Williams Syndrome

Etiology

The genetic etiology underlying Williams syndrome was uncovered in 1993. Williams syndrome is most commonly a spontaneous genetic mutation but is passed via autosomal dominant transmission from an affected parent due to haploinsufficient expression.[3][2] Williams syndrome develops secondary to spontaneous deletions at chromosome band 7q11.23 that involve the elastin gene (ELN). The gene is in the Williams-Beuren Syndrome Critical Region (WBSCR).[1][2] 

The deletion, comprising 26 genes, is detected through dual-color fluorescent in situ hybridization (FISH) or deletion/duplication testing.[2][6] Microarray analysis is another diagnostic test that can identify the size of the elastin deletion. Both FISH and microarray analyses utilize a parenteral blood sample to extract DNA for analysis. An estimated 96% to 98% of patients with Williams syndrome have a deleted ELN gene.[3]

Epidemiology

The estimated frequency of the disorder is cited in studies with a range between 1 in 7,500 to 1 in 20,000 children.[2][3] The disease affects all ethnicities and both sexes equally.[6][7]

Pathophysiology

The deletion areas on chromosome 7 encompass at least 26 known genes. Among those typically deleted are ELN (coding for elastin), CLIP2, GTF2I, GTF2IRD1, and LIMK1. ELN deletion leads to generalized arteriopathy and may affect any artery in the body, but it often affects medium to large-sized arteries, particularly the characteristic supravalvular aortic stenosis. Elastin deficiency may also manifest as hoarseness, bladder diverticula, and hernias in patients with Williams syndrome.[8] 

Haploinsufficiency in genes GTF2I, GTF2IRD1, and LIMK1 has been implicated in difficulties in visual-spatial tasks frequently present in patients with Williams syndrome.[9][10] In addition, haploinsufficiency in Williams syndrome in the CLIP2 gene has been implicated in characteristic personality traits, learning disabilities, and cognitive disabilities.[11]

History and Physical

After birth, infants often present with characteristic facial features and failure to thrive, short stature, and supravascular aortic stenosis.[2] On physical exam, children with Williams syndrome have distinctive facies with elfin-like features, including a short nose and elongated philtrum, periorbital puffiness or stellate iris pattern, and a prominent forehead and relatively under-developed chin.[2] Patients with Williams syndrome born with blue or green eyes often display a "starburst" or stellate pattern on their iris.[2] This "starburst" pattern characteristically shows a white, lacy appearance.[2][12] These facial and physical features should prompt the astute clinician to investigate further.

Due to the defect in elastin, children may also have other elastin arteriopathies, along with peripheral pulmonary stenosis and hypertension.[2] During childhood, patients may have middle ear infections and visual difficulty.[2] Children with Williams syndrome commonly have various endocrine abnormalities.[2] The presence of hypercalcemia and hypercalciuria can result in renal calculi.[2] The patient may also have physical signs of hypothyroidism, delayed growth, or early puberty.[2][13]

Moreover, connective tissue abnormalities often result in hyperextensible joints or hypotonia, resulting in delayed motor milestones or toilet training.[2] The patient may have comorbid psychiatric disorders, including intellectual disability, attention-deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), or generalized anxiety disorder (GAD).[1][14][15]

Evaluation

A definitive diagnosis of Williams syndrome requires fluorescence in situ hybridization (FISH) genetic testing demonstrating the gene deletion in the WBSCR.[2] The following laboratory, imaging, and other tests should be performed to help exclude differential diagnoses and assess for comorbid conditions for patients with suspected Williams syndrome. 

• Body mass index (BMI)
• Complete blood count 
• Complete metabolic panel
• Calcium
• Thyroid-stimulating hormone, including free T3 and free T4
• Hearing and vision screen
• Echocardiogram
• Electrocardiogram (ECG)

Intellectual disability in Williams syndrome is assessed using the Kaufman Brief Intelligence Test, Second Edition (KBIT-2). The assessment computes a composite intelligence quotient and verbal and nonverbal standard scores.[6] Studies utilizing KBIT-2 to measure intelligence quotient in children with Williams syndrome found that their intelligence quotient ranged from average to severe intellectual disability.[6] Children with Williams syndrome often struggle with visuospatial construction, which the KBIT-2 does not measure.[6] The Differential Ability Scale-II (DAS-II) Special Nonverbal Composite assessments and Wechsler intelligence quotient tests may be useful diagnostic tools to measure visuospatial construction.[6][16]

Treatment / Management

Effective management of Williams syndrome requires an interprofessional team due to the various organ systems that may be affected, including:

• Genetic counseling: Upon making the diagnosis, genetic counseling should follow, as a risk to future offspring is present.[2] 

