Williams syndrome

Authors: Wayne R Waz, MD, Teresa M Lee, MD, MS

Section Editors: Helen V Firth, DM, FRCP, FMedSci, Patrick Niaudet, MD
Deputy Editor: Niloufar Tehrani, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review
process is complete.

Literature review current through: Jun 2025. | This topic last updated: May 06,
2025.

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

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 [2].

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 [3]. The critical
region of the deletion contains 25 to 27 genes, including the elastin
gene (ELN), and several noncoding ribonucleic acids (RNAs) [4].
Although ELN and other genes of interest are located in the area of the
deletion, 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 connective tissue of WS as
elastin fibers are a key component of the extracellular matrix and
confer elasticity to tissues and organs [4]. Haploinsufficiency of
adjacent genes, such as LIM domain kinase 1 (LIMK1), probably
accounts for the other manifestations of this disorder, including the
impaired visuospatial constructive cognition and developmental delay
[5].

CLINICAL MANIFESTATIONS

Affected patients present with distinctive facial features; variable

phenotypic expression of cardiac, endocrine, and kidney abnormalities;
and cognitive and neurodevelopmental disabilities [2,6].
Facial dysmorphic features — Persons with WS have distinctive facial
features that are observed in all ages ( picture 1) [6-8]:
● Broad forehead
● Bitemporal narrowness
● Medial eyebrow flare
● Strabismus
 ● Short nose with flat nasal bridge
● Malar flattening
● Long philtrum, full lips, and a wide mouth
With age, the face elongates, and the nasal bridge is no longer flat [4].
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 (AS) and peripheral pulmonary
artery stenosis.
● Supravalvar aortic stenosis – In WS, supravalvar AS appears as
either a discrete hourglass stenosis or diffuse, long segment
stenosis ( image 1) [2,11]. It is the most common cardiac lesion in
WS, with reported prevalence ranging from 35 and 65 percent in
case series [9,12,13]. Approximately 25 percent of children with
supravalvar AS have WS. Supravalvar AS can also occur in families
without features of WS. These cases are largely due to isolated ELN
gene point mutations or intragenic deletions [14]. (See
"Supravalvar aortic stenosis".)
● Pulmonary stenosis:
• Branch or peripheral pulmonary artery stenosis occurs in
roughly 60 percent of infants diagnosed with WS [10]. Most
 cases 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]. (See
"Pulmonic stenosis in infants and children: Clinical
manifestations and diagnosis".)
● 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 patients with WS [2,15,16]. 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 [6,16,19]. 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 healthy age-matched population [23]. The increased incidence
of sudden death in WS is attributed to underlying cardiovascular
anomalies. Patients with significant right or left ventricular outflow
tract obstruction are at increased risk of hemodynamic deterioration
when undergoing anesthesia [2]. Thus, patients with WS should be
assessed by a cardiologist and/or anesthesiologist with appropriate
expertise prior any procedures requiring anesthesia [24,25]. In addition
to the cardiac risks associated with surgery and general anesthesia,
there is an increased incidence of postoperative acute kidney injury in
patients with WS undergoing cardiac surgery compared with matched
controls [26].
● Patients with biventricular outflow tract obstruction (ie, both aortic
and pulmonic stenosis) and can develop biventricular hypertrophy,
which contributes to increased mortality risk [27].
● Coronary artery abnormalities may contribute to the increased risk
of sudden cardiac death due to decreased cardiac output,
myocardial ischemia, and arrhythmia [28].
● Prolonged corrected QT (QTc) interval on electrocardiogram (ECG)
is observed in approximately 15 percent of WS patients and may
contribute to the increased incidence of sudden cardiac death [29-
31]. Persons with nonsyndromic supravalvar AS due to ELN
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 [31].
(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 [32].
If hypercalcemia is present, it is usually mild to moderate, often occurs
in the setting of poor feeding and decreased oral intake, is not typically
symptomatic, and often resolves [32]. Symptomatic hypercalcemia is
most common in the first two years of life and usually resolves during
childhood [2,33]. Symptomatic episodes of hypercalcemia, especially in
infants, present with irritability, vomiting, muscle cramps, or
constipation [2]. Hypercalciuria is often found during episodes of
hypercalcemia and may result in nephrocalcinosis. (See 'Kidney and
urinary tract abnormalities' below.)
The etiology of elevated calcium levels is unknown. The following
mechanisms have been proposed, but none have been confirmed [6]:
● Elevated 1,25 dihydroxyvitamin D levels [34]
● Increased vitamin D sensitivity
● Defective calcitonin synthesis and release [35]
Other endocrine disorders — Other endocrine disorders include:
● Hypothyroidism – Hypothyroidism is observed in 5 to 10 percent
of patients with WS [36]. Additionally, approximately one-third of all
 individuals with WS will have subclinical hypothyroidism (mild
thyroid-stimulating hormone elevation with normal thyroxine [T4])
[37]. 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
[36,38-41]. As a result, thyroid imaging is suggested for all patients
with WS [38]. (See "Clinical features and detection of congenital
