended-release tablets must be swallowed whole and are too large for young children.
        • Nifedipine Oral tablet, extended-release; Adults: Initially, 30 to 60 mg PO once daily. Max: 90 mg/day for most extended-release products; 120 mg/day for Procardia XL.
    • β-blockers
      • May additionally be indicated in patients with prolonged QT interval in consultation with cardiologist
      • Do not use if the patient has asthma, as β-blockers can worsen this condition
      • Labetalol
        • Labetalol Hydrochloride Oral tablet; Children† and Adolescents†: Initially, 1 to 3 mg/kg/day PO; titrate to blood pressure response to a max of 10 to 12 mg/kg/day PO or 1,200 mg/day PO.
        • Labetalol Hydrochloride Oral tablet; Adults: 100 mg PO twice daily, initially. Titrate dosage in increments of 100 to 200 mg PO twice daily at 2- to 3-day intervals. Usual dose: 200 to 400 mg twice daily. Max: 2,400 mg/day.
      • Metoprolol
        • Metoprolol Tartrate Oral tablet; Children† and Adolescents†: Initially, 1 to 2 mg/kg/day PO divided twice daily titrated to a maximum of 6 mg/kg/day PO (Max: 200 mg/day PO).
        • Metoprolol Tartrate Oral tablet; Adults: Initially, 100 mg/day PO, given in single or divided doses. Titrate dosage to response weekly; dose range is 100 to 450 mg/day.
      • Propranolol
        • Propranolol Hydrochloride Oral tablet; Children† and Adolescents†: Initially, 0.5 to 2 mg/kg/day PO in 2 to 4 divided doses. Titrate gradually every 3 to 7 days as needed; heart rate may be dose-limiting. Usual dosage 1 to 6 mg/kg/day. Max: 8 mg/kg/day or 640 mg/day.
        • Propranolol Hydrochloride Oral tablet; Adults: Initially, 40 mg PO twice daily; increase at 3 to 7 day intervals up to 160 to 480 mg/day given in 2 to 3 divided doses. Max: 640 mg/day. In geriatric patients, use conservative initial doses and titrate carefully.
      • Atenolol
        • Atenolol Oral tablet; Children: Initially, 0.8 to 1 mg/kg PO once daily. Usual dose range: 0.8 to 1.5 mg/kg/day. Max: 2 mg/kg/day.
        • Atenolol Oral tablet; Adults: Initially, 25 to 50 mg PO once daily. Increase up to 100 mg/day if needed after 7 to 14 days.
  • Constipation medications
    • Polyethylene glycol
      • Polyethylene Glycol 3350 Oral solution; Infants† and Children† less than 2 years: 0.4 grams/kg/day PO suggested initially; dose ranges of 0.2 to 1.5 grams/kg/day PO have been used in studies; in 1 trial of infants and toddlers, the mean effective doses were 0.8 to 1.1 grams/kg/day PO. Medical supervision is recommended.
      • Polyethylene Glycol 3350 Oral solution; Children† and Adolescents† 2 to 16 years: 0.4 grams/kg/day PO initially has been suggested; dose ranges of 0.2 to 1.8 grams/kg/day PO have been reported. Max: 17 grams/day PO. Medical supervision is recommended; OTC use should not exceed 2 weeks without further evaluation and medical supervision. Doses of 0.8 grams/kg/day or more PO are more likely to cause loose stools and may require dosage reduction.
      • Polyethylene Glycol 3350 Oral solution; Adults: 17 grams of powder in 120 to 240 mL of water, juice, soda, coffee or tea PO once daily.
    • Lactulose
      • Lactulose Oral solution [Constipation]; Children†: 1 to 2 g/kg/day (1.5 to 3 mL/kg/day) PO divided once or twice daily.
      • Lactulose Oral solution [Constipation]; Adults: Initially, 15 to 30 mL PO once daily; may increase to 60 mL PO once daily if needed.

