Williams Syndrome


Background

Originally described independently by Williams and Beuren in 1961, Williams syndrome (WS) is a rare genetic condition. The clinical manifestations include a distinct facial appearance, cardiovascular anomalies that may be present at birth or may develop later in life, idiopathic hypercalcemia, and a characteristic neurodevelopmental and behavioral profile.

Pathophysiology

In virtually all cases of Williams syndrome, haploinsufficiency (loss of 1 of 2 copies) due to a deletion at chromosome band 7q11.23 that involves the elastin gene (ELN) is implicated. Most deletions are not detected through standard karyotyping but rather through fluorescent in situ hybridization (FISH) for a 1.5-Mb deletion (Williams-Beuren syndrome chromosomal region [WBSCR]) or array comparative genomic hybridization. [123The size of the deletion can vary; however, up to 95% of deletions are 1.55 Mb in size. [45678]

Williams syndrome is not solely caused by elastin haploinsufficiency; the deletion involves a region that spans more than 28 genes and, hence, is considered a contiguous gene deletion syndrome. [4910The cardiovascular findings, part of the connective tissue pathology, and facial dysmorphology are attributed to the elastin gene haploinsufficiency. [1112]

Other genes within the region of the deletion are under investigation for their role in the cognitive profile of Williams syndrome, such as LIMK1, GTF1IRD1,GTF2IRD2GTF2I, NCF1, STX1A, BAZ1B, CLIP2, and TFII-1. [10131415161718LIMK1 and a number of other genes are felt to influence the cognitive profile of Williams syndrome, and other genes have been implicated in other features, such as hypercalcemia, facial features, glucose metabolism, and hypertension. However, genotype-phenotype correlations with genes other than elastin are not yet fully elucidated, and the sample size for studies involving individual genes has been small. [919]

Point mutations or small intragenic deletions of ELN have been found in the autosomal dominant disorder familial supravalvular aortic stenosis (SVAS) without other characteristics of Williams syndrome. Point mutations and frameshift mutations in ELN have also been found in some cases of cutis laxa. [2021Copy number variants (CNVs) in the 7q11.23 region have been found to be associated with autism in a study of over 4000 individuals who did not have Williams syndrome. [7]

Etiology

A deletion on band 7q11.23 near the elastin gene is identified in virtually all individuals with Williams syndrome. The underlying etiology is believed to be unequal meiotic crossover events that lead to interstitial deletions. [2223These deletions may result in unbalanced interchromosomal and, to a lesser extent, intrachromosomal rearrangements.

Mechanisms whereby chromosomes paired during meiosis may undergo unequal crossover resulting in Williams syndrome have typically been thought to result from an unequal overlap of repetitive Alu sequences flanking the region, resulting in a type of misalignment of the chromosomal regions during a crossover event. [24]

In addition, another mechanism that has recently been shown includes a familial inversion polymorphism in the Williams syndrome region that may predispose to unequal crossover during meiosis. [25]

Epidemiology

United States data

Williams syndrome occurs in 1 per 7,500-20,000 births. Most cases are sporadic, however, in 25% of cases, a parent is found to have an inversion of chromosome 7 involving WBSCR, compared to 6% of the general population. [26]

Race-, sex-, and age-related demographics

Williams syndrome is panethnic. The prevalence of particular features may vary among populations; for instance, peripheral pulmonary stenosis is more common than SVAS in the Hong Kong Chinese population, [27and people living in Greece have a lower rate of cardiovascular anomalies. [28]

The deletion is equally prevalent in males and females. A greater severity and earlier presentation of cardiovascular disease may be observed in males. [2930]

Clinical manifestations of Williams syndrome are evident from birth through adulthood. However, features that may be detected antenatally include the characteristic cardiovascular lesions. In addition, fetal ultrasonography of neonates with Williams syndrome has revealed multicystic dysplastic kidney in addition to the congenital heart lesions. [31Associated findings on prenatal screening that have been reported include an increased fetal nuchal translucency and low maternal serum alpha fetoprotein (MSAFP); however, none of the prenatal findings has been proven to be a diagnostic marker of Williams syndrome.