hypothyroidism" and "Congenital hypothyroidism: Treatment and
prognosis".)
● 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 [42-44]. (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 [45].
● Decreased bone mineral density - It is common for patients with
WS to have decreased bone mineral density (BMD), and they are at
higher risk for fractures [46]. Bone density should be monitored in
adults with WS.
Intellectual disability and neurodevelopmental findings
● Intellectual disability – Approximately three-quarters of patients
with WS are diagnosed with intellectual disability [2]. Children with
 WS typically have better test scores for language and verbal short-
term memory skills compared with visuospatial and visuomotor
skills [47,48]. Thus, some 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 [49]. Persons with
WS typically have difficulty with writing, drawing, and
mathematics [50].
● Behavior/psychiatric – Many persons with WS have a unique
personality that often includes overfriendliness, excessive
empathy, and a lack of social inhibition. Although speech
acquisition is initially delayed, persons with WS are subsequently
characterized by excessive talking [48,51].
Attention deficit disorders and nonsocial anxiety are common,
occurring in the majority of patients with WS [52,53]. One study
looking at the prevalence of Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition (DSM-IV) psychiatric disorders
found that 80 percent of children met criteria for one or more
neuropsychiatric disorders. The most common diagnosis was
attention deficit hyperactivity disorder, followed by specific
phobias. The prevalence of generalized anxiety disorder varied
significantly with age [52].
Some patients have challenges with emotional regulation and may
exhibit symptoms that overlap with autism spectrum disorder with
repetitive behavior and limited interests [54]. (See "Attention deficit
 hyperactivity disorder in children and adolescents: Clinical features
and diagnosis" and "Autism spectrum disorder in children and
adolescents: Clinical features".)
● Neurologic findings – Abnormal neurologic findings in WS include
axial hypotonia and peripheral hypertonia with increased deep
tendon reflexes in the lower extremities [2]. 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 [55,56]. 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 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, sleep apnea, and decreased sleep efficiency
occur in approximately one-half of patients with WS [2,57,58]. (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 [2].
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 [50].
Kidney and urinary tract abnormalities — Abnormalities include
congenital anomalies of the kidney and urinary tract (CAKUT),
dysfunctional voiding, and nephrocalcinosis due to hypercalciuria
secondary to neonatal hypercalcemia. The reported incidence of kidney
and urinary tract abnormalities ranges from 18 to 29 percent [59-61].
● 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 [16,59-61].
Decreased kidney 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 [16,59]. (See 'Initial
evaluation' below and "Overview of congenital anomalies of the
kidney and urinary tract (CAKUT)" and "Chronic kidney disease in
children: 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 [60,62]. 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. For teenagers,
daytime incontinence is 3 percent, and nocturnal enuresis is 14
percent [63]. (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 kidney ultrasonography
[16,33,59,61,64].
● Urinary tract infection – Urinary tract infection is reported in
approximately 25 percent of patients with WS [2,62]. This increased
risk is probably due to bladder dysfunction.
Other findings — Other findings that are observed in children with WS
include [2]:
● Auditory – Mild-to-moderate sensorineural hearing loss (typically
an adolescent/adult finding) and recurrent otitis media. Patients
are also hypersensitive to sound (hyperacusis) but often have an
affinity to music [65,66].
● Ophthalmologic – Hyperopia, nasolacrimal duct obstruction,
strabismus, esotropia, and stellate appearance in the iris [67].
● Dental – Microdontia, missing teeth, and localized enamel
hypoplasia. Dental aplasia, which occurred in 90 percent of
patients, and primary tooth resorption anomaly, which was found
in 96 percent of patients, are typical dental findings in WS. Fan-
shaped positioning of the front teeth was seen in the majority of
patients [68].
 ● Gastrointestinal – Constipation, feeding difficulties, umbilical and
inguinal hernias, and diverticula are frequent. Many children and
adults with WS have chronic abdominal pain, which can be
secondary to gastroesophageal reflux, peptic ulcer disease,
cholelithiasis, or ischemic bowel disease [69,70].
Chronic constipation is a common lifelong problem associated with
complications of diverticulosis, rectal prolapse, hemorrhoids, and,
rarely, intestinal perforation. Diverticulitis is increased in
adolescents and adults and can have a high complication rate
[71,72].
● Musculoskeletal – Hyperextensible/contractured joints, decreased
BMD, scoliosis, and tight heel cords.
Adults with WS — While patients with WS have early comorbidities,
there are reports on many patients in their 50s and 60s [73]. The typical
age-related medical conditions can appear during late adolescence or
early adulthood, including hypertension, diabetes, and hearing loss
[74]. The most common cause of death is cardiovascular disease
associated with type 2 diabetes followed by malignancies [74]. Joint
contractures and hyperreflexia can occur over time, making motor
tasks difficult [6].

