INTRODUCTION — Williams syndrome (WS, OMIM #194050 [1]), also known as Williams-Beuren syndrome, is a multisystem, contiguous gene deletion syndrome caused by hemizygous deletion of 1.5 to 1.8 Mb on chromosome 7q11.23.
The epidemiology, genetics, clinical manifestations, diagnosis, and management of WS are discussed here.
EPIDEMIOLOGY — First described clinically in 1961 [2], the use of genetic testing to confirm the diagnosis has demonstrated that WS is one of the more common genetic disorders with an estimated incidence of 1:7500 live births [3].
GENETICS — WS is caused by a 1.5 to 1.8 Mb recurrent microdeletion of 7q11.23. While the disease is transmitted in an autosomal dominant fashion, almost all cases are the result of de novo mutations [4]. The deletion encompasses approximately 28 genes, including the elastin gene, ELN [5]. Although ELN and other genes of interest are located in the area of the mutation, no single gene has been identified that results in the full WS phenotype. Hemizygosity for ELN is responsible for the vascular and cardiac valvar abnormalities and some of the facial features of WS as elastin fibers are a key component of the extracellular matrix and confer elasticity to tissues and organs [5]. Haploinsufficiency of adjacent genes, such as LIMK1, probably accounts for the other manifestations of this disorder, including the impaired visuospatial constructive cognition and developmental delay [6].
CLINICAL MANIFESTATIONS — Affected patients present with distinctive facial features; variable phenotypic expression of cardiac, endocrine, and renal abnormalities; and cognitive and neurodevelopmental disabilities [3,5].
Facial dysmorphic features — Young individuals with WS have distinctive "elfin" facies (picture 1) [5,7,8]. Facial features include:
●Broad forehead
●Bitemporal narrowness
●Medial eyebrow flare
●Strabismus
●Flat nasal bridge
●Malar flattening
●Short nose with a long philtrum, full lips, and a wide mouth
Cardiovascular manifestations
Cardiovascular anomalies — Cardiovascular anomalies, particularly those secondary to elastin deficiency, are a major cause of morbidity and mortality in patients with WS, occurring in 80 to 90 percent of patients [9,10]. In one case series of 270 patients with WS, 20 percent underwent surgical or catheter-based intervention for cardiovascular anomalies, the majority before five years of age [9]. The most common lesions were supravalvar aortic stenosis (SVAS) and peripheral pulmonary artery stenosis (PAS).
●Supravalvar aortic stenosis – In WS, SVAS appears as either a discrete hourglass stenosis or diffuse, long segment stenosis (image 1) [3,11]. It is the most common cardiac lesion in WS with reported incidence ranging between 35 and 65 percent in case series [9,12,13]. Approximately one-fourth of children with SVAS will have WS. SVAS can also occur in families without features of WS. These cases are largely due to isolated elastin gene point mutations or intragenic deletions [14]. (See "Valvar aortic stenosis in children".)
●Peripheral PAS and supravalvar pulmonary stenosis
•Branch or peripheral PAS occurs in roughly 60 percent of infants diagnosed with WS [10]. Most cases of peripheral PAS are mild and often display spontaneous improvement [9].
•Supravalvar pulmonary stenosis is seen in approximately 10 percent of patients, with many cases demonstrating spontaneous improvement or complete resolution [9].
●Other cardiovascular abnormalities
•Stenosis can occur in the thoracic or abdominal aorta (middle aortic syndrome), renal and intracranial arteries, and vessels at other sites including the neck and limbs [11].
•Structural congenital heart defects seen in association with WS include septal defects and other valvar abnormalities, such as mitral valve prolapse and regurgitation, and defects of the aortic valve including aortic insufficiency, bicuspid aortic valve, and valvar aortic stenosis [11].
Hypertension — Hypertension may begin in childhood and typically develops in almost half of the patients with WS [3,15,16]. Renal artery stenosis and abdominal aortic stenotic anomalies can result in renovascular hypertension [16-18]. However, in some cases, no renovascular cause for the hypertension is identified [5,16,19]. In these patients, it is thought that increased blood pressure (BP) is caused by arterial vascular stiffness due to defective elastin, resulting in decreased arterial elasticity, proliferation of vascular smooth muscle cell, and increased media-to-intima thickness [17,20,21]. Children with WS may also have abnormalities in sympathetic cardiovascular control that contribute to higher BP [22].
