Database: OMIM
Entry: 194050
LinkDB: 194050


MIM Entry: 194050
Title:
  #194050 WILLIAMS-BEUREN SYNDROME; WBS
  ;;CHROMOSOME 7q11.23 DELETION SYNDROME;;
  WILLIAMS SYNDROME; WMS; WS
  HYPERCALCEMIA, INFANTILE, INCLUDED;;
  SUPRAVALVAR AORTIC STENOSIS, INCLUDED;;
  ELFIN FACIES WITH HYPERCALCEMIA
Text:
  A number sign (#) is used with this entry because William-Beuren
  syndrome (WBS) is a contiguous gene deletion syndrome resulting from the
  hemizygous deletion of several genes on chromosome 7q11.23.
  
  For a discussion of the genes deleted in this syndrome and possible
  genotype/phenotype correlations, see below.
  
  Pober (2010) reviewed the clinical features of Williams-Beuren syndrome
  as well as the genomic and genetic basis and clinical management.
  
  CLINICAL FEATURES
  
  Grimm and Wesselhoeft (1980) suggested that the Williams syndrome is an
  autosomal dominant disorder which in full-blown form includes
  supravalvular aortic stenosis (SVAS), multiple peripheral pulmonary
  arterial stenoses, elfin face, mental and statural deficiency,
  characteristic dental malformation, and infantile hypercalcemia. The
  notorious variability of dominant traits led to the description of
  separate aspects of the syndrome as 2 distinct entities: supravalvular
  aortic stenosis (Sissman et al., 1959) and infantile hypercalcemia
  (Fanconi et al., 1952). Black and Bonham-Carter (1963) pointed out the
  similarity of facies in these 2 syndromes. In a series of cases
  ascertained through supravalvar aortic stenosis, Grimm and Wesselhoeft
  (1980) found patients with mental retardation without elfin facies and
  patients with elfin facies who were mentally normal. Beuren (1972)
  presented compelling evidence that supravalvar aortic stenosis (185500)
  and idiopathic infantile hypercalcemia (143880) are the same disorder.
  (Infantile hypercalcemia and supravalvar aortic stenosis are discussed
  in separate entries, although the possibility remains that they are
  produced by mutation(s) at the same locus as Williams syndrome.)
  
  Among 19 patients with the Williams syndrome not ascertained through a
  cardiologic hospital, Jones and Smith (1975) found 6 without supravalvar
  aortic stenosis, peripheral pulmonary stenosis or hypoplastic aorta.
  Oppenheimer (1938) reported a 17-month-old child with pulmonary artery
  stenosis and calcification of the aorta and pulmonary artery; this may
  have been an early case.
  
  White et al. (1977) described second cousins with the characteristic
  facies and mental retardation but no documented hypercalcemia and no
  cardiovascular abnormality. Preus (1975) pointed out that the iris
  pattern, described by her as 'lacey' and by others as 'stellate,' can be
  a useful diagnostic clue in infants. Holmstrom et al. (1990) had 3
  ophthalmologists and 4 geneticists examine eye photographs from 43
  children with Williams syndrome and 124 control subjects. A stellate
  pattern was noted in the irides of 51% of the Williams syndrome patients
  and in 12% of the control subjects. The pattern was more difficult to
  detect or was absent in heavily pigmented irides. Hotta et al. (1990)
  reported on the iris pattern in 3 cases. Winter et al. (1996) assessed
  the frequency and severity of ophthalmologic features in 152 patients
  with Williams-Beuren syndrome. Eighty-two (54%) had strabismus, while
  149 had esotropia. Blue irides were present in 117 (77%), green irides
  in 10 (7%), and brown irides in 25 (16%). A typical stellate iris
  pattern of the anterior stroma was found in 112 (74%). Whitish anomalies
  were also detected in brown irides. Retinal vascular tortuosity was
  found in 22% of patients with funduscopy. Two 9-year-old patients and a
  46-year-old patient had initial cataract. No ocular manifestations of
  hypercalcemia were noted.
  
  Pankau et al. (1992) analyzed the statural growth in 165 patients (75
  girls and 90 boys). Intrauterine growth retardation was present in 35%
  of the girls and 22% of the boys. Poor growth was noted during the first
  2 years of life. Until age 9 years in girls and 11 years in boys, mean
  growth followed the third percentile. A pubertal growth spurt with
  normal growth rate was seen at age 10 years in girls and 13 years in
  boys, i.e., 1 to 2 years earlier than normal. Menarche also occurred
  earlier than normal. Mean adult height was 153.9 +/- 6.9 cm in 17 girls
  and 168.2 +/- 6.9 cm in 27 boys, approximately corresponding to the
  third percentile in both sexes. The mean deficit of adult height
  compared to target height was 10.2 cm in girls and 9.1 cm in boys.
  Skeletal development progressed at an approximately normal rate in both
  sexes. See review by Burn (1986).
  
  Pankau et al. (1993) conducted a retrospective study of 119 patients
  with Williams syndrome. Results showed limitation of supination at the
  elbow with radioulnar synostosis in 9 patients. One patient had
  bilateral radioulnar synostosis. Pankau et al. (1993) suggested that
  radioulnar synostosis should be considered a common manifestation of the
  syndrome.
  
  Patients with Williams syndrome are often described as having a harsh,
  brassy, or hoarse voice (Gosch et al., 1994). Stewart et al. (1993)
  described a patient with bilateral vocal cord paralysis, developing at
  the age of 9 years, which required tracheostomy. Takamatsu (1996)
  studied 18 cases of bilateral vocal cord paralysis in children,
  including 1 patient with WS. Vaux et al. (2003) described 2 WS patients
  who had bilateral vocal cord abnormalities (1 of whom required
  tracheostomy because of bilateral vocal cord paralysis), bringing to 4
  the number of children with WS in whom such defects had been documented.
  They suggested that vocal cord abnormalities may be a far more common
  feature of WS than previously suspected, and that mild vocal cord
  dysfunction caused by abnormal vocal cord elastin may be the cause of
  the hoarse voice in this condition.
  
  Narin et al. (1993) reported an 8-year-old boy with Williams syndrome
  who had subvalvular aortic stenosis--seemingly the first report of
  subvalvular location of obstruction in this disorder. Wollack et al.
  (1996) described a 19-year-old girl with Williams syndrome who developed
  an ischemic stroke of the internal capsule and putamen but who was not
  found to have stenotic lesion on angiography. They reviewed 5 other
  cases of stroke in Williams syndrome.
  
