Williams Syndrome

INTRODUCTION

Background: Originally described independently by Williams and Beuren in 1961, Williams syndrome (WS) is a rare genetic condition whose clinical manifestations include a distinct facial appearance, cardiovascular anomalies, neonatal hypercalcemia, and a characteristic neurodevelopmental/behavioral profile.

Pathophysiology: Genetics: A submicroscopic deletion on chromosome band 7q11.23 that includes the elastin gene is identified as present in 95-98% of individuals with WS. The size of the deletion is variable, but this does not correlate with the variability of the clinical findings observed in individuals with WS. The vast majority of cases are sporadic, but some examples of autosomal dominant inheritance have been described.

Frequency:

  • In the US: Incidence is 1 per 20,000 births, with mostly sporadic cases.
  • Internationally: Frequency is the same as in the United States.

Mortality/Morbidity: Cardiovascular disease occurs in more than 60% of patients with WS and accounts for virtually all of the early mortality associated with the disease. Patients with significant supravalvular aortic stenosis (SVAS) or coronary arterial stenosis are at risk of sudden death and complications related to their specific cardiac lesion.

Because many other organ systems are involved in WS, a number of other potential sources of morbidity exist. Mental retardation, developmental delay, severe dental disease, strabismus, progressive joint contractures, and bowel and bladder diverticula may lead to potential long-term complications.

Race: WS occurs in all ethnic groups.

Sex: Males and females are affected equally.

Age: WS is a genetic disorder present at birth.

CLINICAL

History: The history obtained from caregivers of WS patients is variable and reflects the wide phenotypic spectrum observed in the syndrome.

  • Children with WS are described as gregarious, hyperactive, and inattentive.
  • Children with WS typically have mild-to-moderate mental retardation with impairment of daily living skills correlating to the retardation.
  • Language and, occasionally, musical skills are described as disproportionately strong when compared to IQ. Some studies dispute the relative language strength and, instead, attribute it to a more evenly distributed intellectual profile that is not as impaired as previously believed.
  • A slightly increased frequency of renal abnormalities and voiding dysfunction is noted. High rate of enuresis is typical in children with WS.

Physical: A wide variation occurs in the phenotypic expression of WS; many physical manifestations of WS, such as cardiac lesions and facies, can be explained by the elastin gene deletion. Current research also is focusing on finding genetic components of the neurodevelopmental manifestations of WS.

  • Children with WS generally are full-term infants. One of the earliest indications of WS may be failure to thrive as an infant.
  • Clinical suspicion may arise after the incidental finding of hypercalcemia or after discovering a cardiac lesion suggestive of WS. Isolated SVAS is rare in children, and a diagnosis of this should lead the clinician to rule out WS. Observing a combination of facial features with developmental-behavioral manifestations also may lead to a diagnosis of WS.
  • WS facies traditionally are described as "elfin." This is a pejorative term and is much discouraged by health care professionals who treat individuals with WS. More than 90% of children with WS have some combination of the following features: short upturned nose, flat nasal bridge, long philtrum, flat malar area, wide mouth, full lips, dental malocclusion, micrognathia, stellate irides, or periorbital fullness.
  • The most common cardiac lesion described is SVAS. Approximately one half of all patients with WS have SVAS, with an overall prevalence of cardiovascular disease higher than 60%.
  • Other commonly described problems include peripheral pulmonary branch stenosis, mitral valve prolapse, and hypertension secondary to progressive renal artery stenosis. Peripheral pulmonary branch stenosis commonly is the presenting cardiovascular abnormality but tends to improve (or normalize) with time, whereas SVAS becomes more apparent and progressive with age.
  • Other findings include strabismus, hyperacusis, hoarse voice, joint hyperelasticity, and contractures.

Causes: A deletion on band 7q11.23 near the elastin gene is identified in 95-98% of individuals with WS. Deletion size varies, which likely accounts for the heterogeneity of clinical presentation. Most cases are sporadic, but some autosomal dominant inheritance is described.