DIAGNOSIS

A clinical diagnosis can usually be made in infancy or early childhood

based upon recognition of the characteristic features of WS; however,
without cardiovascular features, it can be missed. Confirmation of the
diagnosis requires genetic testing documenting a 1.5 to 1.8 Mb
deletion in the 7q11.23 region [2,6]. (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 include epicanthal folds,
large ears, an upturned nose, full cheeks, a wide mouth, a small
jaw, and small teeth. Children with WS may have a long philtrum
and a flattened nasal bridge ( 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 'Kidney 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 [75].
Genetic testing — Confirmation of the diagnosis is made with
specialized 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 ELN gene, one of
approximately 26 to 28 genes located at 7q11.23 [1,6,76].
Chromosomal microarray analysis (also called comparative genomic
hybridization) is also available to make the genetic diagnosis [19]. An
estimated 2 to 5 percent of patients have "atypical" deletions, which
extend in the centromeric and/or telomeric direction from the WS
critical region. A study identified nine patients with atypical deletions
out of 111 patients with WS; these deletions included seven smaller
deletions and two larger deletions [77].

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) [2].
Initial evaluation — Our initial evaluation is based upon a
comprehensive evaluation that includes growth measurements; a
multidisciplinary developmental evaluation; thorough cardiac, kidney,
and neurologic assessments; and laboratory testing [2].
● Growth parameters should be plotted on specially developed
growth charts for children with WS ( figure 1 and figure 2 and
figure 3). British growth curves for WS are also available [78].
● Cardiology evaluation includes four-extremity blood pressure (BP)
measurement, electrocardiogram (ECG), and echocardiography
including Doppler flow studies. Additional cardiac imaging
(computed tomography [CT], magnetic resonance imaging, and
cardiac catheterization) is performed as needed. (See
'Cardiovascular manifestations' above and "Supravalvar aortic
stenosis", section on 'Diagnosis' and "Pulmonic stenosis in infants
and children: Clinical manifestations and diagnosis", section on
'Diagnosis'.)
● Kidney and urinary tract evaluation includes urinalysis, kidney
function studies (ie, serum creatinine and blood urea nitrogen
[BUN]), and kidney/bladder ultrasonography to detect any
malformation, nephrocalcinosis, or bladder diverticula. (See 'Kidney
and urinary tract abnormalities' above.)
● Cognitive and developmental evaluation includes
multidisciplinary assessment of speech, language, motor, and
social skills. Neuropsychological assessments in adults can be
performed using a cognitive test battery [74].
● Audiologic evaluation to detect high-tone sensorineural hearing
loss and conductive 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,
kidney 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 [2]. 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 [2]. 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 three years. Neuropsychiatric assessment can be helpful in
adults.
● Prior to any procedure that requires anesthesia, consultation with
an anesthesiologist with expertise in treating patients with WS
since unexpected cardiac deaths are associated with the
administration of general anesthesia in patients with WS [28,79].
(See 'Sudden cardiac death' above.)
● Laboratory evaluation:
• Annual urinalysis.
• If a congenital anomaly of the kidney and/or urinary tract is
identified, serum creatinine is measured to detect any
progressive kidney 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 if results are normal.
• Serum calcium measurements every four to six 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 years. If normal,
repeat every five years.
• Evaluation for cataracts.
• Evaluations for hypertension, long QT, mitral valve prolapse,
aortic insufficiency, and arterial stenoses.
• Pregnancies are considered high risk, and pregnant persons
with WS should be monitored for the development of
pregnancy-induced hypertension, arrhythmias, and heart failure
[80]. Late in gestation, routine urinalyses should be performed
due to a high incidence of urinary tract infection. Ultrasound
monitoring of the fetus is recommended [80].
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 [81].
● For patients with supravalvar aortic stenosis, surgical intervention
is performed to correct the lesion [82]. Discrete lesions are
generally successfully treated with patch aortoplasty, but diffuse
lesions require more extensive repair and more frequently require
reintervention. Additional details are provided separately. (See
"Supravalvar aortic stenosis", section on 'Surgical repair'.)
● For patients with severe peripheral pulmonary artery stenosis (eg,
right ventricular pressure exceeding two-thirds of the systemic
pressure), surgical correction is the preferred first-line intervention
 [83]. 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 [81,83]. (See "Pulmonic stenosis in infants
and children: Management and outcome", section on 'Surgery'.)
● Cardiology evaluation should occur at least annually until age five
years and then every two to three years after. This surveillance
should include ECG and echocardiogram. Monitoring for coronary
artery disease is difficult as patients often are unable to perform
standard exercise tests [84].
Additional cardiovascular imaging studies (CT, magnetic resonance
angiography [MRA], or cardiac catheterization) may be required in
persons to evaluate for other arterial stenoses, including coronary,
carotid, and mesenteric stenosis.
Hypertension — Some experts, including the authors, recommend an
initial trial of antihypertensive medications and reserve evaluation for
renovascular causes and evidence for end-organ damage for those
patients with WS who have hypertension resistant to pharmacologic
therapy, as it often is challenging to identify the specific lesion [17,85].
However, other experts in the field evaluate all patients with
hypertension for an underlying renovascular etiology because these
discrete vascular lesions may be correctable. Most often 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 hypertension, although no clinically
significant renovascular pathology is found in the majority of patients
evaluated. (See "Hypertension in children and adolescents: Evaluation",
section on 'Initial evaluation'.)
Patients with suspicious or inconclusive studies should be referred to a
clinician with expertise in evaluating pediatric renovascular
hypertension (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 hypertension
[60,85,86].
In patients with WS, effective control of hypertension has been
reported with calcium channel blockers (CCBs) and beta blockers [85].
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 kidney function due to a
reduction in kidney 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 BP 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 kidney
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, CT or MRA can usually provide sufficient information to guide
decisions about further interventions. CT and MRA 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 (MRA), baseline kidney
function (and the associated possible risk of radiographic contrast for
CT), local availability of studies, and clinical experience. (See
"Hypertension in children and adolescents: Evaluation", section on
'Renovascular imaging'.)
Hypercalcemia — No evidence-based recommendations for
hypercalcemia management have been published [32]. 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
[87]. As a result, this therapeutic approach, if undertaken, should be
under medical and nutritional supervision [2]. For patients with
hypercalcemia, serum BUN, 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 laboratory tests 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 [2].
If hypercalcuria is present, a kidney 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 [2]. In
extreme cases, a feeding tube may be beneficial. (See "Poor weight
gain in children younger than two years in resource-abundant
settings: Management", section on 'Overview of 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
[2]. (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 [2]. In one
observational study, oxybutynin was shown to improve urinary
symptoms, including urgency and urge incontinence, in patients
with WS [88]. (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 [45].
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/caregivers, patients, and health care providers.

