Williams syndrome is a neurodevelopmental condition diagnosed by recognizing a collection of clinical signs followed by definitive genetic confirmation. The disorder is characterized by a unique combination of features affecting multiple body systems, including the cardiovascular system, cognitive development, and physical appearance. It is caused by the spontaneous deletion of genetic material on chromosome 7, impacting approximately 25 to 27 genes in a specific region. This article outlines the diagnostic process, from initial clinical suspicion to genetic testing and necessary comprehensive evaluations.
Clinical Indicators Leading to Evaluation
The first step in diagnosis is the recognition of a cluster of clinical indicators that suggest the presence of Williams syndrome (WS), often prompting a referral from a pediatrician to a specialist. These initial “red flags” encompass distinctive physical characteristics, specific medical concerns, and developmental patterns.
One of the most telling physical features is the distinctive facial appearance, often described as having a broad forehead, a small, upturned nose, full cheeks, and a wide mouth with full lips. Infants may also present with low birth weight, poor weight gain, and feeding difficulties, which can be the earliest signs prompting medical investigation.
Crucially, many individuals with WS are born with cardiovascular defects, with supravalvular aortic stenosis (SVAS)—a narrowing just above the aortic valve—being the most common and often the most serious medical indicator. The presence of SVAS, or other vascular narrowings, combined with characteristic facial features, raises a high suspicion for the condition.
Developmental delays are also frequently observed, particularly in motor skills like sitting, crawling, and walking. Behaviorally, children with WS often exhibit an outgoing, hypersocial personality, showing excessive friendliness toward strangers, although this is often coupled with high levels of anxiety. When several of these physical, medical, and developmental signs are noted together, genetic testing is recommended to confirm the suspected diagnosis.
The Role of Definitive Genetic Testing
While clinical indicators provide strong suspicion, a definitive diagnosis of Williams syndrome relies exclusively on confirming the deletion of genetic material. WS is categorized as a contiguous gene syndrome, meaning symptoms arise from the loss of multiple adjacent genes on the 7q11.23 region of chromosome 7. This deletion is identified in nearly all patients (98–99%) who present with typical clinical features.
The most common and historically recognized method for confirming this genetic loss is Fluorescence In Situ Hybridization (FISH) testing. FISH utilizes specialized probes—short pieces of DNA tagged with fluorescent dye—designed to bind specifically to the region of the chromosome that is deleted in WS. The ELN (Elastin) gene, which is often targeted by the FISH probe, is crucial to this region.
In a typical individual, two fluorescent signals are visible, representing the two copies of chromosome 7. If the individual has Williams syndrome, the probe only binds to one copy of the ELN gene region, resulting in only one visible fluorescent signal, which confirms the deletion. This test is highly specific for the region associated with WS.
Increasingly, Chromosomal Microarray (CMA) analysis is being used as a preferred diagnostic tool. CMA is a comprehensive test that scans the entire genome for small missing or extra pieces of DNA, including the specific microdeletion that causes WS. This method provides more detailed information about the exact size of the deletion and the precise number of genes involved, which can offer greater insight into the potential severity of the condition.
The presence of the deletion confirms the diagnosis of Williams syndrome. If a person displays clinical features but genetic tests do not show the deletion, they are considered not to have WS, and the clinical signs are attributed to another cause. Genetic confirmation establishes the diagnosis, paving the way for targeted care.
Comprehensive Post-Diagnostic Assessments
Once the genetic diagnosis of Williams syndrome is confirmed, comprehensive assessments are immediately required to establish a baseline of the person’s health and the severity of the condition. This stage is performed by a team of specialists to ensure all affected systems are evaluated and to guide early interventions.
A thorough cardiology evaluation is paramount, typically involving an echocardiogram and sometimes an electrocardiogram. This assesses the extent of vascular narrowings like SVAS and monitors for other heart complications. Due to the high risk of hypertension and progressive vascular issues, these cardiac assessments often continue throughout life.
Renal and endocrine assessments are necessary, as individuals with WS frequently experience high calcium levels in the blood (hypercalcemia) and structural abnormalities in the kidneys. Evaluations involve blood tests for calcium, creatinine, and thyroid-stimulating hormone (TSH), along with a renal ultrasound.
Formal developmental and cognitive testing maps out the individual’s learning profile. These results establish a baseline for speech, occupational, and physical therapies, which are initiated early to support motor skill development and address learning challenges. An ophthalmological exam is also important to check for strabismus (crossed eyes) and other associated vision issues.