Williams Syndrome

Back

Background

Originally described independently by Williams and Beuren in 1961, Williams syndrome (WS) is a rare genetic condition. The clinical manifestations include a distinct facial appearance, cardiovascular anomalies that may be present at birth or may develop later in life, idiopathic hypercalcemia, and a characteristic neurodevelopmental and behavioral profile.

Pathophysiology

In virtually all cases of Williams syndrome, haploinsufficiency (loss of 1 of 2 copies) due to a deletion at chromosome band 7q11.23 that involves the elastin gene (ELN) is implicated. Most deletions are not detected through standard karyotyping but rather through fluorescent in situ hybridization (FISH) for a 1.5-Mb deletion (Williams-Beuren syndrome chromosomal region [WBSCR]) or array comparative genomic hybridization.[1, 2, 3] The size of the deletion can vary; however, up to 95% of deletions are 1.55 Mb in size.[4, 5, 6, 7, 8]

Williams syndrome is not solely caused by elastin haploinsufficiency; the deletion involves a region that spans more than 28 genes and, hence, is considered a contiguous gene deletion syndrome.[4, 9, 10] The cardiovascular findings, part of the connective tissue pathology, and facial dysmorphology are attributed to the elastin gene haploinsufficiency.[11, 12]

Other genes within the region of the deletion are under investigation for their role in the cognitive profile of Williams syndrome, such as LIMK1, GTF1IRD1,GTF2IRD2, GTF2I, NCF1, STX1A, BAZ1B, CLIP2, and TFII-1.[10, 13, 14, 15, 16, 17, 18] LIMK1 and a number of other genes are felt to influence the cognitive profile of Williams syndrome, and other genes have been implicated in other features, such as hypercalcemia, facial features, glucose metabolism, and hypertension. However, genotype-phenotype correlations with genes other than elastin are not yet fully elucidated, and the sample size for studies involving individual genes has been small.[9, 19]

Point mutations or small intragenic deletions of ELN have been found in the autosomal dominant disorder familial supravalvular aortic stenosis (SVAS) without other characteristics of Williams syndrome. Point mutations and frameshift mutations in ELN have also been found in some cases of cutis laxa.[20, 21] Copy number variants (CNVs) in the 7q11.23 region have been found to be associated with autism in a study of over 4000 individuals who did not have Williams syndrome.[7]

Etiology

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 that lead to interstitial deletions.[22, 23] 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.[24]

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.[25]

Epidemiology

United States data

Williams syndrome occurs in 1 per 7,500-20,000 births. Most cases are sporadic, however, in 25% of cases, a parent is found to have an inversion of chromosome 7 involving WBSCR, compared to 6% of the general population.[26]

Race-, sex-, and age-related demographics

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,[27] and people living in Greece have a lower rate of cardiovascular anomalies.[28]

The deletion is equally prevalent in males and females. A greater severity and earlier presentation of cardiovascular disease may be observed in males.[29, 30]

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 ultrasonography of neonates with Williams syndrome has revealed multicystic dysplastic kidney in addition to the congenital heart lesions.[31] Associated findings on prenatal screening that have been reported include an increased fetal nuchal translucency and low maternal serum alpha fetoprotein (MSAFP); however, none of the prenatal findings has been proven to be a diagnostic marker of Williams syndrome.

Prognosis

Consider the progressive nature of medical problems in Williams syndrome, including vascular stenosis, hypertension, and joint contractures.

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 used in various 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. Few adults with Williams syndrome live entirely independently.

Mild accelerated physical and cognitive aging has been noted.

Morbidity/mortality

For patients with Williams syndrome, cardiovascular involvement is the most common cause of morbidity and mortality.[32] Sudden cardiovascular collapse is a well-known phenomenon, particularly in the periprocedural period.[33] Cardiovascular disease accounts for most cases of early mortality associated with Williams syndrome. Elastin arteriopathy is generalized; thus, virtually any artery may be affected.

