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eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Cardiology

Williams Syndrome

Aneal Khan, MD, MSc, FRCP(C), FAAP, FCCMG, Assistant Professor of Medical Genetics and Pediatrics, University of Calgary; Consulting Staff, Departments of Pediatrics and Medical Genetics, Alberta Children's Hospital, Canada
Lennox H Huang, MD, Associate Chair (Clinical), Assistant Professor, Department of Pediatrics, McMaster University School of Medicine; Interim Chief of Pediatrics, McMaster Children's Hospital; Nathaniel H Robin, MD, Professor, Departments of Genetics and Pediatrics, University of Alabama at Birmingham; Consulting Staff, University of Alabama at Birmingham University Hospital and Children's Hospital of Alabama

Updated: Nov 18, 2009

Introduction

Background

Originally described independently by Williams and Beuren in 1961, Williams syndrome (WS) is a rare genetic condition. The clinical manifestations include a distinct facial appearance, cardiovascular anomalies that may be present at birth or may develop later in life, idiopathic hypercalcemia, and a characteristic neurodevelopmental and behavioral profile.

Pathophysiology

In virtually all cases of Williams syndrome, haploinsufficiency (loss of 1 of 2 copies) due to a deletion at chromosome band 7q11.23 that involves the elastin gene (ELN) is implicated. Most deletions are not detected through standard karyotyping but rather through fluorescent in situ hybridization (FISH) for a 1.5-Mb deletion.1,2,3 The size of the deletion can vary.4,5,6

Williams syndrome is not solely caused by elastin haploinsufficiency; the deletion involves a region that spans more than 25 genes and, hence, is considered a contiguous gene deletion syndrome.4,7 The cardiovascular findings, part of the connective tissue pathology, and facial dysmorphology are attributed to the elastin gene haploinsufficiency.8,9

Other genes under investigation for their role in the cognitive profile of Williams syndrome include LIMK1, GTF1IRD1, and GTF2I.10,11,12 However, genotype-phenotype correlations with genes other than elastin are not yet fully elucidated.13,7 Point mutations or small intragenic deletions of ELN have been found in the autosomal dominant disorder familial supravalvular aortic stenosis (SVAS) without other characteristics of Williams syndrome.

Frequency

United States

Williams syndrome occurs in 1 per 7,500-20,000 births; most cases are sporadic.

Mortality/Morbidity

Cardiovascular disease accounts for most cases of early mortality associated with Williams syndrome. Elastin arteriopathy is generalized; thus, virtually any artery may be affected.

Abnormalities involve local or diffuse stenosis of the medium-sized or large-sized arteries, most commonly in the ascending aorta above the aortic valves (ie, SVAS) or in the pulmonary arteries. Nonetheless, stenosis of the descending aorta, intracranial arteries, and renal arteries have been reported.14,15,16 Overall, unexpected death is rare but is 25-fold to 100-fold higher than in age-matched control subjects.17 Factors implicated in sudden death have included SVAS, severe pulmonary stenosis, and myocardial ischemia secondary to either coronary insufficiency or biventricular outflow tract obstruction with ventricular hypertrophy. Coronary insufficiency appears most likely because of stenosis that results from intimal fibrosis and muscular hypertrophy. Stroke occurring at younger than expected ages has been reported.18,19,20,21

Deaths have been reported after induction of anesthesia for minor surgical procedures, during cardiac catheterization and heart surgery, and with progressive heart failure and respiratory infection.22,17,23 Sudden deaths with no apparent instigating event have also been reported, with apparent underlying myocardial injury.22 Patients with a higher risk of sudden death may show signs of myocardial ischemia on electrocardiography (such as ST segment depression). Echocardiography, Holter monitoring, and careful evaluation should be considered before the use of anesthesia, sedation, or both or prior to an invasive procedure. Patients have also presented with syncope related to SVAS who died during diagnostic cardiac catheterization. Calcified valvular aortic stenosis has also been reported but not with sudden death.24,25

Hypertension develops in approximately 50% of individuals with Williams syndrome, in some cases in relation to renal artery stenosis.21,26

Various GI problems are common, including feeding problems and colic, as well as reflux and chronic constipation.27 Sigmoid diverticulitis in adults is reported at a higher frequency in the Williams syndrome population than in the general population.28

Williams syndrome is a multisystem condition with other potential consequences, including mental retardation, motor delay, hearing loss, severe dental disease, ocular problems, progressive joint contractures, nephrolithiasis, and bowel and bladder diverticula.