SUMMARY AND RECOMMENDATIONS

● Genetics – Williams syndrome (WS, also referred to as Williams-
Beuren syndrome) is a multisystem, contiguous gene deletion
syndrome caused by deletion of 1.5 to 1.8 Mb on chromosome
7q11.23. It is one of the most common genetic disorders, with an
estimated incidence of 1:7500 live births. Most cases arise de novo,
but autosomal dominant inheritance has been documented.
Hemizygosity for elastin is responsible for the vascular and valvar
abnormalities of WS. (See 'Genetics' above and 'Epidemiology'
above.)
● Clinical manifestations – Affected patients present with variable
expression of the following characteristics (see 'Clinical
manifestations' above):
• Distinctive facial features ( picture 1). (See 'Facial dysmorphic
features' above.)
• Cardiovascular anomalies, including the most common lesions
of supravalvar aortic stenosis and peripheral pulmonary artery
stenosis. Although rare, these abnormalities are associated with
an increased risk of sudden death. (See 'Cardiovascular
anomalies' above and 'Sudden cardiac death' above.)
• Hypertension develops in almost one-half of patients with WS.
(See 'Hypertension' above.)
• Endocrine abnormalities including hypercalcemia and
hypothyroidism. Adult patients are at risk for developing type 2
diabetes mellitus. (See 'Endocrine disorders' above.)
• Cognitive profile consists of 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 include congenital anomalies of the
kidney and urinary tract (CAKUT), dysfunctional voiding,
nephrocalcinosis due to hypercalciuria, and recurrent urinary
tract infections. (See 'Kidney and urinary tract abnormalities'
above.)
• Other findings include 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 kidney
abnormalities. (See 'Initial evaluation' above.)
● Continued 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
health supervision guidelines include a series of evaluations based
on patient age. For each age group, evaluation includes
comprehensive history and physical examination with assessment
 of growth and blood pressure (BP) 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.)
● Management for specific complications:
• Prevention 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.)
• 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 kidney 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 (BUN), 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 UpToDate editorial staff acknowledges Patrick Niaudet, MD, who

contributed to earlier versions of this topic review.
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