Abnormalities involve local or diffuse stenosis of the medium-sized or large-sized arteries, most commonly in the ascending aorta above the aortic valves (ie, SVAS) or in the pulmonary arteries. Nonetheless, stenosis of the descending aorta, intracranial arteries, and renal arteries have been reported.[34, 35, 36] Overall, unexpected death is rare, but it is 25-fold to 100-fold higher than in age-matched control subjects.[37] Factors implicated in sudden death have included 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 that results from intimal fibrosis and muscular hypertrophy. Stroke occurring at younger than expected ages has been reported.[38, 39, 40, 41]

A study by Phomakay et al indicated that ventricular hypertrophy is a common finding on electrocardiograms (ECGs) in patients with Williams syndrome and that an association exists between the severity of right- and left-sided obstructive lesions and the presence of right or left ventricular hypertrophy, respectively, on electrocardiography. The study involved 187 patients, who underwent a total of 499 ECGs, with right ventricular hypertrophy being found on one or more ECGs in 57% (106) of patients and left ventricular hypertrophy being revealed on one or more ECGs in 39% (72) of patients.[42]

Deaths in patients with Williams syndrome 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.[37, 43, 44] Sudden deaths with no apparent instigating event have also been reported, with apparent underlying myocardial injury.[37] Patients with a higher risk of sudden death may show signs of myocardial ischemia on electrocardiography (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 but not with sudden death.[45, 46]

Hypertension develops in approximately 50% of individuals with Williams syndrome, in some cases in relation to renal artery stenosis.[41, 47]

A higher frequency of obesity, impaired glucose tolerance and diabetes mellitus have been found in adults with Williams syndrome compared to the general population.[48] Elevated thyroid stimulating hormone (TSH) levels have an increased prevalence in patients with William syndrome, are more common in children younger than 1 year, and are associated with thyroid hypoplasia.[49] Most of the findings are associated with subclinical hypothyroidism, but because TSH levels appear to normalize with age, there remains the possibility of thyroid hypoplasia that may not manifest with an elevated TSH level.

Various gastrointestinal problems are common, including feeding problems and colic, as well as reflux and chronic constipation.[50] Sigmoid diverticulitis in adults is reported at a higher frequency in the Williams syndrome population than in the general population.[51]

Williams syndrome is a multisystem condition with other potential consequences, including developmental delay, motor delay, hearing loss, severe dental disease, ocular problems, progressive joint contractures, nephrolithiasis, and bowel and bladder diverticula.

Royston et al found evidence that individuals with Williams syndrome are at increased risk for developing anxiety disorders. They generated pooled prevalence estimates of anxiety disorders for Williams syndrome based upon 16 papers on Williams syndrome, and they conducted a meta-analysis to compare these estimates with prevalence estimates for the heterogeneous intellectual disability (ID) population and the general population. They found that individuals with Williams syndrome had a higher risk of experiencing anxiety than the general population and that they were four times more likely to experience anxiety than individuals with ID.[52]

History

The history obtained from caregivers of patients with Williams syndrome varies and reflects the wide phenotypic spectrum observed in the syndrome. This includes a pattern of growth and development and a specific neurodevelopmental profile primarily involving four areas: cognitive development, language, auditory function, and visuospatial function, as in the following[53, 54, 55] :

Physical Examination

Phenotypic expression of Williams syndrome widely varies. Virtually all cases have typical facial features that can be recognized even at birth, as in the following:

Laboratory Studies

Fluorescent in situ hybridization

Fluorescent in situ hybridization (FISH) for the 7q11.23 elastin gene deletion or array comparative genomic hybridization (aCGH) should be performed in patients in whom Williams syndrome is suspected. A deletion at 7q11.23 is noted on FISH or aCGH testing is found in 99% of patients. Testing is routinely performed on peripheral blood leukocytes obtained in a heparinized tube in cytogenetics laboratories. Non-cytogenetic–based methods for detection of Williams syndrome involve targeted mutation analysis, include real-time quantitative polymerase chain reaction (PCR), multiplex ligation-dependent probe amplification (MLPA), and heterozygosity testing; this reaches the same sensitivity as FISH analysis. An international list of laboratories offering testing for Williams syndrome is available through GeneTests or the European Directory of DNA Diagnostic Laboratories.

A standard karyotype may be performed because 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.[82]

Because atypical cases of Williams syndrome may have other chromosomal rearrangements not detected by the standard FISH test, further studies should be coordinated through a clinical geneticist.

Testing 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.[83, 84] Although there is an increased risk of a parent being a carrier of a translocation on chromosome 7, this finding is considered to be noninformative, as the translocation is present in a large number of people in the general population who do not have children with Williams syndrome.

Other laboratory tests

Plasma creatine phosphokinase (CPK) levels may be elevated, but the clinical significance is not clear in incidental cases.[28] Further studies are needed to see if this may relate to an underlying myopathy.[85]

Obtain baseline measurements of serum calcium, BUN, and serum creatinine levels. Perform routine urinalysis and obtain spot urine calcium/creatinine ratios. Serum or ionized calcium can be checked in suspected cases before genetic confirmation of the diagnosis.