Race

Williams syndrome is panethnic. The prevalence of particular features may vary among populations; for instance, peripheral pulmonary stenosis is more common than SVAS in the Hong Kong Chinese population,29 and people living in Greece have a lower rate of cardiovascular anomalies.30

Sex

The deletion is equally prevalent in males and females. A greater severity and earlier presentation of cardiovascular disease may be observed in males.31,32

Age

Clinical manifestations of Williams syndrome are evident from birth through adulthood. However, features that may be detected antenatally include the characteristic cardiovascular lesions. In addition, fetal ultrasonography of neonates with Williams syndrome has revealed multicystic dysplastic kidney in addition to the congenital heart lesions.33 Associated findings on prenatal screening that have been reported include an increased fetal nuchal translucency and low maternal serum alpha fetoprotein (MSAFP); however, none of the prenatal findings has been proven to be a diagnostic marker of Williams syndrome.

Clinical

History

The history obtained from caregivers of patients with Williams syndrome varies and reflects the wide phenotypic spectrum observed in the syndrome. This includes a pattern of growth and development and a specific neurodevelopmental profile primarily involving 4 areas: cognitive development, language, auditory function, and visuospatial function.34

  • Children have prenatal and postnatal growth delay and usually present with failure to thrive. Short stature is common in children who are shorter than their family background, and adults reach a mean height that is often below the third percentile. A history of feeding problems and poor weight gain is common.
  • A history of recurrent middle ear infections and/or effusions in childhood and mild-to-moderate high frequency sensorineural hearing loss is noted in most adolescents and adults.
  • A history of visual disturbances is possible. These are mainly related to esotropia, cataracts, and hyperopia in as many as 50% of individuals with Williams syndrome.
  • A history of congenital heart disease is common, and hypertension may be noted.
  • In children, functional problems including a history of increased urinary frequency and daytime wetting is possible.35 Delayed toilet training is not uncommon. A history of renal abnormalities is also possible, as well as a history of hypercalcemia and hypercalciuria.
  • A history of delayed bone age, and decreased insulinlike growth factor-1 (IGF1) levels may be noted.36,37 Early pubertal onset may be noted. Glucose tolerance or overt diabetes mellitus may be detected in patients older than 20 years;20 subclinical hypothyroidism may also be noted.38,39
  • A history of connective tissue abnormalities, such as abnormal joint mobility, hernias, and diverticula, is possible.
  • Children with Williams syndrome typically have mild-to-moderate mental retardation, but the range includes severe mental retardation to average intelligence.34 Abilities should be considered on an individual basis due to the wide variability among individuals.40 Impaired motor development is often apparent before age 42 months.41
  • Early language acquisition is delayed, and although mild-to-moderate language impairments persist throughout life, the quality and affect of speech are relatively normal.
  • Visual-spatial problems impact daily life, with difficulties in handwriting, drawing, and gait apraxia, especially on uneven or sandy surfaces.42
  • Interest and enthusiasm for music is almost universal in patients with Williams syndrome, but the ability to perform professionally is exceptional.
  • As many as half of all children with Williams syndrome may exhibit autism spectrum social and communicative deficits.43
  • Children with Williams syndrome are described as overly friendly, hyperactive, inattentive, and hypersensitive to loud sounds or certain types of sounds.44,45
  • Adults may have a high rate of emotional and behavioral problems, poor social relationships and anxiety, preoccupations and obsessions, phobias, panic attacks, and depression.46,47 Few adults achieve complete independence with daily living.48,49,50

Physical

Phenotypic expression of Williams syndrome widely varies. Virtually all cases have typical facial features that can be recognized even at birth.

  • Children with Williams syndrome are generally full-term infants with prenatal growth delay. Specific growth curves for Williams syndrome have been established.51
  • Microcephaly is observed in one third of children,52 and postnatal failure to thrive is typical.
  • Virtually all children and adults with Williams syndrome have some combination of the following facial features: short upturned nose, flat nasal bridge, long philtrum, flat malar area, wide mouth, full lips, dental malocclusion and widely spaced teeth, micrognathia, and periorbital fullness. A stellate, lacy pattern of the irises can be observed in children with blue eyes. The voice may be hoarse. Nails tend to be hypoplastic and the skin soft and lax, and the halluces have a valgus deviation. "Elfin facies" is considered a pejorative term, and its use should be discouraged.
  • Problems with primary and secondary dentition include small and peg-shaped teeth, increased interdental spacing, absence of one or more primary or secondary teeth, anterior cross-bite malocclusion, and excessive gingival tissue.53,54,55
  • The diagnosis of Williams syndrome should also be considered after an incidental finding of idiopathic hypercalcemia or a characteristic cardiac lesion such as supravalvar aortic stenosis (SVAS). Other cardiac lesions in patients with Williams syndrome can include pulmonary stenosis and mitral valve regurgitation.48,32 Arterial hypertension may be present. If the distinct facial features are not evident, consider referral to a practitioner experienced in examining the facial features of Williams syndrome, such as a clinical geneticist or cardiologist experienced in dysmorphology.
  • Ocular findings can include strabismus (usually due to esotropia), a stellate iris, cataract, retinal vascular tortuosity, and reduced binocular vision; a case of Reiger anomaly has even been reported.56,57,31
  • Sensorineural hearing loss can be present and is likely underdiagnosed.58 It can be aggravated by conductive loss due to middle ear effusions.
  • Examine patients for signs of precocious puberty.
  • Other findings include hyperacusis (despite hearing loss), hoarse voice, joint hyperelasticity, contractures, kyphoscoliosis, and lordosis.
  • Monitor for hypertension at every visit.
  • Generalized hypotonia is found in infants with Williams syndrome and progresses to spasticity with age.55

