Health Care Supervision for Children With Williams Syndrome

Cardiovascular

The majority of children with WS have cardiovascular anomalies secondary to elastin arteriopathy, the major source of morbidity and mortality. Although any artery may be narrowed, the most common problem is SVAS, which may worsen over time, particularly in the first 5 years. Progression is more likely if the severity of the stenosis is moderate or severe and presents in infancy or early childhood.¹⁶ SVAS is most commonly a discrete hourglass stenosis or may be a long segment stenosis (∼15%).¹⁷ Approximately 30% of children with SVAS will require surgical correction.¹⁸ The mortality rate is 6% for cardiac surgery or catheterization.¹⁹ Peripheral pulmonic stenosis is common in infancy but often improves over time when occurring in isolation. Mitral valve prolapse and aortic insufficiency may occur in adolescents or adults. QTc prolongation has been reported in 13% of individuals.²⁰

Hypertension is present in 50% of people with WS, may occur at any age, and is occasionally associated with renal artery stenosis.^21–23 Increased vascular stiffness, which is a risk factor for stroke, is another manifestation of elastin arteriopathy found in both hypertensive and normotensive children and adults with WS.²³ Blood pressure measurement in both arms is recommended at well-child visits with use of a manual cuff at the end of the visit to minimize anxiety. Antihypertensive therapy successfully controls hypertension in most patients and also ameliorates vascular stiffness.^21,23 Consider cardiology or nephrology referral for hypertension (blood pressure >90th percentile for age and height).²⁴

Patients with WS are at increased risk for myocardial ischemia, acute hemodynamic deterioration, and sudden death because of their cardiovascular anomalies, especially in the setting of sedation and anesthesia.²⁵ Individuals with biventricular outflow tract obstruction are at the greatest risk.^19,26 Sudden death in WS (1 per 1000 patient-years)²⁷ may be related to abnormalities of the coronary arteries (ostial or diffuse stenosis or dilatation)²⁸ or biventricular outflow tract obstruction. Because there is an increased risk of adverse events with sedation and aesthesia, recommendations have been developed for management of sedation and anesthesia in individuals with WS.^26,29,30

Children with WS should be evaluated by a pediatric cardiologist with experience in treating WS when feasible. The initial evaluation should include 3 limb blood pressures (2 arms and 1 leg); echocardiogram, including Doppler flow studies; and electrocardiogram. Cardiology follow-up should occur frequently (every 3 months) in the first year of life and at least annually through middle childhood with subsequent intervals dictated by the nature and severity of cardiovascular disease. Children who have decreased pulses, bruits, and/or evidence of diffuse thoracic aortic stenosis will require additional cardiovascular imaging studies (computed tomography, magnetic resonance angiography, or cardiac catheterization) to define the anatomy. Because of the increased risk for serious cardiovascular complications surrounding procedures requiring anesthesia, careful perioperative planning, particularly of nonemergency procedures, is recommended with pediatric anesthesiologists who are familiar with WS and work in centers that can provide multidisciplinary support in the event of serious cardiac decompensation during sedation and anesthesia.^26,29,30

Hypercalcemia

Idiopathic infantile hypercalcemia may contribute to the presence of extreme irritability, vomiting, constipation, and muscle cramps associated with this condition.^6,31 Problems associated with hypercalcemia include dehydration, hypercalciuria, and nephrocalcinosis.³² Symptomatic hypercalcemia is most common in the first 2 years and usually resolves during childhood,^3,33 but lifelong abnormalities of calcium and vitamin D metabolism may persist. Individuals with WS in all age groups have higher median calcium levels than controls.³² There is increased calcium absorption from the gut; the cause of the abnormality in calcium metabolism is unknown.¹⁴

