Sindrome de Williams

Mayo 2016


Sindrome de Williams



I.- Resumen



  • Williams syndrome is a genetic syndrome caused by a microdeletion of contiguous genes in the 7q11.23 region

  • It is a multisystem condition characterized by elfin facies, neurocognitive deficits, supravalvular aortic stenosis, peripheral pulmonary stenosis, and hypercalcemia in infancy

  • Not all patients have all these features

  • The major causes of physical morbidity and mortality are cardiovascular and renal disease

  • Management of these patients will include referral to a range of specialists, including cardiology, genetics, and developmental pediatrics



  • Williams-Beuren syndrome

  • Supravalvular aortic stenosis syndrome

  • Fanconi-type idiopathic infantile hypercalcemia


Key points

  • Williams syndrome is a genetic disorder affecting multiple systems

  • Most morbidity and mortality results from cardiovascular or renal disease

  • The syndrome is characterized by an elfin facies, global developmental delay, and social disinhibition

  • The diagnosis is made by history, physical examination, and genetic analysis

  • Early diagnosis allows for detection of comorbidities, initiation of treatment, and opportunity for family members to obtain support


II.- Background


Cardinal features

  • Characteristic elfin facies with wide mouth, full lips, long flat philtrum, and a small, upturned nose with a flat nasal bridge

  • Characteristic cognitive phenotype with global developmental delay but normal expressive language and loquacious manner

  • Cardiac defects, most commonly supravalvular aortic stenosis and peripheral pulmonary stenosis

  • Infantile hypercalcemia thought to be due to abnormal metabolism of calcium and vitamin D



  • Common causes

    • Genetic - probably autosomal dominant with most cases being new mutations. The cause is a microdeletion in the 7q11.23 region, including the elastin and LIM-kinase genes.



  • Contributory or predisposing factors

    • Presence of the condition in a parent. There are a few cases in the literature of families where one parent and a child both have Williams syndrome.



  • Incidence and prevalence

    • Incidence  :   5-100/100,000 live births.

    • Prevalence  :  5/100,000.

  • Demographics

    • Age :  Present from birth.

    • Genetics : Probably autosomal dominant with most cases being new mutations.

  • Codes  ICD-9 code

    • 758.9 Conditions due to anomaly of unspecified chromosome.


III.-  Diagnosis



Clinical presentation



  • Babies may present with feeding difficulties, failure to thrive, vomiting or constipation due to hypercalcemia , or developmental delay

  • Older children may present with developmental delay, behavioral problems, or symptoms of cardiac disease

Other symptoms include:

  • Outgoing personality with overtalkativeness ('cocktail party manner')

  • Difficulty with peer relationships

  • Poor math skills compared with literacy skills

  • Poor self-care skills

  • Poor visuospatial skills

  • Anxiety , often with obsessions

  • Increased urinary frequency and daytime wetting


  • Upturned nose with bulbous tip and flat nasal bridge

  • Wide mouth with full lower lip

  • Flat midface with full cheeks

  • Periorbital fullness with medial eyebrow flare

  • Epicanthal folds

  • High, prominent forehead

  • Long neck with prominent hyoid in adults

  • Prematurely gray hair in early adulthood in 60%

  • Small hands with relatively short fingers

  • Eye signs - stellate irides, strabismus or refractive errors, tortuosity of retinal vessels

  • Dental anomalies include malocclusion, microdontia, enamel hypoplasia

  • Signs of cardiac disease - heart murmurs, hypertension

  • Musculoskeletal abnormalities include short stature, scoliosis, large joint contractures, radioulnar synostosis and recurrent patellar dislocation, and gross and fine motor delays and clumsiness

  • Inguinal hernia (occurs in over 33%)

  • Developmental delay, specifically an IQ of 40-85; social disinhibition, particularly with adults; and expressive and receptive language delays

  • Early puberty

  • Postnatal growth retardation

  • Hypertonia and hyperreflexia

  • Hyperacusis (in over 90%)

  • Hoarse voice

Associated disorders


A large range of abnormalities have been observed to be more common in patients with Williams syndrome than in the general population.