Obtain baseline thyroid-stimulating hormone (TSH) levels.

Imaging Studies

Perform baseline echocardiography 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 (see image below).



View Image

Two-dimensional suprasternal echocardiographic image of supravalvular aortic stenosis (SVAS).

Cardiovascular management depends on the specific cardiac lesion present.

In addition to ECG and echocardiography, children with supravalvar aortic stenosis (SVAS) may require cardiac catheterization as part of their presurgical evaluation.

Perform renal ultrasonography in the initial workup to not only look for anatomic abnormalities but also for nephrolithiasis caused by hypercalcemia. Structural renal abnormalities are found in 15-20% of patients with Williams syndrome.[78, 86] 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 may help tailor schooling and supplemental developmental assistance for children already diagnosed with Williams syndrome.

Obtain a baseline audiology examination to allow monitoring of changes.

Medical Care

Williams syndrome is a complex multisystem medical condition that requires a multidisciplinary team. A few large tertiary care centers have Williams syndrome clinics, which help organize and coordinate the care of patients with Williams syndrome. Williams Syndrome Associations are available 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.[87]

Hypercalcemia, which is noted in approximately 15% of patients with Williams syndrome, 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 periodically monitored 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 or steroids to control elevated calcium levels.[88, 89] For more information, see Hypercalcemia.

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 frequently monitored because long-term unrestricted use of a low calcium, low vitamin D formula has been reported to lead to rickets in a patient with Williams syndrome.[90]

Nephrocalcinosis and sclerosis of the long bones are occasionally observed.

Systemic hypertension should be treated when identified, and surveillance should include annual blood pressure measurements in both arms. For more information see the Medscape topic in pediatrics for Hypertension or Neonatal Hypertension.

Periodically assess visual problems and hearing loss. Acoustic-visual-behavioral training has been reported to improve symptoms of hyperacusis in an adult.[91] Recurrent otitis media may be treated with placement of tympanostomy tubes.

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.[92] Treatment with gonadotropin-releasing hormone (GnRH) agonists may be considered.

Although data are limited, buspirone has been shown to be effective in the treatment of generalized anxiety disorder in patients with Williams syndrome.[93]

Feeding difficulties in children are common, and referral to a gastroenterologist should be considered.

Thyroid function and glucose tolerance testing should be part of the periodic evaluation.

Early involvement of a dentist is suggested.

Surgical Care

For cardiac findings in children with Williams syndrome, early involvement with a pediatric cardiologist and cardiothoracic surgeon is essential.

Supravalvar aortic stenosis (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.[94] Surgery is generally required in 20%-30% of patients.[95]

Timing of the operative repair depends on the presence of cardiac symptoms, the gradient across the supraaortic obstruction, and whether ischemic changes are noted on a stress test. Peripheral branch pulmonary stenosis usually spontaneously resolves 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 over time, whereas peripheral branch pulmonary stenosis improves over 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. Patients may benefit from music therapy.[96]

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, because of apparent germline mosaicism.[83]

Patients with Williams syndrome are considered to be fertile. If one parent is affected with Williams syndrome, the risk for having an affected child is typically 50% because 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 who are 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.[84]

Long-Term Monitoring

Inform parents or caregivers of the Williams Syndrome Association for supporting resources and education. Williams Syndrome Associations are located in the United States and Canada. They provide valuable resources for parents and caregivers. The Williams Syndrome Association can be contacted by phone (248-244-2229) or through the Williams Syndrome Association Web site.

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.

Author

Joanna Lazier, MD, Resident Physician, Department of Medical Genetics, University of Calgary Faculty of Medicine, Canada

Disclosure: Nothing to disclose.

Coauthor(s)

Aneal Khan, MD, MSc, FRCPC, FCCMG, Assistant Professor of Medical Genetics and Pediatrics, University of Calgary Faculty of Medicine; Consulting Staff, Departments of Pediatrics and Medical Genetics, Alberta Children's Hospital, Canada

Disclosure: Nothing to disclose.

Specialty Editors

Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Ameeta Martin, MD, Clinical Associate Professor, Department of Pediatric Cardiology, University of Nebraska College of Medicine

Disclosure: Nothing to disclose.

Chief Editor

Howard S Weber, MD, FSCAI, Professor of Pediatrics, Section of Pediatric Cardiology, Pennsylvania State University College of Medicine; Director of Interventional Pediatric Cardiology, Penn State Hershey Children's Hospital

Disclosure: Received income in an amount equal to or greater than $250 from: Abbott Medical .