Serum calcium determination should be obtained every 4 to 6 months until 2 years of age, every 2 years thereafter, and when hypercalcemia is suspected clinically. Parents should be educated regarding the signs and symptoms of hypercalcemia. Children with WS and normocalcemia should have the reference daily intake of calcium,³⁴ and parents should be cautioned not to restrict calcium without medical supervision.³¹ Infants with hypercalcemia are usually successfully treated with a low-calcium diet and increased water intake under medical and nutritional supervision, and they require more frequent surveillance of calcium concentrations. Serum blood urea nitrogen, creatinine, vitamin D concentrations (25-hydroxyvitamin D and 1,25-dihydroxyvitamin D), and intact parathyroid hormone should be checked if hypercalcemia is present.³⁵ The urine calcium/creatinine ratio in a random spot urine should be obtained at the time of diagnosis and if hypercalcemia is present (Table 2). If hypercalciuria is found, hydration status should be assessed, serum calcium concentration should be measured, dietary calcium intake should be assessed, and renal ultrasonography should be performed to evaluate for nephrocalcinosis. Referral to a pediatric nephrologist and/or pediatric endocrinologist should be considered for management of persistent hypercalcemia, hypercalciuria, or nephrocalcinosis.³² Multivitamin preparations containing vitamin D should be avoided in early childhood, and vitamin D supplementation should be used with caution in older children and adults.⁴ Approximately 50% of individuals with WS have impaired bone mineral status osteopenia or osteoporosis; the etiology is unknown.^1,14

Gastrointestinal

Infants and toddlers with WS often have difficulty feeding (eg, disordered suck and swallow and textural aversion) and may be brought for medical care because there are symptoms of gastroesophageal reflux, colic, or failure to achieve anticipated weight gain.⁶ Feeding evaluation and therapy may be of benefit for infants having difficulty transitioning to solid foods, for assessment of aspiration risk and dysphagia, and for intervention for failure to gain weight appropriately according to WS growth curves. Feeding gastrostomy tubes are rarely necessary in WS. Obesity may become a problem for older children and adults.¹³

Chronic constipation is a common lifelong problem and must be aggressively treated. Typical interventions include increasing water and fiber in the diet followed by the addition of osmotic laxative treatment. Complications of constipation include rectal prolapse, hemorrhoids, and intestinal perforation. There is an increased incidence of diverticulitis occurring at a young age in adolescents and adults.³⁶ Abdominal pain is a frequent complaint in both children and adults; potential causes include gastroesophageal reflux, hiatal hernia, constipation, cholecystitis, diverticular disease, and discrete arterial stenosis causing ischemia.³⁷

Genitourinary

Urinary tract malformations are present in 10% of children with WS,³⁸ bladder diverticula are present in 50%,^38,39 and a history of urinary tract infection is present in 25%.⁴⁰ Bladder capacity is reduced and detrusor overactivity is found in 60% of patients,³⁶ leading to urinary frequency in 69% and enuresis.⁴⁰ Daytime urinary continence is typically achieved by 4 years of age, and nocturnal continence is present in 50% at 10 years of age.⁶ Children 4 to 12 years of age have a daytime urinary incontinence rate of 18% and nocturnal enuresis rate of 45%, whereas 2.7% of teenagers have daytime incontinence and 13.5% have nocturnal enuresis.⁴¹ Ultrasonography of the kidneys and bladder should be completed at the time of diagnosis. Individuals with recurrent urinary tract infections may require additional urologic evaluation. The practitioner should maintain a low threshold for lower urinary tract imaging (voiding cystourethrography) for the evaluation of voiding dysfunction and/or urinary tract infection. Diverticula may lead to both of these symptoms and can be recurrent after surgical repair. Kidney function should be assessed at the time of diagnosis (serum urea nitrogen and creatinine concentrations and urinalysis).