Sudden cardiac death — Although a rare event, for patients with WS, the estimated risk of sudden cardiac death is 25 to 100 times greater than the normal age-matched population [23,24]. The increased incidence of sudden death in WS is attributed to underlying cardiovascular anomalies, especially in the setting of sedation and anesthesia [3]. Thus, patients with WS should be assessed by a pediatric cardiologist and/or anesthesiologist with appropriate expertise prior any procedures requiring anesthesia [25].
●Patients with both SVAS and PAS have biventricular outflow tract obstruction and can develop biventricular hypertrophy, resulting in higher mortality rates particularly with cardiac intervention [26].
●Coronary artery abnormalities may contribute to the increased risk of sudden cardiac death due to decreased cardiac output, myocardial ischemia, and arrhythmia [23].
●Prolonged corrected QT (QTc) interval on electrocardiogram is observed in approximately 15 percent of WS patients and may contribute to the increased incidence of sudden cardiac death [27-29]. Persons with nonsyndromic SVAS due to elastin mutations do not have an increased propensity of QTc prolongation or sudden cardiac death, which suggests that the etiology of prolonged QTc is not due to ELN haploinsufficiency [29]. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations".)
Endocrine disorders
Elevated calcium levels — Patients with WS generally have higher serum calcium concentration than the general pediatric population, although most values remain in the normal range [30].
If hypercalcemia is present, it is usually mild to moderate and not typically symptomatic [30]. Symptomatic hypercalcemia is most common in the first 2 years of life and usually resolves during childhood [3,31]. Symptomatic episodes of hypercalcemia, especially in infants, present with irritability, vomiting, muscle cramps, or constipation [3]. Hypercalciuria is often found during episodes of hypercalcemia and may result in nephrocalcinosis. (See 'Renal and urinary tract abnormalities' below.)
The etiology of elevated calcium levels is unknown. The following mechanisms have been proposed, but none have been confirmed [5]:
●Elevated 1,25 dihydroxyvitamin D levels [32]
●Increased vitamin D sensitivity
●Defective calcitonin synthesis and release [33]
Other endocrine disorders — Other endocrine disorders include:
●Hypothyroidism – Hypothyroidism is observed in 5 to 10 percent of patients with WS [34]. Additionally, approximately one-third of all individuals with WS will have subclinical hypothyroidism (mild thyroid-stimulating hormone elevation with normal thyroxine [T4]) [35]. Although the underlying mechanism remains uncertain, thyroid hypoplasia detected by thyroid imaging has been reported in case series and reports, suggesting that children with WS are at risk for a congenital structural abnormality of the thyroid gland [34,36-39]. As a result, thyroid imaging is suggested for all patients with WS [36]. (See "Clinical features and detection of congenital hypothyroidism" and "Treatment and prognosis of congenital hypothyroidism".)
●Type 2 diabetes mellitus – Abnormal glucose tolerance test results have been documented in 60 to 75 percent of adults with WS and is associated with an increased prevalence of type 2 diabetes mellitus [40-42]. (See "Epidemiology, presentation, and diagnosis of type 2 diabetes mellitus in children and adolescents" and "Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in adults".)
●Early puberty – Puberty occurs early in approximately 20 percent of females with WS, but true precocious puberty is rare [43].
Intellectual disability and neurodevelopmental findings
●Intellectual disability – Approximately three-quarters of patients with WS are diagnosed with intellectual disability [3]. Children with WS typically have better test scores for language and verbal short-term memory skills compared with visuospatial and visuomotor skills [44,45]. Thus, affected persons exhibit a discrepancy in intelligent quotient (IQ) scores, with higher average verbal scores than performance scores. Reading skills correlate with overall cognitive ability, ranging from normal reading test scores to inability to recognize the letters of the alphabet [46]. Persons with WS typically have difficulty with writing, drawing, and mathematics [47].
●Behavior – Persons with WS have a unique personality that often includes overfriendliness, excessive empathy, and a lack of social inhibition that has been described as a "cocktail party" personality. Although speech acquisition is initially delayed, persons with WS are subsequently characterized by excessive talking [45,48].
Attention deficit disorders and non-social anxiety are common, occurring in the majority of patients with WS [49,50].
Some patients have challenges with emotional regulation and may exhibit symptoms that overlap with autism spectrum disorder with repetitive behavior and limited interests [51]. (See "Attention deficit hyperactivity disorder in children and adolescents: Clinical features and diagnosis" and "Autism spectrum disorder: Clinical features".)
