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Williams syndrome

Williams syndrome
Literature review current through: Jan 2024.
This topic last updated: Dec 01, 2023.

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 (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) [2,11]. 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 ELN 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 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 normal age-matched population [23]. The increased incidence of sudden death in WS is attributed to underlying cardiovascular anomalies, especially in the setting of sedation and 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 both SVAS and PAS have biventricular outflow tract obstruction and can develop biventricular hypertrophy, resulting in higher mortality rates, particularly with cardiac intervention [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 SVAS 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 "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 [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: 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 [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].

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 [70,71].

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 [72]. The typical age-related medical conditions can appear during late adolescence or early adulthood, including hypertension, diabetes, and hearing loss [73]. The most common cause of death is cardiovascular disease associated with type 2 diabetes followed by malignancies [73]. 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 (PAS). (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 [74].

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 [1,6,75]. 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 [76].

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 [77].

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 "Valvar aortic stenosis in children", 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 [73].

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 [28,78]. (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 [79]. Late in gestation, routine urinalyses should be performed due to a high incidence of urinary tract infection. Ultrasound monitoring of the fetus is recommended [79].

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 [80].

For patients with supravalvar aortic stenosis (SVAS), surgical intervention is performed to correct the lesion [81]. 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 stenotic 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 [82]. 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/caregivers 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 [83]. 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 (PAS; right ventricular hypertension with the right-sided pressures exceeding two-thirds of the systemic pressure), surgical correction is the preferred first-line intervention [84]. 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 [80,81].

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 [85].

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 [17,86]. 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 "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 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 [60,86,87].

In patients with WS, effective control of hypertension has been reported with calcium channel blockers (CCBs) and beta blockers [86]. 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 "Evaluation of hypertension in children and adolescents", 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 [88]. 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 '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 [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 [89]. (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 (PAS). 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 PAS. (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.

