Continuing Education Activity
Williams syndrome is a rare genetic and neurodevelopmental disorder that affects multiple organ systems. This disorder is often identified shortly after birth due to characteristic facial features described as elfin-like, along with congenital heart defects such as supravalvular aortic stenosis. The syndrome is associated with systemic hypercalcemia, connective tissue abnormalities, growth delays, intellectual disability, and a distinctively gregarious personality.
This course explores the complexities surrounding this syndrome, including the current diagnostic challenges and multiorgan complications that frequently occur, eg, cardiovascular, endocrine, neurodevelopmental, psychiatric, and intellectual disability issues. This activity for healthcare professionals is designed to enhance the learner's competence in identifying Williams syndrome, performing the recommended evaluation, and implementing an appropriate interprofessional approach when managing this condition.
Objectives:
Identify the etiology of Williams syndrome.
Assess characteristic clinical features of Williams syndrome.
Implement diagnostic studies to confirm Williams syndrome.
Apply interprofessional team strategies to improve care coordination and outcomes in patients with Williams syndrome.
Access free multiple choice questions on this topic.
Introduction
Williams syndrome is a rare genetic and neurodevelopmental disorder due to multiple gene deletions on chromosome 7. Williams syndrome affects many organ systems but is frequently noted shortly after birth with characteristic facial features, and subsequent workup often reveals a characteristic supravalvular aortic stenosis.[1] The distinctive facies are often described as elfin-like features, with a broad forehead, full cheeks, an under-developed chin, and a shortened nose.[2] Other associated features include systemic hypercalcemia, connective tissue abnormalities, growth abnormalities, intellectual disability, behavior deficits, and a gregarious personality.[2][3]
Cardiologist Dr. John Cyprian Phipps Williams first described the syndrome in 1961. In 1962, German physician Dr. A. J. Beuren found similar findings in a series of 3 patients, naming the syndrome Williams-Beuren syndrome, which is still used in some publications.[4][3] In 1975, the definitive treatise on the syndrome's cardiovascular, behavioral, and systemic effects was published.[5]
Etiology
The genetic etiology underlying Williams syndrome was uncovered in 1993. Williams syndrome is most commonly a spontaneous genetic mutation but is passed via autosomal dominant transmission from an affected parent due to haploinsufficient expression.[3][2] Williams syndrome develops secondary to spontaneous deletions at chromosome band 7q11.23 that involve the elastin gene (ELN). The gene is in the Williams-Beuren Syndrome Critical Region (WBSCR).[1][2]
The deletion, comprising 26 genes, is detected through dual-color fluorescent in situ hybridization (FISH) or deletion/duplication testing.[2][6] 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. An estimated 96% to 98% of patients with Williams syndrome have a deleted ELN gene.[3]
Epidemiology
The estimated frequency of the disorder is cited in studies with a range between 1 in 7,500 to 1 in 20,000 children.[2][3] The disease affects all ethnicities and both sexes equally.[6][7]
Pathophysiology
The deletion areas on chromosome 7 encompass at least 26 known genes. Among those typically deleted are ELN (coding for elastin), CLIP2, GTF2I, GTF2IRD1, and LIMK1. ELN deletion leads to generalized arteriopathy and may affect any artery in the body, but it often affects medium to large-sized arteries, particularly the characteristic supravalvular aortic stenosis. Elastin deficiency may also manifest as hoarseness, bladder diverticula, and hernias in patients with Williams syndrome.[8]
Haploinsufficiency in genes GTF2I, GTF2IRD1, and LIMK1 has been implicated in difficulties in visual-spatial tasks frequently present in patients with Williams syndrome.[9][10] In addition, haploinsufficiency in Williams syndrome in the CLIP2 gene has been implicated in characteristic personality traits, learning disabilities, and cognitive disabilities.[11]
History and Physical
After birth, infants often present with characteristic facial features and failure to thrive, short stature, and supravascular aortic stenosis.[2] On physical exam, children with Williams syndrome have distinctive facies with elfin-like features, including a short nose and elongated philtrum, periorbital puffiness or stellate iris pattern, and a prominent forehead and relatively under-developed chin.[2] Patients with Williams syndrome 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][12] These facial and physical features should prompt the astute clinician to investigate further.