Acknowledgements

The authors and editors of Medscape Drugs & Diseases gratefully acknowledge the contributions of previous coauthors Oana Caluseriu, MD, Lennox H Huang, MD, FAAP, and Nathaniel H Robin, MD, to the development and writing of the source article.

References

  1. Ewart AK, Morris CA, Atkinson D, et al. Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nat Genet. 1993 Sep. 5(1):11-6. [View Abstract]
  2. Lowery MC, Morris CA, Ewart A, et al. Strong correlation of elastin deletions, detected by FISH, with Williams syndrome: evaluation of 235 patients. Am J Hum Genet. 1995 Jul. 57(1):49-53. [View Abstract]
  3. Nickerson E, Greenberg F, Keating MT, et al. Deletions of the elastin gene at 7q11.23 occur in approximately 90% of patients with Williams syndrome. Am J Hum Genet. 1995 May. 56(5):1156-61. [View Abstract]
  4. Urban Z, Helms C, Fekete G, et al. 7q11.23 deletions in Williams syndrome arise as a consequence of unequal meiotic crossover. Am J Hum Genet. 1996 Oct. 59(4):958-62. [View Abstract]
  5. Heller R, Rauch A, Luttgen S, et al. Partial deletion of the critical 1.5 Mb interval in Williams-Beuren syndrome. J Med Genet. 2003 Aug. 40(8):e99. [View Abstract]
  6. Hockenhull EL, Carette MJ, Metcalfe K, et al. A complete physical contig and partial transcript map of the Williams syndrome critical region. Genomics. 1999 Jun 1. 58(2):138-45. [View Abstract]
  7. Merla G, Brunetti-Pierri N, Micale L, Fusco C. Copy number variants at Williams-Beuren syndrome 7q11.23 region. Hum Genet. 2010 Jul. 128(1):3-26. [View Abstract]
  8. Bayes M, Magano LF, Rivera N, Flores R, Perez Jurado LA. Mutational mechanisms of Williams-Beuren syndrome deletions. Am J Hum Genet. 2003 Jul. 73(1):131-51. [View Abstract]
  9. Merla G, Ucla C, Guipponi M, Reymond A. Identification of additional transcripts in the Williams-Beuren syndrome critical region. Hum Genet. 2002 May. 110(5):429-38. [View Abstract]
  10. Vandeweyer G, Van der Aa N, Reyniers E, Kooy RF. The contribution of CLIP2 haploinsufficiency to the clinical manifestations of the Williams-Beuren syndrome. Am J Hum Genet. 2012 Jun 8. 90(6):1071-8. [View Abstract]
  11. Mari A, Amati F, Mingarelli R, et al. Analysis of the elastin gene in 60 patients with clinical diagnosis of Williams syndrome. Hum Genet. 1995 Oct. 96(4):444-8. [View Abstract]
  12. Dridi SM, Ghomrasseni S, Bonnet D, et al. Skin elastic fibers in Williams syndrome. Am J Med Genet. 1999 Nov 19. 87(2):134-8. [View Abstract]
  13. Frangiskakis JM, Ewart AK, Morris CA, et al. LIM-kinase1 hemizygosity implicated in impaired visuospatial constructive cognition. Cell. 1996 Jul 12. 86(1):59-69. [View Abstract]
  14. Tassabehji M, Metcalfe K, Fergusson WD, et al. LIM-kinase deleted in Williams syndrome. Nat Genet. 1996 Jul. 13(3):272-3. [View Abstract]
  15. Hirota H, Matsuoka R, Chen XN, et al. Williams syndrome deficits in visual spatial processing linked to GTF2IRD1 and GTF2I on chromosome 7q11.23. Genet Med. 2003 Jul-Aug. 5(4):311-21. [View Abstract]
  16. Euteneuer J, Carvalho CM, Kulkarni S, et al. Molecular and phenotypic characterization of atypical Williams-Beuren syndrome. Clin Genet. 2014 Nov. 86(5):487-91. [View Abstract]
  17. Fusco C, Micale L, Augello B, et al. Smaller and larger deletions of the Williams Beuren syndrome region implicate genes involved in mild facial phenotype, epilepsy and autistic traits. Eur J Hum Genet. 2014 Jan. 22(1):64-70. [View Abstract]
  18. Letavernier E, Rodenas A, Guerrot D, Haymann JP. Williams-Beuren syndrome hypercalcemia: is TRPC3 a novel mediator in calcium homeostasis?. Pediatrics. 2012 Jun. 129(6):e1626-30. [View Abstract]
