Sindrome de Williams
Mayo 2016
Sindrome de Williams
I.- Resumen
Description
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
Synonyms
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
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.
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
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%):
Peripheral pulmonary stenosis
Other valvular and septal defects
Hypertension occurs in around 30%
Ischemic heart disease due to coronary artery stenoses
Cerebrovascular stenoses may give rise to stroke
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:
Nephrocalcinosis secondary to hypercalcemia
Bladder diverticula
Gastrointestinal abnormalities:
Infantile colic
Rectal prolapse (occurs in around 10%)
Eye abnormalities:
Stellate irides (present in 50-75%)
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
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.
Dysmorphic 'elfin' or 'gnome-like' facies
Growth retardation
Emaciation
Breast and clitoral enlargement
Acanthosis nigricans
Hypertrichosis
Pachyderma
Life expectancy less than one year
Diagnosis is confirmed by genetic analysis showing a microdeletion at 7q11.23.
Guidelines
The American Academy of Pediatrics has produced the following guideline :
Committee on Genetics. American Academy of Pediatrics:Health care supervision for children with Williams syndrome . Pediatrics 2001;107:1192-204
Moeschler JB, Shevell M, American Academy of Pediatrics Committee on Genetics. Clinical genetic evaluation of the child with mental retardation or developmental delays . Pediatrics 2006;117:2304-16
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 :
Hill ID, Dirks MH, Liptak GS, et al; North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Guideline for the diagnosis and treatment of celiac disease in children : recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2005;40:1-19
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
Genetic analysis using fluorescence in situ hybridization (FISH) probe to detect microdeletion at 7q11.23
Serum calcium to check for hypercalcemia in infancy. Only necessary in children under 4 years old
Serum electrolytes and creatinine and blood urea nitrogen to assess renal function in older children
Urinalysis is a useful investigative and screening test
Renal ultrasound to detect nephrocalcinosis due to hypercalcemia, which may contribute to renal impairment later in life
Electrocardiography to assess left ventricular size would normally be performed by a pediatric cardiologist
Echocardiography to establish presence of cardiac anomalies would normally be performed by a pediatric cardilogist
Neuropsychological testing would normally be performed by a pediatric psychologist or psychiatrist, or a developmental pediatrician
Blood pressure measurement in all four limbs: hypertension and cardiovascular disease is a major cause of morbidity and mortality in this population. Usually performed by a cardiologist
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
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
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
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
Young children need multidisciplinary therapeutic intervention to minimize the impact of their global developmental delay. The particular therapies required vary from child to child, depending on each child's specific needs, but it is likely that patients will needphysical therapy for gross motor developmental delay (and later physical therapy for musculoskeletal complications ) and occupational therapy for developmental problems
Babies and young children with hypercalcemia need a diet that is low in calcium and vitamin D. This diet should be supervised by a dietitian
Surgery, in particular supravalvular aortic stenosis repair , may be necessary for cardiac lesions
Psychiatric treatment may be necessary for anxiety and forattention deficit hyperactivity disorder
Antibiotic prophylaxis is required for bacterial endocarditis during surgery or dental work
The American Academy of Pediatrics has produced the following guideline:
Committee on Genetics. American Academy of Pediatrics:Health care supervision for children with Williams syndrome . Pediatrics 2001;107:1192-204
Moeschler JB, Shevell M, American Academy of Pediatrics Committee on Genetics. Clinical genetic evaluation of the child with mental retardation or developmental delays . Pediatrics 2006;117:2304-16
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:
Hill ID, Dirks MH, Liptak GS, et al; North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Guideline for the diagnosis and treatment of celiac disease in children : recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2005;40:1-19
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
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
Intraoperative considerations
Postoperative considerations : Cardiologic follow-up will be required due to possibility of restenosis in the future.
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
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
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.
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.
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.
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
Cardiovascular:
Unexpected sudden death
Renal:
Cognitive:
Adults are rarely able to live completely independently because of their poor self-care and money management skills
Patients with Williams syndrome are at risk of having an affected child, and those likely to conceive should be offered genetic counseling.
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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 www.williams-syndrome.org
March of Dimes 1275 Mamaroneck Avenue White Plains, NY 10605 Tel: (914) 428-7100 www.modimes.org
Williams Syndrome Foundation University of California Irvine, CA 92679 Tel: (949) 824-7259 www.wsf.org
Clinical Key