Williams syndrome
Synonyms and keywords: Beuren-Williams syndrome; supravalvular aortic stenosis hypercalcemia syndrome; Williams syndrome; Williams-Beuren syndrome; Chromosome 7q11.23 deletion syndrome, 1.5- to 1.8-mb; WMS;  WS

# Overview
Williams syndrome (also  Williams-Beuren syndrome) is a rare genetic disorder characterized by a distinctive, "elfin" facial appearance, along with a low nasal bridge; an unusually cheerful demeanor and ease with strangers, coupled with unpredictably occurring negative outbursts; mental retardation coupled with unusual (for persons who are diagnosed as mentally retarded)  language skills; a love for music; and cardiovascular problems, such as supravalvular aortic stenosis and transient hypercalcemia.

# Historical Perspective
The syndrome was first identified in 1961 by Dr. J. C. P. Williams of New Zealand.

# Classification
There is no established system for the classification of Williams syndrome.

# Pathophysiology
It is thought that Williams syndrome is caused by the deletion of genetic material that contains elastin (ELN) gene from the region q11.2 of chromosome 7. There are several other genes, apart from ELN gene that contributes to manifestation of williams syndrome and, therefore, is considered a contiguous gene deletion syndrome..  LIMK1 and a number of other genes such as GTF1IRD1, GTF2I, NCF1, STX1A, CLIP2, and TFII-1 are felt to influence the cognitive profile of Williams syndrome. Some other genes are considered for manifestation of conditions such as elevated calcium, glucose metabolism, and hypertension.

# Epidemiology and Demographics
The incidence of Williams syndrome is approximately 1 per 75,000 individuals worldwide. Williams syndrome is considered for about 6% of all genetic cases of developmental disability. William syndrome affects male and female in equal numbers and infants of any race may be affected.

# Risk Factors
There are no established risk factors for Williams syndrome.

# Screening
There is insufficient evidence to recommend routine screening for Williams syndrome.

# Natural History, Complications, and Prognosis
Common complications of Williams syndrome include:
- Cardiovascular disease
- Failure to thrive
- Connective tissue changes
- Endocrine abnormalities
There is no significant reduction in life expectancy in children diagnosed with Williams syndrome unless there is any significant heart condition or problems in the kidney.

# Diagnosis
The clinical diagnosis of Williams syndrome can be made in early childhood based on characteristic facial features. However, the diagnosis of Williams syndrome is confirmed by genetic testing (fluorescent in situ hybridization) that can detect deletion of one elastin gene on chromosome 7.

## Symptoms
The hallmark feature of Williams syndrome is typical 'elfin' facies (upturned nose, wide forehead, and small teeth). A positive history of congenital heart disease and neuro-developmental delay is suggestive of Williams syndrome. Williams syndrome can be manifested with various non- specific complains such as poor growth, short stature, muscle weakness, hyperflexible joints, intellectual disability, visual disturbances, chronic ear infections or hearing loss, dental abnormalities.  

## Physical Examination
Patients with Williams syndrome usually have typical 'elfin facies' in appearance. Physical examination of patients with Williams syndrome is usually remarkable for characteristic cardiac lesion such as supravalvar aortic stenosis (SVAS), pulmonary stenosis and mitral valve regurgitation along with arterial hypertension.
On physical examination, ocular findings in Williams syndrome can include strabismus, a stellate iris, cataract or retinal vascular tortuosity. Audiological evaluation may report  sensorineural hearing loss in some patient. Other findings include joint hyperelasticity, contractures, kyphoscoliosis, and lordosis along with generalised hypotonia.

## Laboratory Findings
Laboratory findings consistent with the diagnosis of Williams syndrome include elevated calcium level with hypercalciuria , mild thyroid-stimulating hormone elevation with normal thyroxine T4 (sub-clinical hypothyroidism in 5 to 10 percent ) , and abnormal glucose tolerance test in 60 to 75 percent. 

## Electrocardiogram
An ECG may be helpful to look for any cardiac anomalies such as septal defects that may be related to Williams syndrome.

## X-ray
There are no x-ray findings associated with Williams syndrome. However, an x-ray may be helpful to look for associated anomalies with Williams syndrome.

## Echocardiography or Ultrasound
Renal ultrasound  may be helpful in the diagnosis of Williams syndrome. Findings on renal ultrasound suggestive of Williams syndrome include bladder diverticula, ectopic or horseshoe kidney, and renal aplasia or hypoplasia. Nephrocalcinosis secondary to hypercalciuria is detected in approximately 5 to 10 percent of patients undergoing renal ultrasound. 

## CT scan
There are no CT scan findings associated with Williams syndrome.

## MRI
There are no MRI findings associated with Williams syndrome.

## Other Imaging Findings
There are no other imaging findings associated with Williams syndrome.

## Other Diagnostic Studies
Other diagnostic studies for Williams syndrome include audiologic evaluation, which demonstrates high tone sensorineural hearing loss, and ophthalmic evaluation, which demonstrates strabismus and refractive errors.

# Treatment
Based on  2020 American Academy of Pediatrics (AAP) healthcare supervision guidelines for Williams Syndrome, the approach to the management of Williams syndrome consists of 3 major steps:
- 1. Initial evaluation- Our initial evaluation is based upon a comprehensive evaluation that includes growth measurements; a multidisciplinary developmental evaluation; thorough cardiac, renal, and neurologic assessments; and laboratory testing. 
- 2. Continued surveillance- Because of the risk of progressive disease, continued surveillance is recommended throughout the lifetime of the affected person to look for any complications associated with Williams syndrome.
- 3. Management of specific conditions- 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. Proper growth of the child with adequate nutrition need to be accessed. Ophthalmic evaluation of child needed for any visual disturbances. Thyroxine supplement for hypothyroid child might be necessary. Proper evaluation and management of any ear infections should be done.

## Medical Therapy
There is no treatment for Williams syndrome; the mainstay of therapy is supportive care and management of specific conditions or complications related to Williams syndrome.

## Surgery
Surgery is the mainstay of treatment for supra-valvular aortic stenosis, which is one of the specific condition related to Williams syndrome.

## Primary Prevention
There are no established measures for the primary prevention of Williams syndrome.

## Secondary Prevention
There are no established measures for the secondary prevention of Williams syndrome.