  19. Osborne LR. Williams-Beuren syndrome: unraveling the mysteries of a microdeletion disorder. Mol Genet Metab. 1999 May. 67(1):1-10. [View Abstract]
  20. Megarbane H, Florence J, Sass JO, et al. An autosomal-recessive form of cutis laxa is due to homozygous elastin mutations, and the phenotype may be modified by a heterozygous fibulin 5 polymorphism. J Invest Dermatol. 2009 Jul. 129(7):1650-5. [View Abstract]
  21. Sugitani H, Hirano E, Knutsen RH, et al. Alternative splicing and tissue-specific elastin misassembly act as biological modifiers of human elastin gene frameshift mutations associated with dominant cutis laxa. J Biol Chem. 2012 Jun 22. 287(26):22055-67. [View Abstract]
  22. Dutly F, Schinzel A. Unequal interchromosomal rearrangements may result in elastin gene deletions causing the Williams-Beuren syndrome. Hum Mol Genet. 1996 Dec. 5(12):1893-8. [View Abstract]
  23. Baumer A, Dutly F, Balmer D, et al. High level of unequal meiotic crossovers at the origin of the 22q11. 2 and 7q11.23 deletions. Hum Mol Genet. 1998 May. 7(5):887-94. [View Abstract]
  24. Robinson WP, Waslynka J, Bernasconi F, et al. Delineation of 7q11.2 deletions associated with Williams-Beuren syndrome and mapping of a repetitive sequence to within and to either side of the common deletion. Genomics. 1996 May 15. 34(1):17-23. [View Abstract]
  25. Osborne LR, Li M, Pober B, et al. A 1.5 million-base pair inversion polymorphism in families with Williams-Beuren syndrome. Nat Genet. 2001 Nov. 29(3):321-5. [View Abstract]
  26. Hobart HH, Morris CA, Mervis CB, et al. Inversion of the Williams syndrome region is a common polymorphism found more frequently in parents of children with Williams syndrome. Am J Med Genet C Semin Med Genet. 2010 May 15. 154C(2):220-8. [View Abstract]
  27. Yau EK, Lo IF, Lam ST. Williams-Beuren syndrome in the Hong Kong Chinese population: retrospective study. Hong Kong Med J. 2004 Feb. 10(1):22-7. [View Abstract]
  28. Amenta S, Sofocleous C, Kolialexi A, et al. Clinical manifestations and molecular investigation of 50 patients with Williams syndrome in the Greek population. Pediatr Res. 2005 Jun. 57(6):789-95. [View Abstract]
  29. Sadler LS, Pober BR, Grandinetti A, et al. Differences by sex in cardiovascular disease in Williams syndrome. J Pediatr. 2001 Dec. 139(6):849-53. [View Abstract]
  30. Bruno E, Rossi N, Thuer O, et al. Cardiovascular findings, and clinical course, in patients with Williams syndrome. Cardiol Young. 2003 Dec. 13(6):532-6. [View Abstract]
  31. Zaghloul N, Hutcheon RG, Tepperberg JH. Visual diagnosis: monozygotic twins who have congenital heart disease and distinctive facial features. Pediatr Rev. 2002 Oct. 23(10):365-7. [View Abstract]
  32. Collins RT 2nd. Cardiovascular disease in Williams syndrome. Curr Opin Pediatr. 2018 Oct. 30(5):609-15. [View Abstract]
  33. 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):133-42. [View Abstract]
  34. Radford DJ, Pohlner PG. The middle aortic syndrome: an important feature of Williams' syndrome. Cardiol Young. 2000 Nov. 10(6):597-602. [View Abstract]
  35. Rose C, Wessel A, Pankau R, Partsch CJ, Bursch J. Anomalies of the abdominal aorta in Williams-Beuren syndrome--another cause of arterial hypertension. Eur J Pediatr. 2001 Nov. 160(11):655-8. [View Abstract]
  36. Ardinger RH Jr, Goertz KK, Mattioli LF. Cerebrovascular stenoses with cerebral infarction in a child with Williams syndrome. Am J Med Genet. 1994 Jul 1. 51(3):200-2. [View Abstract]
  37. Wessel A, Gravenhorst V, Buchhorn R. Risk of sudden death in the Williams-Beuren syndrome. Am J Med Genet A. 2004 Jun 15. 127(3):234-7. [View Abstract]
