| Williams syndromealitis | |
|---|---|
| Classification and external resources | |
| ICD-10 | Q93.8 |
| ICD-9 | 758.9 |
| OMIM | 194050 |
| MedlinePlus | 001116 |
| eMedicine | ped/2439 |
| MeSH | D018980 |
Williams syndrome (WS or WMS; also Williams–Beuren syndrome or WBS) is a rare neurodevelopmental disorder characterized by a distinctive, "elfin" facial appearance, along with a low nasal bridge, an unusually cheerful demeanor and ease with strangers; developmental delay coupled with strong language skills; and cardiovascular problems, such as supravalvular aortic stenosis and transient hypercalcaemia.
It is caused by a deletion of about 26 genes from the long arm of chromosome 7.[1] The syndrome was first identified in 1961 by Dr. J. C. P. Williams of New Zealand[2] and has an estimated prevalence of 1 in 7,500 to 1 in 20,000 births.[1]
Contents |
Williams syndrome was first described by Dr. J.C.P. Williams and his colleagues, who wrote in 1961 of four patients with supravalvular aortic stenosis, mental disability, and facial features including a broad forehead, lowset "drooping" cheeks, widely-spaced eyes, and a wideset mouth. A year after this report, German physician Dr. A. J. Beuren described three new patients with the same presentation. This led to the disorder's full original name of Williams-Beuren syndrome, which is still used in some medical publications. From 1964 to 1975, small research reports broadened medical knowledge of this disorder's cardiovascular problems. Then in 1975, Drs. K. Jones and D. Smith conducted a large-scale report on numerous patients with Williams syndrome, ranging in age from infancy to adulthood, and described the behavioral and observable physical symptoms in greater detail than previously recorded. [3]
| Williams Syndrome genes[4][5] | |
|---|---|
| ASL · BAZ1B · BCL7B · CLDN3 · CLDN4 CLIP2 · EIF4H · ELN · FZD9 · FKBP6 GTF2I · GTF2IRD1 · HIP1 · KCTD7 LAT2 · LIMK1 · MDH2 · NCF1 NSUN5 · POR · RFC2 · STX1A · TBL2 TRIM50 · TRIM73 · TRIM74 WBSCR14 · WBSCR18 · WBSCR21 WBSCR22 · WBSCR23 · WBSCR24 WBSCR27 · WBSCR28 |
Williams syndrome is caused by the deletion of genetic material from the region q11.23 of chromosome 7. The deleted region includes more than 25 genes, and researchers believe that the loss of several of these genes probably contributes to the characteristic features of this disorder. CLIP2, ELN, GTF2I, GTF2IRD1, and LIMK1 are among the genes that are typically deleted in people with Williams syndrome. Researchers have found that loss of the ELN gene, which codes for the protein elastin, is associated with the connective-tissue abnormalities and cardiovascular disease (specifically supravalvular aortic stenosis and supravalvular pulmonary stenosis) found in many people with this syndrome. Studies suggest that deletion of LIMK1, GTF2I, GTF2IRD1, and perhaps other genes may help explain the characteristic difficulties with visual–spatial tasks. Additionally, there is evidence that the loss of several of these genes, including CLIP2, may contribute to the unique behavioral characteristics, learning disabilities, and other cognitive difficulties seen in Williams syndrome.[6]
Williams syndrome has historically been estimated to occur in roughly 1 in every 20,000 live births. [7] However, more recent epidemiological studies have placed the occurrence rate at closer to 1 in every 7,500 live births, a significantly larger prevalence. As an increasing body of evidence suggests that Williams syndrome is more common than originally noted (approximately 6% of all genetic cases of developmental disability), researchers have begun to theorize past under-diagnosis of the disorder. [8] One theorized reason for the increase in epidemiological estimates is that there exists a substantial minority of individuals with the genetic markers of Williams syndrome who lack the characteristic facial features or the diminished IQ considered to be diagnostic of the disorder, who often are not immediately recognized as people with the syndrome.[3] [9]
According to the Williams Syndrome Association, diagnosis of Williams syndrome begins with recognition of physical symptoms and markers, which is followed by a confirmatory genetic test. The physical signs that often indicate a suspected case of Williams syndrome include puffiness around the eyes, a long philtrum, and a stellate pattern in the iris. Physiological symptoms that often contribute to a Williams syndrome diagnosis are cardiovascular problems, particularly aortic or pulmonary stenosis, as well as feeding disturbance in infants. Developmental delays are often taken as an initial sign of the disorder, as well. [10]
If a physician suspects a case of Williams syndrome, the diagnosis is confirmed using one of two possible genetic tests: micro-array analysis or the fluorescent in situ hybridization (FISH) test. The FISH test examines chromosome #7 and probes for the existence of two copies of the elastin gene. Since 99-98% of individuals with Williams syndrome lack half of the 7q11.23 region of chromosome #7, where the elastin gene is located, the presence of only one copy of the gene is a strong sign of the disorder.[10] This confirmatory genetic test has been validated in empidemiological studies of the disorder, and has been demonstrated to be a more effective method of identifying Williams syndrome than previous methods, which often relied on the presence of cardiovascular problems and facial features (which, while common, are not always present). [11]
Some diagnostic studies suggest that reliance on facial features to identify Williams syndrome may cause a misdiagnosis of the condition. Among the more reliable features suggestive of Williams are congenital heart disease, periorbital fullness ("puffy" eyes), and the presence of a long smooth philtrum. Less reliable signs of the syndrome include anteverted nostrils,a wide mouth, and an elongated neck. Researchers indicate that even with significant clinical experience, it is difficult to reliably identify William syndrome based on facial features alone. [12]
