AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

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, hypercalcemia, and a characteristic neurodevelopmental/behavioral profile.

Pathophysiology

Haploinsufficiency (loss of 1 out of 2 copies) due to a deletion at chromosome band 7q11.23 involving the elastin gene, ELN, is implicated in virtually all cases of Williams syndrome. Most deletions are not detected through standard karyotyping but rather through fluorescent in situ hybridization (FISH) for a 2-Mb deletion (Ewart, 1993; Lowery, 1995; Nickerson, 1995). The size of the deletion can be variable (Urban, 1996; Hockenhull, 1999; Heller, 2003).

Williams syndrome is not caused solely by elastin haploinsufficiency; the deletion involves a region spanning over 20 genes and, hence, is considered a contiguous gene deletion syndrome (Urban, 1996; Merla, 2002). The cardiovascular and connective tissue pathology, as well as facial dysmorphology, is attributed to the elastin gene haploinsufficiency (Mari, 1995; Dridi, 1999).

Other genes being investigated for their role in the cognitive profile of Williams syndrome include LIMK1, GTF1IRD1, and GTF2I (Frangiskakis, 1996; Tassabehji, 1996; Hirota, 2003). However, genotype-phenotype correlations with genes other than elastin are not yet fully elucidated (Osborne, 1999; Merla, 2002).

Frequency

United States

Williams syndrome occurs in 1 per 20,000 births; cases are largely sporadic.

International

Frequency worldwide is the same as in the United States.

Mortality/Morbidity

Cardiovascular disease accounts for most early mortality associated with Williams syndrome. Overall, unexpected death is rare, but it is 25- to 100-fold higher than in age-matched control subjects (Wessel, 2004). Factors implicated in sudden death have included supravalvar aortic stenosis (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 resulting from intimal fibrosis and muscular hypertrophy.

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 (Bird, 1996; Wessel, 2004; Bragg, 2005). Sudden deaths with no apparent instigating event have also been reported but with apparent underlying myocardial injury (Bird, 1996). Patients with a higher risk of sudden death may show signs of myocardial ischemia on electrocardiogram (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 (Horowitz, 2002), but not with sudden death (Yetkin, 2004).

Sigmoid diverticulitis in adults is reported at a higher frequency in the Williams syndrome population than in the general population (Partsch, 2005).

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, 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 (Yau, 2004), and people living in Greece have a lower rate of cardiovascular anomalies (Amenta, 2005).

Sex

The deletion is equally prevalent in males and females. A greater severity and earlier presentation of cardiovascular disease may exist in males (Sadler, 2001; Bruno, 2003).

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 ultrasounds of neonates with Williams syndrome have revealed multicystic dysplastic kidney in addition to the congenital heart lesions (Zaghloul, 2002). Associated findings on prenatal screening that have been reported include an increased fetal nuchal translucency (Gicquel, 1998) and low maternal serum alpha fetoprotein (MSAFP) (Bernard, 1997), although none of the prenatal findings has been proven to be a diagnostic marker of Williams syndrome.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

History

The history obtained from caregivers of patients with Williams syndrome is variable and reflects the wide phenotypic spectrum observed in the syndrome. The neurodevelopmental profile primarily involves 4 areas: cognitive development, language, auditory function, and visuospatial function (Mervis, 2000).

• Children with Williams syndrome are described as overly friendly, hyperactive, inattentive, and hypersensitive to loud sounds or certain types of sounds (Blomberg, 2005).
• Intellectual, motor, and language skills are typically delayed. Children with Williams syndrome typically have mild-to-moderate mental retardation, but the range includes severe mental retardation to average intelligence (Mervis, 2000). Abilities should be considered on an individual basis due to the wide variability among individuals (Porter, 2005).
• Older children have relative strengths in language and auditory memory with significant weaknesses in visual-spatial cognition.
• Visual-spatial problems may present as gait apraxia, especially on uneven or sandy surfaces (Withers, 1996).
• A history of hearing deficits and visual disturbances is possible.
• Adults may have a high rate of emotional and behavioral problems, poor social relationships and anxiety, preoccupations and obsessions, and communication disturbances. Few adults achieve complete independence (Einfeld, 2001; Davies, 1997; Davies, 1998).
• In children, a history of increased urinary frequency and daytime wetting is possible (Schulman, 1996). A history of renal abnormalities is also possible.
• Children may have a history of postnatal growth delay including short stature with delayed bone age (Partsch, 1999), growth hormone deficiency (Spadoni, 1983), and decreased insulinlike growth factor–1 (IGF1) levels (Kuijpers, 1999; Xekouki, 2005).
• A history of hypertension may exist.
• A history of connective tissue abnormalities, such as abnormal joint mobility, hernias, and diverticula, is possible.

