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Williams-Beuren Syndrome

Williams Syndrome

Williams syndrome (Williams–Beuren syndrome) is a rare neurodevelopmental disorder characterized by mental retardation, hypercalcemia of infants, heart defects, characteristic facial features ("elfin" facial appearance) and failure to thrive. It is caused by a deletion on chromosome 7.


Presentation

The clinical features of Williams syndrome are manifold and include the following.

Other clinical features in these patients include:

Short Stature
  • stature, and specific intellectual disabilities (such as visual spatial problems).[ncbi.nlm.nih.gov]
  • ウィキペディア 分類 病気, developmental defect during embryogenesis 上位クラス chromosomal deletion syndrome, 大動脈弁上狭窄症, syndromic developmental defect of the eye, multiple congenital anomalies/dysmorphic syndrome-intellectual disability, malformation syndrome with short[commons.wikimedia.org]
  • Williams syndrome (WS) is characterized by some or all or the following features: craniofacial dysmorphism (e.g. elfin facies) oral abnormalities short stature (50% of cases) mild to moderate mental retardation supravalvular aortic stenosis 2 pulmonary[radiopaedia.org]
Feeding Difficulties
  • Williams-Beuren Syndrome (WBS) is a well-described microdeletion syndrome characterized by specific dysmorphic facial features, peripheral pulmonic stenosis, supravalvular aortic stenosis, hypercalcemia, feeding difficulties, gastroesophageal reflux,[ncbi.nlm.nih.gov]
  • A combination of specific facial characteristics including a stellate pattern in the iris, long philtrum and puffiness around the eyes; cardiovascular disease - especially aortic or pulmonary stenosis; feeding difficulties (in infants) and developmental[web.archive.org]
  • Cardiac abnormalities; Supravalvular aortic stenosis (SVAS), pulmonary stenosis Hypertension Kidney abnormalities Hernias Rectal Prolapse Chronic Ear Infections Hoarse Voice Hypotonia Hypercalcemia Feeding difficulties in infants GERD Strabismus Urinary[parentingspecialneeds.org]
Multiple Congenital Anomalies
  • ウィリアムズ症候群 neurodevelopmental disorder メディアをアップロード ウィキペディア 分類 病気, developmental defect during embryogenesis 上位クラス chromosomal deletion syndrome, 大動脈弁上狭窄症, syndromic developmental defect of the eye, multiple congenital anomalies/dysmorphic syndrome-intellectual[commons.wikimedia.org]
  • Winter and Michael Baraitser, A catalogue of multiple congenital anomaly syndromes, Multiple Congenital Anomalies, 10.1007/978-1-4899-3109-2_1, (1-672), (1991). Judy Reilly, Edward S.[doi.org]
Fatigue
  • "They get easily fatigued, and we're still trying to understand why. There's also a higher incidence of diabetes and hypothyroidism, as well as cardiovascular disease." And behaviorally? "Friendliness, oh my gosh. Lots, lots of social interest.[theatlantic.com]
  • This is one reason why our children have speech delays and often fatigue after a while when speaking. Katie is working up her endurance but she’ll often get some words or sentences out and then revert to babble.[understandingwilliamssyndrome.blogspot.com]
Dysmorphic Face
  • It is characterized by dysmorphic face, cardiovascular disease, idiopathic hypercalcemia, mental retardation, and an uneven profile of cognitive-linguistic abilities and deficits.[ncbi.nlm.nih.gov]
Colic
  • Irritability (colic during infancy): Many infants with Williams syndrome have an extended period of colic or irritability. This typically lasts from 4 to 10 months of age, then resolves. It is sometimes attributed to hypercalcemia.[web.archive.org]
  • Despite multiple medical problems in infancy, including feeding problems, failure to thrive, colic, and otitis media, mean age at diagnosis was 6.4 years. Developmental disabilities and cardiovascular disease were the major concerns in childhood.[ncbi.nlm.nih.gov]
  • Irritability (colic during infancy) Many infants with Williams syndrome have an extended period of colic or irritability. This typically lasts from 4 to 10 months of age, then resolves.[williams-syndrome.org]
  • There are several characteristics of Williams Syndrome, such as: Characteristic facial appearance Heart and blood vessel problems Hypercalcemia (elevated blood calcium levels) Feeding problems Irritability (colic during infancy) Dental abnormalities Kidney[rideforchristian.com]
Failure to Thrive
  • 4 months male child presented with failure to thrive. On general examination child had normal O2 saturation with characteristic elfin facies.[ncbi.nlm.nih.gov]
Constipation
  • We present an 11-month-old girl child with complaints of constipation, cough, fever, vomiting and growth retardation. On examination, she had facial dysmorphism, hypertension and murmur.[ncbi.nlm.nih.gov]