  38. Soper R, Chaloupka JC, Fayad PB, et al. Ischemic stroke and intracranial multifocal cerebral arteriopathy in Williams syndrome. J Pediatr. 1995 Jun. 126(6):945-8. [View Abstract]
  39. Cherniske EM, Carpenter TO, Klaiman C, et al. Multisystem study of 20 older adults with Williams syndrome. Am J Med Genet A. 2004 Dec 15. 131(3):255-64. [View Abstract]
  40. Lee WD, Hsu JJ, Huang FC, Chao MC, Chang YL, Huang MH. Ischemic stroke in Williams-Beuren syndrome: a case report. Kaohsiung J Med Sci. 2009 Apr. 25(4):212-6. [View Abstract]
  41. Broder K, Reinhardt E, Ahern J, et al. Elevated ambulatory blood pressure in 20 subjects with Williams syndrome. Am J Med Genet. 1999 Apr 23. 83(5):356-60. [View Abstract]
  42. Phomakay V, Gossett JM, Kaplan PB, Swearingen CJ, Collins RT 2nd. Ventricular hypertrophy on electrocardiogram correlates with obstructive lesion severity in Williams syndrome. Congenit Heart Dis. 2015 Jul-Aug. 10(4):302-9. [View Abstract]
  43. Bird LM, Billman GF, Lacro RV, et al. Sudden death in Williams syndrome: report of ten cases. J Pediatr. 1996 Dec. 129(6):926-31. [View Abstract]
  44. Bragg K, Fedel GM, DiProsperis A. Cardiac arrest under anesthesia in a pediatric patient with Williams syndrome: a case report. AANA J. 2005 Aug. 73(4):287-93. [View Abstract]
  45. Horowitz PE, Akhtar S, Wulff JA, et al. Coronary artery disease and anesthesia-related death in children with Williams syndrome. J Cardiothorac Vasc Anesth. 2002 Dec. 16(6):739-41. [View Abstract]
  46. Yetkin U, Bal F, Bayata S, Gurbuz A. Severely calcified valvular aortic stenosis firstly diagnosed in monozygotic male twins with suspected Williams-Beuren syndrome. Jpn Heart J. 2004 Sep. 45(5):877-83. [View Abstract]
  47. Hertzberg J, Nakisbendi L, Needleman HL, Pober B. Williams syndrome--oral presentation of 45 cases. Pediatr Dent. 1994 Jul-Aug. 16(4):262-7. [View Abstract]
  48. Stagi S, Lapi E, Cecchi C, et al. Williams-beuren syndrome is a genetic disorder associated with impaired glucose tolerance and diabetes in childhood and adolescence: new insights from a longitudinal study. Horm Res Paediatr. 2014. 82(1):38-43. [View Abstract]
  49. Selicorni A, Fratoni A, Pavesi MA, Bottigelli M, Arnaboldi E, Milani D. Thyroid anomalies in Williams syndrome: investigation of 95 patients. Am J Med Genet A. 2006 May 15. 140(10):1098-101. [View Abstract]
  50. Axelsson S, Bjornland T, Kjaer I, Heiberg A, Storhaug K. Dental characteristics in Williams syndrome: a clinical and radiographic evaluation. Acta Odontol Scand. 2003 Jun. 61(3):129-36. [View Abstract]
  51. Partsch CJ, Siebert R, Caliebe A, et al. Sigmoid diverticulitis in patients with Williams-Beuren syndrome: relatively high prevalence and high complication rate in young adults with the syndrome. Am J Med Genet A. 2005 Aug 15. 137(1):52-4. [View Abstract]
  52. 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):3765-77. [View Abstract]
  53. Mervis CB, Robinson BF, Bertrand J, et al. The Williams syndrome cognitive profile. Brain Cogn. 2000 Dec. 44(3):604-28. [View Abstract]
  54. Leyfer O, John AE, Woodruff-Borden J, Mervis CB. Factor structure of the Children's Behavior Questionnaire in children with Williams syndrome. J Autism Dev Disord. 2012 Nov. 42(11):2346-53. [View Abstract]
  55. Cowie D, Braddick O, Atkinson J. Visually guided step descent in children with Williams syndrome. Dev Sci. 2012 Jan. 15(1):74-86. [View Abstract]
  56. Schulman SL, Zderic S, Kaplan P. Increased prevalence of urinary symptoms and voiding dysfunction in Williams syndrome. J Pediatr. 1996 Sep. 129(3):466-9. [View Abstract]