The most common symptoms of Williams syndrome are mental disability, heart defects, and unusual facial features. Other symptoms include failure to gain weight appropriately in infancy (failure to thrive) and low muscle tone. Individuals with Williams Syndrome tend to have widely spaced teeth, a long philtrum, and a flattened nasal bridge.[13]
Most individuals with Williams syndrome are highly verbal relative to their IQ, and are overly sociable, having what has been described as a "cocktail party" type personality.[3] Individuals with WS hyperfocus on the eyes of others in social engagements.[14]
Individuals with Williams syndrome experience many cardiac problems, commonly heart murmurs and the narrowing of major blood vessels as well as supravalvular aortic stenosis.Other symptoms may include gastrointestinal problems, such as severe or prolonged colic,[15] abdominal pain and diverticulitis, nocturnal enuresis (bed wetting) and urinary difficulties, dental irregularities and defective tooth enamel, as well as hormone problems, the most common being hypercalcemia (elevated calcium levels in the blood).[16] Hypothyroidism has been reported to occur in children, although there is no proof of it occurring in adults; adults with WS have a higher risk of developing diabetes, with some cases apparent as young as 21 years old.[17]
Individuals with Williams syndrome often have hyperacusis and phonophobia which resembles noise-induced hearing loss, but this may be due to a malfunctioning auditory nerve.[18][19] However, individuals with WS can also tend to demonstrate a love of music,[2] and appear significantly more likely to possess perfect pitch.[20] There also appears to be a higher prevalence of left-handedness and left-eye dominance.[21]
Furthermore, individuals with Williams syndrome have problems with visual processing, but this is related to difficulty in dealing with complex spatial relationships rather than to issues with depth perception.[22]
Because of the multiple genes that are missing in people with Williams syndrome, there are many effects on the brain, including abnormalities in the cerebellum, right parietal cortex, and left frontal cortical regions. This pattern is consistent with the visual-spatial disabilities and problems with behavioral timing often seen in Williams syndrome.
Frontal-cerebellar pathways, involved in behavioral timing, are often abnormally developed in individuals with Williams syndrome, which may be related to their deficits in coordination and execution of fine motor tasks such as drawing and writing. In addition, people with Williams syndrome often exhibit gross motor difficulties, including trouble walking down stairs, as well as overactive motor reflexes (hyperreflexia) and hyperactive, involuntary movement of the eyes (nystagmus).[7]
Williams syndrome is also noteworthy for exhibiting abnormalities in the parietal-dorsal areas of the neocortex, but not the ventral areas. The parietal-dorsal area handles visual processing that supports visual-spatial analysis of the environment, while the ventral is related to semantic recognition of visual stimuli, as well as the recognition of faces. Thus, individuals with Williams syndrome are often able to visually identify and recognize whole objects, and refer to them by name, but struggle with visuospatial construction (seeing an object as being composed of many smaller parts, and recreating it) and orienting themselves in space.[7]
People with Williams syndrome are often affable and hyperverbal, demonstrating the decreased inhibition ability that stems from dorsal-frontal deficits.[23] Some studies suggest that the amygdala of a person with Williams syndrome has greater volume than the average person's (though it is smaller than average in childhood).[24] In general, neuroimaging studies demonstrate that individuals with Williams syndrome have diminished amygdala reactivity in response to socially frightening stimuli (such as disapproving faces), but demonstrate hyperreactivity in the amygdala when presented with nonsocial fear stimuli (such as frightening animals).[7] This may partially account for the apparent absence of social inhibition observed in individuals with the syndrome, as well as the prevalance of anxious symptoms (but see fear for details on the relationship between the amygdala and fear response).[25]
Increased volume and activation of the left auditory cortex has been observed in people with Williams Syndrome, which has been interpreted as a neural correlate of patients' rhythm propensity and fondness of music. Similar sizes of the auditory cortex have been previously reported only in professional musicians.[26]
The earliest observable symptoms of Williams syndrome include low birth weight, failure to thrive, trouble breastfeeding, nocturnal irritability and gastroesophageal reflux. Facial dysmorphies thought to be characteristic of the syndrome are also present early in development, as is heart murmur. Research on the development of the syndrome suggest that congenital heart disease is typically present at an early age, often at the infant's first pediatric appointment. Heart problems in infancy often lead to the initial diagnosis of Williams syndrome.[27]
Developmental delays are present in most cases of Williams syndrome, and include delay of language abilities and delayed motor skill development. Individuals with Williams syndrome develop language abilities quite late relative to other children, with the child's first word often occurring as late as three years of age. Language abilities are often observed to be deficient until adolescence, in terms of semantics, morphology, and phonology, though not in vocabulary.[28]