  • Pediatric Gastroenterology - Evaluates and offers suggestions for treatment for problems with slow bowel motility, constipation, or gastroesophageal reflux (GER). Pediatric Orthopaedics - Monitors and treats bone and muscle issues.[urmc.rochester.edu]
  • Adults: 25% have GERD 50% have constipation Hypercalcemia may recur periodically and can contribute to constipation and vomiting Sigmoid diverticulitis occurs with increased frequency and at younger age ( 5,6 Celiac disease may be more common, as in children[vkc.mc.vanderbilt.edu]
  • […] to nutritionist/gastroenterologist Constipation Consider polyethylene-glycol-electrolyte solution and a good bowel regimen, encouraging fluids, and high fiber foods Chronic abdominal pain Consider gastroesophageal reflux, hiatal hernia, peptic ulcer[clinicaladvisor.com]
  • Idiopathic infantile hypercalcemia is an intriguing feature of WS that can contribute to the presence of extreme irritability, vomiting, constipation, and muscle cramps associated with this condition. 4,9 Symptomatic hypercalcemia usually resolves during[pediatrics.aappublications.org]
Vomiting
  • The most common oro-facial findings were detected as high palate (87%), diastema (60%), failure to thrive (60%), feeding difficulties (60%), vomiting (47%), macroglossi (47%), microdontia (40%) and frenulum hyperplasia (40%).[ncbi.nlm.nih.gov]
  • Symptoms Delayed speech that may later turn into strong speaking ability and strong learning by hearing Developmental delay Easily distracted, attention deficit disorder (ADD) Feeding problems including colic, reflux, and vomiting Inward bend of the small[web.archive.org]
  • Endocrine abnormalities , which include short stature, hypercalcemia (irritability, vomiting, constipation, muscle cramps), diabetes mellitus, and hypothyroidism. GU/Kidney abnormalities, such as dysfunctional voiding and nephrolithiasis.[pedclerk.bsd.uchicago.edu]
  • Spotting the signs Everyone with Williams syndrome will be be different, but some of the early signs of Williams syndrome in children can include: low birth weight and slow growth excessive vomiting and difficulty feeding constipation trouble sleeping[mencap.org.uk]
Abdominal Pain
  • It is important to take diverticulitis into consideration when examining a patient with Williams syndrome presenting with abdominal pain and consider surgical treatment if necessary.[ncbi.nlm.nih.gov]
  • Young adults continue to experience abdominal pain. Diabetes is another common complication. Children with this condition usually develop diabetes by age of 13. Hearing loss is also common. These medical problems usually cause a premature death.[mentalhelp.net]
  • Adolescents and adults with the disorder commonly experience chronic abdominal pain.[disabled-world.com]
Small Teeth
  • People may also experience dental issues, such as crooked, missing, or small teeth. People with Williams syndrome often have both learning disabilities and cognitive challenges.[beyondceliac.org]
  • Then the doctor will look for facial features like an upturned nose, wide forehead, and small teeth. An electrocardiogram ( EKG ) or ultrasound can check for heart problems. A bladder and kidney ultrasound can check for urinary tract conditions.[webmd.com]
  • Dental Children: Missing or small teeth, malocclusion and other dental anomalies are common.[vkc.mc.vanderbilt.edu]
Hypertension
  • People with Williams syndrome whose NCF1 gene is not deleted have a higher risk of developing hypertension.[web.archive.org]
  • We report a 38-year-old patient who presented with pulmonary hypertension and right ventricular dysfunction due to pulmonary artery stenoses as a manifestation of Williams syndrome, mimicking chronic thromboembolic pulmonary hypertension.[ncbi.nlm.nih.gov]
Heart Murmur
  • In consultation, facial dysmorphies and heart murmur are detected. There is also low birth weight, failure to thrive, unsuccessful breastfeeding, and gastroesophageal reflux. All these symptoms are strongly suggestive of Williams syndrome.[ncbi.nlm.nih.gov]
  • Dr Riby says there is no pre-natal screening, but often doctors can pick up clues if a young child has heart murmurs, and problems putting on weight.[bbc.com]
  • “From the early days of being born with a heart murmur and taken straight to intensive care, we asked what was wrong.[sbs.com.au]
Joint Limitation
  • The older children developed progressive joint limitation and hypertonia. Adult patients were handicapped by their developmental disabilities. Hypertension, and gastrointestinal and genitourinary problems occurred frequently.[ncbi.nlm.nih.gov]
  • Joint limitation or laxity and soft lax skin. Intellectual disability: Most patients have intellectual disability ranging from mild to severe. Some individuals have normal intelligence.[patient.info]