DIFFERENTIALS

Aortic Stenosis, Supravalvar
Attention-Deficit/Hyperactivity Disorder
Failure to Thrive
Hypercalcemia

WORKUP

Lab Studies:

  • Fluorescent in situ hybridization (FISH) may be used to confirm diagnosis.
    • WS may be confirmed by using FISH to search for the elastin gene deletion thought to be present in 95-98% of individuals with WS.
    • In the past, WS was a purely clinical diagnosis made by the presence of a constellation of findings.
  • Obtain a serum calcium measurement if WS is suspected.
    • Hypercalcemia frequently causes no symptoms and generally resolves spontaneously.
    • The major complication of hypercalcemia relates to the timing of any corrective cardiac surgery.
    • Nephrocalcinosis and sclerosis of the long bones occasionally are observed in severe cases.
  • Obtain baseline blood urea nitrogen (BUN) and serum creatinine levels as part of the screening for associated renal disorders.
  • Systemic hypertension may occur.

Imaging Studies:

  • Perform a baseline echocardiogram in all patients diagnosed with WS, regardless of cardiac physical examination findings. Approximately one half of all children with WS will have a significant cardiac lesion.
  • Cardiovascular management is dependent on the specific cardiac lesion present. In addition to ECGs and echocardiograms, children with SVAS may require cardiac catheterization as part of their presurgical evaluation.
  • Obtain a renal ultrasound in the initial workup to look not only for anatomic abnormalities but also for nephrolithiasis caused by hypercalcemia. The incidence of renal abnormalities is low in WS, but it is significantly higher than in the general population.

Other Tests:

  • Full neurodevelopmental testing may aid the general practitioner in identifying suspected cases of WS, and it may help tailor schooling and supplemental developmental assistance for children already diagnosed with WS.
  • Obtain thyroid function studies because hypothyroidism is far more common in WS than the general population, although the exact prevalence is not known.

TREATMENT

Medical Care: WS is a complex multisystem medical condition that requires the attention of multiple health care professionals. A few large tertiary care centers have WS clinics, which help organize and coordinate the care of WS patients. WS Associations exist in the United States and Canada, and are a valuable resource for both parents and health care professionals.

Tailor specific management of WS to the presenting clinical spectrum. Initial care often centers on failure to thrive, hypercalcemia, or repair of the cardiac lesion. School performance, physical therapy, hyperactivity, and the child's eventual role in society are long-term issues that need to be addressed on an ongoing basis. Anticipatory guidance is essential to help parents prepare for future needs of children with WS.

  • Hypercalcemia observed in patients with WS usually is asymptomatic and generally resolves spontaneously by age 4 years.
    • Symptomatic hypercalcemia may be managed with dietary calcium restriction and vitamin D.
    • Severe cases occasionally require prednisone, calcitonin, or bisphosphonates.
  • For WS children with cardiac findings, early involvement with a pediatric cardiologist and cardiothoracic surgeon is essential.
  • Systemic hypertension should be treated when identified.

Surgical Care:

  • SVAS is the most frequently observed operable cardiac lesion in WS.
  • Timing of the operative repair depends on the presence of cardiac symptoms, the gradient across the supraaortic obstruction, or if ischemic changes are noted on a stress test. Peripheral branch pulmonary stenosis usually resolves spontaneously and generally should not be treated with catheter or surgical intervention.
  • In general, the degree of supraaortic obstruction in WS patients tends to progress with time, whereas peripheral branch pulmonary stenosis improves with time.

Consultations:

  • For WS children with cardiac findings, early involvement of a pediatric cardiologist and cardiothoracic surgeon is essential.
  • WS requires the attention of multiple health care professionals, depending on the specific phenotypic manifestations. Geneticists, dentists, ophthalmologists, orthopedists, physical/occupational therapists, and psychologists all contribute to the care of the patient with WS.
  • Many large tertiary care centers have WS clinics that help organize and coordinate the care of patients with WS.

FOLLOW-UP

Further Outpatient Care:

  • School performance, hyperactivity, and the child’s eventual role in society are long-term issues that need to be addressed on an ongoing basis.
  • Anticipatory guidance is essential to help parents prepare for future needs of children with WS.

Prognosis:

  • Medical complications may occur, especially related to the cardiovascular system. However, most individuals with WS are healthy and lead active full lives.
  • Most adults with WS are employed in a variety of settings and can perform self-care tasks.
  • Some adults with WS require the daily care of parents or caregivers; however, others may live with less supervision and care.

Patient Education:

  • Inform parents or caregivers of the Williams Syndrome Association (WSA) for supporting resources and education. WSAs are located in the United States and Canada. They provide valuable resources for parents and caregivers. The WSA can be contacted by phone (248-541-3630) or through their Web site www.williams-syndrome.org