WILLIAMS SYNDROME: CAUSES, SYMPTOMS, TREATMENT, LATEST RESEARCH AND MORE

Medically Reviewed by Dr. Sony Sherpa (MBBS)

Williams Syndrome (WS), or Williams-Beuren Syndrome, is a rare sporadic genetic disorder that appears in approximately 1 of every 10,000-20,000 people worldwide^[1]. It is the result of missing genetic material on chromosome 7 that gives rise to various physical and developmental manifestations that characterize the condition.

Those with the disorder have distinct physical features, a remarkable ability with languages, connective tissue issues, cardiovascular difficulties, and developmental issues. WS occurs equally in males and females of all ethnicities.

This article will explore the prevalence, causes, signs and symptoms, diagnosis, treatment, and latest research on Williams Syndrome.

Causes of Williams Syndrome

Large gene deletions from a specific band on the long arm of chromosome 7 cause Williams Syndrome. This band was named the Williams-Beuren Syndrome Critical Region (WBSCR) after the two physicians who discovered the disorder: Dr. John Cyprian Phipps Williams and Dr. A. J. Beuren^[2].

While 28 genes in the WBSCR are associated with the condition, some of which contribute more often than others, no single gene can cause WS. Chromosome 7 codes for many proteins in the body, which explains the commonalities and broad spectrum of symptoms in those affected by WS^[3]. There are many duplicate genes on both the long and short arms of chromosome 7, which possibly helps to promote large gene deletions, as seen in those with WS^[4].

One example of a ubiquitous WS gene deletion is that of the elastin gene (ELN), which is responsible for elastin production. This protein gives tissues and organs their elasticity. Most cases of Williams syndrome possess this gene deletion, causing an elastin deficiency that underpins some of the physical and developmental symptoms associated with Williams Syndrome^[5].

Other gene deletions include:

• LIMK1 (also called LIM kinase-1) may cause the visual-spatial issues usually seen in Williams syndrome.
• GTF2IRD1 may contribute to the distinctive facial features often associated with this condition.

The exact role of other affected genes is still under investigation.

While some cases of Williams Syndrome are inherited, most cases are spontaneous. The condition may arise due to embryonic or fetal damage that occurs during pregnancy, yet the exact causes remain unclear. Gene deletions may be inherited from a parent with WS who carries them. In these cases, the parent has a 50% chance of passing on their condition, irrespective of the child's gender.

Traits and Symptoms of Williams Syndrome

The physical and developmental symptoms of Williams Syndrome can vary from person to person.

People with Williams Syndrome are known for their outgoing, friendly, and sociable personalities. They often have musical talents, are exceptional with language, and may have a strong memory for songs and lyrics.

Some common signs and symptoms of the condition include:

• Distinct facial features: Individuals with Williams Syndrome often have distinct "elfin-like" facial features, such as a small upturned nose, epicanthal folds of skin (where the eyes meet the nose), full cheeks, large ears, a wide mouth, and small jaw and chin complete with small teeth.
• Cardiovascular problems: The deletion of the elastin gene results in the narrowing of major blood vessels, which can cause cardiovascular problems such as high blood pressure and heart murmurs.^[6]
• Developmental delays: Children with Williams Syndrome may reach developmental milestones later than unaffected children, such as sitting, crawling, and walking. They may also have problems with tasks requiring fine motor skills and speech.
• Connective tissue abnormalities: These often cause hyperextensible joints or muscles that lack tone, leading to delays in motor milestones.
• Endocrine issues: Children with Williams syndrome often have hormonal imbalances. Too much calcium in their blood (hypercalcemia) and urine (hypercalciuria) can cause kidney stones. They may also show signs such as slow growth, hypothyroidism, or premature puberty.
• Intellectual disability: Most individuals with Williams Syndrome have mild to moderate intellectual disability and difficulties with learning. They may need help with abstract thinking, problem-solving, and attention.
• Visual problems: Some with WS see images as fragments or reconstruct parts of the image differently. This issue with visual-spatial processing can affect their ability to learn and contribute to delayed development. Later in life, some patients may need reading glasses to treat far-sightedness or have misaligned eyes.
• Mental comorbidities: Comorbid mental health problems may be present as well, such as Attention-Deficit Hyperactivity Disorder (ADHD), Obsessive-Compulsive Disorder (OCD), or Generalized Anxiety Disorder (GAD).
• Auditory sensitivity: Those with WS may be sensitive to loud sounds, and some children are susceptible to middle ear infections. As adults, a large proportion may acquire sensorineural hearing loss.

There are many more symptoms associated with the condition, including digestive issues and speech difficulties (related to a low muscle tone), dental problems like malocclusion, scoliosis (increased sideways spinal curvature), low sleep quality, and urinary issues.^[7]

Diagnosis and Early Intervention

A WS diagnosis may be suspected based on slow infantile development, cardiovascular problems, muscle laxity, and other physical characteristics. These problems may surface during routine follow-up appointments to assess the health of the infant or child when abnormalities become apparent.