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] Children with Williams syndrome 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][13]
Moreover, connective tissue abnormalities often result in hyperextensible joints or hypotonia, resulting in delayed motor milestones or toilet training.[2] The patient may have comorbid psychiatric disorders, including intellectual disability, attention-deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), or generalized anxiety disorder (GAD).[1][14][15]
Evaluation
A definitive diagnosis of Williams syndrome requires fluorescence in situ hybridization (FISH) genetic testing demonstrating the gene deletion in the WBSCR.[2] The following laboratory, imaging, and other tests should be performed to help exclude differential diagnoses and assess for comorbid conditions for patients with suspected Williams syndrome.
Intellectual disability in Williams syndrome is assessed using the Kaufman Brief Intelligence Test, Second Edition (KBIT-2). The assessment computes a composite intelligence quotient and verbal and nonverbal standard scores.[6] Studies utilizing KBIT-2 to measure intelligence quotient in children with Williams syndrome found that their intelligence quotient ranged from average to severe intellectual disability.[6] Children with Williams syndrome often struggle with visuospatial construction, which the KBIT-2 does not measure.[6] The Differential Ability Scale-II (DAS-II) Special Nonverbal Composite assessments and Wechsler intelligence quotient tests may be useful diagnostic tools to measure visuospatial construction.[6][16]
Treatment / Management
Effective management of Williams syndrome requires an interprofessional team due to the various organ systems that may be affected, including:
Genetic counseling: Upon making the diagnosis, genetic counseling should follow, as a risk to future offspring is present.
[2]
Obstetrical issues: All pregnancies in patients with Williams syndrome are considered high risk due to the risk of arrhythmia, heart failure, and hypertension.
[2] In addition to routine ultrasound of the fetus, urinalysis is necessary due to the risk of urinary tract infections. Genetic counseling may follow during pregnancy, and prenatal testing is available.
[2]
Cardiac abnormalities: At birth, children with Williams syndrome often need cardiac care for supravascular 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, which can also lead to pulmonary artery stenosis, mitral valve insufficiency, and renal artery stenosis.
[2]
Metabolic disorders: Endocrinologists often manage hypercalcemia, hypothyroidism, and growth reduction in Williams syndrome patients.
[2][13] 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 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.
[13] Children with Williams syndrome often require thyroid hormone replacement therapy.
[13]
Feeding abnormalities: Gastroenterology referral is warranted for children with feeding difficulties, as they may require a permanent feeding tube.
[2]
Nutritional issues: Infants with feeding difficulties often require feeding therapy and consultation with a nutritionist.
[2]
Psychiatric conditions: Psychiatric evaluation is recommended to determine the need for medications or psychotherapy to treat comorbid ADHD, OCD, or GAD.
[2][17][18]
Ancillary services: Due to neurodevelopmental deficits and intellectual disability, children with Williams syndrome often require special education programs, occupational therapy, physical therapy, speech therapy, and sensory integration therapies.
[2] Physical therapy, with a focus on the range of motion, is recommended to prevent joint contractures that may occur.
[2] Hearing and vision screening are strong recommendations for all children with neurodevelopmental disorders.
[2] Children with Williams syndrome are at risk of hyperopia and recurrent otitis media; therefore, they require routine testing for hearing and vision loss.
[2]
Dental conditions: Refer to an orthodontist or dentist is also recommended due to the risk of malocclusion and dental abnormalities.