●Neurologic findings – Abnormal neurologic findings in WS include axial hypotonia and peripheral hypertonia with increased deep tendon reflexes in the lower extremities [3]. Ataxia and tremor may increase with age. Brain imaging has shown reduced brain size with reduced gray matter volume, notably in the parietal and occipital regions [52,53]. Posterior fossa size is also reduced in WS, which may contribute to Chiari I malformation in some patients. Patients with symptoms of headache, dizziness, and dysphagia should be referred to a pediatric neurologist for assessment of a possible Chiari I malformation. (See "Chiari malformations".)
Neurologic and connective tissue (hyperextensible/contractured joints) abnormalities contribute to delayed development of motor skills.
●Sleep impairment – Sleep disorders, including sleep delay, frequent awakening, and decreased sleep efficiency occur in approximately one-half of patients with WS [3,54,55]. (See "Assessment of sleep disorders in children", section on 'Difficulty initiating or maintaining sleep'.)
Growth and short stature — Growth in children with WS is approximately 75 percent of the expected normal growth rate [3]. Growth abnormalities are observed with intrauterine growth restriction, failure to thrive in infancy, and poor weight and linear growth during childhood with ultimate short stature. Growth for children with WS should be plotted on specially developed growth charts. (See 'Initial evaluation' below.)
Poor growth, with children falling off WS growth charts, may also occur, as feeding difficulties are common, especially in infants and young children [47].
Renal and urinary tract abnormalities — Abnormalities include congenital anomalies of the kidney and urinary tract (CAKUT), dysfunctional voiding, and nephrocalcinosis due to hypercalciuria. The reported incidence of kidney and urinary tract abnormalities ranges from 18 to 29 percent [56-58]. Patients with WS are also more likely to develop urinary tract infections.
●Congenital anomalies of the kidney and urinary tract (CAKUT) – In several case series, renal ultrasonography has demonstrated a wide spectrum of structural abnormalities in approximately 10 percent of patients with WS, including bladder diverticula, ectopic or horseshoe kidney, and renal aplasia or hypoplasia [16,56-58]. Decreased renal function has been noted in a small number of patients, but there are no data regarding progression of chronic kidney disease (CKD) in these individuals [16,56]. (See 'Initial evaluation' below and "Overview of congenital anomalies of the kidney and urinary tract (CAKUT)" and "Chronic kidney disease in children: Definition, epidemiology, etiology, and course", section on 'Progression of chronic kidney disease'.)
●Dysfunctional voiding – Children with WS are at risk for dysfunctional voiding (eg, increased urinary frequency, enuresis, and urgency) and abnormal urodynamic findings, including detrusor overactivity [57,59]. For children between 4 and 12 years of age, the reported incidence of daytime urinary incontinence is 18 percent and nocturnal enuresis is 45 percent; and for teenagers, daytime incontinence is 3 percent and nocturnal enuresis is 14 percent [60]. (See "Etiology and clinical features of bladder dysfunction in children".)
●Nephrocalcinosis – Nephrocalcinosis caused by hypercalciuria during episodes of hypercalcemia is detected in approximately 5 to 10 percent of patients undergoing renal ultrasonography [16,31,56,58,61].
●Urinary tract infection – Urinary tract infection is reported in approximately 25 percent of patients with WS [3]. This increased risk is probably due to bladder dysfunction.
Other findings — Other findings that are observed in children with WS include [3]:
●Auditory – Mild to moderate sensorineural hearing loss and recurrent otitis media. Patients are also hypersensitive to sound (hyperacusis), but often have an affinity to music [62,63].
●Ophthalmologic – Hyperopia, nasolacrimal duct obstruction, and strabismus.
●Dental – Microdontia, missing teeth, and localized enamel hypoplasia.
●Gastrointestinal – Constipation, feeding difficulties, umbilical and inguinal hernias, and diverticula. Chronic constipation is a common lifelong problem associated with complications of diverticulosis, rectal prolapse, hemorrhoids, and rarely, intestinal perforation.
●Musculoskeletal – Hyperextensible/contractured joints.
DIAGNOSIS — A clinical diagnosis can usually be made in infancy or early childhood based upon recognition of the characteristic features of WS. However, confirmation of the diagnosis requires genetic testing documenting a 1.5 to 1.8 Mb deletion in the 7q11.23 region [3,5]. (See 'Genetic testing' below.)