  57. Kuijpers GM, De Vroede M, Knol HE, Jansen M. Growth hormone treatment in a child with Williams-Beuren syndrome: a case report. Eur J Pediatr. 1999 Jun. 158(6):451-4. [View Abstract]
  58. Xekouki P, Fryssira H, Maniati-Christidi M, et al. Growth hormone deficiency in a child with Williams-Beuren syndrome. The response to growth hormone therapy. J Pediatr Endocrinol Metab. 2005 Feb. 18(2):205-7. [View Abstract]
  59. Stagi S, Bindi G, Neri AS, et al. Thyroid function and morphology in patients affected by Williams syndrome. Clin Endocrinol (Oxf). 2005 Oct. 63(4):456-60. [View Abstract]
  60. Toomey KE. Medical genetics for the practitioner. Pediatr Rev. 1996 May. 17(5):163-74. [View Abstract]
  61. Porter MA, Coltheart M. Cognitive heterogeneity in Williams syndrome. Dev Neuropsychol. 2005. 27(2):275-306. [View Abstract]
  62. Tsai SW, Wu SK, Liou YM, Shu SG. Early development in Williams syndrome. Pediatr Int. 2008 Apr. 50(2):221-4. [View Abstract]
  63. Dixit A, McKee S, Mansour S, et al. 7q11.23 Microduplication: a recognizable phenotype. Clin Genet. 2013 Feb. 83(2):155-61. [View Abstract]
  64. Mervis CB, Velleman SL. Children with Williams syndrome: language, cognitive, and behavioral characteristics and their implications for intervention. Perspect Lang Learn Educ. 2011 Oct 1. 18(3):98-107. [View Abstract]
  65. Withers S. A new clinical sign in Williams syndrome. Arch Dis Child. 1996 Jul. 75(1):89. [View Abstract]
  66. Klein-Tasman BP, Mervis CB, Lord C, Phillips KD. Socio-communicative deficits in young children with Williams syndrome: performance on the Autism Diagnostic Observation Schedule. Child Neuropsychol. 2007 Sep. 13(5):444-67. [View Abstract]
  67. Blomberg S, Rosander M, Andersson G. Fears, hyperacusis and musicality in Williams syndrome. Res Dev Disabil. 2006 Nov-Dec. 27(6):668-80. [View Abstract]
  68. Gallo FJ, Klein-Tasman BP, Gaffrey MS, Curran P. Expecting the worst: observations of reactivity to sound in young children with Williams syndrome. Res Dev Disabil. 2008 Nov-Dec. 29(6):567-81. [View Abstract]
  69. Huang L, Sadler L, O'Riordan MA, Robin NH. Delay in diagnosis of Williams syndrome. Clin Pediatr (Phila). 2002 May. 41(4):257-61. [View Abstract]
  70. Lopez-Rangel E, Maurice M, McGillivray B, Friedman JM. Williams syndrome in adults. Am J Med Genet. 1992 Dec 1. 44(6):720-9. [View Abstract]
  71. Einfeld SL, Tonge BJ, Rees VW. Longitudinal course of behavioral and emotional problems in Williams syndrome. Am J Ment Retard. 2001 Jan. 106(1):73-81. [View Abstract]
  72. Davies M, Udwin O, Howlin P. Adults with Williams syndrome. Preliminary study of social, emotional and behavioural difficulties. Br J Psychiatry. 1998 Mar. 172:273-6. [View Abstract]
  73. Davies M, Howlin P, Udwin O. Independence and adaptive behavior in adults with Williams syndrome. Am J Med Genet. 1997 May 16. 70(2):188-95. [View Abstract]
  74. Morris CA, Demsey SA, Leonard CO, Dilts C, Blackburn BL. Natural history of Williams syndrome: physical characteristics. J Pediatr. 1988 Aug. 113(2):318-26. [View Abstract]
  75. Pankau R, Partsch CJ, Neblung A, et al. Head circumference of children with Williams-Beuren syndrome. Am J Med Genet. 1994 Sep 1. 52(3):285-90. [View Abstract]
  76. Canargiu F, Erriu M, Piras A, Dibart SN. Modifications of periodontal tissues associated with Williams syndrome. A case report. Minerva Stomatol. 2009 Jul-Aug. 58(7-8):375-81. [View Abstract]
  77. Carrasco X, Castillo S, Aravena T, Rothhammer P, Aboitiz F. Williams syndrome: pediatric, neurologic, and cognitive development. Pediatr Neurol. 2005 Mar. 32(3):166-72. [View Abstract]