[2]
Differential Diagnosis
Excluding other neurodevelopmental disorders that can resemble Williams syndrome is essential, including:
Autosomal dominant supravalvular aortic stenosis is another condition that should be ruled out, as this condition is a separate disorder from Williams syndrome.[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 Williams syndrome.[2]
Prognosis
The morbidity of Williams syndrome is primarily due to the presence of arteriopathy and congenital heart disease.[2] Approximately 80% of Williams syndrome patients experience cardiovascular abnormalities, eg, stenosed large arteries or ventricular outflow tracts that require cardiothoracic surgery.[19] During the perioperative period, patients have a risk of sudden cardiovascular collapse that may contribute to morbidity and mortality.[20]
In terms of inheritance, parents with Williams syndrome have a 50% chance of passing the microdeletion to their children.[2] If a parent has 1 child with Williams syndrome but the parent is unaffected, the risk of a sibling acquiring Williams syndrome is low.[2] Patients with Williams syndrome can live semi-independently or, in some cases, independently and are often able to work. As each individual with Williams syndrome has different needs, completion of an individualized life transition plan is recommended, preferably before the age of 13 or 14.
Complications
When patients with Williams syndrome undergo open-heart surgery, the risk for complications is exacerbated by elastin deficiency.[19][21] A multicenter registry followed patients with Williams syndrome who underwent surgery for the right ventricular outflow tract, left ventricular outflow tract, or supravalvular aortic stenosis.[19] The registry found that 9% of patients with Williams syndrome who had open-heart surgery had major adverse cardiac events, such as arrhythmia or coronary artery disease.[19][22] In cases of coronary artery disease after surgical repair of stenosis, revascularization may be necessary.[22]
Consultations
The treatment of Williams syndrome requires an interprofessional approach. After the birth of a child with Williams syndrome, the pediatrician should obtain a consultation from cardiology and cardiothoracic surgery.[2] Later, case discussions with endocrinology, gastroenterology, nephrology, and psychiatry may also be warranted.[2] Additional consultations with occupational therapy, physical therapy, speech therapy, sensory integration therapies, orthodontists, dentists, and psychotherapists may be options.[2] The parents of a child with Williams syndrome 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. The Williams Syndrome Association (WSA) website provides more information on the disorder.[Williams syndrome] Each patient with Williams syndrome is unique, and overall functional and life goals will be similarly individual and developed as a part of each patient's life plan.
As the vast majority of Williams syndrome cases occur due to spontaneous, de novo genetic mutations, no known mitigation strategies or risk factors to adjust have been established. When counseling patients with William syndrome regarding the risks of transmitting the disease to their children, clinicians should educate patients that the syndrome is an autosomal dominant condition, indicating a 50% risk of transmission if 1 parent has William syndrome. Prenatal genetic testing is available.
Enhancing Healthcare Team Outcomes
Effective management of Williams syndrome requires a collaborative, interprofessional approach to ensure comprehensive, patient-centered care. Physicians, including pediatricians, cardiologists, endocrinologists, and geneticists, play a central role in diagnosing and monitoring the condition, utilizing genetic testing and routine screenings for endocrine and neurodevelopmental abnormalities. Advanced practitioners and pediatric nurses are essential in coordinating routine care by tracking growth parameters such as weight and BMI, monitoring calcium levels, thyroid function, and metabolic panels, and ensuring regular hearing and vision assessments. Pharmacists contribute by advising on medication management for associated conditions, including hypercalcemia and behavioral disorders, while also identifying potential drug interactions that could impact cardiovascular or metabolic health.
Interprofessional communication is vital to enhance patient safety and optimize team performance. Clear, ongoing communication among clinicians ensures that medical, developmental, and behavioral interventions are aligned and consistently applied. Care coordination among specialists, therapists, and social workers supports individualized treatment plans, helping patients access necessary therapies such as speech, occupational, and physical therapy. Nurses and advanced practitioners act as patient advocates, educating families about Williams syndrome and connecting them with support resources. By fostering collaboration across disciplines, healthcare professionals improve patient outcomes, reduce complications, and create a seamless care experience that prioritizes both medical management and quality of life for individuals with Williams syndrome.
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.
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]
- 4.
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]
- 5.