  1. National Center for Biotechnology Information, Online Mendelian Inheritance in Man. Williams-Beuren Syndrome (WBS) MIM #194050. http://www.ncbi.nlm.nih.gov/omim/194050.
  2. Morris CA, Braddock SR, COUNCIL ON GENETICS. Health Care Supervision for Children With Williams Syndrome. Pediatrics 2020; 145.
  3. Metcalfe K, Simeonov E, Beckett W, et al. Autosomal dominant inheritance of Williams-Beuren syndrome in a father and son with haploinsufficiency for FKBP6. Clin Dysmorphol 2005; 14:61.
  4. Kozel BA, Barak B, Kim CA, et al. Williams syndrome. Nat Rev Dis Primers 2021; 7:42.
  5. Gregory MD, Mervis CB, Elliott ML, et al. Williams syndrome hemideletion and LIMK1 variation both affect dorsal stream functional connectivity. Brain 2019; 142:3963.
  6. Pober BR. Williams-Beuren syndrome. N Engl J Med 2010; 362:239.
  7. Jones KL, Smith DW. The Williams elfin facies syndrome. A new perspective. J Pediatr 1975; 86:718.
  8. Morris CA, Demsey SA, Leonard CO, et al. Natural history of Williams syndrome: physical characteristics. J Pediatr 1988; 113:318.
  9. Collins RT 2nd, Kaplan P, Somes GW, Rome JJ. Long-term outcomes of patients with cardiovascular abnormalities and williams syndrome. Am J Cardiol 2010; 105:874.
  10. Collins RT 2nd, Kaplan P, Somes GW, Rome JJ. Cardiovascular abnormalities, interventions, and long-term outcomes in infantile Williams syndrome. J Pediatr 2010; 156:253.
  11. Collins RT 2nd. Cardiovascular disease in Williams syndrome. Circulation 2013; 127:2125.
  12. Yau EK, Lo IF, Lam ST. Williams-Beuren syndrome in the Hong Kong Chinese population: retrospective study. Hong Kong Med J 2004; 10:22.
  13. Sadler LS, Pober BR, Grandinetti A, et al. Differences by sex in cardiovascular disease in Williams syndrome. J Pediatr 2001; 139:849.
  14. Hayano S, Okuno Y, Tsutsumi M, et al. Frequent intragenic microdeletions of elastin in familial supravalvular aortic stenosis. Int J Cardiol 2019; 274:290.
  15. Broder K, Reinhardt E, Ahern J, et al. Elevated ambulatory blood pressure in 20 subjects with Williams syndrome. Am J Med Genet 1999; 83:356.
  16. Ingelfinger JR, Newburger JW. Spectrum of renal anomalies in patients with Williams syndrome. J Pediatr 1991; 119:771.
  17. Pober BR, Johnson M, Urban Z. Mechanisms and treatment of cardiovascular disease in Williams-Beuren syndrome. J Clin Invest 2008; 118:1606.
  18. Rose C, Wessel A, Pankau R, et al. Anomalies of the abdominal aorta in Williams-Beuren syndrome--another cause of arterial hypertension. Eur J Pediatr 2001; 160:655.
  19. Waxler JL, Levine K, Pober BR. Williams syndrome: a multidisciplinary approach to care. Pediatr Ann 2009; 38:456.
  20. Faury G, Pezet M, Knutsen RH, et al. Developmental adaptation of the mouse cardiovascular system to elastin haploinsufficiency. J Clin Invest 2003; 112:1419.
  21. Kozel BA, Danback JR, Waxler JL, et al. Williams syndrome predisposes to vascular stiffness modified by antihypertensive use and copy number changes in NCF1. Hypertension 2014; 63:74.
  22. Maloberti A, Cesana F, Hametner B, et al. Increased nocturnal heart rate and wave reflection are early markers of cardiovascular disease in Williams-Beuren syndrome children. J Hypertens 2015; 33:804.
  23. Wessel A, Gravenhorst V, Buchhorn R, et al. Risk of sudden death in the Williams-Beuren syndrome. Am J Med Genet A 2004; 127A:234.
  24. Collins Ii RT, Collins MG, Schmitz ML, Hamrick JT. Peri-procedural risk stratification and management of patients with Williams syndrome. Congenit Heart Dis 2017; 12:133.
  25. Olsen M, Fahy CJ, Costi DA, et al. Anaesthesia-related haemodynamic complications in Williams syndrome patients: a review of one institution's experience. Anaesth Intensive Care 2014; 42:619.
  26. Yokota R, Kwiatkowski DM, Journel C, et al. Postoperative Acute Kidney Injury in Williams Syndrome Compared With Matched Controls. Pediatr Crit Care Med 2022; 23:e162.
  27. Pham PP, Moller JH, Hills C, et al. Cardiac catheterization and operative outcomes from a multicenter consortium for children with williams syndrome. Pediatr Cardiol 2009; 30:9.
  28. Bird LM, Billman GF, Lacro RV, et al. Sudden death in Williams syndrome: report of ten cases. J Pediatr 1996; 129:926.
  29. Collins RT 2nd, Aziz PF, Gleason MM, et al. Abnormalities of cardiac repolarization in Williams syndrome. Am J Cardiol 2010; 106:1029.
  30. Collins RT 2nd. Clinical significance of prolonged QTc interval in Williams syndrome. Am J Cardiol 2011; 108:471.
  31. McCarty HM, Tang X, Swearingen CJ, Collins RT 2nd. Comparison of electrocardiographic QTc duration in patients with supravalvar aortic stenosis with versus without Williams syndrome. Am J Cardiol 2013; 111:1501.
