Williams Syndrome


Article Author:
Marcia Wilson


Article Editor:
Iverson Carter


Editors In Chief:
David Wood
Andrew Wilt
Hajira Basit


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Abbey Smiley
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
6/16/2019 12:34:39 PM

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 the 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 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 that are 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 a multidisciplinary 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 both 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 Side 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 ages 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 a multidisciplinary 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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Williams Syndrome - Questions

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A 2-year-old female with growth abnormalities and hypercalcemia presents for follow-up with her parents in regards to her genetic testing. The genetic testing revealed a deletion in the elastin gene on chromosome band 7q11.23. The deletion in the elastin gene may lead to which rare disorder that requires a sub-specialist referral?



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A 7-year-old female with intellectual disability, hypercalcemia, distinctive facial features, gregarious personality, and white lacy pattern on her iris presents with her parents to her pediatrician. Which of the following is a major concern for those born with this syndrome that warrants referral to a specialist?



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A 5-year-old female with supra-valvular aortic stenosis presents with her parents for genetic counseling. She has elfin-like features, moderate intellectual disability, hyperacusis, and outgoing personality. Through fluorescent in situ hybridization (FISH), she is found to have a deletion of the elastin gene on chromosome band 7q11.23 in the Williams-Beuren syndrome critical region (WBSCR), confirming the suspected diagnosis. Which of the following is another classic physical finding noted in those born with the Williams Syndrome?



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A 1-year-old female is referred to pediatric cardiothoracic surgery by her pediatrician after a systolic heart murmur is heard at the right sternal border. An echocardiogram is completed revealing supravalvar aortic stenosis and pulmonary artery stenosis. Referral to genetic counseling is recommended to the parents, as the child also is found to have hypercalcemia and has the characteristic facial features of Williams Syndrome. Which of the following types of specimens is tested in order to definitively diagnose Williams Syndrome?



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A 13-year-old female with mild intellectual disability and growth abnormalities presents with her parents to her physician's office. During the interview, the child is noted to be gregarious with distinctive facial features and blue eyes with a stellate pattern. What should the physician inform her parents about the likely progression for those born with this syndrome?



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A 5-year-old boy is noted to have microcephaly, a large mouth with thick lips, microdontia, and limited joint movement. The child is friendly and talkative and used good syntax, but displayed perseveration when using colloquial expressions. Which of the following is most likely?



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A 4-year-old male with a history of a congenital heart lesion, intellectual disability, and elfin-like facial features presents to the hospital with right side paresis and fever. An echocardiogram reveals vegetations on both his arteries and heart valves. Blood cultures return positive for streptococcus parasanguis, and he is started on dicloxacillin and ceftriaxone. Which of the following cardiac abnormalities significantly contribute to this patient's morbidity and mortality?



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Williams Syndrome - References

References

Performance on the Kaufman Brief Intelligence Test-2 by Children With Williams Syndrome., Pitts CH,Mervis CB,, American journal on intellectual and developmental disabilities, 2016 Jan     [PubMed]
Elastin deficiency in Williams syndrome may explain postoperative major adverse cardiac events., Protopapas AD,, The Journal of thoracic and cardiovascular surgery, 2015 Nov     [PubMed]
Coronary Artery Involvement of Williams Syndrome in Infants and Surgical Revascularization Strategy., Federici D,Ranghetti A,Merlo M,Terzi A,Di Dedda GB,Marcora S,Marrone C,Ciuffreda M,Seddio F,Galletti L,, The Annals of thoracic surgery, 2016 Jan     [PubMed]
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. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. 2006 Sep 5;     [PubMed]
Morris CA, Williams Syndrome 1993;     [PubMed]
Lenhoff HM,Teele RL,Clarkson PM,Berdon WE, John C. P. Williams of Williams-Beuren syndrome. Pediatric radiology. 2011 Feb;     [PubMed]
Martens MA,Wilson SJ,Reutens DC, Research Review: Williams syndrome: a critical review of the cognitive, behavioral, and neuroanatomical phenotype. Journal of child psychology and psychiatry, and allied disciplines. 2008 Jun;     [PubMed]
Hornik CP,Collins RT 2nd,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. The Journal of thoracic and cardiovascular surgery. 2015 Jun;     [PubMed]
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. Journal of autism and developmental disorders. 2017 Dec;     [PubMed]
Collins Ii RT,Collins MG,Schmitz ML,Hamrick JT, Peri-procedural risk stratification and management of patients with Williams syndrome. Congenital heart disease. 2017 Mar;     [PubMed]
Chen WJ,Ji C,Yao D,Zhao ZY, Thyroid evaluation of children and adolescents with Williams syndrome in Zhejiang Province. Journal of pediatric endocrinology     [PubMed]

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