Nondrug and supportive care

Treatment of hypercalcemia

  • Avoid extra calcium and vitamin D
    • Adjust diet so that calcium intake is not higher than 100% of the recommended daily intake 6
    • Avoid any multivitamin supplements containing vitamin D 6

Nonpharmacologic treatment for hypertension

  • Diet modifications (Dietary Approaches to Stop Hypertension) and regular engagement in physical activity 20

Physical therapy

  • Range of motion exercises to prevent contractures 6

Prevention of obesity

  • Registered dietitian counseling for energy-balanced diet 23
  • Moderate physical activity prescription (at least 20-60 minutes 5 days per week) 23

Feeding therapy

  • Feeding team management in consultation with a gastroenterologist for infants and children 6
Procedures
Arterioplasty of constricted vessels

Required for supravalvular aortic or pulmonary artery stenosis, mitral valve insufficiency, and/or renal artery stenosis

General explanation

  • Surgical repair or reconstruction of an artery

Indication

  • Significant arterial narrowing on arteriography or ultrasonogram

Contraindications

  • Care with anesthesia in patients with Williams syndrome due to risk of sudden death

Monitoring

  • Regular monitoring by the primary care physician is indicated for early recognition and initiation of treatment of Williams Syndrome for expected complications 3 6
    • Blood pressure (taken bilaterally in upper extremities) and careful palpation of femoral pulses with each visit
    • Serum calcium level every 4 to 6 months in patients aged younger than 2 years, then every 2 years thereafter
    • Spot urine calcium-creatinine ratio every 2 years
    • Urinalysis annually
    • Serum creatinine clearance every 4 years
    • Renal and bladder ultrasonography at diagnosis and every 5 to 10 years thereafter, depending on presence and severity of disease
    • TSH measurement every 3 to 4 years
    • Hearing and vision screening with a formal objective audiologic evaluation and an ophthalmologic evaluation annually before age 3 years and again in later childhood (ages 5-12 years)
    • Multidisciplinary developmental assessment and referral to early intervention treatment for patients aged 0 to 3 years, and school-based programs for patients aged 3 years and older
    • Oral glucose tolerance test at age 30, repeated every 5 years if not otherwise indicated 6
    • Cardiology monitoring
      • Annual physical examination (cardiac) for first 5 years, then every few years depending on cardiovascular disease severity
      • Screen all adults periodically for mitral valve prolapse, aortic insufficiency, and arterial stenosis

Complications and Prognosis

Complications 9

  • ACQUIRED DISEASE
    • Cardiovascular disease
      • Supravalvular aortic stenosis 4
        • May worsen with time but remains stable in most patients from birth
      • Aortic and mitral valve disease
        • 20% of patients develop myxomatous degeneration of 1 or both valves 2
        • When severe, will progress to obstruction
        • Progression can occur at any age, but rapid progression between ages 3 and 5 years is most often observed 4 6
        • Aortic valve
          • Adhesion of leaflets to sinotubular junction (50%) can result in obstruction of coronary flow 4
        • Mitral valve prolapse (9%-27%) 4
      • Long QT syndrome
        • 13.6% of patients develop prolonged QT interval 4 6
          • On ECG, the finding of a QTc interval 500 milliseconds or higher indicates very high risk for sudden death 4
      • Hypertension
        • Develops in approximately 50% of cases 2
        • May develop at any age and is often difficult to treat
          • May occur due to renal artery stenosis in some cases
      • Elastin arteriopathy 6
        • May affect any vessel, but greatest mortality from supravalvular aortic stenosis, and if left untreated will lead to elevated left-heart pressure, cardiac hypertrophy, and cardiac failure
        • Renal artery stenosis found in 50% of cases 6
        • Coarctation of the aorta
        • Coronary abnormalities can lead to angina and sudden death
  • Mental health
    • 50% to 90% adolescents and adults have anxiety disorder, phobic disorder, and/or attention deficit/hyperactivity disorder 2
    • Sleep dysregulation is common
    • Autism spectrum disorder is common
  • Growth
    • Short stature in most
  • Endocrinopathies
    • Hypercalcemia (idiopathic) 11
      • Results in hypercalciuria (10%-30%) and nephrocalcinosis (under 5%) 2 3 6
      • 5% to 50% of patients have 1 episode of acute hypercalcemia 2
      • Infants present with irritability, constipation, and vomiting
    • Diabetes mellitus
      • Impaired glucose tolerance and silent diabetes are very common, possibly occurring in up to 90% of adults 2
    • Subclinical hypothyroidism
      • Diagnosed in 15% to 30% 2
    • Early puberty (50%) 3
      • Children develop pubertal changes on average 2 years earlier than controls 2
    • Celiac disease
      • 9.6% of children 6
  • Sensorineural hearing loss
    • 63% of children 6
    • 92% of adults 6
  • Ocular problems
    • Amblyopia, strabismus, and/or hyperopia in 50% of cases 6
  • Vocal cord paralysis
    • Most have hoarse, low-pitched voice
  • Musculoskeletal problems
    • Joint hypermobility in 90% 3
    • Joint contractures in 50% 3
    • Kyphosis in 20% 3
    • Lordosis in 40% 3
  • Obesity (30%) 3
  • Chronic abdominal pain
    • Chronic constipation
    • Diverticulitis in adolescents and adults
    • Ischemic bowel
    • Gastroesophageal reflux
    • Cholelithiasis
    • Somatization of anxiety
  • Urinary tract abnormalities
    • Urinary frequency, enuresis, and/or incontinence in 50% of children 6
    • Bladder diverticula in 40% 6
    • Vesicoureteral reflux reported
    • Recurrent urinary tract infection in 30% of adults 6
  • Osteopenia
    • Marked decrease in bone mineral density may require bisphosphonate therapy
  • Premature aging
    • Graying of hair in approximately 80% of patients 10
    • Cataracts
    • Wrinkles
  • Complications
    • Sudden death
      • Most occur in the periprocedural and perianesthetic setting
      • Sudden cardiovascular collapse
        • Incidence of sudden death is 25- to 100-fold higher than age-matched controls, and is caused by: 4 6
          • Bilateral outflow tract obstruction
          • Coronary arterial stenosis
          • Prolonged QT interval–related arrhythmia
    • Recurrent/chronic otitis media in 50% of children 6