Physical

A wide variation occurs in the phenotypic expression of Williams syndrome. Virtually all cases have typical facial features that can be recognized even at birth.

• Children with Williams syndrome are generally full-term infants.
• Microcephaly in one third of children (Pankau, 1994) and postnatal failure to thrive is typical.
• The diagnosis of Williams syndrome should also be considered after an incidental finding of idiopathic hypercalcemia or a characteristic cardiac lesion such as SVAS. Other cardiac lesions in patients with Williams syndrome can include pulmonary stenosis and mitral valve regurgitation (Eronen, 2002; Bruno, 2003). 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.
• 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, stellate irides, and periorbital fullness. The voice may be harsh. Nails tend to be hypoplastic and the skin soft and lax, and the hallices have a valgus deviation. "Elfin facies" is considered a pejorative term, and its use should be discouraged.
• 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 (Greenberg, 1988; Kapp, 1995; Sadler, 1996).
• Sensorineural hearing loss can be present and is likely underdiagnosed (Marler, 2005). 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.

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 leading to interstitial deletions (Dutly, 1996; Baumer, 1998). 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 (Robinson, 1996). 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 (Osborne, 2001).

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Lab 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). Testing is routinely performed on peripheral blood leukocytes. FISH testing and karyotype are performed in cytogenetics laboratories. 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 (von Dadelszen, 2000).
  • Since atypical cases of Williams syndrome may have other chromosomal rearrangements not detected by the standard FISH test, further studies, such as high resolution chromosome analysis and testing for ELN gene mutations 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.
• Plasma creatine phosphokinase (CPK) levels may be elevated, but the clinical significance is not clear in incidental cases (Amenta, 2005). Further studies are needed to see if this may relate to an underlying myopathy (Voit, 1991).
• Obtain baseline measurements of serum calcium, blood urea nitrogen (BUN), and serum creatinine levels. Perform routine urinalysis and obtain spot urine calcium/creatinine ratios. Serum calcium can be checked in suspected cases before genetic confirmation of the diagnosis.
• Obtain a baseline thyroid-stimulating hormone (TSH) levels.

Imaging Studies

• Perform a baseline echocardiogram 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 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 in Williams syndrome is significantly higher than that in the general population (Sforzini, 2002). 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 it may help tailor schooling and supplemental developmental assistance for children already diagnosed with Williams syndrome.

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Medical Care

Williams syndrome is a complex multisystem medical condition that requires the attention of multiple health care professionals. A few large tertiary care centers have Williams syndrome clinics, which help organize and coordinate the care of Williams syndrome patients. Williams Syndrome Associations exist 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.

• Hypercalcemia 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 monitored periodically 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 (Cagle, 2004; Oliveri, 2004).
  • 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 monitored frequently since long-term unrestricted use of low calcium, low vitamin D formula has been reported to lead to rickets in a patient with Williams syndrome (Mathias, 2000).
  • Nephrocalcinosis and sclerosis of the long bones are occasionally observed.
• Systemic hypertension should be treated when identified.
• Periodically assess visual problems and hearing loss. Middle ear infusions should be done periodically. Acoustic-visual-behavioral training has been reported to improve symptoms of hyperacusis in an adult (Miani, 2001).
• 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 (Partsch, 2002).
• Feeding difficulties in children are common, and referral to a gastroenterologist should be considered.
• 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.

• 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 (Wessel, 1994).
• 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 Williams syndrome patients tends to progress with time, whereas peripheral branch pulmonary stenosis improves with 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 due to apparent germline mosaicism (Kara-Mostefa, 1999). If one parent is affected with Williams syndrome, the risk for having an affected child is typically 50% since 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 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 (Mulik, 2004).

FOLLOW-UP

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

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

• 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 employed in a variety of 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.

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 the Williams Syndrome Association Web site.

MISCELLANEOUS

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to perform an echocardiogram 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

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Mar 17, 2006