Williams Syndrome

OVERVIEW: What every practitioner needs to know

Williams syndrome (WS) is a disorder caused by a microdeletion on chromosome 7 which leads to characteristic facial features, heart disease (supravalvular aortic stenosis), developmental delay and/ or intellectual disability and failure to thrive.

Patients with this diagnosis can have hypercalcemia and should be restricted from taking vitamins with calcium and vitamin D. Anesthesia can be a real risk, with sudden death in a small group of patients, especially those with coronary artery stenosis. Therefore, unnecessary sedation should be restricted, and when absolutely required, a knowledgeable pediatric sedation team at an experienced WS center is optimal.

Hypertension can be severe, and cardiologic and renal evaluation to find out the etiology is important.

Are you sure your patient has Williams syndrome? What are the typical findings for this disease?

Children with WS are born with thin appearing lips that over time appear full, and they often have an appearance of periorbital fullness with a stellate and lacy pattern of the iris. The face may coarsen with age.

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Failure to thrive and developmental delay may be the first signs that bring these children to medical attention. After about four years, catch-up growth usually occurs, and children with WS are often low-normal for adult height.

Other children with WS present with a cardiac murmur, since 75% have supravalvular aortic stenosis, characterized by a crescendo-decrescendo low pitched murmur best heard at the base of the heart, and some children have pulmonic stenosis or other cardiac anomalies.

As mentioned, some children have hypertension secondary to renal artery stenosis, or essential hypertension.

Other children may present with irritability or gastrointestinal symptoms caused by hypercalcemia, which can be discovered on serum calcium, ionized calcium, and calcium/ creatinine determination on spot urine.

Other key findings in Williams syndrome

The personality of children with WS is described as a “cocktail personality”: big vocabulary and long sentences mask intellectual disability. The children are often friendly and affectionate, even with complete strangers. Some children have uncanny musical abilities, and most children really enjoy music. A few children have autism. The voice of children with WS may sound hoarse, thought to be an abnormality of the elastin around the vocal cords.

What other disease/condition shares some of these symptoms?

There are many conditions that present with developmental delay and congenital heart disease, which may be confused with WS.

Microdeletions that may be mistaken for WS include deletion 22q11 deletion syndrome (DiGeorge or velocardiofacial syndrome), Smith-Magenis syndrome, and 22q13.3 deletion syndrome.

The 22q11 deletion syndrome is characterized by variable presence of craniofacial features such as hooded eyelids and prominent nose, developmental delay, heart defects including tetralogy of Fallot, ventricular septal defect (VSD) and atrial septal defect (ASD), and sometimes cleft palate.

Smith-Magenis syndrome (a 17p11.2 microdeletion) is characterized by global delay, behavioral abnormalities such as head banging and self-injury, and disrupted sleep.

Noonan syndrome is a single gene disorder often presenting with hypertelorism, blue irides, low-set ears with thickened helices, a webbed neck, pulmonic stenosis or, less commonly, hypertrophic cardiomyopathy, as well as mild to moderate developmental delay.

Another disorder commonly mistaken for WS is fetal alcohol syndrome: typical findings include small palpebral fissures, a long smooth philtrum, a thin upper lip, microcephaly, and thin body habitus.

Finally, some children are evaluated for WS when they are found to have supravalvular aortic stenosis (SVAS), and while this is indicated, SVAS can also be isolated or associated with cutis laxa (wrinkly skin). Some patients with isolated SVAS have a mutation in the elastin gene, one of the genes deleted in WS.

What caused this disease to develop at this time?

Williams syndrome is caused by a deletion of chromosome 7q11.2, which involves the Williams-Beuren syndrome critical region (WBSCR) that encompasses the elastin gene. Elastin is important in keeping blood vessels from becoming narrowed, and thus its absence can be associated with SVAS, renal artery stenosis, and/ or narrowing of the other vessels.

Most cases of WS occur de novo, as an accident in the egg or sperm before conception. Rarely, a parent may be affected and not discovered until a child is diagnosed. If one of the parents is affected, the recurrence risk is 50 percent. If neither parent is affected, the recurrence risk is < 1 percent. Some studies have found an increased incidence of an inversion in 7q11.2 in the parents of children with WS, possibly predisposing to the condition, though even in these families there is rarely a recurrence of the syndrome in future pregnancies.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The mainstay for the diagnosis for years has been fluorescent in situ hybridization (FISH) for the WBSCR region, but now many physicians are sending for array comparative genomic hybridization (array CGH) testing instead, which looks for deletions across all of the chromosomes and also includes the WBSCR region.