Clinical diagnosis — A clinical diagnosis is based upon the presence of the following clinical features (see 'Clinical manifestations' above):
●Evidence of growth impairment (see 'Growth and short stature' above)
●Behavior and developmental findings of intellectual disability, characteristic overly friendly personality, anxiety, visuospatial challenges, hypersensitivity to sound, and excessive talking (see 'Intellectual disability and neurodevelopmental findings' above)
●Characteristic facial dysmorphic features described as "elfin facies" (picture 1) (see 'Facial dysmorphic features' above)
●Cardiovascular anomalies such as supravalvar aortic stenosis and peripheral pulmonary artery stenosis (see 'Cardiovascular anomalies' above)
●Hypercalcemia and hypercalciuria (see 'Elevated calcium levels' above)
●Connective tissue abnormalities including inguinal hernia, bowel or bladder diverticula, and hyperextensible joints (see 'Renal and urinary tract abnormalities' above and 'Other findings' above)
The 2001 American Academy of Pediatrics (AAP) healthcare supervision guidelines for WS provides a scoring system to facilitate making the diagnosis based upon clinical features [64].
Genetic testing — Confirmation of the diagnosis is made with chromosomal analysis that demonstrates the deletion at 7q.11.23. The genetic defect is detected by fluorescence in situ hybridization (FISH) with probes specific to the elastin gene, one of approximately 26 to 28 genes located at 7q11.23 [1,5,65]. Chromosomal microarray analysis (also called comparative genomic hybridization) is also available to make the genetic diagnosis [19].
MANAGEMENT — Once the diagnosis of WS has been made by genetic testing, initial evaluation and ongoing surveillance are focused on determining whether the affected patient has or will subsequently develop any of the significant complications associated with this genetic disorder. Our management approach is consistent with the 2020 American Academy of Pediatrics (AAP) healthcare supervision guidelines for WS, which provides anticipatory guidance for the initial evaluation, continued surveillance, and management of associated complications (table 1) [3].
Initial evaluation — Our initial evaluation is based upon a comprehensive evaluation that includes growth measurements; a multidisciplinary developmental evaluation; thorough cardiac, renal, and neurologic assessments; and laboratory testing [3].
●Growth parameters should be plotted on specially developed growth charts for children with WS (figure 1 and figure 2 and figure 3).
●Cardiology evaluation includes 4-extremity blood pressure (BP) measurement, electrocardiogram, and echocardiography including Doppler flow studies. Additional cardiac imaging (computed tomography, magnetic resonance imaging, and cardiac catheterization) is performed as needed. (See 'Cardiovascular manifestations' above and "Valvar aortic stenosis in children", section on 'Diagnosis'.)
●Renal and urinary tract evaluation includes urinalysis, renal function studies (ie, serum creatinine and blood urea nitrogen [BUN]), and renal/bladder ultrasonography to detect any malformation, nephrocalcinosis, or diverticulitis. (See 'Renal and urinary tract abnormalities' above.)
●Cognitive and developmental evaluation includes multidisciplinary assessment of speech, language, motor, and social skills.
●Audiologic evaluation to detect high-tone sensorineural hearing loss.
●Ophthalmologic evaluation to detect strabismus and refractive errors.
●Laboratory evaluation includes measuring serum calcium, urinary calcium, thyroid function tests, and, as previously mentioned, renal function studies (serum creatinine and BUN), and urinalysis.
●Genetic counseling.
Continued surveillance — Because of the risk of progressive disease, continued surveillance is recommended throughout the lifetime of the affected person [3]. Routine medical monitoring will detect complications that may require referral to a subspecialist.
Our approach is consistent with the 2020 American Academy of Pediatrics (AAP) healthcare supervision guidelines for WS for ongoing surveillance based upon patient age [3]. The frequency of health care visits is greatest in the first year of life and decreases to a minimum of yearly visits after six years of age.
Health maintenance surveillance components include:
●Comprehensive history and physical examination with measurement of growth and BP at every visit.
●Nutrition and gastrointestinal assessment to determine caloric intake and detect feeding problems at each visit during the first year of life and as needed for feeding issues. Evaluation for constipation also occurs at each visit during the first year and then yearly.
●Cardiology evaluation is recommended every three months during the first year of life, annually until six years of age and then every two years depending on the nature and severity of cardiac disease.
●Auditory and ocular screening yearly.