  • If results of previous evaluations are negative, repeated cardiology evaluation (for arterial stenoses, hypertension) should be performed at puberty Ophthalmologic evaluation for strabismus and hyperopia Orthopedic problems (eg, joint limitation, kyphosis[pediatrics.aappublications.org]
Epicanthal Folds
  • folds ) Partially missing teeth, defective tooth enamel, or small, widely spaced teeth Exams and Tests Signs include: Blood vessel narrowing including supravalvular aortic stenosis, pulmonary stenosis, and pulmonary artery stenosis Farsightedness High[web.archive.org]
  • Other common features of Williams syndrome include: Characteristic facial features, especially in childhood, such as: full cheeks, wide mouth, prominent lips, small jaw, large ears, short/upturned nose, epicanthal folds (vertical skin folds that cover[my.clevelandclinic.org]
  • These may exhibit as a flattened nasal bridge with small upturned nose, skin that covers the inner corner of the eye (called epicanthal folds) and prominent lips with an open mouth.[questia.com]
  • Before her diagnosis, they were firstly puzzled over Natasha’s physicalities like her pronounced epicanthic folds (the skin of the upper eyelid), biggish lips and a wide mouth, but also her refusal to eat and delayed motor skill milestones.[sbs.com.au]
Esotropia
  • Because of the high prevalence of esotropia in patients with Williams syndrome (72%) compared to the general population (0.1%), we postulate a genetic link between Williams syndrome and the hereditary form of infantile esotropia.[ncbi.nlm.nih.gov]
  • Visual defects may also be present, particularly strabismus, esotropia, nystagmus and abnormal visual processing Recurrent middle ear infections in childhood may have occurred Sensorineural hearing loss may be present.[symptoma.com]
  • Strabismus (usually esotropia) occurs in more than half of patients. Retinal vessel tortuosity is present in 22% of patients. Cataracts may be found in younger individuals but are uncommon. Hyperopia is the most common refractive error.[disorders.eyes.arizona.edu]
  • . , 1994 Hillsdale, NJ Erlbaum Monocular acuity and stereopsis in infantile esotropia , Invest Ophthalmol Vis Sci , 1985 , vol. 26 (pg. 1624 - 30 ) Form and motion coherence activate independent, but not dorsal/ventral segregated, networks in the human[doi.org]
Periorbital Fullness
  • Distinctive facies: Broad forehead, bitemporal narrowing, periorbital fullness. Stellate iris pattern, strabismus. Short nose with broad nasal tip. Long philtrum, wide mouth with thick vermilion of upper and lower lips.[patient.info]
  • Children with WS are born with thin appearing lips that over time appear full, and they often have an appearance of periorbital fullness with a stellate and lacy pattern of the iris. The face may coarsen with age.[clinicaladvisor.com]
  • Facial features often include periorbital fullness, short nose with bulbous nasal tip, long philtrum, wide mouth, full lips, and mild micrognathia.[pediatrics.aappublications.org]
  • The details of the scoring system are as follows (see also Table 1 ): • The occurrence of typical facial dysmorphisms (bitemporal narrowing, broad forehead, periorbital fullness, full cheeks, short upturned nose, long philtrum, wide mouth, thick lips)[scielo.br]
Friendly Personality
  • This is especially important because people with Williams syndrome have a sometimes overly friendly personality and can also have impulse control problems, including sexual impulse control, which may increase their chances of being taken advantage or[thinkgenetic.com]
  • Mental retardation (MR) and the friendly personality occurred in 95% of all patients, ie, in all patients with genomic deletions and in 2 of the 3 patients without deletions.[scielo.br]
Thick Lips
  • The details of the scoring system are as follows (see also Table 1 ): • The occurrence of typical facial dysmorphisms (bitemporal narrowing, broad forehead, periorbital fullness, full cheeks, short upturned nose, long philtrum, wide mouth, thick lips)[scielo.br]
Irritability
  • Irritability (colic during infancy): Many infants with Williams syndrome have an extended period of colic or irritability. This typically lasts from 4 to 10 months of age, then resolves. It is sometimes attributed to hypercalcemia.[web.archive.org]
  • Initial pediatric signs are developmental delay and nocturnal irritability. In consultation, facial dysmorphies and heart murmur are detected.[ncbi.nlm.nih.gov]
  • Irritability (colic during infancy) Many infants with Williams syndrome have an extended period of colic or irritability. This typically lasts from 4 to 10 months of age, then resolves.[williams-syndrome.org]
  • There are several characteristics of Williams Syndrome, such as: Characteristic facial appearance Heart and blood vessel problems Hypercalcemia (elevated blood calcium levels) Feeding problems Irritability (colic during infancy) Dental abnormalities Kidney[rideforchristian.com]