Prognosis

Consider the progressive nature of medical problems in Williams syndrome, including vascular stenosis, hypertension, and joint contractures.

Medical complications may occur, especially related to the cardiovascular system. However, most individuals with Williams syndrome are healthy and lead active full lives.

Most adults with Williams syndrome are used in various settings and can perform self-care tasks. Some adults with Williams syndrome require the daily care of parents or caregivers; however, others may live with less supervision and care. Few adults with Williams syndrome live entirely independently.

Mild accelerated physical and cognitive aging has been noted.

Morbidity/mortality

For patients with Williams syndrome, cardiovascular involvement is the most common cause of morbidity and mortality. [32Sudden cardiovascular collapse is a well-known phenomenon, particularly in the periprocedural period. [33Cardiovascular disease accounts for most cases of early mortality associated with Williams syndrome. Elastin arteriopathy is generalized; thus, virtually any artery may be affected.

Abnormalities involve local or diffuse stenosis of the medium-sized or large-sized arteries, most commonly in the ascending aorta above the aortic valves (ie, SVAS) or in the pulmonary arteries. Nonetheless, stenosis of the descending aorta, intracranial arteries, and renal arteries have been reported. [343536Overall, unexpected death is rare, but it is 25-fold to 100-fold higher than in age-matched control subjects. [37Factors implicated in sudden death have included SVAS, severe pulmonary stenosis, and myocardial ischemia secondary to either coronary insufficiency or biventricular outflow tract obstruction with ventricular hypertrophy. Coronary insufficiency appears most likely because of stenosis that results from intimal fibrosis and muscular hypertrophy. Stroke occurring at younger than expected ages has been reported. [38394041]

A study by Phomakay et al indicated that ventricular hypertrophy is a common finding on electrocardiograms (ECGs) in patients with Williams syndrome and that an association exists between the severity of right- and left-sided obstructive lesions and the presence of right or left ventricular hypertrophy, respectively, on electrocardiography. The study involved 187 patients, who underwent a total of 499 ECGs, with right ventricular hypertrophy being found on one or more ECGs in 57% (106) of patients and left ventricular hypertrophy being revealed on one or more ECGs in 39% (72) of patients. [42]

Deaths in patients with Williams syndrome have been reported after induction of anesthesia for minor surgical procedures, during cardiac catheterization and heart surgery, and with progressive heart failure and respiratory infection. [374344Sudden deaths with no apparent instigating event have also been reported, with apparent underlying myocardial injury. [37Patients with a higher risk of sudden death may show signs of myocardial ischemia on electrocardiography (such as ST segment depression). Echocardiography, Holter monitoring, and careful evaluation should be considered before the use of anesthesia, sedation, or both or prior to an invasive procedure. Patients have also presented with syncope related to SVAS who died during diagnostic cardiac catheterization. Calcified valvular aortic stenosis has also been reported but not with sudden death. [4546]

Hypertension develops in approximately 50% of individuals with Williams syndrome, in some cases in relation to renal artery stenosis. [4147]

A higher frequency of obesity, impaired glucose tolerance and diabetes mellitus have been found in adults with Williams syndrome compared to the general population. [48Elevated thyroid stimulating hormone (TSH) levels have an increased prevalence in patients with William syndrome, are more common in children younger than 1 year, and are associated with thyroid hypoplasia. [49Most of the findings are associated with subclinical hypothyroidism, but because TSH levels appear to normalize with age, there remains the possibility of thyroid hypoplasia that may not manifest with an elevated TSH level.