●Developmental assessment yearly until six years of age and then every 3 years.
●Prior to any procedure that requires anesthesia, consultation with a pediatric anesthesiologist with expertise in treating patients with WS, since unexpected cardiac deaths are associated with the administration of general anesthesia in patients with WS [23,66]. (See 'Sudden cardiac death' above.)
●Laboratory evaluation:
•Annual urinalysis.
•If a congenital anomaly of the renal and/or urinary tract is identified, serum creatinine is measured to detect any progressive renal function decline every four months for the first year of life, every four to six months until two years of age and then every two years.
•Thyroid function tests yearly until three years of age and then every two years.
•Serum calcium measurements every 4 to 6 months until two years of age then every two years, unless hypercalcemia is suspected clinically. If serum calcium is elevated, a urinary calcium should be obtained to detect hypercalciuria. (See 'Elevated calcium levels' above.)
●Adult patients should have:
•Oral glucose tolerance test starting at age 20
•Evaluation for cataracts
Management for specific conditions
Cardiovascular anomalies — There are no effective pharmacologic agents to treat arterial stenosis. As a result, approximately one-third of patients with cardiovascular anomalies undergo surgical or catheter-based intervention [67].
●For patients with supravalvar aortic stenosis (SVAS), surgical intervention is performed to correct the lesion [68]. Discrete lesions are generally successfully treated with patch aortoplasty but diffuse lesions require more extensive repair and more frequently require reintervention. (See "Subvalvar aortic stenosis (subaortic stenosis)".)
The indications for intervention for SVAS are not as well defined as for other types of valvar disease. Although the American Heart Association and the American College of Cardiology summarized its recommendations in a 2014 practice guideline for valvar aortic stenosis, there were no details regarding the indications and timing of intervention for subvalvar aortic stenosis and SVAS [69]. As a result, a multiservice team (medical cardiologists, interventionalists, and surgeons) typically coordinates clinical-decision making, including surgical repair based upon thorough assessment of the patient's cardiac function and symptoms in discussion with the family, and if competent, the patient.
The largest case series of SVAS in patients with WS who underwent surgical repair included only 28 patients over a 30-year time span [70]. In this cohort, most patients had localized stenosis and one-third of the patients had an associated cardiac lesion that was repaired at the same time. Mean age of surgical repair was 5.2 years of age (range 3 months to 13 years).
●For patients with severe peripheral pulmonary artery stenosis (right ventricular hypertension with the right-sided pressures exceeding two-thirds of the systemic pressure), surgical correction is the preferred first-line intervention [71]. Although catheter-based interventions have been performed, they have not been as successful and should be avoided. In fact, stent implementation may cause marked intimal hyperplasia resulting in restenosis [67,68].
Hypertension — The finding of hypertension (HTN) in a patient with WS should prompt a search for discrete vascular lesions that may be correctable and evidence for end-organ damage. In these cases, a renal ultrasound with Doppler flow studies of the renal arteries and abdominal aorta is performed because of the increased likelihood that renal artery stenosis is the cause of HTN. (See "Evaluation of hypertension in children and adolescents", section on 'Initial evaluation'.)
Patients with suspicious or inconclusive studies should be referred to a clinician with expertise in evaluating pediatric renovascular HTN (eg, pediatric cardiologist, nephrologist, interventional radiologist, or vascular surgeon) who can assess the relative merits of pharmacologic or corrective therapies, such as renal angioplasty. However, the results of surgical repair or percutaneous transluminal angioplasty are poor with either persistent or recurrent HTN [57,72,73]. As a result, some experts, including the authors, recommend an initial trial of antihypertensive medications as it often is challenging to identify the specific lesion [17,72]. Evaluation for renovascular causes is reserved for those patients resistant to pharmacologic therapy. However, other experts in the field would evaluate all patients with hypertension for an underlying renovascular etiology.
In patients with WS, effective control of hypertension has been reported with calcium channel blockers (CCBs) and beta blockers [72]. Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) may also be effective, but should not be used if there is any suspicion of middle aortic syndrome or bilateral renal artery stenosis as they may compromise renal function due to a reduction in renal perfusion. (See "Treatment of bilateral atherosclerotic renal artery stenosis or stenosis to a solitary functioning kidney", section on 'Medical therapy'.)