Lashkari A, Smith AK, Graham JM. Williams-Beuren syndrome: an update and review for the primary physician.
Clin Pediatr (Phila). 1999 Apr;38(4):189-208. [
PubMed: 10326175]
- 6.
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]
- 7.
Kozel BA, Barak B, Kim CA, Mervis CB, Osborne LR, Porter M, Pober BR. Williams syndrome.
Nat Rev Dis Primers. 2021 Jun 17;7(1):42. [
PMC free article: PMC9437774] [
PubMed: 34140529]
- 8.
Francke U. Williams-Beuren syndrome: genes and mechanisms.
Hum Mol Genet. 1999;8(10):1947-54. [
PubMed: 10469848]
- 9.
Tassabehji M, Metcalfe K, Karmiloff-Smith A, Carette MJ, Grant J, Dennis N, Reardon W, Splitt M, Read AP, Donnai D. Williams syndrome: use of chromosomal microdeletions as a tool to dissect cognitive and physical phenotypes.
Am J Hum Genet. 1999 Jan;64(1):118-25. [
PMC free article: PMC1377709] [
PubMed: 9915950]
- 10.
Alesi V, Loddo S, Orlando V, Genovese S, Di Tommaso S, Liambo MT, Pompili D, Ferretti D, Calacci C, Catino G, Falasca R, Dentici ML, Novelli A, Digilio MC, Dallapiccola B. Atypical 7q11.23 deletions excluding ELN gene result in Williams-Beuren syndrome craniofacial features and neurocognitive profile.
Am J Med Genet A. 2021 Jan;185(1):242-249. [
PubMed: 33098373]
- 11.
Hoogenraad CC, Eussen BH, Langeveld A, van Haperen R, Winterberg S, Wouters CH, Grosveld F, De Zeeuw CI, Galjart N. The murine CYLN2 gene: genomic organization, chromosome localization, and comparison to the human gene that is located within the 7q11.23 Williams syndrome critical region.
Genomics. 1998 Nov 01;53(3):348-58. [
PubMed: 9799601]
- 12.
Nassisi M, Mainetti C, Aretti A, Sperti A, Nicotra V, Rinaldi B, Natacci F, Bedeschi MF, Viola F. Ocular features in Williams-Beuren syndrome: a review of the literature.
Curr Opin Ophthalmol. 2023 Nov 01;34(6):514-521. [
PubMed: 37589562]
- 13.
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]
- 14.
Thom RP. Psychiatric and behavioral manifestations of Williams syndrome.
Curr Opin Psychiatry. 2024 Mar 01;37(2):65-70. [
PubMed: 38085853]
- 15.
Kleberg JL, Riby D, Fawcett C, Björlin Avdic H, Frick MA, Brocki KC, Högström J, Serlachius E, Nordgren A, Willfors C. Williams syndrome: reduced orienting to other's eyes in a hypersocial phenotype.
J Autism Dev Disord. 2023 Jul;53(7):2786-2797. [
PMC free article: PMC9020553] [
PubMed: 35445369]
- 16.
Serrano-Juárez CA, Prieto-Corona B, Rodríguez-Camacho M, Sandoval-Lira L, Villalva-Sánchez ÁF, Yáñez-Téllez MG, López MFR. Neuropsychological Genotype-Phenotype in Patients with Williams Syndrome with Atypical Deletions: A Systematic Review.
Neuropsychol Rev. 2023 Dec;33(4):891-911. [
PubMed: 36520254]
- 17.
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]
- 18.
Thom RP, Pober BR, McDougle CJ. Psychopharmacology of Williams syndrome: safety, tolerability, and effectiveness.
Expert Opin Drug Saf. 2021 Mar;20(3):293-306. [
PubMed: 33369485]
- 19.
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]
- 20.
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]
- 21.
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]
- 22.
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: Ryan Winters declares no relevant financial relationships with ineligible companies.
Disclosure: Iverson Carter declares no relevant financial relationships with ineligible companies.