  Cortada et al. (1980) reported the disorder in mother and both twin
  daughters, presumably dizygotic. One twin had supravalvar and valvular
  aortic stenosis. The other twin had mild peripheral pulmonary stenosis
  and mild coarctation of the left pulmonary artery. One twin, who died
  during cardiac surgery, and the mother had mitral valve prolapse.
  Intelligence was normal. A stellate pattern of the irides was present in
  both twins. All 3 had pectus excavatum, hypoplastic nails, and hallux
  valgus. Murphy et al. (1990) added 2 sets of concordantly affected
  monozygotic twins to the 2 previously reported sets. To the 5 sets of
  monozygotic twins with WMS previously reported, Pankau et al. (1993)
  added a pair concordant for the disorder but showing variable
  expression. Both had typical facial appearance, developmental delay,
  mild supravalvular aortic stenosis, hypoplasia of both pulmonary
  arteries, multiple peripheral pulmonary stenoses, and inguinal hernia.
  One twin had unilateral renal agenesis. A presumably separate disorder
  was cleft palate in both twins; the father, grandfather, and
  great-grandfather all had cleft lip with or without cleft palate.
  
  To the 6 pairs of previously reported monozygotic twins with Williams
  syndrome, Castorina et al. (1997) added 2 further sets. Monozygosity was
  confirmed by DNA microsatellite analysis and the clinical diagnosis was
  confirmed by FISH using a WS-specific probe. Analysis of concordance was
  assisted by a long follow-up. Most clinical signs were concordant in the
  twins of each pair, with differences present at younger ages, mainly
  minor facial anomalies, being attenuated with time. Developmental delay
  was substantially concordant. Inguinal hernia was present in a single
  twin in 1 pair. Facial anomalies and other signs attributable to
  connective tissue abnormalities were also displayed by only 1 twin in
  both sets, suggesting that the WS genotype has only a predisposing role
  in the development of these signs.
  
  Greenberg (1990) expressed the opinion that no well-documented cases of
  parent-to-child transmission of classic Williams syndrome have been
  reported. Preus (1984), in 2 companion articles, used numerical taxonomy
  (Preus, 1980) to sharpen the definition of the Williams syndrome and
  used the diagnostic index so derived in the differential diagnosis of
  the Williams and Noonan syndromes. Biesecker et al. (1987) described a
  19-year-old patient with Williams syndrome who had renal cystic
  dysplasia and gradual deterioration of renal function, with recurrent
  episodes of dehydration secondary to a concentrating defect. They
  suggested that this is a more frequent complication than previously
  realized. In studies of 40 persons with Williams syndrome who were
  assessed at an average age of about 7 years, Pober et al. (1993) found
  renal abnormalities in 7: nephrocalcinosis in 2, marked asymmetry in
  kidney size in 2, small kidneys in 1, solitary kidney in 1, and pelvic
  kidney in 1. Renal artery stenosis was sought in 9 persons who underwent
  abdominal angiography during cardiac catheterization. Unilateral or
  bilateral mild renal artery narrowing was found in 4 persons and normal
  renal arteries in the remaining 5. Persistent hypertension was found in
  only 2 individuals and did not correlate with renal artery status.
  
  Knudtzon et al. (1987) described 2 brothers with Williams syndrome who
  did not have hypercalcemia. One boy died during the first month of life.
  His brother developed severe microcephaly and cataract and died at the
  age of 9 years. The skeleton was osteosclerotic at birth and became
  osteoporotic by the age of 2 years. This brother had persistently
  elevated 1,25-dihydroxyvitamin D levels during the first 2 years of
  life, in spite of normocalcemia. At autopsy, microcalcifications were
  found in the brain and kidneys. Maisuls et al. (1987) described 2
  patients with Williams syndrome and severe mitral regurgitation
  requiring surgical treatment at ages 8 and 11. Another patient had
  coarctation of the abdominal aorta. Hallidie-Smith and Karas (1988)
  described the cardiologic findings in 66 patients with the
  Williams-Beuren syndrome; systemic hypertension was present in 7.8% of
  the patients, mitral valve prolapse by clinical and echocardiographic
  criteria in 15%, and bicuspid aortic valve in 11.6%.
  
  Morris et al. (1988) reviewed the natural history of Williams syndrome.
  After delayed growth in the first 4 years of life, catch-up growth
  occurred with the ultimate attainment of low-normal adult height. Older
  children developed progressive joint limitation and hypertonia.
  Hypertension was frequent in adulthood, being present in 8 of 17 adults.
  Morris et al. (1988) referred to the Williams Syndrome National
  Association, which was a source of patients for review. Morris et al.
  (1990) evaluated 13 adults with Williams syndrome and reviewed the case
  reports of 16 patients older than 16 years. Hypercalcemia may persist
  into adulthood. Hypertension was common. Recurrent urinary tract
  infections led to studies that showed urethral stenosis in some patients
  and bladder diverticula and vesicoureteral reflux in others.
  Gastrointestinal problems included chronic constipation and
  diverticulosis.
  
  In 10 adults with Williams syndrome, Lopez-Rangel et al. (1992) found
  supravalvular aortic stenosis in 4, mitral valve prolapse in 3, bicuspid
  aortic valve in 1, valvular aortic stenosis in 1, and pulmonary stenosis
  with right ventricular hypertrophy in 1. Mental retardation was seen in
  all patients. Verbal skills were better developed than motor skills. All
  patients led active lives and most were involved in sports. Some held
  supervised jobs. Conway et al. (1990) reported 3 children, aged 8 years,
  16 years, and 59 months, who died suddenly with myocardial ischemia
  following cardiac catheterization. In addition to supravalvar aortic
  stenosis, all showed stenosis of the left coronary artery and its
  branches and regions of recent and/or remote myocardial infarction. Voit
  et al. (1991) pointed to clinical and morphologic evidence of myopathy
  in this syndrome giving rise to hypotonia in infancy, delayed walking,
  joint contractures, scoliosis, and increased exhaustion on exertion.
  
  Wessel et al. (1994) reported results of follow-up cardiologic
  examination of 59 patients with Williams syndrome. Supravalvular aortic
  stenosis was found in 57 patients, 17 of whom underwent surgery because
  of severe stenosis. Aortic hypoplasia was diagnosed in 24 patients,
  peripheral pulmonary stenosis in 49, and coarctation of the aorta in 4.
  If patients with SVAS had a pressure gradient of less than 20 mm Hg in
  infancy, their gradient remained unchanged for the next 20 years. If
  patients with SVAS had a pressure gradient of more than 20 mm Hg in
  infancy, their gradient increased in later life. Four of 6 patients with
  aortic hypoplasia and surgery for SVAS developed restenosis, whereas
  patients without aortic hypoplasia remained free of restenosis.
  