Prognosis of Williams Syndrome

  • Most adults with Williams syndrome live with parents, in group homes, or in other supervised living situations 9
  • Life expectancy is very broad, ranging from 1 to 55 years 2
  • Cardiovascular-associated mortality is 25- to 100-fold higher than the general population 2

Screening and Prevention

Screening

  • SCREENING FOR ASSOCIATED CONGENITAL ANOMALIES (indicated at the time of diagnosis/birth) 3
    • Cardiologist evaluation and consultation
      • Obtain echocardiogram, ECG, 24-hour ambulatory ECG monitoring, and 4-extremity blood pressure measurement on all patients
      • Refer all patients to cardiologist for evaluation and management of supravalvular aortic stenosis, hypertension, long QT interval, elastin arteriopathy, and any other vascular abnormalities
        • Detailed cardiovascular screening is imperative to identify variety of arterial anomalies seen in patients with Williams syndrome
        • This may include cardiac CT, magnetic resonance angiography, or cardiac catheterization
    • Urologist
      • Renal and bladder ultrasonography at diagnosis
      • Renal function studies
        • Serum creatinine clearance and BUN level
        • Urinalysis
    • Endocrinologist
      • Thyroid function studies
      • Calcium determinations
        • Serum calcium levels
        • Spot urine calcium level and creatinine clearance
    • Ophthalmologic evaluation
    • Multidisciplinary developmental evaluation (older than 2 years)