Other tests may help to narrow down the diagnosis and rule out neurodevelopmental conditions before genetic testing can confirm the presence of WS. As the symptoms can vary, several tests can aid in the diagnosis, including:

• Complete blood count
• Metabolic panel
• Thyroid hormone tests
• Screening for hearing or vision anomalies
• Cardiovascular assessment
• IQ testing for general intelligence and visual-spatial ability

There are only two currently recognized genetic tests that can diagnose WS:

1. Chromosomal Microarray (CMA) determines the copy number of sequences on chromosome 7 and identifies missing duplicate genes characteristic of WS.
2. Fluorescence In Situ Hybridization (FISH) testing performs targeted deletion analysis and highlights the specific genes missing on chromosome 7.

Early intervention is crucial for individuals with Williams Syndrome to improve lifelong outcomes. Early detection allows for the swift implementation of necessary therapeutic services, such as speech therapy, occupational therapy, and physiotherapy. These therapies can help improve developmental delays and support the individual's overall growth and development.

Genetic counseling is equally important for parents of children with WS as it equips them to deal with the challenges and to know what to expect. As many physical, mental, and developmental problems can occur in those with the disorder, parents need to be aware of the potential complications, including cardiovascular conditions.

Treatment or Management of Williams Syndrome

The life expectancy of WS individuals is not necessarily different from that of the general population. However, those affected may have a higher risk of developing cardiovascular problems and other health conditions that influence their life span.

No cure for Williams Syndrome currently exists. Treatment aims to manage symptoms and support the individual's overall well-being. Options for WS individuals may include:

• Corrective heart surgery: After birth, those with WS may require corrective heart surgery to alleviate pressure or other problems caused by typical narrowing of the blood vessels.
• Dietary adjustments: Due to calcium excesses and hormonal imbalances, an endocrinologist or highly skilled dietician will need to advise tailoring the diet to minimize calcium intake while avoiding deficiency. Some infants may need a feeding tube if they battle to eat.
• Hormone replacement: Some children with WS are deficient in growth hormone and other vital hormones. In these cases, the administration of synthetic hormones can help improve developmental outcomes.
• Medications: Medications can help lessen symptoms of other conditions, such as high blood pressure, anxiety, attention deficit hyperactivity disorder (ADHD), and other comorbidities.
• Therapies: Various therapies, such as speech therapy, occupational therapy, and physical therapy, can help improve developmental delays and support overall growth and development.

As the person with WS ages, they may need additional treatments for complications that arise, including hearing aids, eye surgery or eyeglasses, and additional cardiovascular treatments.

Living with Williams Syndrome

Living with Williams Syndrome can present challenges. With proper support and resources, individuals with this disorder can lead fulfilling lives.

Their endearing personality traits and strengths, such as their friendly, sociable nature, affinity for music, and proficiency with language, allow them to integrate into school and lead independent lives as adults. According to the Williams Syndrome Association, many affected individuals can enroll in academic and life-skills-oriented post-secondary programs after school.

Children with Williams Syndrome may benefit from specialized education tailored to their unique learning needs. Many can learn to read and perform basic arithmetic with such educational programs. Education that takes advantage of their social, musical, and linguistic abilities is ideal.

Some may need assistance with daily tasks, social skills training, and support for independent living.

Families and caregivers need to educate themselves about Williams Syndrome and connect with support groups and resources in their community.

Can Williams Syndrome Be Prevented?

As Williams Syndrome is a genetic disorder, it cannot be prevented. Genetic counseling can help families with a history of Williams Syndrome or parents who have a child with the disorder.

Latest Research and Advancements

Research on Williams Syndrome is ongoing, with few advancements in understanding the disorder and potential treatments.

Some current areas of research include:

• Elastin gene therapy: Researchers are exploring the potential of gene therapy to replace the missing elastin gene in a wide variety of connective tissue disorders, including Williams Syndrome. Current studies are assessing the efficacy of several methods in genetically modified elastin-deficient cells, with some promising results.^[8]
• Genetic analysis: Over the last several years, more gene deletions have surfaced that can contribute to WS development with a greater understanding of their role. For instance, one review suggests that underlying the hypersociability of WS is the deletion of the GTF2I gene, which may play a role in excess calcium, nervous transmission, and stem cell induction.^[9]

With more time and research, a comprehensive understanding of WS gene deletions can assist with the development of better diagnostic tools and personalized treatment options.

Conclusion

Williams Syndrome is a rare disorder that arises sporadically in approximately 1 in every 10,000 individuals globally. It results from a spontaneous deletion of genetic material on chromosome 7, which leads to various physical and developmental symptoms. While there is no cure for Williams Syndrome, early detection, symptoms assessment, and management can significantly improve outcomes for individuals with this disorder. With continued research and advancements, we can continue to improve the lives of those living with Williams Syndrome.