  In 3 unrelated families, Morris et al. (1993) described Williams
  syndrome in parent and child: father and son in 1 family and mother and
  daughter in the other 2. None of the patients had supravalvular aortic
  stenosis or chromosomal abnormalities. In all 3 families, the parent was
  diagnosed after identification of the syndrome in the affected child.
  Sadler et al. (1993) reported Williams syndrome in mother and son. Ounap
  et al. (1998) reported WBS in mother and son. The diagnosis was
  confirmed in the son by molecular cytogenetic analysis using FISH; the
  mother was deceased and was thus not studied by FISH. Two traits
  uncommon in WBS were unilateral renal hypoplasia in the mother and a
  hemivertebra at L5 in the son.
  
  Kaplan et al. (1995) pointed out that stenoses in the cerebral arteries
  can cause strokes with brain damage and chronic hemiparesis in children
  with Williams syndrome. Increased irritability, loss of consciousness,
  and seizures were initial signs in 2 patients. One patient, aged 22
  years, had episodes of cerebral vascular insufficiency beginning at the
  age of 3 years at which time moyamoya was diagnosed.
  
  Scothorn and Butler (1997) reported the case of a girl with Williams
  syndrome who had onset of puberty at 7.5 years of age and menarche at
  8.5 years of age. They suggested that because intellectual and emotional
  development of children with this disorder are delayed, pharmacologic
  and hormonal intervention to delay puberty may be warranted to allow for
  intellectual and emotional maturation.
  
  Partsch et al. (2002) reported a mean age of menarche of 11.5 +/- 1.7
  years in 86 females with Williams syndrome compared with 12.9 +/- 1.1
  years in a contemporary cohort of 759 girls. They estimated the
  prevalence of precocious puberty in Williams syndrome as 1 in 5 to 6
  girls (18.3%).
  
  Broder et al. (1999) confirmed previous findings of hypertension in
  Williams syndrome. They studied blood pressure using 24-hour ambulatory
  BP monitoring in 20 WS subjects and found that they had significantly
  higher ambulatory blood pressures than controls. The diagnosis of WS
  added approximately 10 mm Hg to mean daytime and nighttime BPs.
  Hypertension, defined by elevated mean daytime BP, was present in 40% of
  WS patients versus 14% of controls; among the children studied, this
  difference was even more dramatic, with 46% of WS children versus 6% of
  control children classified as hypertensive. Parental reporting of a
  history of infantile hypercalcemia was strongly associated with the
  presence of hypertension.
  
  Since the elastin protein is a major component of elastic fibers in the
  dermis of the skin, Dridi et al. (1999) evaluated elastic fibers in the
  dermis of 10 Williams syndrome patients, all of whom were shown by FISH
  to have 7q11.23 deletions. Patients with Williams syndrome showed
  disorganized pre-elastic and mature elastic fibers when compared with 5
  healthy children and 1 patient with isolated supravalvular aortic
  stenosis. The authors concluded that skin biopsies may provide a simple
  means to elucidate the extracellular matrix anomalies associated with
  Williams syndrome.
  
  The Committee on Genetics American Academy of Pediatrics (2001)
  published a set of guidelines to assist in the health care supervision
  of children with Williams syndrome.
  
  Sadler et al. (2001) did a retrospective analysis of the incidence and
  severity of cardiovascular disease in Williams syndrome in 127 patients.
  The prevalence of SVAS was 44 of 127 (35%). Statistical analysis
  revealed that the severity of both SVAS and total cardiovascular disease
  was significantly greater in male than female patients. Sadler et al.
  (2001) also observed that the clinical diagnosis of WS was made at a
  significantly younger age in male patients and that this was partly
  because of increased incidence and severity of cardiovascular disease.
  Rose et al. (2001) followed 112 patients with WS since 1975 and studied
  25 of them by aortography. Twenty of 25 patients had vascular stenosis,
  of whom 19 were affected by segmental narrowing either of the thoracic
  aorta (9) or the abdominal aorta (7) or both (3). Hypoplasia of the
  abdominal aorta was characterized by the smallest diameters at the renal
  artery level and an increased diameter of the infrarenal abdominal
  aorta. Eleven patients had renal artery stenosis associated with
  narrowing of other aortic segments in 10 cases. Of 17 patients with
  hypertension, 2 had no vascular lesions; and in the remaining 15
  patients, stenosis was present in more than 1 segment. Rose et al.
  (2001) concluded that hypertension is a common symptom and must be
  regarded as a manifestation of generalized arteriopathy rather than
  renal hypoperfusion.
  
  Giannotti et al. (2001) reported a study of celiac disease (212750) in
  63 Italian WS patients. The dosage of antigliadin antibodies and
  antiendomisium antibodies was analyzed, and 6 patients positive for
  these antibodies underwent small bowel biopsy. Celiac disease was
  present in 6 (9.5%) WS patients, compared with 1 of 184 (0.54%) Italian
  children (p less than 0.001). Giannotti et al. (2001) suggested
  screening for celiac disease in patients with WS.
  
  In a retrospective study of 75 patients with WS, Eronen et al. (2002)
  found that cardiovascular symptoms were evident in 35 patients (47%) at
  birth. The most common abnormalities were SVAS (73%) and pulmonary
  artery stenosis (41%). Arterial hypertension was found in 55% of adults.
  
  In a study of the natural history of Williams syndrome, Cherniske et al.
  (2004) performed multisystem assessment of 20 affected adults over 30
  years of age and documented a high frequency of problems in multiple
  organ systems. The most consistent and striking findings were: abnormal
  body habitus; mild to moderate high-frequency sensorineural hearing
  loss; cardiovascular disease and hypertension; gastrointestinal
  symptoms, including diverticular disease; diabetes and abnormal glucose
  tolerance on standard oral glucose tolerance testing; subclinical
  hypothyroidism; decreased bone mineral density on dual energy x-ray
  absorptiometry (DEXA) scanning; and a high frequency of psychiatric
  symptoms, most notably anxiety, often requiring multimodal therapy.
  Brain MRI scans did not demonstrate consistent pathology. The adults
  were not living independently and the great majority were not
  competitively employed. One of the patients reported by Cherniske et al.
  (2004) had hypercalcemia, indicating that this feature is not restricted
  to infancy. Most of the adults had premature graying of the hair
  starting as early as 16 years of age, a finding that had been reported
  by Morris et al. (1988). This feature, together with an earlier than
  expected onset of cataracts and high-frequency sensorineural hearing
  loss, suggested mild accelerated aging, which may additionally
  complicate the long-term course of older adults with WS.
  