In our practice, we begin therapy with amlodipine or sustained-release nifedipine (dihydropyridine CCBs) in patients whose initial work-up for hypertension is negative or inconclusive. If blood pressure cannot be controlled with a single agent, labetalol, an alpha- and beta blocker, or beta-blocking drug is added. If hypertension remains difficult to control on both a CCB and a beta blocker, the choice of a third antihypertensive agent depends upon the unique situation of each patient. If reasonably confident that hypertension is not related to renal artery stenosis, ACE inhibitors or ARBs may be introduced with careful monitoring of renal function. Other third-line medications include diuretics, minoxidil, or clonidine.
Further evaluation is indicated for patients with Doppler ultrasound evidence of renal artery stenosis and for those who are refractory to pharmacologic therapy with three agents. Arteriography, an invasive procedure, is the gold standard to diagnose renovascular hypertension and may be performed in patients with refractory hypertension. If available, computed tomographic or magnetic resonance angiography can usually provide sufficient information to guide decisions about further interventions. Computed tomography and magnetic resonance angiography have similar sensitivity and specificity in diagnosing renal artery stenosis. The choice of study should be based on individual patient characteristics including the need for/risk of sedation for the procedure (magnetic resonance angiography), baseline renal function (and the associated possible risk of radiographic contrast for computed tomography), local availability of studies, and clinical experience. (See "Evaluation of hypertension in children and adolescents", section on 'Renovascular imaging'.)
Hypercalcemia — No evidence-based recommendations for hypercalcemia management have been published. Some experts in the field recommend treatment of hypercalcemia with a low-calcium diet, increased fluid intake and vitamin D restriction, but in one case report, this therapy resulted in the development of rickets in an infant [74]. As a result, this therapeutic approach, if undertaken, should be under medical and nutritional supervision [3]. For patients with hypercalcemia, serum blood urea nitrogen, creatinine, vitamin D concentrations (25-hydroxyvitamin and 1,25-dihydroxyvitamin D), intact parathyroid hormone, and a spot calcium/creatinine ratio (detect hypercalciuria) should be checked at the time of initial evaluation. Subsequent monthly monitoring of these labs should be continued until hypercalcemia resolves. Vitamin D supplementation, including multivitamins, should be avoided in children with WS, and sunscreen should be used to minimize the autologous production of vitamin D [3]. If hypercalcuria is present, a renal ultrasound should be obtained to evaluate for nephrocalcinosis. Patients with persistent hypercalcemia, hypercalciuria, or nephrocalcinosis should be referred to a pediatric nephrologist or endocrinologist.
Other complications
●Infants and toddlers with difficulty feeding and poor growth should be evaluated and managed by a nutritional/feeding team [3]. In extreme cases, a feeding tube may be beneficial. (See "Poor weight gain in children younger than two years in resource-abundant countries: Management", section on 'Initial management' and "Overview of enteral nutrition in infants and children".)
●Constipation should be identified and aggressively treated to avoid development of diverticulosis, hemorrhoids, and rectal prolapse [3]. (See "Chronic functional constipation and fecal incontinence in infants, children, and adolescents: Treatment".)
●For patients with hypothyroidism, oral levothyroxine is provided. (See "Acquired hypothyroidism in childhood and adolescence", section on 'Treatment and prognosis'.)
●For patients with ocular disorders, corrective lenses for hyperopia and patching or surgery for strabismus are provided. (See "Refractive errors in children" and "Evaluation and management of strabismus in children".)
●Patients with recurrent otitis media are treated with placement of tympanotomy tubes. (See "Otitis media with effusion (serous otitis media) in children: Management", section on 'Tympanostomy tubes'.)
●For patients with symptoms of dysfunctional voiding or recurrent urinary tract, further diagnostic evaluation includes voiding cystourethrography and urodynamic studies [3]. In one observational study, oxybutynin was shown to improve urinary symptoms, including urgency and urge incontinence in patients with WS [75]. (See "Etiology and clinical features of bladder dysfunction in children" and "Management of bladder dysfunction in children", section on 'Oxybutynin'.)
●In prepubescent females, early puberty may be treated with gonadotrophin-releasing hormone agonist. This intervention delays menarche and results in increased height [43].
Support groups for patient and families — Additional information and support for patients and families are provided by the Williams Syndrome Association. This resource provides medical, educational, emotional, and networking support for families from parents, patients, and health care providers.