Neurology, Development, Cognition, and Behavior

Neurologic problems include axial hypotonia and peripheral hypertonia with increased deep tendon reflexes in the lower extremities. Signs of cerebellar dysfunction, such as ataxia and tremor, may increase with age.⁴² Posterior fossa size is reduced in WS, although cerebellar volume is preserved and may contribute to Chiari I malformation in some individuals with WS.⁴³ Symptoms of headache, dizziness, and dysphagia should prompt the clinician to consider a pediatric neurology referral for evaluation for Chiari malformation. Developmental milestones are delayed,⁶ and children should be referred to an early intervention program for physical, occupational, and speech therapy evaluation and treatment. Hippotherapy referral may be considered; hippotherapy uses equine movement during physical, occupational, and/or speech therapy and addresses problems of balance.⁴⁴ Although joint laxity is present in young children, joint contractures occur in older children and adults and lead to an awkward gait.⁴⁵ Nightly stretching range-of-motion exercises are often recommended. Radioulnar synostosis, found in 10% of affected children, does not respond to physiotherapy or surgical intervention.⁴⁶ Lordosis and kyphosis are common at all ages; 18% have scoliosis.^6,47

Children with WS have a unique cognitive and behavioral profile.^7,48,49 Cognitive, motor, and language delay are universal, and in 75% of children, intellectual disability is ultimately diagnosed. Children demonstrate a relative strength in language and verbal short-term memory, with a significant weakness in visuospatial construction.⁷ A detailed psychoeducational evaluation with information provided by the primary care pediatrician to the school regarding the unique cognitive and behavioral profile is important for school-aged children to develop an appropriate educational plan. A referral to a neuropsychologist may be of benefit. Speech and language, physical, and occupational therapies are important for school-aged children.

Behavioral problems may include hypersensitivity to sound, attention-deficit/hyperactivity disorder (ADHD), and nonsocial anxiety.⁵⁰ Approximately 50% of children with WS will require pharmacologic treatment of ADHD and/or anxiety. Although overfriendliness and an empathetic nature are commonly observed, many individuals have difficulty with emotional regulation.⁵¹ In young children who have limited language, there may be symptom overlap with autism spectrum disorder, such as restricted interests and repetitive behaviors.⁵² A referral for assessment for autism may be considered in those children. Behavioral interventions based on applied behavior analysis may be helpful, and older children benefit from social skills training and training to master daily living skills.⁴⁸ Adaptive behavior skills in both children and adults are often more impaired than would be expected for IQ.^53,54 Adults require vocational training and instruction in community living skills. Mental health problems, most commonly anxiety, are reported in 25% to 75% of adults.^13,55

Sleep disorders are common (50% to 65%), including sleep onset delay, frequent awakenings, decreased sleep efficiency, and increased respiratory-related arousals.^56,57 An abnormal or absent melatonin peak may explain disturbance of circadian rhythm in some children.^58,59 The clinician should discuss appropriate sleep hygiene and consider a sleep study if obstructive sleep apnea is suspected.

Ocular and Auditory

Hyperopia, nasolacrimal duct obstruction, and strabismus are common in WS.⁶⁰ An ophthalmologic evaluation should be performed at the time of diagnosis with follow-up as necessary. Mild to moderate sensorineural hearing loss is present in 60% of children and 90% of adults.⁶¹ Audiologic assessment should be performed between 6 and 12 months of age and repeated annually.⁶¹ Recurrent otitis media is common. The use of noise-canceling headphones is helpful to children who have increased sensitivity to sound or specific phobia for loud noises. Earwax buildup is a common problem and may be treated with cerumen-softening drops.¹³

Dental

Dental problems include microdontia, missing teeth, and localized enamel hypoplasia.⁶² Poor fine motor skills cause difficulty with maintenance of dental hygiene and increase the risk of dental caries. A dental home should be established by 1 year of age or within 6 months of the eruption of the first tooth. The dental recall interval should be based on caries risk; dental cleaning every 4 months has been recommended.⁴ Caregivers should be instructed to assist with brushing and flossing. If dental procedures require anesthesia, WS-specific sedation and anesthesia recommendations should be followed.^29,30 Dental malocclusion is present in 85% of individuals with WS and responds to orthodontic treatment. An orthodontic assessment should be part of the evaluation in the dental home.