Various gastrointestinal problems are common, including feeding problems and colic, as well as reflux and chronic constipation. [50Sigmoid diverticulitis in adults is reported at a higher frequency in the Williams syndrome population than in the general population. [51]

Williams syndrome is a multisystem condition with other potential consequences, including developmental delay, motor delay, hearing loss, severe dental disease, ocular problems, progressive joint contractures, nephrolithiasis, and bowel and bladder diverticula.

Royston et al found evidence that individuals with Williams syndrome are at increased risk for developing anxiety disorders. They generated pooled prevalence estimates of anxiety disorders for Williams syndrome based upon 16 papers on Williams syndrome, and they conducted a meta-analysis to compare these estimates with prevalence estimates for the heterogeneous intellectual disability (ID) population and the general population. They found that individuals with Williams syndrome had a higher risk of experiencing anxiety than the general population and that they were four times more likely to experience anxiety than individuals with ID. [52]

CLINICAL PRESENTATION


History

The history obtained from caregivers of patients with Williams syndrome varies and reflects the wide phenotypic spectrum observed in the syndrome. This includes a pattern of growth and development and a specific neurodevelopmental profile primarily involving four areas: cognitive development, language, auditory function, and visuospatial function, as in the following [535455:

  • Children have prenatal and postnatal growth delay and usually present with failure to thrive. Short stature is common in children who are shorter than their family background, and adults reach a mean height that is often below the third percentile. A history of feeding problems and poor weight gain is common.

  • A history of recurrent middle ear infections and/or effusions in childhood and progressive mild-to-moderate high frequency sensorineural hearing loss is noted in most adolescents and adults.

  • A history of visual disturbances is possible. These are mainly related to esotropia, cataracts, and hyperopia in as many as 50% of individuals with Williams syndrome.

  • A history of congenital heart disease is common, and hypertension may be noted.

  • In children, functional problems, including a history of increased urinary frequency and daytime wetting, is possible. [56Delayed toilet training is not uncommon. A history of renal abnormalities is also possible, as well as a history of hypercalcemia and hypercalciuria.

  • A history of delayed bone age, and decreased insulinlike growth factor-1 (IGF1) levels may be noted. [5758Early pubertal onset may be noted. Glucose tolerance or overt diabetes mellitus may be detected in patients older than 20 years [40; subclinical hypothyroidism may also be noted. [5960]

  • A history of connective tissue abnormalities, such as abnormal joint mobility, hernias, and diverticula, is possible.

  • Children may have histories of chronic abdominal pain, and they are at increased risk for celiac disease.

  • Children with Williams syndrome typically have mild-to-moderate mental retardation, but the range includes severe mental retardation to average intelligence. [53Abilities should be considered on an individual basis due to the wide variability among individuals. [61Impaired motor development is often apparent before age 42 months. [62]

  • Early language acquisition is delayed, [6364and although mild-to-moderate language impairments persist throughout life, the quality and affect of speech are relatively normal.

  • Visual-spatial problems impact daily life, with difficulties in handwriting, drawing, and gait apraxia, especially on uneven or sandy surfaces. [65]

  • Interest and enthusiasm for music is almost universal in patients with Williams syndrome, but the ability to perform professionally is exceptional.

  • As many as half of all children with Williams syndrome may exhibit autism spectrum social and communicative deficits. [66]

  • Children with Williams syndrome are described as overly friendly, hyperactive, inattentive, and hypersensitive to loud sounds or certain types of sounds. [6768]

  • Adults may have a high rate of emotional and behavioral problems, poor social relationships and anxiety, preoccupations and obsessions, phobias, panic attacks, and depression. [6970Few adults achieve complete independence with daily living. [717273]

Physical Examination

Phenotypic expression of Williams syndrome widely varies. Virtually all cases have typical facial features that can be recognized even at birth, as in the following:

  • Children with Williams syndrome are generally full-term infants with prenatal growth delay. Specific growth curves for Williams syndrome have been established. [74]

  • Microcephaly is observed in one third of children, [75and postnatal failure to thrive is typical.