  32. Sindhar S, Lugo M, Levin MD, et al. Hypercalcemia in Patients with Williams-Beuren Syndrome. J Pediatr 2016; 178:254.
  33. Sforzini C, Milani D, Fossali E, et al. Renal tract ultrasonography and calcium homeostasis in Williams-Beuren syndrome. Pediatr Nephrol 2002; 17:899.
  34. Garabédian M, Jacqz E, Guillozo H, et al. Elevated plasma 1,25-dihydroxyvitamin D concentrations in infants with hypercalcemia and an elfin facies. N Engl J Med 1985; 312:948.
  35. Culler FL, Jones KL, Deftos LJ. Imparied calcitonin secretion in patients with Williams syndrome. J Pediatr 1985; 107:720.
  36. Kim YM, Cho JH, Kang E, et al. Endocrine dysfunctions in children with Williams-Beuren syndrome. Ann Pediatr Endocrinol Metab 2016; 21:15.
  37. Palacios-Verdú MG, Segura-Puimedon M, Borralleras C, et al. Metabolic abnormalities in Williams-Beuren syndrome. J Med Genet 2015; 52:248.
  38. Selicorni A, Fratoni A, Pavesi MA, et al. Thyroid anomalies in Williams syndrome: investigation of 95 patients. Am J Med Genet A 2006; 140:1098.
  39. Stagi S, Manoni C, Salti R, et al. Thyroid hypoplasia as a cause of congenital hypothyroidism in Williams syndrome. Horm Res 2008; 70:316.
  40. Bini R, Pela I. New case of thyroid dysgenesis and clinical signs of hypothyroidism in Williams syndrome. Am J Med Genet A 2004; 127A:183.
  41. Cammareri V, Vignati G, Nocera G, et al. Thyroid hemiagenesis and elevated thyrotropin levels in a child with Williams syndrome. Am J Med Genet 1999; 85:491.
  42. Pober BR, Wang E, Caprio S, et al. High prevalence of diabetes and pre-diabetes in adults with Williams syndrome. Am J Med Genet C Semin Med Genet 2010; 154C:291.
  43. Masserini B, Bedeschi MF, Bianchi V, et al. Prevalence of diabetes and pre-diabetes in a cohort of Italian young adults with Williams syndrome. Am J Med Genet A 2013; 161A:817.
  44. Shaikh S, Waxler JL, Lee H, et al. Glucose and lipid metabolism, bone density, and body composition in individuals with Williams syndrome. Clin Endocrinol (Oxf) 2018; 89:596.
  45. Partsch CJ, Japing I, Siebert R, et al. Central precocious puberty in girls with Williams syndrome. J Pediatr 2002; 141:441.
  46. Palmieri S, Bedeschi MF, Cairoli E, et al. Bone involvement and mineral metabolism in Williams' syndrome. J Endocrinol Invest 2019; 42:337.
  47. Mervis CB, Robinson BF, Bertrand J, et al. The Williams syndrome cognitive profile. Brain Cogn 2000; 44:604.
  48. Mervis CB, John AE. Cognitive and behavioral characteristics of children with Williams syndrome: implications for intervention approaches. Am J Med Genet C Semin Med Genet 2010; 154C:229.
  49. Levy Y, Smith J, Tager-Flusberg H. Word reading and reading-related skills in adolescents with Williams syndrome. J Child Psychol Psychiatry 2003; 44:576.
  50. Morris CA. Williams Syndrome. GeneReviews. https://www.ncbi.nlm.nih.gov/books/NBK1249/ (Accessed on July 27, 2020).
  51. Doyle TF, Bellugi U, Korenberg JR, Graham J. "Everybody in the world is my friend" hypersociability in young children with Williams syndrome. Am J Med Genet A 2004; 124A:263.
  52. Leyfer OT, Woodruff-Borden J, Klein-Tasman BP, et al. Prevalence of psychiatric disorders in 4 to 16-year-olds with Williams syndrome. Am J Med Genet B Neuropsychiatr Genet 2006; 141B:615.
  53. Woodruff-Borden J, Kistler DJ, Henderson DR, et al. Longitudinal course of anxiety in children and adolescents with Williams syndrome. Am J Med Genet C Semin Med Genet 2010; 154C:277.
  54. Klein-Tasman BP, van der Fluit F, Mervis CB. Autism Spectrum Symptomatology in Children with Williams Syndrome Who Have Phrase Speech or Fluent Language. J Autism Dev Disord 2018; 48:3037.
  55. Jackowski AP, Rando K, Maria de Araújo C, et al. Brain abnormalities in Williams syndrome: a review of structural and functional magnetic resonance imaging findings. Eur J Paediatr Neurol 2009; 13:305.
  56. Eisenberg DP, Jabbi M, Berman KF. Bridging the gene-behavior divide through neuroimaging deletion syndromes: Velocardiofacial (22q11.2 Deletion) and Williams (7q11.23 Deletion) syndromes. Neuroimage 2010; 53:857.
  57. Stinton C, Elison S, Howlin P. Mental health problems in adults with Williams syndrome. Am J Intellect Dev Disabil 2010; 115:3.
  58. Annaz D, Hill CM, Ashworth A, et al. Characterisation of sleep problems in children with Williams syndrome. Res Dev Disabil 2011; 32:164.
  59. Pankau R, Partsch CJ, Winter M, et al. Incidence and spectrum of renal abnormalities in Williams-Beuren syndrome. Am J Med Genet 1996; 63:301.