  Marler et al. (2005) studied auditory system function in 27 William
  syndrome patients aged 6 to 48 years. They found sensorineural hearing
  loss in 14 of 18 patients aged 21 or younger. The degree of hearing loss
  was greater in adults than in children, suggesting early-onset,
  progressive hearing loss.
  
  Gothelf et al. (2006) found that 41 (84%) of 49 patients with Williams
  syndrome had moderate to severe hyperacusis beginning in infancy. The
  most frequent sounds of daily life to which the children were sensitive
  included electric machines, thunder, bursting balloons, and fireworks.
  The children responded with marked fear and exhibited aversive
  behaviors. Hyperacusis peaked at age 5.7 years and tended to decrease
  somewhat thereafter. Quantitative testing of 21 of these patients
  revealed discomfort at sound intensities on average 20 dB lower than
  control individuals. Pure-tone audiometry and distortion product
  otoacoustic emission tests revealed high-frequency cochlear hearing
  loss. An absence of ipsilateral acoustic reflex responses to maximum
  stimulation was also observed. On brain auditory evoked response (BAER)
  testing, patients with Williams syndrome had a significant prolongation
  in wave I latency. Gothelf et al. (2006) noted that hearing loss in
  Williams syndrome resembled the configuration of noise-induced hearing
  loss and suggested that hyperacusis and hearing loss in Williams
  syndrome resulted from a deficiency in the normally protective acoustic
  reflex as a result of auditory nerve dysfunction.
  
  Tassabehji et al. (2005) identified an atypical Williams-Beuren syndrome
  individual with a smaller genetic deletion relative to classic
  Williams-Beuren syndrome cases but including 2 extratelomeric genes,
  CYLN2 (603432) and GTF2IRD1 (604318). The patient was a 4.5-year-old
  girl with surgically corrected pulmonary artery stenosis. Her
  birthweight and growth appeared normal, and at 4.5 years her height was
  just above the 50th centile. Facial features were suggestive of but not
  classic for Williams-Beuren syndrome. Early developmental milestones
  such as sitting and walking were within normal limits; however, by 18
  months she had a vocabulary of only a few single words and by age 4 she
  continued to show a delay in language acquisition as well as serious
  deficits in spatial cognition, but to a lesser degree than that seen in
  Williams-Beuren syndrome patients.
  
  Game et al. (2010) emphasized the urinary abnormalities in patients with
  WBS, including urinary frequency, urgency, nocturia, bladder
  diverticula, structural renal anomalies, and recurrent urinary tract
  infections. The authors noted that urodynamic testing has suggested
  evidence of detrusor overactivity and detrusor-sphincter dyssynergia in
  patients with WBS.
  
  OTHER FEATURES
  
  Ewart et al. (1993) commented that the IQ in patients with Williams
  syndrome varies from 20 to 106 (mean = 58). Specific cognitive deficits
  include poor visual-motor integration. As a result, affected individuals
  have problems visualizing a complete picture but instead see only the
  parts. Affected individuals also suffer from attention deficit disorder.
  Language development, by contrast, is relatively spared and some
  elements of speech may be enhanced, particularly the quantity and
  quality of vocabulary, auditory memory, and social use of language. Many
  patients sing or play musical instruments with considerable expertise
  and they rarely forget a name. Because of their engaging personalities,
  language skills, and loquaciousness, mental retardation is often
  underestimated in children with Williams syndrome. Gosch and Pankau
  (1996) used 2 methods to examine the cognitive abilities of 18 affected
  children (9 girls and 9 boys) with a mean age of 6.6 years at year one
  (T1) and approximately 2 years later (T2). The Draw A Person Test showed
  stable results (mean IQ of 63.5 at T1 and 65 at T2). The Columbia Mental
  Maturity Scale revealed a significant decrease of IQ (mean IQ of 77 at
  T1 and 68 at T2). Gosch and Pankau (1996) contended that this change
  represented a decrease of developmental rate of special abilities such
  as the application of classifications.
  
  Plissart et al. (1994) studied the psychologic and behavioral
  characteristics of 11 adult Belgian patients, aged 17 to 66 years.
  Mental retardation in all patients was moderate or severe. Verbal skills
  were superior to visuospatial and motor abilities. The most frequent
  behavioral problems were poor concentration, attention-seeking behavior,
  and restlessness. The behavioral and emotional disturbances typical for
  children with Williams syndrome persisted into adulthood. Most patients
  achieved a good level of autonomy, with the majority living at home with
  parents and attending a day center.
  
  Lenhoff et al. (1997) described the remarkable musical and verbal
  abilities of individuals with Williams syndrome, who perform poorly on
  standard IQ tests. They usually read and write poorly and struggle with
  simple arithmetic, but display a facility not only for spoken language
  but also for recognizing faces. As a group, they tend to be empathetic,
  loquacious, and sociable. Lenhoff et al. (1997) presented pictures,
  suggesting that children with Williams syndrome were an inspiration for
  pixie legends, and pointed out that the 'wee, magical people' of
  assorted folktales were often musicians and storytellers.
  
  Gosch and Pankau (1994) compared behavioral characteristics in 19
  children with Williams syndrome, aged 4 to 10 years, to those in a
  control group matched for age, gender, and nonverbal reasoning
  abilities. The children with Williams syndrome were more unreserved with
  and more willing to follow strangers, hypersensitive to sounds, and less
  socially adjusted than the control children.
  
  Mervis et al. (1999) discussed the subject of visuospatial constructive
  abilities in persons with normal intelligence and in persons with
  Williams syndrome or small deletions in the Williams syndrome region.
  They reviewed behavioral genetic studies of visuospatial constructive
  ability, which suggested that a substantial portion of the individual
  differences found among people of normal intelligence has a genetic
  basis.
  