Causes

  • A deletion on band 7q11.23 near the elastin gene is identified in virtually all individuals with Williams syndrome. The underlying etiology is believed to be unequal meiotic crossover events that lead to interstitial deletions.59,60 These deletions may result in unbalanced interchromosomal and, to a lesser extent, intrachromosomal rearrangements.
  • Mechanisms whereby chromosomes paired during meiosis may undergo unequal crossover resulting in Williams syndrome have typically been thought to result from an unequal overlap of repetitive Alu sequences flanking the region, resulting in a type of misalignment of the chromosomal regions during a crossover event.61
  • In addition, another mechanism that has recently been shown includes a familial inversion polymorphism in the Williams syndrome region that may predispose to unequal crossover during meiosis.62

Differential Diagnoses

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

Workup

Laboratory Studies

  • Fluorescent in situ hybridization (FISH) for the 7q11.23 elastin gene deletion should be performed in patients in whom Williams syndrome is suspected, in addition to a routine chromosomal analysis (karyotype). A deletion at 7q11.23 is noted on FISH testing in 99% of patients. FISH testing is routinely performed on peripheral blood leukocytes obtained in a heparinized tube. FISH testing and karyotype are performed in cytogenetics laboratories. Non-FISH-based methods for detection of Williams syndrome involve targeted mutation analysis, include real-time quantitative polymerase chain reaction (PCR), genomic microarray analysis, and heterozygosity testing; this reaches the same sensitivity as FISH analysis. An international list of laboratories offering FISH testing for Williams syndrome is available through GeneTests or the European Directory of DNA Diagnostic Laboratories.
    • A standard karyotype should always be performed since a negative FISH result for Williams syndrome does not exclude the possibility of an underlying chromosomal abnormality, and chromosomal translocation in the region affected by Williams syndrome has been reported.63
    • Because atypical cases of Williams syndrome may have other chromosomal rearrangements not detected by the standard FISH test, further studies should be coordinated through a clinical geneticist.
    • FISH testing and chromosomal analysis in the parents is not routinely indicated, unless either parent has associated physical features or other findings for which Williams syndrome is suspected, a positive family history of Williams syndrome, or other affected children with Williams syndrome.64,65
  • Plasma creatine phosphokinase (CPK) levels may be elevated, but the clinical significance is not clear in incidental cases.30 Further studies are needed to see if this may relate to an underlying myopathy.66
  • Obtain baseline measurements of serum calcium, BUN, and serum creatinine levels. Perform routine urinalysis and obtain spot urine calcium/creatinine ratios. Serum or ionized calcium can be checked in suspected cases before genetic confirmation of the diagnosis.
  • Obtain baseline thyroid-stimulating hormone (TSH) levels.

Imaging Studies

  • Perform baseline echocardiography in all patients diagnosed with Williams syndrome, regardless of cardiac physical examination findings. Approximately one half of all children with Williams syndrome have a significant cardiac lesion.
  • Cardiovascular management depends on the specific cardiac lesion present.

  • Two-dimensional suprasternal echocardiographic im...

    Two-dimensional suprasternal echocardiographic image of supravalvular aortic stenosis (SVAS).


  • In addition to ECG and echocardiography, children with supravalvar aortic stenosis (SVAS) may require cardiac catheterization as part of their presurgical evaluation.
  • Perform renal ultrasonography in the initial workup to not only look for anatomic abnormalities but also for nephrolithiasis caused by hypercalcemia. Structural renal abnormalities are found in 15-20% of patients with Williams syndrome.67,55 Further management may require referral to a urologist, nephrologist, or both.