Workup

Diagnosis of Williams syndrome is made on the basis of the following [7]:

  • Physical and behavioral symptoms
  • Physical examination consisting of: Blood pressure, ocular tests, hearing tests, testing for hypotonia in infants
  • Bone age assessment
  • Glucose tolerance tests
  • Cardiovascular tests to check for abnormalities: Electrocardiography (ECG), echocardiography
  • Blood tests with particular focus on: Plasma creatine phosphokinase (CPK) levels, serum calcium levels, serum blood urea nitrogen (BUN)
  • Urinalysis
  • Thyroid function tests
  • Micro-array analysis
  • Gene karyotyping
  • Targeted mutation analysis
  • Polymerase chain reaction (PCR)
  • Heterozygosity testing
  • Fluorescent in situ hybridization (FISH) test for detection of gene deletion
  • Prenatal screening consisting of: Alpha fetoprotein levels (AFP), increased fetal nuchal translucency

Treatment

Being a genetic defect, Williams syndrome does not have a cure. Symptomatic treatment is, however, possible. Cardiac, visual, gastrointestinal and urinary system and orthopedic abnormalities should be thoroughly assessed and treated accordingly.

The patients should be treated on the basis of their particular tendency for music to placate them and relieve the anxiety and phobias. Surgical interventions for cardiovascular or ocular complications might be required [8] [9] [10]. Genetic counseling of parents should be done.

Prognosis

Mortality rate due to Williams syndrome is high due to cardiovascular complications. However, most of the patients lead healthy life and live to an old age.

Etiology

Deletion of a cascade (approximately more than 25) of genes from the long arm of chromosome 7 (q11.23) resulting in gene haplodeficiency is the underlying etiology of Williams syndrome. The gene defect is usually acquired, occurring in the eggs or sperms during their formation. The genes most commonly deleted are:

  • CLIP2
  • ELN
  • GTF2I
  • GTF2IRD1
  • LIMK1
  • NCF1 

Epidemiology

The incidence of the disease is approximately 1 in 7,500 to 20,000 live births. Most of the cases of the disease are sporadic. The incidence of the disease is equal among the males and females. Symptoms of the disease vary among different races. Chinese populations are more prone to cardiovascular complications whereas Greek populations have low incidence of cardiovascular system abnormalities.