Williams syndrome is also marked by a delay in development of motor skills. Infants with Williams develop the ability to lift their heads and sit without support months later than typically-developing children. These delays continue into childhood, where patients with Williams syndrome are delayed in learning to walk.[29] In young children, the observed motor delay is around five to six months, though some research suggests that children with Williams syndrome have a delay in development that becomes more extreme with age.[30] Children with motor delays as a result of Williams syndrome are particularly behind in development of coordination, fine motor skills such as writing and drawing, response time, and strength and dexterity of the arms. Impaired motor ability persists (and possibly worsens) as children with Williams syndrome reach adolescence.[31]
Adults and adolescents with Williams syndrome typically achieve a below-average height and weight, compared with non-affected populations. As individuals with Williams syndrome age, they frequently develop joint limitations and hypertonia, or diminished and weakened muscle tone. Hypertension, gastrointestinal problems, and genitourinary symptoms often persist into adulthood, as well as cardiovascular problems. Adults with Williams syndrome are typically limited in their ability to live independently or work in competitive employment settings, but this developmental impairment is attributed more to psychological symptoms than physiological problems.[32]
Individuals with Williams syndrome report higher anxiety levels as well as phobia development, which may be associated with hyperacusis (high sensitivity to certain frequencies of sound).[33] Williams syndrome is also strongly associated with Attention Deficit Hyperactivity Disorder and related psychological symptoms such as poor concentration, hyperactivity, and social disinhibition.[3]
Cognitively, individuals with Williams syndrome typically have global Intelligence Quotient scores in the 50s and 60s (an IQ score of 100 is the average in nonaffected populations), though higher scores are occasionally observed. In particular, individuals with Williams syndrome experience challenges in visual-motor skills and visuospatial construction. Most affected individuals cannot spatially orient themselves in space, or reconstruct an object from smaller parts. Many adults with Williams syndrome cannot complete a simple six-piece puzzle designed for young children, for example. These visuospatial decificts may be related to damage to the dorsal cortical pathway for visual processing.[34]
Despite their physical and cognitive deficits, individuals with Williams syndrome exhibit impressive social and verbal abilities. Williams patients can be highly verbal relative to their IQ. When children with Williams syndrome are asked to name an array of animals, they may well list such a wild assortment of creatures as a koala, saber-toothed tiger, vulture, unicorn, sea lion, yak, ibex and "Brontosaurus rex", a far greater verbal array than would be expected of children with IQs in the 60s.[35] The language used by individuals with Williams syndrome differs notably from unaffected populations, including individuals matched for IQ. People with Williams syndrome tend to use speech that is rich in emotional descriptors, high in prosody (exaggerated rhythm and emotional intensity), and features unusual terms and strange idioms.[34]
Among the hallmark traits of individuals with Williams syndrome is an apparent lack of social inhibition. Infants with Williams syndrome make normal and frequent eye contact, and young children with Williams will often approach and hug strangers. Individuals affected by Williams syndrome typically have high empathy, and are rarely observed displaying aggression. The level of friendliness observed in people with Williams is often inappropriate for the social setting, however, and teens and adults with Williams syndrome often experience social isolation, frustration, and loneliness despite their clear desire to connect to other people.[34]
In one experiment, a group of children with Williams syndrome showed no signs of racial bias, unlike children without the syndrome. Both samples showed gender bias, demonstrating differing mechanisms for the two biases. [36]
Some cultural historians believe that the adjective "elfin" came to be used to describe the facial features of people with Williams syndrome because, before Williams syndrome's scientific cause was understood, people believed that sufferers of the syndrome, who have very charming and extraordinarily kind personalities in comparison to most people, were gifted with extraordinary, even magical, powers. This is often believed to be the origin of the folklore of elves, fairies and other forms of the 'good people' or 'wee folk' present in English folklore.[37] Even though they are often described in the literature as "elfin-faced", Steven Pinker says in The Language Instinct that to him they often appear "more like Mick Jagger".[38]
In a large review of the symptoms and features of the disorder, physicians Laskari, Smith, and Graham emphasized that family members of individuals with Williams syndrome typically reject use of terminology such as "elfin", as well as descriptions of social symptoms as "Cocktail Party Syndrome". Physicians, family members of individuals with Williams syndrome, and Williams syndrome associations alike have called for the curtailment of such terms. [3]
There is no cure for Williams syndrome. Suggestions include avoiding taking extra calcium and vitamin D, and treating high levels of blood calcium, if present. Blood vessel narrowing can be a significant health problem as well, and is treated on an individual basis. Physical therapy is helpful to patients with joint stiffness and low muscle tone. Developmental and speech therapy can also help children and increase the success of their social interactions. Other treatments are based on a patient's particular symptoms.[13]
The American Academy of Pediatrics recommends annual cardiology evaluations for individuals with Williams syndrome. Other recommended assessments include: opthalmologic evaluations, an examination for inguinal hernia, objective hearing assessment, blood pressure measurement, developmental and growth evaluation, orthopedic assessments on joints, muscle tone, and ongoing feeding and dietary assessments to manage constipation and urinary problems. [39]