Other Tests

  • Full neurodevelopmental testing may aid the general practitioner in identifying suspected cases of Williams syndrome and may help tailor schooling and supplemental developmental assistance for children already diagnosed with Williams syndrome.

Treatment

Medical Care

Williams syndrome is a complex multisystem medical condition that requires a multidisciplinary team. A few large tertiary care centers have Williams syndrome clinics, which help organize and coordinate the care of patients with Williams syndrome. Williams Syndrome Associations are available in the United States and Canada and are a valuable resource for both parents and health care professionals.

Tailor specific management of Williams syndrome 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 Williams syndrome. Anticipatory care guidelines and growth curves for children with Williams syndrome are available through the American Academy of Pediatrics.68

  • Hypercalcemia, which is noted in approximately 15% of patients with Williams syndrome, is frequently asymptomatic and resolves in the first few years of life but can be lifelong.
    • Signs and symptoms of hypercalcemia, in addition to blood calcium levels, should be periodically monitored throughout life and prior to the administration of any anesthetic or sedative agent and prior to any invasive procedure. Symptomatic hypercalcemia can present with decreased feeding, irritability, and severe colic in infants and may require multidisciplinary management through restriction of calcium, vitamin D intakes (including vitamin formulations), specialized formulas and some patients may require bisphosphonates to control elevated calcium levels.69,70 For more information, see Hypercalcemia.
    • The goal of managing calcium and vitamin D levels is to monitor and achieve levels in the normal range for age at intakes adequate for bone growth. The need for dietary manipulation and medication to control hypercalcemia should be frequently monitored because long-term unrestricted use of a low calcium, low vitamin D formula has been reported to lead to rickets in a patient with Williams syndrome.71
    • Nephrocalcinosis and sclerosis of the long bones are occasionally observed.
  • Systemic hypertension should be treated when identified. For more information see the eMedicine topic in pediatrics for Hypertension or Neonatal Hypertension.
  • Periodically assess visual problems and hearing loss. Middle ear infusions should be periodically performed. Acoustic-visual-behavioral training has been reported to improve symptoms of hyperacusis in an adult.72
  • Patients with short stature should have a bone age assessment and be referred to an endocrinologist for assessment and management of growth hormone deficiency.
  • Monitor for signs of precocious puberty and arrange referrals with an endocrinologist as necessary.73
  • Feeding difficulties in children are common, and referral to a gastroenterologist should be considered.
  • Thyroid function and glucose tolerance testing should be part of the periodic evaluation.
  • Early involvement of dentist is suggested.

Surgical Care

For cardiac findings in children with Williams syndrome, early involvement with a pediatric cardiologist and cardiothoracic surgeon is essential.

  • Supravalvar aortic stenosis (SVAS) is the most frequently observed operable cardiac lesion in Williams syndrome. SVAS may be progressive in some individuals, and life-long cardiac follow-up is recommended.74
  • Timing of the operative repair depends on the presence of cardiac symptoms, the gradient across the supraaortic obstruction, and whether ischemic changes are noted on a stress test. Peripheral branch pulmonary stenosis usually spontaneously resolves and generally should not be treated with catheter or surgical intervention.
  • In general, the degree of supraaortic obstruction in Williams syndrome patients tends to progress over time, whereas peripheral branch pulmonary stenosis improves over time.

Consultations

Williams syndrome requires the attention of multiple health care professionals, depending on the specific phenotypic manifestations. Many large tertiary care centers have Williams syndrome clinics that help organize and coordinate the care of patients with Williams syndrome.

  • For cardiac findings in children with Williams syndrome, early involvement of a pediatric cardiologist and cardiothoracic surgeon is essential.
  • An anesthesiologist should be consulted prior to administration of anesthetics. Sedation should be administered only by physicians experienced in pediatric procedural sedation.
  • Geneticists, dentists, ophthalmologists, orthopedists, physical and occupational therapists, and psychologists all contribute to the care of the patient with Williams syndrome.
  • Parents of children with Williams syndrome should be offered genetic counseling to review their recurrence risks and options for prenatal diagnosis. If neither parent is affected with Williams syndrome, the risk of having another affected child with Williams syndrome is usually less than 1%. However, recurrences of Williams syndrome have been reported, even with unaffected parents, because of apparent germline mosaicism.64
  • Patients with Williams syndrome are considered to be fertile. If one parent is affected with Williams syndrome, the risk for having an affected child is typically 50% because the deletion behaves in an autosomal dominant manner. When of appropriate age, affected children should receive genetic counseling prior to considering having children of their own.
  • Women with Williams syndrome who are considering pregnancy or who are pregnant should be referred to a maternal-fetal medicine specialist for close monitoring. In particular, a pregnant woman with Williams syndrome should be monitored for hypertension, hypercalcemia, and cardiovascular and other complications.65

Medication

See Treatment.

