William’s Syndrome

William’s syndrome (WMS) is a rare genetic disorder caused by the deletion of a specific chromosome region resulting in the absence of 26 to 28 genes (1). Core features of WMS include below-average overall intellectual ability, cardiovascular issues, and facial dysmorphology (2). Given its unique genetic basis, WMS has been widely studied in order to better understand the relationship between the genetics and its related cognitive and behavioral presentation (3). Treatment of WMS is focused on management of symptoms and general supportive therapies.

Symptoms

Common symptoms of WMS span cognitive, behavioral, and physical domains. Cardiovascular issues are often diagnosed, including supravalvular aortic stenosis which is found in 70% of individuals with WMS (1). This and other cardiovascular abnormalities are major causes of death in WMS (1). Other common medical conditions associated with WMS include hypercalcemia (increased calcium levels in the bloodstream), diabetes, and atypical thyroid function (1). Behavioral symptoms include hypersociability – individuals with WMS are often described as overly friendly (3).  This social disinhibition may be a disadvantage, encouraging exploitation of these individuals or difficult interpersonal relationships (3).

While overall intellectual functioning is typically lower than average in WMS, studies of different cognitive domains reflect specific strengths and weaknesses (2).  Generally, overall language abilities are relatively intact, although acquisition of language may be delayed (3).  On the other hand, visual-spatial abilities are often particularly weak in WMS with recognition and processing of faces specifically noted as a relative strength (2, 3).  Interestingly, many individuals with WMS have been noted to have strong musical skills (especially in the context of other cognitive weaknesses), although objective research of this quality has reached variable conclusions and more confirmatory studies are needed (3).

Psychiatric symptoms are also rather common in WMS. Impulsivity and inattention are often observed, leading to a diagnosis of attention-deficit/hyperactivity disorder in some (4). Individuals with WMS also have significantly higher rates of both generalized anxiety and specific fears or phobias (4). The presence of significantly elevated anxiety has important implications for both treatment and functioning, with evidence suggesting more serious social dysfunction and poorer quality of life associated with higher anxiety (1, 5). Additionally, at least one longitudinal study revealed that anxiety symptoms often persist and generalize over time and are related to difficulties in behavioral regulation (6).

Course and Prevalence

Diagnosis of WMS usually occurs during infancy, with clinical features appearing as early as four months of age (7). Typically, a fluorescence in situ hybridization (a technique using a microscope to examine prepared samples) confirms a diagnosis through the identification of atypical genetic markers, namely the presence of one allele rather than two (1). WMS is very rare, with estimated prevalence rates ranging from approximately 1:20,000 to 1:50,000 (7).

Individuals with WMS typically require consistent medical attention given the frequency and severity of numerous physical comorbidities (1). WMS is also suspected to be associated with mild accelerated aging, given evidence of premature graying of the hair, hearing loss, and declining memory or dementia relatively early in life (1). While few may be able to function independently, most require supervision and assistance throughout adulthood (1).

Neuroanatomy

Multiple studies using various neuroimaging techniques have identified neuroanatomical differences in individuals with WMS compared to typical controls, including reduced cerebral volume with reductions in white matter volume and relatively spared gray matter volume. Structural atypicality in the parietal and occipital cortices are likely reflective of the visual-spatial deficits commonly observed in WMS, while preserved areas in the temporal cortex may be linked to strengths in language and music. There is some functional imaging evidence suggesting that individuals with WMS may have a greater emotional reaction to music, and limbic areas (brain regions involved with the recognition and processing of emotion) are typically unaffected in WMS (3).

Treatment

Given that WMS is an irreversible genetic condition, its treatment is primarily supportive. Ongoing medical management of related health issues is crucial and may include surgery to address cardiovascular issues and various medications to resolve hypertension and thyroid problems (1). Routine screening and monitoring of glucose and calcium levels is recommended given predispositions to increased levels of both. These may be balanced through insulin and calcium or Vitamin D, respectively (1).

Treatment of anxiety may include cognitive-behavioral therapy and/or medications such as selective serotonin-reuptake inhibitors, although more empirical evidence is needed to confirm the benefits of both (1, 4).  It is likely that biofeedback and neurofeedback could be helpful for this syndrome, since training the patient in diaphragmatic breathing, heart rate variability, muscle relaxation and neurofeedback could help the above noted symptoms and reduce or eliminate the use of medication.  To date, however, there are no studies of biofeedback for Williams Syndrome.

—S. Jacobs and J. Thomas

References

1. Pober, B (2010). Williams–Beuren syndrome. New England Journal of Medicine, 362(3), 239-252.  https://www.ncbi.nlm.nih.gov/pubmed/20089974
2. Bellugi, U, Lichtenberger, L, Jones, W, Lai, Z, & St. George, M (2000). I. The neurocognitive profile of Williams Syndrome: a complex pattern of strengths and weaknesses. Journal of cognitive neuroscience, 12(Supplement 1), 7-29.
3. Martens, M, Wilson, S, & Reutens, D (2008). Research Review: Williams syndrome: a critical review of the cognitive, behavioral, and neuroanatomical phenotype. Journal of Child Psychology and Psychiatry, 49(6), 576-608.
4. Dykens, E (2003). Anxiety, fears, and phobias in persons with Williams syndrome. Developmental neuropsychology, 23(1-2), 291-316. https://www.ncbi.nlm.nih.gov/pubmed/12730029
5. Riby, D, Hanley, M, Kirk, H, Clark, F, Little, K, Fleck, R, … & Allday, M (2014). The interplay between anxiety and social functioning in Williams syndrome. Journal of Autism and Developmental Disorders, 44(5), 1220-1229.
6. Woodruff‐Borden, J, Kistler, D, Henderson, D, Crawford, N, & Mervis, C (2010, May). Longitudinal course of anxiety in children and adolescents with Williams syndrome. In American Journal of Medical Genetics Part C: Seminars in Medical Genetics(Vol. 154, No. 2, pp. 277-290). Hoboken: Wiley Subscription Services, Inc., A Wiley Company.
7. Sugayama, S, Leone, C, Chauffaille, M, Okay, T, & Kim, C (2007). Williams syndrome: Development of a new scoring system for clinical diagnosis. Clinics, 62(2), 159-166.