There are several advantages of array CGH over FISH:

1. If the diagnosis is not WS, other syndromes (such as 22q11 deletion syndrome), can be detected;

2. Some children with WS have an additional microdeletion/ duplication syndrome, which otherwise would not be diagnosed;

3. If the child has an atypically large or small deletion, this would be detectable by array CGH and not FISH;

4. Parental testing is sometimes available free of charge (inquiries should be made to the specific laboratory).

Would additional laboratory, imaging studies, and referrals be helpful? If so, which ones?

1. Echocardiogram with Doppler flow studies, especially to rule out supravalvular aortic stenosis

2. Renal sonogram with Dopplers of renal arteries to rule out renal artery stenosis, especially important if the child is hypertensive, and sonogram of the bladder

3. Laboratory studies: serum BUN/ Cr; serum calcium or ionized calcium; calcium/creatinine determination in a spot urine sample; thyroid function tests

4. Referrals: developmental, ophthalmologic, genetic, and audiology evaluations on an out-patient basis

See Table I for follow-up care guidelines.

Table I.
Interval/Age Test/Measurement
Annual • Laboratory studies: calcium/creatinine ratio in a random spot urine and urinalysis• Routine follow-up: blood pressure measurement, remind patients that multivitamins with calcium and vitamin D should be avoidedCardiology follow-up as indicated for pediatric patients, and annually in adults to screen for aortic insufficiency, and arterial stenosis
Every 2-3 years • Serum calcium every 2 years• TSH and FT4 every 3 years
Every 5 years • Audiology examination
Every 10 years • Renal and bladder sonogram
In adults

• Oral glucose tolerance test starting at age 30• Evaluation for cataracts• Nutritionist referral

Confirming the diagnosis

For all patients with developmental delay, array CGH, which will detect WS, is considered a first-line step. Therefore, when the diagnosis is considered, but not certain, aCGH is indicated. If WS is obvious, FISH confirmation may be considered instead if more readily available, cheaper, or faster. Additionally, echocardiogram, serum calcium, and thyroid studies would be indicated in the initial evaluation. Consultation with a geneticist would be helpful.

If you are able to confirm that the patient has Williams syndrome, what treatment should be initiated?

See Table II.

Table II.
Problem Treatment
Colic Consider gastroesophageal reflux, constipation, or hypercalcemia, and treat accordingly
Failure to thrive Make sure to plot on WS curve, and if failing to thrive for WS, then treat; consider referral to nutritionist/gastroenterologist
Constipation Consider polyethylene-glycol-electrolyte solution and a good bowel regimen, encouraging fluids, and high fiber foods
Chronic abdominal pain Consider gastroesophageal reflux, hiatal hernia, peptic ulcer disease, cholelithiasis, diverticulitis, ischemic bowel disease, chronic constipation, and somatization of anxiety
Developmental delay Refer to a developmental pediatrician and advocate for a good IEP; encourage lots of music and consider music therapy
Going to strangers easily Good supervision and play groups; teach appropriate boundaries
Hypertension Medication management or surgical intervention when indicated by cardiologist or nephrologist
Hearing problems Consider excess cerumen; consider hearing aids; for hyperacusis, may benefit from occupational therapy
Depression and anxiety Screen during visits and consider behavioral and pharmacological treatments
Severe abdominal pain Consider diverticulitis, constipation, or stenosis of the mesenteric arteries
Chronic weight loss, diarrhea

Consider celiac disease, which has a higher incidence in WS

What are the adverse effects associated with each treatment option?

Any sedated procedures could have a risk of sudden death. Dietary supplements must be monitored for Vitamin D content, which should be limited due to the possibility of causing hypercalcemia. Conversely, limiting vitamin D may cause rickets; thus consultation with an endocrinologist may be helpful in balancing these issues.

What are the possible outcomes of WS?

Most patients with WS live to adulthood and lead happy lives with some extra medical attention. Adults often live with a parent or sometimes in assisted living or group homes. Some adults do exceptionally well and work independently. There have been opera singers and writers who have WS.