Cardiovascular abnormalities (occur in 75%):

Cognitive and behavioral abnormalities:

Endocrinology and growth:

  • Hypercalcemia in infancy thought by some to be due to increased intestinal absorption of calcium and elevated levels of 1,25-dihydroxyvitamin D. Resolves within first 4 years of life and usually within first 18 months

  • Idiopathic hypercalcemia (occurs in 15%), hypercalciuria (occurs in 30%)

Renal abnormalities:

Gastrointestinal abnormalities:

Eye abnormalities:


Differential diagnosis

  • In general, Williams syndrome needs to be differentiated from:

    • Other causes of learning difficulty

    • Other causes of microcephaly

    • Other causes of growth retardation

    • Other causes of hypercalcemia, e.g. neonatal hyperparathyroidism, parathyroid hyperplasia of infancy, hypophosphatasia, familial hypocalciuric hypercalcemia

  • Rubella embryopathy

    • Intrauterine infection of fetus with rubella virus.

    • Features

      • Microcephaly

      • Intrauterine growth retardation

      • Pulmonary artery stenosis

      • Developmental delay

      • Sensorineural hearing loss

      • Cataract

  • Familial hypocalciuric hypercalcemia

    • Parathormone-independent renal tubular calcium reabsorption defect.

    • Features

      • Hypocalciuria

      • Hypercalcemia

      • Hypermagnesemia

      • Autosomal recessive

      • Otherwise normal children without other problems

  • Supravalvular aortic stenosis

    • Supravalvular aortic stenosis is seen as an isolated defect as well as part of Williams syndrome.

    • Features

      • May be associated with other cardiac lesions such as pulmonary valvular or artery stenosis

      • Autosomal dominant

      • Caused by mutation in elastin gene

  • Leprechaunism

    • Very rare condition with poor prognosis.

    • Features

      • Dysmorphic 'elfin' or 'gnome-like' facies

      • Growth retardation

      • Emaciation

      • Breast and clitoral enlargement

      • Acanthosis nigricans

      • Hypertrichosis

      • Pachyderma

      • Life expectancy less than one year





Diagnostic decision




Questions to ask

  • Presenting condition

    • Since the patient is very likely to be under 3 years old, these questions would normally be addressed to parents/caregivers:

    • Do the parents have any features of Williams syndrome?Autosomal dominant inheritance is seen in some families

    • Does the child have any behavioral or learning difficulties?This is characteristic of the syndrome.

    • Does the child have any symptoms of cardiac disease (such as reduced exercise tolerance)?The cardiac complications are the major causes of mortality and physical morbidity in the syndrome and need prompt referral to a cardiologist

  • Family history

    • Does a close family member have the condition?Autosomal dominant condition, so there is a high risk if a parent or a monozygotic twin has the condition.



  • Examine the facial features and body habitus.Look for characteristic dysmorphic features

  • Examine the eyes. Strabismus and visual acuity should be assessed

  • Examine the teeth.Look for anomalies of shape and size

  • Examine the heart. Supravalvular aortic stenosis results in a systolic murmur with thrill, which is transmitted into the jugular notch and carotid vessels. Less commonly there may be an early diastolic aortic regurgitation murmur due to fusion of one or more aortic valve cusps. As the stenosis progresses, there may be evidence of left ventricular hypertrophy with palpable heave. Peripheral pulmonary stenosis will result in a late systolic or continuous murmur heard bilaterally over the lung fields

  • Record the blood pressure.There may be significant disparity between blood pressures in the arms and the legs, with the right arm pressure tending to be higher than that in the left arm.Hypertension may result from renal disease

  • Developmental assessment.This will show global delay in gross and fine motor development and cognitive skills, but abnormally sociable with seemingly advanced language skills

Summary of tests



  • Body fluids

    • Fluorescence in situ hybridization (FISH) studies for genetic analysis

      • Description :  Blood sample for FISH test of Williams syndrome chromosomal region. Interpretation by genetics specialist.

      • Advantages/disadvantages :  Advantage: safe and easy to obtain venous sample.

      • Normal  :   Negative FISH probe for relevant microdeletion.

      • Abnormal : FISH probe detection of microdeletion in the 7q11.23 region.

      • Cause of abnormal result   :   Genetic abnormality causing Williams syndrome.

    • Serum calcium

      • Description:  Venous blood sample.

      • Advantages/disadvantages  : Advantage: safe and easy to obtain sample.

      • Normal :  Total calcium: 8.8-10.8mg/dL (2.2-2.7mmol/L).

      • Abnormal :   Total calcium >10.8mg/dL (2.7mmol/L).

      • Cause of abnormal result  : 

      • Thought to be due to increased intestinal absorption of calcium and abnormal vitamin D metabolism.

      • Medications, disorders and other factors that may alter results

      • If the child is already on a low calcium and vitamin D diet, the serum calcium may be within the normal range.