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 Williams syndrome.

Prognosis

  • Consider the progressive nature of medical problems in Williams syndrome, including vascular stenosis, hypertension, and joint contractures.
  • Medical complications may occur, especially related to the cardiovascular system. However, most individuals with Williams syndrome are healthy and lead active full lives.
  • Most adults with Williams syndrome are used in various settings and can perform self-care tasks.
  • Some adults with Williams syndrome require the daily care of parents or caregivers; however, others may live with less supervision and care.
  • Mild accelerated physical and cognitive aging has been noted.

Patient Education

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

Miscellaneous

Medicolegal Pitfalls

  • Failure to perform echocardiography or to refer patients to a pediatric cardiologist in the presence of any cardiac history or findings
  • Failure to consider risks in a patient with Williams syndrome who is pregnant
  • Failure to discuss the options of prenatal care and recurrence risks
  • Failure to screen and manage high-risk patients prior to anesthetic and sedation procedures, cardiac catheterization, or surgery

Multimedia

Two-dimensional suprasternal echocardiographic im...

Media file 1: Two-dimensional suprasternal echocardiographic image of supravalvular aortic stenosis (SVAS).

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Keywords

Williams syndrome, WS, Williams' syndrome, Williams-Beuren syndrome, elfin facies syndrome, hypercalcemia, mental retardation, microcephaly, failure to thrive, treatment, diagnosis, symptoms

Contributor Information and Disclosures

Author

Aneal Khan, MD, MSc, FRCP(C), FAAP, FCCMG, Assistant Professor of Medical Genetics and Pediatrics, University of Calgary; Consulting Staff, Departments of Pediatrics and Medical Genetics, Alberta Children's Hospital, Canada
Aneal Khan, MD, MSc, FRCP(C), FAAP, FCCMG is a member of the following medical societies: American Academy of Pediatrics, American Society of Human Genetics, Canadian Medical Association, Canadian Paediatric Society, and Ontario Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

Lennox H Huang, MD, Associate Chair (Clinical), Assistant Professor, Department of Pediatrics, McMaster University School of Medicine; Interim Chief of Pediatrics, McMaster Children's Hospital
Lennox H Huang, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Physician Executives, Canadian Medical Association, Ontario Medical Association, and Society of Critical Care Medicine
Disclosure: Nothing to disclose.

Nathaniel H Robin, MD, Professor, Departments of Genetics and Pediatrics, University of Alabama at Birmingham; Consulting Staff, University of Alabama at Birmingham University Hospital and Children's Hospital of Alabama
Nathaniel H Robin, MD is a member of the following medical societies: American Cleft Palate/Craniofacial Association, American College of Medical Genetics, American Society of Human Genetics, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor

Jeffrey Allen Towbin, MD, MSc, FAAP, FACC, FAHA, Professor, Departments of Pediatrics (Cardiology), Cardiovascular Sciences, and Molecular and Human Genetics, Baylor College of Medicine; Chief of Pediatric Cardiology, Foundation Chair in Pediatric Cardiac Research, Texas Children's Hospital
Jeffrey Allen Towbin, MD, MSc, FAAP, FACC, FAHA is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Cardiology, American College of Sports Medicine, American Heart Association, American Medical Association, American Society of Human Genetics, Cardiac Electrophysiology Society, New York Academy of Sciences, Society for Pediatric Research, Texas Medical Association, and Texas Pediatric Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Ameeta Martin, MD, Clinical Associate Professor, Department of Pediatric Cardiology, University of Nebraska College of Medicine
Ameeta Martin, MD is a member of the following medical societies: American College of Cardiology
Disclosure: Nothing to disclose.

CME Editor

Gilbert Z Herzberg, MD, Assistant Professor, Department of Pediatrics, Section of Pediatric Cardiology, New York Medical College; Consulting Staff, Department of Pediatrics, Sound Shore Medical Center
Gilbert Z Herzberg, MD is a member of the following medical societies: American Academy of Pediatrics
Disclosure: Nothing to disclose.

Chief Editor

Stuart Berger, MD, Professor of Pediatrics, Division of Cardiology, Medical College of Wisconsin; Chief of Pediatric Cardiology, Medical Director of Pediatric Heart Transplant Program, Medical Director of The Heart Center, Children's Hospital of Wisconsin
Stuart Berger, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Cardiology, American College of Chest Physicians, American Heart Association, and Society for Cardiac Angiography and Interventions
Disclosure: Nothing to disclose.

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