Continuing Education Activity

Williams syndrome is a rare genetic disorder with congenital heart disease, distinctive facial features (elfin-like faces), hypercalcemia, neurodevelopmental, and behavioral deficits. This activity reviews the diagnostic evaluation, treatment, and interprofessional management of Williams syndrome and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Identify the etiology and epidemiology of Williams syndrome.
• Describe the appropriate history, physical examination, and evaluation for patients with Williams syndrome.
• Summarize the management strategies and treatment options available for patients with Williams syndrome.
• Outline strategies that interprofessional teams may use to improve management and outcomes in patients with Williams syndrome.

Introduction

Williams syndrome (WS) is a rare genetic and neurodevelopmental disorder. WS often presents at birth when the child is discovered to have supra-vascular aortic stenosis.[1] The child also shows distinctive facies (elfin-like features), hypercalcemia, connective tissue abnormalities, growth abnormalities, intellectual disability, behavior deficits, and a gregarious personality.[2]

Cardiologist Dr. John Cyprian Phipps Williams discovered the syndrome in 1961.[3][4] In 1962, Dr. A. J. Beuren found similar findings, resulting in the naming of the syndrome as Williams-Beuren syndrome. 

Etiology

The genetic cause of Williams syndrome was uncovered in 1993. The disorder is due to deletion at chromosome band 7q11.23 that involves the elastin gene (ELN). The gene is in the Williams-Beuren Syndrome Critical Region (WBSCR).[1][2] The gene deletion, comprising 26 genes, is detected through dual-color fluorescent in situ hybridization (FISH) or deletion/duplication testing.[2][5] Microarray analysis is another diagnostic test that can identify the size of the elastin deletion. Both FISH and microarray analyses utilize a parenteral blood sample to extract DNA for analysis. From 96 to 98% of patients with WS have a deleted elastin gene.[4] The genetic disorder shows autosomal dominant transmission.[2] The defect in elastin leads to generalized arteriopathy and may affect any artery in the body, but it often affects medium to large-sized arteries. 

Epidemiology

The estimated frequency of the disorder is cited in studies with a range between 1 in 7500 to 1 in 75000 children.[2][4] The disease affects all ethnicities and both sexes equally.[5]

History and Physical

After birth, infants often present with failure to thrive, short stature, and supra-vascular aortic stenosis.[2] Due to the defect in elastin, children may also have other elastin arteriopathies, along with peripheral pulmonary stenosis and hypertension.[2] During childhood, patients may have middle ear infections and visual difficulty.[2] On physical exam, all children with Williams syndrome have characteristic distinctive facies with elfin-like features.[2] 

Children with WS commonly have various endocrine abnormalities.[2] The presence of hypercalcemia and hypercalciuria can result in renal calculi.[2] The patient may also have physical signs of hypothyroidism, delayed growth, or early puberty.[2][6]

Connective tissue abnormalities often result in hyperextensible joints or hypotonia, resulting in delayed motor milestones or toilet training.[2] 

Patients with WS born with blue or green eyes often display a "starburst" or stellate pattern on their iris.[2] This "starburst" pattern characteristically shows a white, lacy appearance.[2]

The patient may have comorbid psychiatric disorders, including intellectual disability (ID), attention-deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), or generalized anxiety disorder (GAD).[1] 

A definitive diagnosis of WS requires FISH genetic testing demonstrating the gene deletion in the WBSCR.[2] 

Evaluation

The following laboratory, imaging, and other tests are necessary for patients with suspected Williams syndrome. 

• Body mass index (BMI)
• Complete blood count (CBC)
• Complete metabolic panel (CMP)
• Calcium
• Thyroid stimulating hormone (TSH), including free T3 and free T4
• Hearing and vision screen
• Echocardiogram
• Electrocardiogram (ECG)

Intellectual disability (ID) in WS is assessed using the Kaufman Brief Intelligence Test, Second Edition (KBIT-2). The assessment computes a composite IQ, along with both verbal and non-verbal standard scores (SSs).[5] Studies utilizing KBIT-2 to measure IQ in children with WS found that their IQ ranged from average to severe ID.[5] Children with WS often struggle with visuospatial construction, which the KBIT-2 does not measure.[5] To measure visuospatial construction, the Differential Ability Scale-II (DAS-II) Special Nonverbal Composite assessments and Wechsler IQ tests may be useful diagnostic tools.[5] 

Treatment / Management

Effective treatment and management of children with WS require an interprofessional team, including:

• Genetic Counseling: Upon making the diagnosis, genetic counseling should follow.[2] 
• Obstetrics: All pregnancies in patients with WS are considered high risk due to the risk of arrhythmia, heart failure, and hypertension.[2] In addition to routine ultrasound of the fetus, urinalysis (UA) is necessary due to the risk of urinary tract infections (UTI).[2] Genetic counseling may follow during pregnancy, and prenatal testing is available.[2] 
• Cardiology and Cardiothoracic Surgery: At birth, children with WS often need cardiac care for supra-vascular aortic stenosis, which requires open-heart surgery by a cardiothoracic surgeon. Following surgery, patients should be closely monitored by a cardiologist due to the risk of hypertension and arteriopathy that can also lead to pulmonary artery stenosis, mitral valve insufficiency, and renal artery stenosis.[2]
• Endocrinology: Endocrinologists often manage hypercalcemia, hypothyroidism, and growth reduction in WS patients.[2][6] Due to the risk of hypercalcemia, dietary modification is necessary so that excess calcium is not ingested and then excreted through the kidneys.[2] In addition to diet modification, oral corticosteroids or intravenous (IV) pamidronate may be used.[2] Calcium levels in patients require careful management, as a low calcium diet may lead to rickets. If the child's short stature is apparent,  treatment with growth hormone is also an option. An endocrinologist routinely monitors both glucose and thyroid function.[6] Children with WS often require thyroid hormone replacement therapy.[6]
• Nephrology: If renal calculi develop due to hypercalciuria, referral to a nephrologist is made for lithotripsy. 
• Gastroenterology: Gastroenterology referral is warranted for children with feeding difficulties, as they may require a permanent feeding tube.[2] 
• Nutritionist: Infants with feeding difficulties often require feeding therapy and consultation with a nutritionist.[2]
• Psychiatry: Psychiatric evaluation is recommended to determine the need for medications or psychotherapy to treat comorbid ADHD, OCD, or GAD.[2][7]
• Ancillary Services: Due to neurodevelopmental deficits and intellectual disability, children with WS often require special education programs, occupational therapy (OT), physical therapy (PT), speech therapy (ST), and sensory integration therapies.[2] PT, with a focus on the range of motion, is recommended to prevent joint contractures that may occur.[2] For all children with neurodevelopmental disorders, hearing and vision screening are strong recommendations.[2] Children with WS are at risk of hyperopia and recurrent otitis media; therefore, they require routine testing for hearing and vision loss.[2]
• Dentist and Orthodontist: Due to the risk of malocclusion and dental abnormalities, referral to an orthodontist and/or dentist is also a recommendation.[2]

Differential Diagnosis

It is essential to rule out other neurodevelopmental disorders that can resemble WS, including:

• Fetal alcohol syndrome
• DiGeorge syndrome (deletion 22q11.2)
• Noonan syndrome
• Smith-Magenesis syndrome
• Kabuki syndrome
• Marshall syndrome

Autosomal dominant supra-valvular aortic stenosis is another condition that should be ruled out, as it is a separate disorder from WS.[2] 

Toxicity and Adverse Effect Management

Due to the risk of hypercalcemia, supplements with calcium and vitamin D, including multivitamins, should be avoided in children with WS.[2] 

Prognosis

The morbidity of WS is largely due to the presence of arteriopathy and congenital heart disease.[2] Eighty percent of WS patients experience cardiovascular abnormalities, such as stenosed large arteries or ventricular outflow tracts that require cardiothoracic surgery.[8] During the perioperative period, there is a risk of sudden cardiovascular collapse that may contribute to morbidity and mortality.[9]

In terms of inheritance, there is a 50% chance of parents with WS passing the microdeletion to their children.[2] If a parent has one child with WS but the parent is unaffected, the risk of a sibling acquiring WS is low.[2] 

Patients with WS can live semi-independently to independently and are often able to work. As each individual with WS has different needs, it is recommended to complete an individualized life transition plan, preferably before the age of 13 or 14. 

Complications

When patients with WS have open-heart surgery, there is a risk for complications, often exacerbated by or secondary to the elastin deficiency.[8][10] A multicenter registry followed patients with WS who underwent surgery for right ventricular outflow tract (RVOT), left ventricular outflow tract (LVOT), or supra-valvular aortic stenosis.[8] The registry found that 9% of patients with WS who had open-heart surgery had major adverse cardiac events, such as arrhythmia or coronary artery disease.[8][11] In cases of coronary artery disease after surgical repair of stenosis, revascularization may be necessary.[11] 

Consultations

The treatment of WS requires an interprofessional approach. After the birth of a child with WS, the pediatrician should obtain a consultation from cardiology and cardiothoracic surgery.[2] Later, case discussion with endocrinology, gastroenterology, nephrology, and psychiatry may also be warranted.[2] Additional consultations with occupational therapy (OT), physical therapy (PT), speech therapy (ST), sensory integration therapies, orthodontist, dentist, and psychotherapy may be options.[2] The parents of a child with WS may obtain a referral to a couples therapist or family therapist for counseling and support.