Most children with WS have significant delays in both motor skills and speech. Intellectual disability occurs in 75% of individuals with WS. The cognitive profile consists of strengths in verbal short-term memory and language but extreme weakness in visuospatial constructive cognition. Difficulty with writing, drawing, and mathematics is significant; however, many adults with WS are able to perform simple addition.

The greatest morbidity and mortality comes from cardiovascular disease, and the most frightening possibility is sudden death.

What causes WS and how frequent is it?

WS occurs in about 1/ 10,000 live births. There is no difference in gender distribution or seasonality of birth. There are no known environmental influences that predispose a person to having WS. Persons with WS have a deletion of 7q11.23, 1.55 megabases in length for most, including over 25 genes. Most of the time this is a sporadic disorder, though rarely a parent of a child with WS may have a chromosomal rearrangement predisposing to the deletion.

How do these pathogens/genes/exposures cause the disease?

ELN encodes elastin, which is responsible for the cardiovascular findings in WS, and possibly also for the hoarse voice. LIMK1 is linked to the cognitive deficits. GTF2 and GF21RD1 have recently been implicated in the distinctive personality. NCF1, which is variably deleted in WS, is implicated in risk for developing hypertension. Many of the other genes deleted in the WBSCR have not yet been correlated with phenotypic findings.

Other clinical manifestations that might help with diagnosis and management

Other manifestations of WS may include hypothyroidism (10%), which is often subclinical, and precocious puberty (50%).

What complications might you expect from the disease or treatment of the disease?

Complications for persons with WS vary by age and the specific manifestations of the disease.

During infancy, the more common and severe complications include those related to congenital heart disease and to feeding difficulties with failure to thrive.

During childhood, the more common complications include developmental delays with the associated difficulty of finding school placement.

Adolescents with WS may develop anxiety and phobias that interfere with everyday functioning, and a lack of stranger anxiety carries increased safety risks as children become more independent.

Adults with WS face new complications, including weight gain, with increased risk of diabetes mellitus, premature osteoporosis, diverticulosis, and sensorineural hearing loss.

Are additional laboratory studies available; even some that are not widely available?

Laboratory studies for persons with WS are recommended above. For persons with SVAS but without other features of WS and with a normal microarray or FISH, sequencing of the ELN gene is commercially available.

How can Williams syndrome be prevented?

There are currently no methods to prevent WS. Prenatal testing is available for this condition for families with predisposing factors, or who have had a child previously with WS. This can be done by chorionic villus sampling (10-12 weeks of pregnancy) or amniocentesis (15-18 weeks of pregnancy) using FISH or array CGH technology. As more women of advanced maternal age opt for amniocentesis that includes testing for microdeletion syndromes, WS may increasingly be diagnosed prenatally.

What is the evidence?

“Health care supervision for children with Williams syndrome”. Pediatrics. vol. 107. 2001. pp. 1192-204. (This reference is the gold standard for managing patients with Williams syndrome; the quality is excellent. The reference is most relevant to pediatric patients, but also includes information on adults.)

Antonell, A, Del Campo, M, Magano, LF. “Partial 7q11.23 deletions further implicate GTF2I and GTF2IRD1 as the main genes responsible for the Williams-Beuren syndrome neurocognitive profile”. J Med Genet.. vol. 47. 2010. pp. 312-20. (This reference is interesting in terms of considering phenotype-genotype, has a high quality of investigation, and is not key to clinical management.)

Morris, C. “Williams syndrome”. at GeneTests: Medical Genetics Information Resource (database online). (This reference is outstanding since it is written by leading experts in genetics; the quality is excellent; and the reference is relevant to pediatric and adult patients.)

(This reference is useful as an adjunct, but the primary references for clinical management are from the AAP and www.genetests (as listed above), the quality is standard for OMIM; and the reference is a reasonable general overview.)

Pober, BR, Morris, CA. “Diagnosis and management of medical problems in adults with Williams-Beuren syndrome”. Am J Med Genet C Semin Med Genet.. vol. 145C. 2007. pp. 280-90. (This reference is outstanding because Dr. Barbara Pober is a world-expert on Williams syndrome; the quality is excellent. This reference is aimed at clinical geneticists for the management of both adult and pediatric patients.)

Ongoing controversies regarding etiology, diagnosis, treatment

Research continues to uncover the function of many of the genes in the WBSCR. Scientists are also working to develop ways to reverse or prevent the effects of the haploinsufficiency of many of the genes, with research in elastin leading the work. The future may bring improved medical and/or gene therapy treatments.