  60. Sugayama SM, Koch VH, Furusawa EA, et al. Renal and urinary findings in 20 patients with Williams-Beuren syndrome diagnosed by fluorescence in situ hybridization (FISH). Rev Hosp Clin Fac Med Sao Paulo 2004; 59:266.
  61. Pober BR, Lacro RV, Rice C, et al. Renal findings in 40 individuals with Williams syndrome. Am J Med Genet 1993; 46:271.
  62. Sammour ZM, Gomes CM, Duarte RJ, et al. Voiding dysfunction and the Williams-Beuren syndrome: a clinical and urodynamic investigation. J Urol 2006; 175:1472.
  63. von Gontard A, Niemczyk J, Borggrefe-Moussavian S, et al. Incontinence in children, adolescents and adults with Williams syndrome. Neurourol Urodyn 2016; 35:1000.
  64. Cote G, Jequier S, Kaplan P. Increased renal medullary echogenicity in patients with Williams syndrome. Pediatr Radiol 1989; 19:481.
  65. Levitin DJ, Cole K, Lincoln A, Bellugi U. Aversion, awareness, and attraction: investigating claims of hyperacusis in the Williams syndrome phenotype. J Child Psychol Psychiatry 2005; 46:514.
  66. Thakur D, Martens MA, Smith DS, Roth E. Williams Syndrome and Music: A Systematic Integrative Review. Front Psychol 2018; 9:2203.
  67. Lillvis J, Traboulsi EI. Williams syndrome (Williams-Beurin syndrome). In: A Compendium of Inherited Disorders and the Eye, Traboulsi EI (Ed), Oxford University Press, 2005.
  68. Tarjan I, Balaton G, Balaton P, et al. Facial and dental appearance of Williams syndrome. Postgrad Med J 2003; 79:241.
  69. Morris CA. Williams syndrome. In: GeneReviews, Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A. (Eds), University of Washington, 2023.
  70. 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; 137:52.
  71. Stagi S, Lapi E, Chiarelli F, de Martino M. Incidence of diverticular disease and complicated diverticular disease in young patients with Williams syndrome. Pediatr Surg Int 2010; 26:943.
  72. Searcy YM, Lincoln AJ, Rose FE, et al. The relationship between age and IQ in adults with Williams syndrome. Am J Ment Retard 2004; 109:231.
  73. Sauna-Aho O, Bjelogrlic-Laakso N, Sirén A, et al. Cognition in adults with Williams syndrome-A 20-year follow-up study. Mol Genet Genomic Med 2019; 7:e695.
  74. Committee on Genetics. American Academy of Pediatrics: Health care supervision for children with Williams syndrome. Pediatrics 2001; 107:1192.
  75. 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; 57:49.
  76. Lugo M, Wong ZC, Billington CJ Jr, et al. Social, neurodevelopmental, endocrine, and head size differences associated with atypical deletions in Williams-Beuren syndrome. Am J Med Genet A 2020; 182:1008.
  77. Martin ND, Smith WR, Cole TJ, Preece MA. New height, weight and head circumference charts for British children with Williams syndrome. Arch Dis Child 2007; 92:598.
  78. Burch TM, McGowan FX Jr, Kussman BD, et al. Congenital supravalvular aortic stenosis and sudden death associated with anesthesia: what's the mystery? Anesth Analg 2008; 107:1848.
  79. Lin AE, Basson CT, Goldmuntz E, et al. Adults with genetic syndromes and cardiovascular abnormalities: clinical history and management. Genet Med 2008; 10:469.
  80. Collins RT 2nd. Cardiovascular disease in Williams syndrome. Curr Opin Pediatr 2018; 30:609.
  81. Brown JW, Ruzmetov M, Vijay P, Turrentine MW. Surgical repair of congenital supravalvular aortic stenosis in children. Eur J Cardiothorac Surg 2002; 21:50.
  82. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 129:2440.
  83. Fricke TA, d'Udekem Y, Brizard CP, et al. Surgical repair of supravalvular aortic stenosis in children with williams syndrome: a 30-year experience. Ann Thorac Surg 2015; 99:1335.
  84. Monge MC, Mainwaring RD, Sheikh AY, et al. Surgical reconstruction of peripheral pulmonary artery stenosis in Williams and Alagille syndromes. J Thorac Cardiovasc Surg 2013; 145:476.
  85. Giordano U, Turchetta A, Giannotti A, et al. Exercise testing and 24-hour ambulatory blood pressure monitoring in children with Williams syndrome. Pediatr Cardiol 2001; 22:509.
  86. Bouchireb K, Boyer O, Bonnet D, et al. Clinical features and management of arterial hypertension in children with Williams-Beuren syndrome. Nephrol Dial Transplant 2010; 25:434.
  87. Courtel JV, Soto B, Niaudet P, et al. Percutaneous transluminal angioplasty of renal artery stenosis in children. Pediatr Radiol 1998; 28:59.
  88. Mathias RS. Rickets in an infant with Williams syndrome. Pediatr Nephrol 2000; 14:489.
  89. Sammour ZM, Gomes CM, de Bessa J Jr, et al. The effects of oxybutynin on urinary symptoms in children with Williams-Beuren syndrome. J Urol 2012; 188:253.
Topic 6127 Version 28.0

References

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