Deterrence and Patient Education

Patients and their families should direct questions to their interprofessional team. More information on the disorder is available through the Williams Syndrome Association (WSA), at williams-syndrome.org. 

Enhancing Healthcare Team Outcomes

Effective treatment of patients with WS requires interprofessional communication and collaboration to improve patient outcomes. Healthcare providers, including physicians, specialists, and pediatric nurses, should monitor children with WS for associated endocrine and neurodevelopmental abnormalities by obtaining weight, BMI, calcium, TSH, CMP, hearing screen, and vision screen at baseline and routinely during treatment.[2]

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References

1.

Leyfer OT, Woodruff-Borden J, Klein-Tasman BP, Fricke JS, Mervis CB. Prevalence of psychiatric disorders in 4 to 16-year-olds with Williams syndrome. Am J Med Genet B Neuropsychiatr Genet. 2006 Sep 05;141B(6):615-22. [PMC free article: PMC2561212] [PubMed: 16823805]

2.

Morris CA. Williams Syndrome. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews^® [Internet]. University of Washington, Seattle; Seattle (WA): Apr 9, 1999. [PubMed: 20301427]

3.

Lenhoff HM, Teele RL, Clarkson PM, Berdon WE. John C. P. Williams of Williams-Beuren syndrome. Pediatr Radiol. 2011 Feb;41(2):267-9. [PubMed: 21107555]

4.

Martens MA, Wilson SJ, Reutens DC. Research Review: Williams syndrome: a critical review of the cognitive, behavioral, and neuroanatomical phenotype. J Child Psychol Psychiatry. 2008 Jun;49(6):576-608. [PubMed: 18489677]

5.

Pitts CH, Mervis CB. Performance on the Kaufman Brief Intelligence Test-2 by Children With Williams Syndrome. Am J Intellect Dev Disabil. 2016 Jan;121(1):33-47. [PMC free article: PMC5005797] [PubMed: 26701073]

6.

Chen WJ, Ji C, Yao D, Zhao ZY. Thyroid evaluation of children and adolescents with Williams syndrome in Zhejiang Province. J Pediatr Endocrinol Metab. 2017 Nov 27;30(12):1271-1276. [PubMed: 29127763]

7.

Royston R, Howlin P, Waite J, Oliver C. Anxiety Disorders in Williams Syndrome Contrasted with Intellectual Disability and the General Population: A Systematic Review and Meta-Analysis. J Autism Dev Disord. 2017 Dec;47(12):3765-3777. [PMC free article: PMC5676825] [PubMed: 27696186]

8.

Hornik CP, Collins RT, Jaquiss RD, Jacobs JP, Jacobs ML, Pasquali SK, Wallace AS, Hill KD. Adverse cardiac events in children with Williams syndrome undergoing cardiovascular surgery: An analysis of the Society of Thoracic Surgeons Congenital Heart Surgery Database. J Thorac Cardiovasc Surg. 2015 Jun;149(6):1516-22.e1. [PMC free article: PMC4464977] [PubMed: 25791950]

9.

Collins Ii RT, Collins MG, Schmitz ML, Hamrick JT. Peri-procedural risk stratification and management of patients with Williams syndrome. Congenit Heart Dis. 2017 Mar;12(2):133-142. [PubMed: 28382779]

10.

Protopapas AD. Elastin deficiency in Williams syndrome may explain postoperative major adverse cardiac events. J Thorac Cardiovasc Surg. 2015 Nov;150(5):1380. [PubMed: 26546206]

11.

Federici D, Ranghetti A, Merlo M, Terzi A, Di Dedda GB, Marcora S, Marrone C, Ciuffreda M, Seddio F, Galletti L. Coronary Artery Involvement of Williams Syndrome in Infants and Surgical Revascularization Strategy. Ann Thorac Surg. 2016 Jan;101(1):359-61. [PubMed: 26694280]

Disclosure: Marcia Wilson declares no relevant financial relationships with ineligible companies.

Disclosure: Iverson Carter declares no relevant financial relationships with ineligible companies.