  • Virtually all children and adults with Williams syndrome have some combination of the following facial features: short upturned nose, flat nasal bridge, long philtrum, flat malar area, wide mouth, full lips, dental malocclusion and widely spaced teeth, micrognathia, and periorbital fullness. A stellate, lacy pattern of the irises can be observed in children with blue eyes. The voice may be hoarse. Nails tend to be hypoplastic and the skin soft and lax, and the halluces have a valgus deviation.

  • Problems with primary and secondary dentition include small and peg-shaped teeth, increased interdental spacing, absence of one or more primary or secondary teeth, anterior cross-bite malocclusion, and excessive gingival tissue. [767778]

  • The diagnosis of Williams syndrome should also be considered after an incidental finding of idiopathic hypercalcemia or a characteristic cardiac lesion such as supravalvar aortic stenosis (SVAS). Other cardiac lesions in patients with Williams syndrome can include pulmonary stenosis and mitral valve regurgitation. [3071Arterial hypertension may be present. If the distinct facial features are not evident, consider referral to a practitioner experienced in examining the facial features of Williams syndrome, such as a clinical geneticist or cardiologist experienced in dysmorphology.

  • Ocular findings can include strabismus (usually due to esotropia), a stellate iris, cataract, retinal vascular tortuosity, and reduced binocular vision; a case of Reiger anomaly has even been reported. [297980]

  • Sensorineural hearing loss can be present and is likely underdiagnosed. [81It is often progressive in nature, and it can be aggravated by conductive loss due to middle ear effusions.

  • Examine patients for signs of precocious puberty.

  • Other findings include hyperacusis (despite hearing loss), hoarse voice, joint hyperelasticity, contractures, kyphoscoliosis, and lordosis.

  • Monitor for hypertension at every visit.

  • Generalized hypotonia is found in infants with Williams syndrome and progresses to spasticity with age. [78]

  • Dental issues can include microdontia, enamel hypoplasia, and malocclusion.

DDx

Differential Diagnoses

TREATMENT AND MANAGEMENT

Medical Care

Williams syndrome is a complex multisystem medical condition that requires a multidisciplinary team. A few large tertiary care centers have Williams syndrome clinics, which help organize and coordinate the care of patients with Williams syndrome. Williams Syndrome Associations are available in the United States and Canada and are a valuable resource for both parents and health care professionals.

Tailor specific management of Williams syndrome to the presenting clinical spectrum. Initial care often centers on failure to thrive, hypercalcemia, or repair of the cardiac lesion. School performance, physical therapy, hyperactivity, and the child's eventual role in society are long-term issues that need to be addressed on an ongoing basis. Anticipatory guidance is essential to help parents prepare for future needs of children with Williams syndrome. Anticipatory care guidelines and growth curves for children with Williams syndrome are available through the American Academy of Pediatrics. [87]

Hypercalcemia, which is noted in approximately 15% of patients with Williams syndrome, is frequently asymptomatic and resolves in the first few years of life but can be lifelong. Signs and symptoms of hypercalcemia, in addition to blood calcium levels, should be periodically monitored throughout life and prior to the administration of any anesthetic or sedative agent and prior to any invasive procedure. Symptomatic hypercalcemia can present with decreased feeding, irritability, and severe colic in infants and may require multidisciplinary management through restriction of calcium, vitamin D intakes (including vitamin formulations), specialized formulas and some patients may require bisphosphonates or steroids to control elevated calcium levels. [8889For more information, see Hypercalcemia.

The goal of managing calcium and vitamin D levels is to monitor and achieve levels in the normal range for age at intakes adequate for bone growth. The need for dietary manipulation and medication to control hypercalcemia should be frequently monitored because long-term unrestricted use of a low calcium, low vitamin D formula has been reported to lead to rickets in a patient with Williams syndrome. [90]

Nephrocalcinosis and sclerosis of the long bones are occasionally observed.