Sex distribution
Age distribution

Pathophysiology

The gene deletions include the deletion of ELN gene that encodes for the protein elastin which is a part of many of the connective tissues including the arterial walls. Loss of elastin results in connective tissue abnormalities in many of the body viscera predominantly in the heart. Pulmonary and aortic valvular stenoses are common manifestations. The loss of elastin manifests in the integumentary system as fullness of the cheeks. Vocal cords are also affected causing hoarseness of voice. Diverticuli are common, especially in the bladder.

Loss of GTF2I, GTF2IRD1 and LIMK1 genes result in visual as well as spatial defects. Deletion of CLIP2 gene results in behavioral changes associated with the disease (eg. irritability) as well as cognitive defects. The deletion or overexpression of NCF1 gene has been linked to the risk of hypertension in people with Williams syndrome. Recent studies have implicated familial inversion polymorphism in the region of chromosome 7 as an underlying cause of Williams syndrome.

Prevention

Prenatal screening for gene abnormalities is helpful in genetic and anticipatory counseling of the parents and in the management of this condition. Lifelong monitoring of the patients with Williams syndrome should be ensured.

Summary

Williams syndrome, also known as Beuren syndrome or Elfin Facies syndrome is a rare disorder that arises due to gene defect. The distinctive features of the disease include characteristic facial features and congenital cardiovascular problems [1].

Individuals with Williams syndrome are quite sociable and have a cheery demeanor but are unable to form lasting relationships as they are unable to understand the subtleties involved in social interactions. Development delay and cognitive defects are also common in these patients.

Patient Information

Williams syndrome is a gene defect that gives rise to a particular set of symptoms in the patients. The individuals have characteristic facial features including low set nose and wide tip of nose, wide mouth and a broad forehead. The patients have low intelligence levels but have particular fondness for music. Developmental milestones are achieved quite late. Difficulty in coordinated movements like drawing is also faced. Hearing and visual defects are also common. Heart problems are widely observed in these patients.

No cure is available for this disease. The patients can be monitored for heart defects. Such individuals mostly lead a long healthy life but heart abnormalities may become the cause of death.

References

Article

  1. Lashkari A, Smith AK, Graham JM, Jr. Williams-Beuren syndrome: an update and review for the primary physician. Clinical pediatrics. Apr 1999;38(4):189-208.
  2. Trucchi G, Rolando S, Cottafava F. [The Williams elfin face syndrome. Considerations on a case]. Minerva pediatrica. Mar 15 1982;34(5):225-228.
  3. Kataria S, Goldstein DJ, Kushnick T. Developmental delays in Williams ("Elfin facies") syndrome. Applied research in mental retardation. 1984;5(4):419-423.
  4. Babbitt DP, Dobbs J, Boedecker RA. Multiple bladder diverticula in Williams "Elfin-Facies" syndrome. Pediatric radiology. Feb 26 1979;8(1):29-31.
  5. Williams RL, Azouz EM. Aortic anomalies in an adolescent with the Williams' elfin facies syndrome. Pediatric radiology. 1984;14(2):122-124.
  6. Fontaine JL, Vernant P, Graveleau D, Lagardere B, Elchardus JF. [Elfin facies, mental retardation and cardiovascular anomalies (Williams and Beuren's syndrome). Report of two cases]. Annales de pediatrie. Jan 2 1976;23(1):37-42.
  7. Gustafson R, Traub D. Williams syndrome: a guide to diagnosis and treatment. South Dakota journal of medicine. Mar 1997;50(3):89-91.
  8. Sudoh Y, Takahara Y, Sunazawa T. [Surgical treatment of diffuse supravalvular aortic stenosis with Williams syndrome]. [Zasshi] [Journal]. Nihon Kyobu Geka Gakkai. May 1997;45(5):764-768.
  9. Abadir S, Dauphin C, Lecompte Y, Lusson JR. [The Williams-Beuren syndrome: reconstruction of the thoracic aorta combining surgery and endovascular treatment]. Archives des maladies du coeur et des vaisseaux. May 2007;100(5):466-469.
  10. Meng Q, Sun LZ, Chang Q, Zhu JM, Wang SY, Hu SS. [Surgical treatment of Williams syndrome combined with cardiovascular disease]. Zhonghua wai ke za zhi [Chinese journal of surgery]. May 15 2005;43(10):644-646.

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Last updated: 2019-07-11 21:35