    • Serum electrolytes and creatinine and blood urea nitrogen

      • Description:  Venous blood sample.

      • Advantages/disadvantages:  Advantage: safe, inexpensive, widely available test that is easy to perform.

      • Normal

        • Potassium:

          • 2-12 months of age: 3.5-6.0mEq/L (3.5-6.0mmol/L)

          • >12 months of age: 3.5-5.0mEq/L (3.5-5.0mmol/L)

        • Blood urea nitrogen:   5-18mg/dL (2.5-6.4mmol/L)

        • Creatinine:

          • Child: 0.3-0.7mg/dL (27-62mmol/L))

          • Adolescent: 0.5-1.0mg/dL (44-88mmol/L)

      • Abnormal  :   Potassium, blood urea nitrogen, and creatinine may be raised individually or together in renal impairment.

      • Cause of abnormal result:

        • Possible renal impairment.

        • Medications, disorders and other factors that may alter results

        • Blood urea nitrogen may be raised if the child is dehydrated.

    • Urinalysis

      • Advantages/disadvantages :  Advantage: safe and easy to obtain sample.

      • Normal  : No blood and/or RBC.

      • Abnormal  :   Blood and/or RBC.

      • Cause of abnormal result  :   Hematuria can be one indication of nephrocalcinosis secondary to hypercalciuria.

    • Tests of function

      • Blood pressure measurement in limbs

        • Description  :   Blood pressure should be obtained to assess for hypertension.

        • Normal :  Normal blood pressure measurement.

        • Cause of abnormal result  :   BP should be obtained in the right arm and either leg with special attention paid to to a significant difference between the two, this may indicate aortic narrowing.


      • Renal ultrasound

        • Description :  CPT code

        • Advantages/disadvantages :   Advantage: safe, noninvasive test that does not expose the patient to ionizing radiation.

        • Normal   :   No nephrocalcinosis seen.

        • Abnormal  :  Nephrocalcinosis.

        • Cause of abnormal result :  

          • Hypercalcemia.

          • Medications, disorders and other factors that may alter results

      • Electrocardiography (ECG)

        • Description : CPT code

        • Advantages/disadvantages  : 

          • Advantages:

          • Relatively easy to perform

          • Noninvasive

          • Provides useful initial information

        • Normal

        • Abnormal  :   Left ventricular hypertrophy.

        • Cause of abnormal result :

          • Most commonly due to aortic supravalvular stenosis and subsequent left heart strain.

          • Medications, disorders and other factors that may alter results

      • Echocardiography

        • Description :  CPT code

        • Advantages/disadvantages

          • Advantages:

            • Noninvasive

            • Provides detailed information about cardiac anatomy and function

          • Disadvantages :

            • Unlikely to be available in primary care office; requires referral

            • Interpretation requires experience

        • Normal

        • Abnormal

          • Narrowing of the aorta above the aortic valve

          • Possibly pulmonary artery stenosis

          • Possibly other valvular or septal defects

          • Left ventricular hypertrophy

        • Cause of abnormal result

          • Abnormalities of cardiac anatomy, e.g. aortic supravalvular stenosis and left ventricular hypertrophy

          • Impaired left ventricular systolic function

          • Valvular or septal defects

          • Medications, disorders and other factors that may alter results

    • Otros tests

      • Neuropsychological testing

        • Description

          • Detailed evaluation of cognitive function and behavior used to determine presence of Williams syndrome

          • A battery of tests assess overall IQ, language skills, behavior and temperment, and motor skills

        • CPT code

        • Advantages/disadvantages

        • Normal  :   No cognitive/behavioral dysfunction identified.

        • Abnormal

          • Cognitive/behavioral dysfunction identified

          • Keep in mind the possibility of a falsely abnormal result

        • Cause of abnormal result

          • Medications, disorders and other factors that may alter results

          • Sedatives may alter performance on neuropsychological testing.



Clinical pearls

  • Early diagnosis of this condition offers families the opportunity to find support from other parents of children with the syndrome and to begin treatments early in the life of the patient, therefore consider early consultation with a genetics specialist when the diagnosis is being considered

  • Diagnosis is often delayed because signs/symptoms can be subtle

  • Slow growth is prominent in infancy, and failure to thrive may be the only recognizable clue to Williams syndrome

  • Delayed onset of colic is another feature of Williams syndrome; although the colic resolves, it takes longer than is typical of most infants with colic.