Systemic hypertension should be treated when identified, and surveillance should include annual blood pressure measurements in both arms. For more information see the Medscape topic in pediatrics for Hypertension or Neonatal Hypertension.

Periodically assess visual problems and hearing loss. Acoustic-visual-behavioral training has been reported to improve symptoms of hyperacusis in an adult. [91Recurrent otitis media may be treated with placement of tympanostomy tubes.

Patients with short stature should have a bone age assessment and be referred to an endocrinologist for assessment and management of growth hormone deficiency.

Monitor for signs of precocious puberty and arrange referrals with an endocrinologist as necessary. [92Treatment with gonadotropin-releasing hormone (GnRH) agonists may be considered.

Although data are limited, buspirone has been shown to be effective in the treatment of generalized anxiety disorder in patients with Williams syndrome. [93]

Feeding difficulties in children are common, and referral to a gastroenterologist should be considered.

Thyroid function and glucose tolerance testing should be part of the periodic evaluation.

Early involvement of a dentist is suggested.

Surgical Care

For cardiac findings in children with Williams syndrome, early involvement with a pediatric cardiologist and cardiothoracic surgeon is essential.

Supravalvar aortic stenosis (SVAS) is the most frequently observed operable cardiac lesion in Williams syndrome. SVAS may be progressive in some individuals, and life-long cardiac follow-up is recommended. [94Surgery is generally required in 20%-30% of patients. [95]

Timing of the operative repair depends on the presence of cardiac symptoms, the gradient across the supraaortic obstruction, and whether ischemic changes are noted on a stress test. Peripheral branch pulmonary stenosis usually spontaneously resolves and generally should not be treated with catheter or surgical intervention.

In general, the degree of supraaortic obstruction in Williams syndrome patients tends to progress over time, whereas peripheral branch pulmonary stenosis improves over time.

Consultations

Williams syndrome requires the attention of multiple health care professionals, depending on the specific phenotypic manifestations. Many large tertiary care centers have Williams syndrome clinics that help organize and coordinate the care of patients with Williams syndrome.

For cardiac findings in children with Williams syndrome, early involvement of a pediatric cardiologist and cardiothoracic surgeon is essential.

An anesthesiologist should be consulted prior to administration of anesthetics. Sedation should be administered only by physicians experienced in pediatric procedural sedation.

Geneticists, dentists, ophthalmologists, orthopedists, physical and occupational therapists, and psychologists all contribute to the care of the patient with Williams syndrome. Patients may benefit from music therapy. [96]

Parents of children with Williams syndrome should be offered genetic counseling to review their recurrence risks and options for prenatal diagnosis. If neither parent is affected with Williams syndrome, the risk of having another affected child with Williams syndrome is usually less than 1%. However, recurrences of Williams syndrome have been reported, even with unaffected parents, because of apparent germline mosaicism. [83]

Patients with Williams syndrome are considered to be fertile. If one parent is affected with Williams syndrome, the risk for having an affected child is typically 50% because the deletion behaves in an autosomal dominant manner. When of appropriate age, affected children should receive genetic counseling prior to considering having children of their own.

Women with Williams syndrome who are considering pregnancy or who are pregnant should be referred to a maternal-fetal medicine specialist for close monitoring. In particular, a pregnant woman with Williams syndrome should be monitored for hypertension, hypercalcemia, and cardiovascular and other complications. [84]

Long-Term Monitoring

Inform parents or caregivers of the Williams Syndrome Association for supporting resources and education. Williams Syndrome Associations are located in the United States and Canada. They provide valuable resources for parents and caregivers. The Williams Syndrome Association can be contacted by phone (248-244-2229) or through the Williams Syndrome Association Web site.

School performance, hyperactivity, and the child's eventual role in society are long-term issues that need to be addressed on an ongoing basis.

Anticipatory guidance is essential to help parents prepare for future needs of children with Williams syndrome.