  The behavioral phenotype in Williams syndrome suggests a dorsal and/or
  ventral developmental dissociation, with defects in dorsal but not the
  ventral hemispheric visual stream. A shortened extent of the dorsal
  central sulcus had been observed in autopsy specimens. Galaburda et al.
  (2001) compared gross anatomic features between the dorsal and ventral
  portions of the cerebral hemispheres by examining the dorsal extent of
  the central sulcus in MRI images from 21 subjects with WMS and age- and
  sex-matched control subjects. They found that the dorsal central sulcus
  was less likely to reach the interhemispheric fissure in subjects with
  WMS than in controls for both right and left hemispheres. No differences
  between the groups were found in the ventral extent of the central
  sulcus. They concluded that early neurodevelopmental problems affect the
  development of the dorsal forebrain and are probably related to the
  deficits in visuospatial ability and behavioral timing often observed in
  Williams syndrome.
  
  Schmitt et al. (2001) performed brain MRI on 20 patients with Williams
  syndrome to determine how cerebral shape differs from that of normal
  controls. In Williams syndrome, both cerebral hemispheres and the corpus
  callosum bend to a lesser degree in the sagittal plane, which the
  authors believed to be due to variation in the parietooccipital region.
  In addition, the cerebral hemispheres and corpus callosum midline
  lengths were decreased in Williams syndrome. Schmitt et al. (2001)
  suggested that the brain findings are consistent with aberrant premature
  termination of brain development, which proceeds normally in the
  rostrocaudal direction.
  
  Lenhoff et al. (2001) evaluated 5 patients with Williams syndrome for
  absolute musical pitch (AP; see 159300), which is the ability to
  recognize, name, and reproduce the pitch of a musical note without
  reference. The 5 patients had a mean IQ of 58 but were able to read
  musical notation. They began to play music at ages 5, 7, 8, 10, and 11
  years, respectively. As a group, the 5 patients scored 97.5% on 1,084
  absolute pitch trials, indicating that they possessed exceptional
  abilities in absolute pitch. By comparison, cognitively intact musicians
  who claim to have AP scored 84.3% on similar tests. Lenhoff et al.
  (2001) suggested that the prevalence of AP in individuals with Williams
  syndrome is higher than that in the general Western population (1 in
  10,000) and noted that the age window of AP acquisition in Williams
  syndrome appears to be extended compared to the general population.
  Hickok et al. (1995) reported that brain imaging of patients with
  Williams syndrome suggested an exaggerated left-right asymmetry of the
  planum temporale, which had also been found in musicians with absolute
  pitch (Schlaug et al., 1995), suggesting a neuroanatomical correlate to
  the ability.
  
  Patients with Williams syndrome have relatively good abilities in face
  recognition and discrimination. Using functional MRI to assess facial
  recognition, Mobbs et al. (2004) found that 11 patients with WS showed
  increased activation in the right fusiform gyrus and several frontal and
  temporal regions, including subcortical structures. By contrast, control
  individuals showed greater activation in the primary and secondary
  visual cortices. The findings suggested that patients with WS have
  impairments in the visual cortical regions and use frontal and temporal
  regions as a compensatory mechanism.
  
  Primate visual cortex is organized into 2 functionally specialized,
  hierarchically organized processing pathways: a ventral stream for
  object processing and a dorsal stream for spatial processing. Patients
  with Williams syndrome show a visuospatial constructive deficit, which
  is an inability to visualize an object as a set of parts or to construct
  a replica. Using multimodal neuroimaging techniques, Meyer-Lindenberg et
  al. (2004) found that 13 high-functioning individuals with WS showed
  significant hypoactivation in dorsal stream areas during different
  visual tasks compared to controls. No differences were found in the
  ventral stream. Structural imaging studies showed that individuals with
  WS had gray matter volume reduction in the
  parietooccipital/intraparietal sulcus, immediately adjacent to the
  region of hypofunction, suggesting a structural-functional connection.
  
  Meyer-Lindenberg et al. (2005) used multimodal neuroimaging to
  characterize hippocampal structure, function, and metabolic integrity in
  12 normal-intelligence patients with Williams syndrome and 12 age-,
  sex-, and IQ-matched healthy controls. PET and functional MRI studies
  showed profound reduction in resting blood flow and absent differential
  response to visual stimuli in the anterior hippocampal formation in
  patients with Williams syndrome. Spectroscopic measures of
  N-acetylaspartate, a marker of synaptic activity, were reduced.
  Hippocampal size was preserved, but subtle alterations in shape were
  present. Meyer-Lindenberg et al. (2005) suggested that hippocampal
  dysfunction might contribute to neurocognitive abnormalities in Williams
  syndrome.
  
  Castelo-Branco et al. (2007) presented evidence of a neural defect in
  the retina of WBS patients. High-resolution imaging techniques found
  that WBS patients had decreased retinal thickness, abnormal optic disc
  concavity, and impaired visual responses compared to controls. Low-level
  magnocellular performance was independent of deficits in the integration
  of information at higher levels.
  
  Marenco et al. (2007) performed brain diffusion tensor MRI to assess
  white matter integrity in 5 high-functioning WBS patients. Patients
  showed significant differences in white matter tissue organization
  compared to controls, particularly with respect to alterations in the
  main orientation of fibers underlying abnormalities in the gray matter.
  There appeared to be an increase in anterior-posterior longitudinal
  fibers and a reduction in right-to-left transverse axis fibers in the
  patients, consistent with the finding of other midline defects, such as
  dysgenesis of the corpus callosum. Marenco et al. (2007) hypothesized
  that there is specific alteration in the development of U fibers in the
  later stages of neuronal migration in patients with WBS and suggested
  that these abnormal patterns result from deletions of genes within the
  critical region.
  
  BIOCHEMICAL FEATURES
  
  In a study of patients with Williams syndrome, Rae et al. (1998) found a
  correlation between performance on neuropsychologic tests and decreases
  in the amount of neocerebellar N-acetylaspartate when normalized to
  choline or creatine. They speculated that this could either reflect a
  global decrease of this neuronal marker in the entire brain, or perhaps
  evidence of cerebellar involvement.
  