• Obstetrical issues: All pregnancies in patients with Williams syndrome are considered high risk due to the risk of arrhythmia, heart failure, and hypertension.[2] In addition to routine ultrasound of the fetus, urinalysis is necessary due to the risk of urinary tract infections. Genetic counseling may follow during pregnancy, and prenatal testing is available.[2] 

• Cardiac abnormalities: At birth, children with Williams syndrome often need cardiac care for supravascular aortic stenosis, which requires open-heart surgery by a cardiothoracic surgeon. Following surgery, patients should be closely monitored by a cardiologist due to the risk of hypertension and arteriopathy, which can also lead to pulmonary artery stenosis, mitral valve insufficiency, and renal artery stenosis.[2]

• Metabolic disorders: Endocrinologists often manage hypercalcemia, hypothyroidism, and growth reduction in Williams syndrome patients.[2][13] Due to the risk of hypercalcemia, dietary modification is necessary so that excess calcium is not ingested and then excreted through the kidneys.[2] In addition to diet modification, oral corticosteroids or intravenous pamidronate may be used.[2] Calcium levels in patients require careful management, as a low calcium diet may lead to rickets. If the child's short stature is apparent, treatment with growth hormone is also an option. An endocrinologist routinely monitors both glucose and thyroid function.[13] Children with Williams syndrome often require thyroid hormone replacement therapy.[13]

• Renal conditions: If renal calculi develop due to hypercalciuria, a referral to a nephrologist is made for lithotripsy.

• Feeding abnormalities: Gastroenterology referral is warranted for children with feeding difficulties, as they may require a permanent feeding tube.[2] 

• Nutritional issues: Infants with feeding difficulties often require feeding therapy and consultation with a nutritionist.[2]

• Psychiatric conditions: Psychiatric evaluation is recommended to determine the need for medications or psychotherapy to treat comorbid ADHD, OCD, or GAD.[2][17][18]
(A1)

• Ancillary services: Due to neurodevelopmental deficits and intellectual disability, children with Williams syndrome often require special education programs, occupational therapy, physical therapy, speech therapy, and sensory integration therapies.[2] Physical therapy, with a focus on the range of motion, is recommended to prevent joint contractures that may occur.[2] Hearing and vision screening are strong recommendations for all children with neurodevelopmental disorders.[2] Children with Williams syndrome are at risk of hyperopia and recurrent otitis media; therefore, they require routine testing for hearing and vision loss.[2]

• Dental conditions: Refer to an orthodontist or dentist is also recommended due to the risk of malocclusion and dental abnormalities.[2]

Differential Diagnosis

Excluding other neurodevelopmental disorders that can resemble Williams syndrome is essential, including:

• Fetal alcohol syndrome
• DiGeorge syndrome (deletion 22q11.2)
• Noonan syndrome
• Smith-Magenesis syndrome
• Kabuki syndrome
• Marshall syndrome

Autosomal dominant supravalvular aortic stenosis is another condition that should be ruled out, as this condition is a separate disorder from Williams syndrome.[2] 

Toxicity and Adverse Effect Management

Due to the risk of hypercalcemia, supplements with calcium and vitamin D, including multivitamins, should be avoided in children with Williams syndrome.[2] 

Prognosis

The morbidity of Williams syndrome is primarily due to the presence of arteriopathy and congenital heart disease.[2] Approximately 80% of Williams syndrome patients experience cardiovascular abnormalities, eg, stenosed large arteries or ventricular outflow tracts that require cardiothoracic surgery.[19] During the perioperative period, patients have a risk of sudden cardiovascular collapse that may contribute to morbidity and mortality.[20] 

In terms of inheritance, parents with Williams syndrome have a 50% chance of passing the microdeletion to their children.[2] If a parent has 1 child with Williams syndrome but the parent is unaffected, the risk of a sibling acquiring Williams syndrome is low.[2] Patients with Williams syndrome can live semi-independently or, in some cases, independently and are often able to work. As each individual with Williams syndrome has different needs, completion of an individualized life transition plan is recommended, preferably before the age of 13 or 14. 

Complications

When patients with Williams syndrome undergo open-heart surgery, the risk for complications is exacerbated by elastin deficiency.[19][21] A multicenter registry followed patients with Williams syndrome who underwent surgery for the right ventricular outflow tract, left ventricular outflow tract, or supravalvular aortic stenosis.[19] The registry found that 9% of patients with Williams syndrome who had open-heart surgery had major adverse cardiac events, such as arrhythmia or coronary artery disease.[19][22] In cases of coronary artery disease after surgical repair of stenosis, revascularization may be necessary.[22]