  • Hyperacusis is often seen, and the sensitivity is such that ordinary sounds may be painful to the infant or child with Williams syndrome


Consider consult

  • All children with Williams syndrome need referral after diagnosis for cardiac, renal, ophthalmic, and neuropsychological assessment

  • Genetic opinion and counseling for the family should be sought



IV.-    Treatment



  • To maximize physical health by appropriate management of cardiac, renal, and musculoskeletal problems in collaboration with the appropriate specialists

  • To minimize developmental, educational, and psychological problems by referral to, and liaison with, appropriate early intervention services, schools, and psychology services

  • To support parents and families in caring for a child and subsequently adult with a range of chronic problems. This may be by helping families access appropriate services, including genetic counseling


Immediate action


Therapeutic options


Summary of therapies




The American Academy of Pediatrics has produced the following guideline:

The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition has produced the following guuidelines that discusses Williams syndrome in the context of celiac disease:


Efficacy of therapies

  • Treatment of hypercalcemia , if adhered to, is generally successful until it resolves spontaneously

  • Moderate to severe supravalvular aortic stenosis is generally successfully treated by experienced teams in pediatric cardiology and cardiothoracic surgery, although patients must be carefully followed for life for complications such as restenosis

  • Orthopedic problems, such as joint contractures, can often be avoided by preventive physical therapy

  • Early educational, social, and behavioral evaluation and management offers the best outlook for optimal functioning by patients as adults


Surgical therapy

  • Supravalvular aortic stenosis repair

  • Description of operation :  May require open repair with grafting rather than balloon angioplasty.

  • CPT code

  • Indication :  Surgery, in particular supravalvular aortic stenosis repair , may be necessary for the most severe lesions (accounting for up to 30% of patients).


  • Contraindication

  • Risks/benefits  :   Surgical approach is not entirely quantified because of the rarity of this condition. Risks of general anesthesia may be greater for children with Williams syndrome, and there have been cases reported of sudden death associated with anesthesia for cardiac catheterization in this condition. Restenosis may also occur and require further intervention. This is more common in children who have associated hypoplasia of the aorta



  • Preoperative considerations

  • Intraoperative considerations

  • Postoperative considerations  :   Cardiologic follow-up will be required due to possibility of restenosis in the future.


Physical therapy

  • Physical therapy for gross motor developmental delay

    • Patient and caregiver information

    • Physical therapist should follow patient as appropriate; physician should monitor for gross motor development.

    • Efficacy  :    Can help patients whose gross motor development is delayed.

  • Physical therapy for musculoskeletal complications

    • Patient and caregiver information

      • Physical therapist should follow patient as appropriate; physician should monitor for worsening musculoskeletal problems

      • Generally acceptable to patient, although time consuming and sometimes tiring

    • Efficacy

      • Useful for treating early joint laxity and hypotonia

      • Also useful for treating joint stiffness and contractures that may emerge as the patient is older

      • Helps improve muscle strength and tone and preserve range of motion of joints

  • Occupational therapy

    • Occupational therapy to improve fine motor and visual/perception skills

    • Patient and caregiver information

      • Although time consuming for patients and families, participation in occupational therapy is associated with improvement in skills

      • Generally acceptable to patient, although the therapy can be time consuming and may appear slow in its results

    • Efficacy :    Occupational therapy may improve fine motor skills and visual/perception skills, which are often impaired in children with Williams syndrome.



  • Diet low in calcium and vitamin D

    • For babies and young children with hypercalcemia , a diet with low calcium and vitamin D is required

    • This diet should be supervised by a dietitian

    • Children usually grow out of the hypercalcemia around 18-24 months of age, and all will have by age 4 years

  • Benefits:

    • Appropriate diet can reduce calcium levels in hypercalcemic infants with Williams syndrome

    • Maintaining the serum calcium in the normal range helps prevent nephrocalcinosis

  • Monitor :  Serum calcium should be checked at regular intervals, as should growth while the child is on this diet.