  Grimm and Wesselhoeft (1980) pointed out that supravalvular aortic
  stenosis has been described as a rare feature of the Marfan syndrome and
  occurs as a phenocopy of the genetic disorder induced by rubella
  embryopathy (Varghese et al., 1969), by experimental vitamin D excess
  (Friedman and Roberts, 1966), and possibly by thalidomide (Jorgensen,
  1972). Taylor et al. (1982) investigated the effects of pharmacologic
  doses of vitamin D2 given for 4 days to normal children and to children
  with Williams disease and their sibs. The results indicated an
  exaggerated increase in serum 25-OH-D in response to challenge with
  vitamin D in patients with the Williams syndrome and in some of their
  sibs with no clinical features of the syndrome. Despite the increases in
  serum 25-OH-D, none of the patients became hypercalcemic. Garabedian et
  al. (1985) found high plasma concentrations of 1,25-(OH)2D in 4 children
  with hypercalcemia and elfin facies. The levels were higher than in 3
  children with elfin facies but without hypercalcemia or dysmorphia. In
  Williams syndrome, a low calcium diet controlled the hypercalcemia. They
  suggested that an abnormal synthesis or degradation of 1,25-(OH)2D is
  present in this syndrome. Others (e.g., Martin et al., 1985) questioned
  this work. From a study of calcium metabolism in 27 normocalcemic
  children and adults, aged 2 to 47 years, with WBS, Kruse et al. (1992)
  concluded that neither deficient calcitonin secretion nor increased
  renal sensitivity to parathyroid hormone is a feature in normocalcemic
  patients. Furthermore, they did not find a significant disturbance in
  vitamin D metabolism.
  
  Cherniske et al. (2004) reported studies of 20 adults with Williams
  syndrome (age range 30 to 51 years) in which they observed a 25%
  prevalence of elevation of serum thyroid-stimulating hormone (TSH; see
  188540) concentration. Stagi et al. (2005) analyzed thyroid function and
  morphology in another 20 patients with Williams syndrome (age range 1.7
  to 34.9 years). They likewise found that 25% of the patients showed a
  TSH elevation; they related this finding to the hypoplasia of the
  thyroid gland which was evident in about 70% of their patients.
  Selicorni et al. (2006) reported the results of a morphologic and
  functional study of the thyroid gland in 95 patients with WS, who
  periodically underwent a complete survey to detect early complications
  related to the condition. The study confirmed the increased incidence of
  both elevated TSH serum values (37.9%) and thyroid gland hypoplasia
  (74.7%). Moreover, they demonstrated that TSH elevation declined with
  age.
  
  POPULATION GENETICS
  
  Grimm and Wesselhoeft (1980) estimated the frequency of Williams
  syndrome to be 1 in 10,000.
  
  Stromme et al. (2002) estimated that the Williams-Beuren syndrome occurs
  at a frequency of approximately 1 in 7500 live births, with
  approximately two-thirds of the deletion events being intrachromosomal.
  
  CYTOGENETICS
  
  Osborne (1999) reviewed Williams-Beuren syndrome, including the
  phenotype and the genes that have been identified as mapping within the
  WBS common deletion. They discussed the mechanism of deletion and the
  correlation between extent of deletion and phenotype.
  
  - Deletion at the ELN Gene Locus
  
  In studies in 4 familial and 5 sporadic cases of Williams syndrome,
  Ewart et al. (1993) identified hemizygosity at the elastin locus (ELN;
  130160) resulting from deletion. Loss of heterozygosity for DNA markers
  was the first clue; fluorescence in situ hybridization and quantitative
  Southern analysis confirmed this finding. The neurobehavioral features
  of Williams syndrome described earlier are not easily explained by
  hemizygosity at the ELN locus. The linkage and physical mapping data of
  Ewart et al. (1993) suggested that the deletions associated with
  Williams syndrome extend beyond the ELN locus, spanning at least 114 kb.
  Additional genes, therefore, are probably deleted and one or more of the
  genes could be involved in the pathogenesis of this disease. The
  severity of mental retardation may be related to the size of the
  deletion. Taking advantage of a large series (27 cases) of sporadic
  Williams syndrome, Gilbert-Dussardier et al. (1995) explored the
  potential application of novel microsatellite DNA markers in the rapid
  detection of hemizygosity in WMS. They found that a highly informative
  marker at locus D7S1870 could detect failure of parental inheritance in
  almost 75% of cases in their series.
  
  Nickerson et al. (1995) investigated the frequency of deletions of the
  ELN gene in patients with Williams syndrome using both fluorescence in
  situ hybridization (FISH) and PCR amplification of a dinucleotide repeat
  polymorphism. In 40 of the 44 patients tested (91%), FISH demonstrated
  deletion of the ELN gene. Using the DNA polymorphism, both maternally
  (39%) and paternally (61%), derived deletions were found. Thus, FISH
  analysis proved a rapid and informative test to confirm a clinical
  diagnosis of Williams syndrome. However, the presence of 2 copies of the
  ELN locus in a patient does not rule out the diagnosis. In a series of
  235 patients, Lowery et al. (1995) identified molecular cytogenetic
  deletions by FISH in 96% of patients with classic WMS. Patients included
  195 solicited through the Williams Syndrome Association, plus 40
  clinical cytogenetics cases referred by primary-care physicians. On the
  basis of photographs and medical records of most subjects from the
  Association, 114 of the patients were identified as 'classic' and 39
  'uncertain.' Whereas 96% of the classic WMS subjects showed deletion,
  only 3 of 39 of the uncertain patients showed a deletion. Of the 42 who
  were not classified phenotypically, because of lack of clinical
  information, 25 patients (60%) showed a deletion. In 15 of 40 (38%) of
  clinical cytogenetics cases, they found an ELN deletion and no
  cytogenetic deletion by banded analysis. Results supported the
  usefulness of FISH for the detection of elastin deletions as an initial
  diagnostic assay for WMS.
  
  Mari et al. (1995) used an intragenic RFLP and gene dosage of the
  elastin gene with a new probe to analyze 60 sporadic cases with the
  clinical diagnosis of Williams syndrome. Deletion of the ELN gene was
  shown in 54 cases; clinical reevaluation of the 6 patients without
  demonstrable deletion did not confirm the diagnosis of WMS. The results
  supported the genetic homogeneity of WMS and the high accuracy of ELN
  molecular analysis. By using FISH as a diagnostic tool, Borg et al.
  (1995) demonstrated hemizygosity at the ELN locus in all 5 cases
  considered to be classic Williams syndrome and in 3 of 5 atypical cases.
  Prominence of the thyroid cartilage and thinning of the cheeks (with
  loss of jowls) occurred with advancing age. A friendly disposition was
  found in all patients with the microdeletion, but the degree of
  loquacity decreased as the severity of mental retardation increased.
  Hyperacusis was also a constant feature. Hypercalcemia was documented in
  only 2 of the patients with submicroscopic microdeletion but
  surprisingly was documented in both patients lacking the chromosomal
  abnormality. By FISH, Brewer et al. (1996) found hemizygosity for an ELN
  gene probe in all of 16 children in adolescence with a firm clinical
  diagnosis of Williams syndrome.
  
