Williams Syndrome
Overview
Plain-Language Overview
Williams Syndrome is a rare genetic disorder that affects many parts of the body. It is caused by a small deletion of genes on chromosome 7. People with this condition often have distinctive facial features, such as a broad forehead and a wide mouth. They may also experience heart problems, especially narrowing of the arteries. Many individuals with Williams Syndrome have learning difficulties but are often very social and friendly.
Clinical Definition
Williams Syndrome is a multisystem genetic disorder caused by a microdeletion of approximately 1.5 to 1.8 megabases on chromosome 7q11.23, which includes the elastin gene (ELN). This deletion results in a characteristic constellation of clinical features including distinctive craniofacial dysmorphisms such as a broad forehead, periorbital fullness, a short nose with a broad tip, and a wide mouth with full lips. Cardiovascular abnormalities are common, particularly supravalvular aortic stenosis and peripheral pulmonary artery stenosis due to elastin deficiency. Patients often exhibit mild to moderate intellectual disability with a unique cognitive profile characterized by relative strengths in verbal short-term memory and language alongside deficits in visuospatial construction. Behavioral phenotypes include an overly friendly and social personality, heightened empathy, and increased anxiety. Other systemic manifestations may include hypercalcemia in infancy, connective tissue abnormalities, and endocrine issues such as hypothyroidism. Diagnosis is confirmed by fluorescence in situ hybridization (FISH) or microarray demonstrating the 7q11.23 deletion. Management requires multidisciplinary care addressing cardiovascular, developmental, and behavioral needs.
Inciting Event
- Williams Syndrome is caused by a genetic deletion occurring during gametogenesis or early embryogenesis.
- There is no external inciting event or environmental trigger.
Latency Period
- none
Diagnostic Delay
- Mild or nonspecific early symptoms can lead to delayed recognition of the syndrome.
- Lack of awareness of the characteristic facial features and cardiovascular findings may delay diagnosis.
- Variable severity of cardiovascular disease can postpone clinical suspicion.
Clinical Presentation
Signs & Symptoms
- Distinctive facial features described as elfin facies.
- Cardiovascular abnormalities including supravalvular aortic stenosis and hypertension.
- Developmental delays with mild to moderate intellectual disability.
- Hypercalcemia in infancy causing irritability and feeding difficulties.
- Overfriendly personality and strong verbal skills relative to other cognitive domains.
History of Present Illness
- Infants may present with feeding difficulties and failure to thrive.
- Characteristic facial features include a broad forehead, periorbital fullness, and a wide mouth with full lips.
- Developmental delays, especially in motor and language skills, are common.
- Patients often exhibit a distinctive personality with overfriendliness and strong verbal abilities.
- Cardiovascular symptoms may include signs of heart murmur or exertional fatigue due to vascular stenosis.
Past Medical History
- History may include supravalvular aortic stenosis or other vascular abnormalities diagnosed in infancy or childhood.
- Frequent hypercalcemia episodes in infancy may be reported.
- Developmental delays and learning disabilities are common past medical issues.
Family History
- Most cases are sporadic with no family history due to de novo deletions.
- Rarely, autosomal dominant inheritance can be observed if a parent carries the deletion.
- Family history may reveal relatives with similar cardiovascular or developmental features.
Physical Exam Findings
- Characteristic elfin facial features including a broad forehead, short nose with a broad tip, full cheeks, and a wide mouth with a prominent chin.
- Supravalvular aortic stenosis may be detected as a systolic murmur best heard at the right upper sternal border.
- Hypercalcemia signs may include irritability and hypotonia in infants.
- Short stature and growth delays are often observed.
- Dental abnormalities such as widely spaced teeth and malocclusion are common.
Diagnostic Workup
Diagnostic Criteria
Diagnosis of Williams Syndrome is based on the presence of characteristic clinical features including distinctive facial appearance, cardiovascular abnormalities such as supravalvular aortic stenosis, and a unique neurocognitive profile with mild to moderate intellectual disability and hypersociability. Confirmation requires genetic testing demonstrating a microdeletion at chromosome 7q11.23, typically via fluorescence in situ hybridization (FISH) or chromosomal microarray analysis.
Pathophysiology
Key Mechanisms
- Williams Syndrome results from a hemizygous deletion of 26-28 genes on chromosome 7q11.23, including the ELN gene encoding elastin.
