Williams Beuren Syndrome

Williams-Beuren Syndrome: Controversies in the Complex Behavioral and Cognitive Profile of a Unique Genetic Disorder

Zachary Blaker
November 12, 2015
(3,982 words)

Introduction
Williams-Beuren Syndrome (WBS) is a rare neurodevelopmental disorder typically characterized by distinctive facial features, cognitive delays accompanied by comparatively strong language and verbal skills, deficits in visuospatial construction, and hyper-social personality traits (Martens et al. 2008). The cognitive aspects of this disorder have been largely controversial, partially due to the difficulty of choosing an appropriate comparison group. Many early studies used other disorders with mental disabilities such as Down Syndrome
and autism spectrum disorders as comparison groups, but more contemporary studies argue that these comparisons have led to inaccurate characterization of certain aspects of the WBS as intact when they are, in reality, deficient compared to typically developing individuals. A large number of affected individuals present with some type of cardiovascular disease, which is subsequently the most common cause of death related to the disorder (Pober et al. 2008). The cause of WBS is now known to be due to an approximately 1.5Mb hemizygous deletion of about 28 genes at 7q11.23 (Meyer-Lindenberg et al. 2006). The vast majority of known cases are sporadic, although there have been some reported cases of familial transmission (Morris 2010). Prior to the identification of this deletion, WBS was diagnosed primarily based on phenotype, especially the unique facial features (facies) that are almost ubiquitously expressed in affected individuals. Now, following this discovery, it is possible to diagnose the disease using a simple blood test known as chromosome fluorescence in situ hybridization (FISH). A number of studies have shown that 96% to 98% of individuals with a clinical diagnosis of WBS test positive for deletions in this region (Morris and Mervis 2000). This review will focus on the clinical presentation of WBS, including physical characteristics, cognitive and behavioral phenotypes, and the genetic background of the disorder. It will address some of the many controversies regarding the complex cognitive and behavioral phenotype observed in this disorder and outline gaps in the current literature.
Prevalence
As with many low-frequency disorders, the incidence and prevalence of WBS is difficult to confidently ascertain. Literature estimates of prevalence vary greatly, from 1 in 7,500 (Strømme et al. 2002) to 1 in 25,000 (Bellugi et al. 2000). Although the disease has long been distinctly recognizable due to its highly distinctive physical characteristics, data on its prevalence remains limited due to a lack of studies and the relative recency of its discovery and description. However, with diagnosis using FISH becoming common practice, future studies should be able to more accurately pinpoint the prevalence of this disorder.

Clinical Presentation
Physical Characteristics
Facies.
Individuals with WBS present a wide variety of symptoms. Most obvious are their outward physical characteristics, which typically include a wide, open mouth with thick lips, a delicate and pointed chin, fullness around the eyes, retroussé nose, misaligned teeth, and full cheeks below the cheekbones (Figure 1) (Winter et al. 1996). These features have been termed “elfin facies”, and are generally most distinct between the ages of one and five. They tend to be so clear that individuals with WBS may appear more closely related to one another than to direct family members. However, with age these features tend to stiffen and skin appears to age at an increased rate (Tassabehji et al. 1997). These facial features and premature aging of the skin are generally attributed to the deletion of the elastin gene, located on chromosome 7 and known to be deleted in more than 90% of individuals with WBS (Nickerson et al.
1995). Growth Rate. Another notable physical phenotype of WBS is an abnormal growth pattern. Many studies have observed especially decreased heights during infancy and early childhood. One study of nine patients at the Children’s Orthopedic Hospital and Medical Center in Seattle found that eight of the nine were between the fifth and 25th percentiles for height, and all had been at or below the fifth percentile for height through three years of age, and often into later childhood (Pagon et al. 1987). However, this study came before the genetic deletion 7q11.23 had been discovered and used as a diagnostic tool, inviting the possibility for error in the clinical diagnoses of these subjects. A later longitudinal study of 169 British children and adults confirmed to have WBS based on this deletion measured their heights on up to four occasions over the course of four years (Martin et al. 2007). They found the average heights of individuals with WBS to be 159 centimeters (~62.5 inches) and 152 centimeters (~60 inches) in males and females, respectively. These heights were 18 centimeters (~7 inches) and 12 centimeters (~5 inches) shorter than reference British individuals. The results obtained in this study signify that patients with WBS tend to have extremely deficient growth rates at a young age, with those effects tapering out as they reach adulthood, yet still remaining significant.
There are a variety of possibilities for the cause of the short stature observed in these individuals. One is that one or multiple of the deleted genes in these individuals are necessary for prenatal and early infant growth. Another possibility is a general failure to thrive during infancy due to feeding difficulties that may be present due to increased anxiety and other behavioral present in WBS. Unfortunately, a general lack of research is prominent in this area.
Medical Complications
Cardiovascular abnormalities.
Individuals with WBS often present with a variety of medical complications. Most prevalent among them are cardiovascular abnormalities, which are observed in upwards of 80% of cases and are the most frequent cause of death among patients. Of these, supravulvar aortic stenosis (SVAS) is most frequent, occurring at a frequency of about 45% (Collins et al. 2010). As with the distinctive facial features present in WBS, this disease has been linked to deletions in the elastin gene (Ewart et al. 1994). Sexual differences in the prevalence and severity of cardiovascular abnormalities in WBS remain controversial. A study of 127 patients with WBS found that males presented with cardiovascular abnormalities at a higher frequency and with a higher severity than females (Sadler et al. 2001). More recently, a study of 270 cases of WBS evaluated at the Children’s Hospital of Philadelphia found no significant difference in severity or distribution between genders (Collins et al. 2010). Notably, in the study by Sadler and colleagues, males presented earlier than females. This may explain the observed gender bias as cardiovascular abnormalities that present earlier tend to be more
severe.
Hypercalcemia. Approximately 15% of WBS patients present with infantile hypercalcemia (Cagle 2004). Although this diagnosis is typically not severe and tends to resolve itself without intervention prior to adulthood, it can lead to vomiting and constipation. Such symptoms may contribute to difficulties in feeding and the failure to thrive that is often present in children with WBS. The cause of this deficit in calcium metabolism is currently unknown.