  Perez Jurado et al. (1996) investigated the deletion size and frequency
  on chromosome 7q11.23, determined the parental origin, and correlated
  the molecular results with the clinical findings in 65 patients with
  Williams syndrome. They carried out genotyping of WS patients and
  available parents for 13 polymorphisms and determined that 94% of
  patients had a deletion of the ELN locus. Analysis of polymorphic
  markers suggested that the commonly deleted region extended from D7S489B
  through D7S1870. The D7S489B locus was deleted in all informative
  patients. No variability in the size of the deletion was detected in the
  WS patients by genotyping of polymorphic markers. The investigators were
  able to visualize the common deletion in WS, estimated to be 1.5-2.5 Mb.
  The D7S489B locus constitutes a lower-copy repeat with at least 2 copies
  which map close to the WS deletion breakpoints. Perez Jurado et al.
  (1996) proposed that these repeats may provide a mechanism for aberrant
  recombination or replication events. All 4 patients with normal dosage
  at the ELN locus had biparental inheritance at all informative loci
  tested. Perez-Jurado et al. (1996) noted that clinical reevaluation of
  these 4 patients was consistent with a diagnosis of WS based on the
  presence, during some period of development, of characteristic facial
  features, mental retardation, and strongly suggestive cognitive and
  personality profiles. They noted that 3 of the 4 patients were above the
  fiftieth centile for height and head circumference. None of them had
  hypercalcemia or vascular stenoses. Perez Jurado et al. (1996) reported
  that in 39 families informative for parental origin, all deletions were
  de novo and 18 were paternally and 21 maternally derived. They noted
  that comparison of clinical data collected in a standardized
  quantifiable format revealed more severe growth retardation and
  microcephaly in the maternal deletion group. Perez Jurado et al. (1996)
  proposed that an imprinted locus, silent on the paternal chromosome and
  contributing to statural growth, may be affected by the deletion.
  
  Dutly and Schinzel (1996) carried out molecular genetic studies in 15
  families with WBS. They demonstrated deletion of the ELN gene in all of
  the probands. The 15 families consisting of patients, parents, and
  paternal or maternal grandparents were genotyped using microsatellites
  adjacent to the centromeric or telomeric end of ELN. They demonstrated
  that in 10 out of 15 WBS families (67%) with a de novo deletion within
  7q11.23, the segment flanking the deleted region contained recombined
  haplotypes. These recombination events indicated that deletion was the
  result of an unequal crossing-over event between the chromosome 7
  homologs during gametogenesis. In 5 of the 15 families there was no
  recombination on either side of the deletion. Dutly and Schinzel (1996)
  postulated that in these families there may be intrachromosomal
  recombination. They noted that unequal recombination events are mediated
  by related gene sequences or repetitive elements and that the elastin
  gene has relatively large introns characterized by repetitive elements.
  Frangiskakis et al. (1996) reported that breakpoints in the LIM kinase-1
  gene (LIMK1; 601329), which is adjacent to ELN, occur within Alu
  repeats. Dutly and Schinzel (1996) concluded that a practical
  consequence of their findings is improved prediction of recurrence risks
  for sibs of a WBS-affected proband since a recombination event around
  the deleted segment indicates meiotic recombination which is unlikely to
  recur.
  
  Pankau et al. (2001) reported 2 families in which girls had inherited
  Williams-Beuren syndrome from their mothers. In all 4 patients the
  clinical diagnosis was supported by the molecular cytogenetic detection
  of a hemizygous deletion at 7q11.23. Considerable variation in the
  clinical manifestations of the syndrome within and between these
  families was noted.
  
  - Deletion of the RFC2 Gene 
  
  Peoples et al. (1996) reported that the RFC2 (600404) gene product was
  deleted in 18 of 18 patients with Williams syndrome. Deletion of RFC2
  was demonstrated by analysis of somatic cell hybrids in which the normal
  and the Williams causing chromosome from a particular patient were
  separated. RFC2 deletion was also demonstrated by FISH. They noted that
  the 40-kD protein product encoded by RFC2 is one of 5 subunits of the
  replication factor C complex. They postulated that deletion of RFC2
  subunits may lead to reduced efficiency of DNA replication, which could
  account for growth deficiency as well as developmental disturbances.
  
  -  Deletion of the LIMK1 Gene
  
  Tassabehji et al. (1996) found that in addition to the ELN gene
  (130160), the gene that encodes LIM kinase (LIMK1; 601329) is deleted in
  Williams syndrome. To identify genes important for human cognitive
  development, Frangiskakis et al. (1996) studied Williams syndrome
  patients who show poor visuospatial constructive cognition. They
  described 2 families with a partial WS phenotype; affected members had
  the specific WS cognitive profile and vascular disease, but lacked other
  WS features. Submicroscopic 7q11.23 deletions cosegregated with the
  phenotype in both families. DNA sequence analyses of the region affected
  by the smallest deletion (83.6 kb) revealed both the ELN gene and the
  LIMK1 gene. The latter is strongly expressed in the brain. Because ELN
  mutations cause vascular disease but not cognitive abnormalities,
  Frangiskakis et al. (1996) suggested that LIMK1 hemizygosity is
  implicated in the impaired visuospatial constructive cognition of
  Williams syndrome.
  
  - Deletion of the GTF2IRD1/GTF2I Gene Cluster
  
  Tassabehji et al. (2005) identified an atypical WBS individual with a
  smaller genetic deletion relative to classic WBS cases but including 2
  extratelomeric genes, CYLN2 (603432) and GTF2IRD1 (604318). The patient
  showed milder facial dysmorphism and cognitive deficits than those seen
  in classic WBS cases. Studies in mouse showed that homozygous loss of
  Gtf2ird1 results in craniofacial abnormalities reminiscent of those seen
  in WBS, together with growth retardation and neurologic abnormalities.
  Taken together, these observations implicated GTF2IRD1 in mammalian
  craniofacial and cognitive development. Tassabehji et al. (2005)
  suggested that cumulative dosage of TFII-I family genes explains the
  main phenotypes of WBS; Gtf2ird1-null mice and classic WBS individuals
  have 2 functioning copies (in trans and cis, respectively), whereas the
  atypical patient had 3 functioning genes of the GTF2IRD1/GTF2I (601679)
  cluster and showed milder WBS phenotypes. Edelmann et al. (2007)
  reported a 6.5-year-old girl with autism (209850) who also had the
  cognitive-behavioral profile associated with WBS, including severely
  impaired visuospatial processing and friendly personality despite
  impaired social interaction. However, she did not have other classic
  medical or physical features of WBS. Molecular studies detected a large
  de novo heterozygous 2.4 to 3.1-kb deletion that overlapped slightly
  with the distal end of the WBS critical region, including the GTF2IRD1,
  GTF2I, and about 15 other genes. Edelmann et al. (2007) suggested that
  the findings implicated hemizygosity for GTF2IRD1 and GTF2I in the
  visuospatial construction deficit characteristic of WBS.
  