- The loss of elastin leads to connective tissue abnormalities and vascular stenosis, particularly supravalvular aortic stenosis.
- Deletion of genes affecting neurodevelopment causes characteristic cognitive and behavioral features.
| Involvement | Details |
|---|---|
| Organs | Heart is affected by supravalvular aortic stenosis and other vascular abnormalities. |
| Brain shows developmental differences leading to cognitive and behavioral phenotypes. | |
| Kidneys may be involved due to vascular abnormalities affecting renal arteries. | |
| Tissues | Vascular smooth muscle tissue is abnormal, causing supravalvular aortic stenosis and other arterial stenoses. |
| Connective tissue abnormalities lead to characteristic facial features and joint laxity. | |
| Cells | Elastin-producing fibroblasts are affected due to elastin gene deletion causing vascular abnormalities. |
| Cardiomyocytes may be hypertrophied secondary to increased afterload from vascular stenosis. | |
| Chemical Mediators | Elastin is deficient due to gene deletion on chromosome 7, leading to connective tissue abnormalities. |
| Angiotensin II may be elevated contributing to hypertension and vascular remodeling. |
Treatment
Pharmacological Treatments
Antihypertensives
- Mechanism: Lower blood pressure to manage supravalvular aortic stenosis and systemic hypertension
- Side effects: hypotension, dizziness, fatigue
Calcium channel blockers
- Mechanism: Reduce vascular resistance and improve arterial compliance
- Side effects: edema, headache, constipation
Non-pharmacological Treatments
- Regular cardiovascular monitoring to assess for progression of vascular stenosis.
- Early intervention with surgery for severe supravalvular aortic stenosis.
- Speech and occupational therapy to address developmental delays and cognitive deficits.
- Nutritional support to manage feeding difficulties and promote growth.
Prevention
Pharmacological Prevention
- Use of antihypertensive agents to manage hypertension and reduce cardiovascular risk.
- Treatment of hypercalcemia with calcium restriction and medications such as bisphosphonates if severe.
Non-pharmacological Prevention
- Regular cardiovascular monitoring including echocardiography to detect and manage vascular stenoses early.
- Early developmental interventions including speech, occupational, and physical therapy.
- Nutritional management to prevent complications of hypercalcemia and support growth.
- Genetic counseling for affected families.
Outcome & Complications
Complications
- Cardiovascular complications including heart failure and sudden cardiac death from severe stenosis.
- Persistent hypertension leading to end-organ damage.
- Hypercalcemia-related complications such as nephrocalcinosis.
- Developmental and behavioral challenges impacting quality of life.
| Short-term Sequelae | Long-term Sequelae |
|---|---|
|
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Differential Diagnoses
Williams Syndrome versus 22q11.2 Deletion Syndrome (DiGeorge Syndrome)
| Williams Syndrome | 22q11.2 Deletion Syndrome (DiGeorge Syndrome) |
|---|---|
| Supravalvular aortic stenosis and peripheral pulmonary artery stenosis are typical. | Conotruncal cardiac defects such as tetralogy of Fallot are frequent. |
| Hypercalcemia in infancy is a feature of Williams syndrome. | Hypocalcemia due to parathyroid hypoplasia is common. |
| Distinctive 'elfin' facial features and strong social personality are characteristic. | Cleft palate and immunodeficiency are often present. |
Williams Syndrome versus Marfan Syndrome
| Williams Syndrome | Marfan Syndrome |
|---|---|
| Supravalvular aortic stenosis rather than aortic root dilation is seen in Williams syndrome. | Aortic root dilation and mitral valve prolapse are common cardiac findings. |
| Short stature and broad chest contrast with Marfan's tall habitus. | Tall stature with long limbs and arachnodactyly are typical skeletal features. |
| Distinctive facial features and hypercalcemia are not features of Marfan syndrome. | Lens dislocation (ectopia lentis) is a frequent ocular manifestation. |
Williams Syndrome versus Noonan Syndrome
| Williams Syndrome | Noonan Syndrome |
|---|---|
| Supravalvular aortic stenosis is characteristic of Williams syndrome. | Pulmonary valve stenosis is common in Noonan syndrome. |
| Elfin facies with a broad forehead and periorbital fullness are typical. | Short stature and webbed neck are typical features. |
| Mild to moderate intellectual disability with strong verbal skills is common. | Normal cognitive development or mild learning difficulties are usual. |