  • Patient and caregiver information

    • Families should be educated about avoiding dehydration, which may increase serum calcium

    • Parents should call their primary care practitioner if constipation develops since this may be caused by hypercalcemia

    • Children usually outgrow hypercalcemia at 18-24 months of age, and all do by 4 years of age

    • May be difficult to maintain a young child on a low-calcium diet



Clinical pearls

  • Hypotonia and joint laxity may pose significant problems for patients with Williams syndrome early in life, whereas joint stiffness and contractures may emerge when the patients are older. Physical therapy is an important aspect of caring for patients with Williams syndrome to improve muscle strength and tone and preserve range of motion of joints

  • Do not treat with multi-vitamins containing calcium and vitamin D; can exacerbate hypercalcemia

  • Monitor for constipation. This can be a sign of hypercalcemia, and may lead to rectal prolapse

  • Monitor growth on a Williams syndrome growth chart; monitor blood pressure for signs of hypertension


Patient and caregiver issues

  • Forensic and legal issues

  • Impact on career, dependants, family, friends

  • Questions patients ask

    • Will my child live an independent adult life?  Unfortunately, few adults with Williams syndrome can live completely independent lives because of their poor self-care and money management skills


    • Does my child have a normal life expectancy?People with Williams syndrome may have a shortened life expectancy, mainly as a result of cardiovascular disease, so the child's current cardiac problems will influence the answer to this question


    • Health-seeking behavior



  • Plan for review :   All children will need multidisciplinary follow-up throughout childhood. The basic minimum will include regular monitoring of blood pressure, renal function, and cardiac function if cardiac anomaly is present.


  • Information for patient or caregiver  :   Families find it useful to be referred to the Williams Syndrome Association (WSA) soon after diagnosis.


Ask for advice

  • Question 1

    • Should all infants with aortic stenosis be tested for Williams syndrome?

    • Most specialists advise that the diagnosis be considered in infants with supravalvular stenosis and that such infants be evaluated for genetic testing by a pediatric geneticist.


  • Question 2


    • Is the presence of stellate irides diagnostic of Williams syndrome?


    • No. Stellate irides may also appear in normal patients and are only present in about half of patients with Williams syndrome.


  • Question 3

    • Are Williams syndrome patients infertile?

    • No. Although the number of affected patients who have conceived is low, it is not zero.

  • Question 4

    • What problems are prominent in adult patients with Williams syndrome?

    • Hypertension is common, and patients must be followed carefully to detect this problem. Frequent bladder infections in adult patients often arise due to bladder diverticula.


Consider consult


Although primary care practitioners can manage general health issues in patients with Williams syndrome, all affected patients require care from subspecialist physicians in several disciplines, including cardiology, genetics, neurodevelopment, and usually nephrology.



V.-  Outcomes

  • Prognosis   :  The life expectancy of patients with Williams syndrome depends on the extent of their cardiac and renal disease. Most patients live to adulthood.

  • Factors affecting prognosis

    • The Williams Syndrome Association (WSA) is devoted to improving the lives of affected patients and can offer information and support to families

    • Given the verbal and social abilities of many patients with the syndrome, practitioners must take care not to minimize or underestimate the degree of mental retardation of patients since to do so might limit the services necessary for optimal education

    • An individual educational plan is needed to help the patient reach their full potential


Clinical complications





  • Adults are rarely able to live completely independently because of their poor self-care and money management skills


VI.-  Prevention


Patients with Williams syndrome are at risk of having an affected child, and those likely to conceive should be offered genetic counseling.



VII.-  Resources


Further reading

  • Carrasco X, Castillo S, Aravena T, et al. Williams syndrome: pediatric, neurologic, and cognitive development. Pediatr Neurol 2005;32:166-72

  • Bruno E, Rossi N, Thuer O, et al. Cardiovascular findings, and clinical course, in patients with Williams syndrome. Cardiol Young 2003;13:532-6

  • Eronen M, Peippo M, Hiippala A, et al. Cardiovascular manifestations in 75 patients with Williams syndrome. J Med Genet 2002;39:554-8

  • Mervis CB. Williams syndrome: 15 years of psychological research. Dev Neuropsychol 2003;23:1-12

  • Karmiloff-Smith A, Grant J, Ewing S, et al. Using case study comparisons to explore genotype-phenotype correlations in Williams-Beuren syndrome. J Med Genet 2003;40:136-40

  • Tassabehji M. Williams-Beuren syndrome: a challenge for genotype-phenotype correlations. Hum Mol Genet 2003;12 Spec No 2:R229-37

  • Metcalfe K. Williams syndrome: an update on clinical and molecular aspects. Arch Dis Child 1999;81:198-200



  • Williams Syndrome Association   Box 297     Clawson, MI 48017     Tel: (248) 541-3630

  • March of Dimes     1275 Mamaroneck Avenue   White Plains, NY 10605   Tel: (914) 428-7100

  • Williams Syndrome Foundation University of California    Irvine, CA 92679  Tel: (949) 824-7259