Endocrine

Hypothyroidism is present in 5% to 10% of children³³ At a minimum, thyroid function should be assessed at the time of diagnosis, annually for the first 3 years, and every 2 years thereafter. Subclinical hypothyroidism (mild thyroid-stimulating hormone elevation with normal thyroxine [T4]) is present in 30%.⁶³ Puberty often occurs early (18% of girls), but true precocious puberty is rare.⁶⁴ A gonadotropin-releasing hormone agonist may be used to treat early puberty; treatment in girls successfully delays menarche and results in taller height compared with controls.⁶⁵ Abnormal glucose tolerance test results have been documented in 60% to 75% of adults with WS with an increased prevalence of type 2 diabetes mellitus.^66,67 An oral glucose tolerance test is recommended at 30 years of age and should be repeated every 5 years if results are normal.¹³

Medical Home and Transition

Establish a medical home with a clear emphasis on continuity of care and the role of the family members as partners in the ongoing management and care of the child. A summary of anticipatory guidance is provided in Table 3. Counsel the family regarding networks of support, such as extended family, friends, clergy, support groups, and community agencies that serve children and adults with disabilities. The diagnosis should be reviewed and discussed with the affected individual in adolescence with referral to support groups for the adolescent (see American Academy of Pediatrics policy statement “Transition of Care Provided for Adolescents With Special Needs”).⁶⁸

Assist in transition to adult care (especially for cardiology care). Many pediatricians feel comfortable continuing to provide primary care well into young adulthood. Pediatricians can educate the adult and family regarding medical management for adults with WS.³⁷ Counseling should be provided regarding sexuality and reproductive issues, and genetic counseling should be provided. Vocational training and social skills training are essential for successful transition to independent functioning within the community for adults.

Lead Authors

Colleen A. Morris, MD

Stephen R. Braddock, MD

Council on Genetics Executive Committee, 2017–2018

Emily Chen, MD, PhD, FAAP, Co-Chairperson

Tracy L. Trotter, MD, FAAP, Co-Chairperson

Susan A. Berry, MD, FAAP

Leah W. Burke, MD, FAAP

Timothy A. Geleske, MD, FAAP

Rizwan Hamid, MD, PhD, FAAP

Robert J. Hopkin, MD, FAAP

Wendy J. Introne, MD, FAAP

Michael J. Lyons, MD, FAAP

Angela E. Scheuerle, MD, FAAP

Joan M. Stoler, MD, FAAP

Former Executive Committee Members

Debra L. Freedenberg, MD, FAAP

Marilyn C. Jones, MD, FAAP

Robert A. Saul, MD, FAAP, Chairperson

Beth Anne Tarini, MD, MS, FAAP

Liaisons

Katrina M. Dipple, MD, PhD – American College of Medical Genetics

Melissa A. Parisi, MD, PhD – Eunice Kennedy Shriver National Institute of Child Health and Human Development

Britton D. Rink, MD – American College of Obstetricians and Gynecologists

Joan A. Scott, MS, CGC – Health Resources and Services Administration, Maternal and Child Health Bureau

Stuart K. Shapira, MD, PhD – Centers for Disease Control and Prevention

Contributors

R. Thomas Collins II, MD – Williams Syndrome Association Professional Advisory Board

Paige Kaplan, MD – Williams Syndrome Association Professional Advisory Board

Beth A. Kozel, MD, PhD – Williams Syndrome Association Professional Advisory Board

Carolyn B. Mervis, PhD – Williams Syndrome Association Professional Advisory Board

Barbara R. Pober, MD – Williams Syndrome Association Professional Advisory Board

Leslie Smoot, MD – Williams Syndrome Association Professional Advisory Board

Jennifer Walton, MD, MPH – Williams Syndrome Association Professional Advisory Board

Staff

Paul Spire