Prevention

  • Genetic counseling
    • The microdeletion is sporadic, so the chance of asymptomatic parents giving birth to an additional child with Williams syndrome is far less than 1% 2
    • A parent with Williams syndrome has a 50% chance of passing the inheritance of the syndrome to his or her offspring 2
  • Preimplantation genetic screening results can be used to remove affected genes during in vitro fertilization attempts 6
    • An option for families with a known disease-causing deletion
    • Option for the rare case of an affected parent with Williams syndrome planning pregnancy
Sources
  • 1: Martens M et al: Research review: Williams syndrome: a critical review of the cognitive, behavioral, and neuroanatomical phenotype. J Child Psychol Psychiatry. 49(6):576–608, 2008 Cross Reference  
  • 2: Pober BR: Williams–Beuren syndrome. N Engl J Med. 362(3):239-52, 2010
  • 3: Committee on Genetics: American Academy of Pediatrics: health care supervision for children with Williams syndrome. Pediatrics. 107(5):1192-204, 2001 Note: Erratum: Pediatrics 109: 329 only, 2002 
  • 4: Collins RT: Cardiovascular disease in Williams syndrome. Circulation. 127: 2125-34, 2013 http://circ.ahajournals.org/content/127/21/2125.full
  • 5: Richards C et al: Prevalence of autism spectrum disorder phenomenology in genetic disorders: a systematic review and meta-analysis. Lancet Psychiatry. 2(10):909-16, 2015
  • 6: Morris CA: Williams syndrome. In: Adam MP et al, eds. GeneReviews [Internet]. Initial posting April 9, 1999. Last update June 13, 2013. Accessed March 23, 2018. http://www.ncbi.nlm.nih.gov/books/NBK1249/
  • 7: CDC National Center on Birth Defects and Developmental Disabilities: Fetal Alcohol Syndrome: Guidelines for Referral and Diagnosis. CDC website. Published May 2005. Accessed March 23, 2016. http://www.cdc.gov/ncbddd/fasd/documents/fas_guidelines_accessible.pdf
  • 8: American Academy of Pediatrics Committee on Genetics: Health care supervision for children with Williams syndrome. Table 1. Medical problems in Williams syndrome by organ system and age. AAP website. Reaffirmed September, 2006. Accessed April 5, 2018. http://pediatrics.aappublications.org/content/107/5/1192.figures-only#fig-data-tables
  • 9: Jones KL: Smith’s Recognizable Pattern of Human Malformation. 5th ed. Philadelphia, PA: Saunders; 1997
  • 10: Williams-Beuren syndrome. Online Mendelian Inheritance in Man. OMIM website. Johns Hopkins University. Updated August 18, 2017. Accessed February 23, 2018. http://www.omim.org/entry/194050
  • 11: Stokes VJ et al: Hypercalcemic disorders in children. J Bone Miner Res. ePub, 2017
  • 12: AACE/AAES Task Force on Primary Hyperparathyroidism: The American Association of Clinical Endocrinologists and the American Association of Endocrine Surgeons position statement on the diagnosis and management of primary hyperparathyroidism. Endocr Pract. 11(1):49-54, 2005
  • 13: Shulman L et al: Invasive prenatal genetic techniques. The Global Library of Women’s Medicine. Global Library of Women’s Medicine website. Published 2008. Accessed February 23, 2018. http://www.glowm.com/section_view/heading/Invasive%20Prenatal%20Genetic%20Techniques/item/220
  • 14: Tabor A et al: Fetal loss rate after chorionic villus sampling and amniocentesis: an 11-year national registry study. Ultrasound Obstet Gynecol. 34(1):19-24, 2009 
  • 15: McDonald-McGinn DM et al: 22q11.2 deletion syndrome. GeneReviews [Internet]. Initial posting September 23, 1999. Last update February 28, 2013. Accessed March 23, 2018. http://www.ncbi.nlm.nih.gov/books/NBK1523/
  • 16: Allanson JE et al: Noonan syndrome. GeneReviews [Internet]. Initial posting November 15, 2009. Last update February 25, 2016. Accessed March 23, 2018. http://www.ncbi.nlm.nih.gov/books/NBK1124/
  • 17: Smith ACM et al: Smith-Magenis syndrome. GeneReviews [Internet]. Initial posting October 22, 2001. Last update June 28, 2002. Accessed March 23, 2018. http://www.ncbi.nlm.nih.gov/books/NBK1310/
  • 18: Adam MP et al: Kabuki syndrome. GeneReviews [Internet]. Initial posting September 1, 2011. Last revision May 16, 2013. Accessed March 23, 2018. http://www.ncbi.nlm.nih.gov/books/NBK62111/
  • 19: National Heart, Lung, and Blood Institute: Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: Summary Report. NIH website. Published October, 2012. Accessed March 23, 2018. http://www.nhlbi.nih.gov/health-pro/guidelines/current/cardiovascular-health-pediatric-guidelines/summary
  • 20: Flynn JT et al: Clinical practice guideline for screening and management of high blood pressure in children and adolescents [published corrections appear in Pediatrics. 140(6):e20173035 and Pediatrics. 142(3):e20181739]. Pediatrics. 140(3), 2017
  • 21: Bouchireb K et al: Clinical features and management of arterial hypertension in children with Williams-Beuren syndrome. Nephrol Dial Transplant. 25(2):434-8, 2010 
  • 22: Oliveri B et al: Long-term control of hypercalcaemia in an infant with Williams-Beuren syndrome after a single infusion of biphosphonate (Pamidronate). Acta Paediatr. 93(7):1002-3, 2004
  • 23: Styne DM et al: Pediatric obesity: assessment, treatment, and prevention: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 102(3):709-757, 2017
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