  78. Pankau R, Partsch CJ, Winter M, Gosch A, Wessel A. Incidence and spectrum of renal abnormalities in Williams-Beuren syndrome. Am J Med Genet. 1996 May 3. 63(1):301-4. [View Abstract]
  79. Greenberg F, Lewis RA. The Williams syndrome. Spectrum and significance of ocular features. Ophthalmology. 1988 Dec. 95(12):1608-12. [View Abstract]
  80. Kapp ME, von Noorden GK, Jenkins R. Strabismus in Williams syndrome. Am J Ophthalmol. 1995 Mar. 119(3):355-60. [View Abstract]
  81. Marler JA, Elfenbein JL, Ryals BM, et al. Sensorineural hearing loss in children and adults with Williams syndrome. Am J Med Genet A. 2005 Nov 1. 138(4):318-27. [View Abstract]
  82. von Dadelszen P, Chitayat D, Winsor EJ. De novo 46,XX,t(6;7)(q27;q11;23) associated with severe cardiovascular manifestations characteristic of supravalvular aortic stenosis and Williams syndrome. Am J Med Genet. 2000 Feb 14. 90(4):270-5. [View Abstract]
  83. Kara-Mostefa A, Raoul O, Lyonnet S, et al. Recurrent Williams-Beuren syndrome in a sibship suggestive of maternal germ-line mosaicism. Am J Hum Genet. 1999 May. 64(5):1475-8. [View Abstract]
  84. Mulik VV, Temple KI, Howe DT. Two pregnancies in a woman with Williams syndrome. BJOG. 2004 May. 111(5):511-2. [View Abstract]
  85. Voit T, Kramer H, Thomas C. Myopathy in Williams-Beuren syndrome. Eur J Pediatr. 1991 May. 150(7):521-6. [View Abstract]
  86. Sforzini C, Milani D, Fossali E, et al. Renal tract ultrasonography and calcium homeostasis in Williams-Beuren syndrome. Pediatr Nephrol. 2002 Nov. 17(11):899-902. [View Abstract]
  87. Committee on Genetics. American Academy of Pediatrics: Health care supervision for children with Williams syndrome. Pediatrics. 2001 May. 107(5):1192-204. [View Abstract]
  88. Cagle AP, Waguespack SG, Buckingham BA, et al. Severe infantile hypercalcemia associated with Williams syndrome successfully treated with intravenously administered pamidronate. Pediatrics. 2004 Oct. 114(4):1091-5. [View Abstract]
  89. Oliveri B, Mastaglia SR, Mautalen C, et al. Long-term control of hypercalcaemia in an infant with williams-Beuren syndrome after a single infusion of biphosphonate (Pamidronate). Acta Paediatr. 2004 Jul. 93(7):1002-3. [View Abstract]
  90. Mathias RS. Rickets in an infant with Williams syndrome. Pediatr Nephrol. 2000 Jun. 14(6):489-92. [View Abstract]
  91. Miani C, Passon P, Bracale AM, et al. Treatment of hyperacusis in Williams syndrome with bilateral conductive hearing loss. Eur Arch Otorhinolaryngol. 2001 Sep. 258(7):341-4. [View Abstract]
  92. Partsch CJ, Japing I, Siebert R, et al. Central precocious puberty in girls with Williams syndrome. J Pediatr. 2002 Sep. 141(3):441-4. [View Abstract]
  93. Thom RP, Keary CJ, Waxler JL, Pober BR, McDougle CJ. Buspirone for the treatment of generalized anxiety disorder in Williams syndrome: a case series. J Autism Dev Disord. 2019 Nov 14. [View Abstract]
  94. Wessel A, Pankau R, Kececioglu D, et al. Three decades of follow-up of aortic and pulmonary vascular lesions in the Williams-Beuren syndrome. Am J Med Genet. 1994 Sep 1. 52(3):297-301. [View Abstract]
  95. Collins RT 2nd, Kaplan P, Somes GW, Rome JJ. Long-term outcomes of patients with cardiovascular abnormalities and Williams syndrome. Am J Cardiol. 2010 Mar 15. 105(6):874-8. [View Abstract]
  96. Lense MD, Shivers CM, Dykens EM. (A)musicality in Williams syndrome: examining relationships among auditory perception, musical skill, and emotional responsiveness to music. Front Psychol. 2013. 4:525. [View Abstract]

Two-dimensional suprasternal echocardiographic image of supravalvular aortic stenosis (SVAS).

Two-dimensional suprasternal echocardiographic image of supravalvular aortic stenosis (SVAS).