SUMMARY AND RECOMMENDATIONS
●Definition and genetics – Williams syndrome (WS; also referred to as William-Beuren syndrome) is a multisystem, contiguous gene deletion syndrome caused by deletion of 1.5 to 1.8 Mb on chromosome 7q11.23. Hemizygosity for elastin is responsible for the vascular and valvar abnormalities of WS. (See 'Genetics' above.)
●Clinical manifestations – Affected patients present with variable expression of the following characteristics (see 'Clinical manifestations' above):
•"Elfin" facies (picture 1) (see 'Facial dysmorphic features' above)
•Cardiovascular anomalies (see 'Cardiovascular anomalies' above and 'Sudden cardiac death' above)
•Hypertension (see 'Hypertension' above)
•Endocrine abnormalities including hypercalcemia and hypothyroidism; type 2 diabetes mellitus in adults (see 'Endocrine disorders' above)
•Intellectual disability accompanied by a friendly, social personality (see 'Intellectual disability and neurodevelopmental findings' above)
•Short stature (see 'Growth and short stature' above)
•Genitourinary abnormalities (see 'Renal and urinary tract abnormalities' above)
•Auditory, ophthalmologic, dental, gastrointestinal, and musculoskeletal abnormalities (see 'Other findings' above)
●Diagnosis – A clinical diagnosis is usually made in infancy or early childhood based on recognition of the characteristic features of WS. Confirmation of the diagnosis requires genetic testing demonstrating deletion of 1.5 to 1.8 Mb on chromosome 7q11.23. (See 'Diagnosis' above.)
●Initial evaluation – Once the diagnosis of WS has been confirmed by genetic testing, initial evaluation is performed to detect any of the significant associated clinical complications of this disorder, including hypertension and cardiovascular, endocrine, and renal abnormalities. (See 'Initial evaluation' above.)
●Ongoing surveillance – Because of the risk of progressive disease, routine surveillance is performed throughout the lifetime of the affected person. The 2020 American Academy of Pediatrics (AAP) health supervision guidelines include a series of evaluations based on patient age (table 1). For each age group, evaluation includes comprehensive history and physical examination with assessment of growth and blood pressure measurements, developmental assessment, cardiovascular evaluation, and annual hearing and vision screening. Additional screening and testing are dependent upon the age of the patient and the results of previous testing. (See 'Continued surveillance' above.)
●Risk of sudden cardiac death – Patients with WS are at increased risk for sudden cardiac death during interventional procedures such as cardiac catheterization and surgery. Patients should be assessed by a pediatric cardiologist and/or anesthesiologist with appropriate expertise prior to any intervention requiring anesthesia. (See 'Sudden cardiac death' above.)
●Management of complications
•Cardiac anomalies – Surgical correction may be needed for patients with supravalvar aortic stenosis and peripheral pulmonary artery stenosis. (See 'Cardiovascular anomalies' above.)
•Hypertension (see 'Hypertension' above):
-Pediatric patients with WS and hypertension should be evaluated for discrete, potentially correctable vascular lesions using renal ultrasound with Doppler flow and for evidence of end-organ damage.
-In patients with a negative initial work-up, we suggest antihypertensive therapy (Grade 2C). Antihypertensive agents include calcium channel blockers (CCBs; amlodipine, nifedipine), angiotensin-converting enzyme (ACE) inhibitors (enalapril), labetalol (an alpha and beta blocker), or beta blockers (eg, atenolol). In our practice, we generally use amlodipine, a CCB.
•Hypercalcemia – For patients with hypercalcemia, serum blood urea nitrogen, creatinine, vitamin D concentrations (25-hydroxyvitamin and 1,25-dihydroxyvitamin D), intact parathyroid hormone, and a spot calcium/creatinine ratio (to detect hypercalciuria) should be checked. Vitamin D supplementation, including multivitamins, should be avoided in children with WS, and sunscreen should be used to minimize the autologous production of vitamin D. For symptomatic infants, a low-calcium diet and vitamin D restriction may be used but only under direct medical and nutritional supervision. (See 'Elevated calcium levels' above.)
•Constipation – Constipation should be identified and aggressively treated to avoid development of diverticulosis, hemorrhoids, and rectal prolapse.
•Dysfunction voiding – For patients with symptoms of dysfunctional voiding or recurrent urinary tract infection, further diagnostic evaluation includes voiding cystourethrography and urodynamic studies to identify those with bladder dysfunction.
ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Patrick Niaudet, MD, who contributed to an earlier version of this topic review.