  Collette et al. (2009) used quantitative RT-PCR to determine the
  transcriptional level of 14 WBS markers in a cohort of 77 WBS patients
  and 48 controls, and observed that the parental origin of the deletion
  contributes to the level of expression of GTF2I independently of age and
  gender, with significantly lower expression when the single remaining
  copy is located on the paternally derived chromosome (p = 0.0002).
  Correlation of expression of GTF2I and some other genes in the WBS
  region differed between WBS patients and controls, pointing to a
  regulatory role for the GTF2I gene.
  
  - Deletion of the FKBP6 Gene
  
  Metcalfe et al. (2005) described a Bulgarian father and son with WBS
  detected by fluorescence in situ hybridization (with an elastin gene
  probe) and loss of heterozygosity mapping using microsatellite markers
  located in the critical region. The father and son appeared to have a
  common WBS heterozygous deletion, confirming the expected dominant
  transmission and adding to the few familial cases reported. The deletion
  included the FKBP6 gene (604839) which has been shown to play a role in
  homologous chromosome pairing in meiosis and male fertility in mouse
  models.
  
  - Delineation of the WBS Critical Region
  
  Urban et al. (1996) analyzed 7q deletions in 31 sporadic WS cases.
  Patients and family members were genotyped for 3 ELN gene markers. These
  included a tetranucleotide repeat polymorphism within the first intron
  of elastin, a CA-repeat polymorphism within intron 18, and an RmaI RFLP
  within exon 20 of the ELN gene. In addition, 6 dinucleotide repeat
  polymorphic markers were analyzed. Urban et al. (1996) used genotype
  data to generate haplotypes. They reported that the ELN gene markers
  detected hemizygosity in 25 informative Williams syndrome patients. One
  D7S1870 allele was deleted in 27 informative WS patients. Another distal
  locus (D7S849) was hemizygous in 4 of the 31 patients. This finding led
  Urban et al. (1996) to conclude that size heterogeneity of the Williams
  region exists. Their mapping and haplotype studies indicated that a
  large portion of genomic DNA distal to the ELN gene is missing in most
  WS patients with supravalvular aortic stenosis. Their results were
  consistent with deletions spanning 0.9 to 2.5 Mb, and they concluded
  that these deletions may involve several genes, suggesting that WS is a
  contiguous gene syndrome. Urban et al. (1996) reported that WS patients
  in all of the 12 families analyzed by them were not only deleted for at
  least 1 marker in the ELN region but also had apparent recombination
  between proximal and distal markers flanking the deletion. In contrast,
  homologous chromosomes in the same WS patients did not show any
  recombination event. Urban et al. (1996) concluded that these data
  implicated meiotic recombination as the underlying mechanism of the
  deletion associated with WS.
  
  Osborne et al. (1996) constructed a physical map of a 500-kb region in
  7q11.23 that they determined to be deleted in a collection of 30 WBS
  patients. This region, which extends 35 kb 5-prime and 430 kb 3-prime of
  the ELN gene, contains 9 transcription units, including the ELN, LIMK1,
  RFC2, and WSCR1 (603431) genes.
  
  Wu et al. (1998) defined the minimal critical deletion region on 7q in
  63 WMS patients, using 10 microsatellite markers and 5 fluorescence in
  situ hybridization probes flanking the ELN gene. These studies showed
  deletions of consistent size. In all informative cases deleted at ELN,
  the deletion extended from D7S489U to D7S1870. The genetic distance
  between these 2 markers is about 2 cM. Of the 51 informative patients
  with deletions, 29 were maternal and 22 were paternal in origin. There
  was no evidence for effects on stature by examining gender, ethnicity,
  cardiac status, or parental origin of the deletion. Heteroduplex
  analysis for the LIMK1 gene did not show any mutations in patients with
  WMS in this series who did not have deletions at ELN. On the other hand,
  LIMK1 deletions were found in all elastin-deletion patients who had WMS.
  One patient, who had isolated supravalvular aortic stenosis and an
  elastin deletion, did not have a deletion at LIMK1.
  
  Meng et al. (1998) undertook to identify genes involved in the
  contiguous gene deletion syndrome of Williams that explained phenotypic
  features. Hemizygosity of elastin (ELN; 130160) had been shown to be
  responsible for supravalvular aortic stenosis, and hemizygosity for
  LIM-kinase 1 (LIMK1; 601329) had been implicated as contributing factor
  to impaired visual-spatial constructive cognition in Williams syndrome.
  Additional genes were sought to account for other features such as
  mental retardation, infantile hypercalcemia, and unique personality
  profile. They presented a physical mapping encompassing 1.5 Mb DNA that
  is commonly deleted in individuals with WS. Three novel genes were
  identified in the common deletion region: TBL2 (605842), BCL7B (605846),
  and WBSCR14 (605678).
  
  Botta et al. (1999) described 2 patients with the full Williams syndrome
  phenotype who carried deletions from the ELN gene to marker D7S1870.
  This region excludes the candidate genes STX1A (186590) and FZD9
  (601766), and defines a region estimated to be less than 1 Mb.
  
  Wu et al. (1999) reported a child with typical features of Williams
  syndrome, including supravalvular aortic stenosis, short stature,
  hypercalcemia, facial dysmorphism, and stellate irides. In addition,
  severe mental retardation with little speech, macrocephaly, and retinal
  changes not seen in Williams syndrome were present. The child had a
  cytogenetically visible deletion extending from D7S849 to beyond D7S440
  telomeric of D7S1870. Wu et al. (1999) also demonstrated that the
  deletion included the CACNL2A gene (114204) and suggested that the
  patient might be susceptible to malignant hyperthermia (see 154276).
  
  Duba et al. (2002) investigated a family with a cytogenetically balanced
  translocation t(7;16)(q11.23;q13) in which the 5 translocation carriers
  manifested a wide variation in phenotype, ranging from a hoarse voice as
  the only feature, partial WBS with or without SVAS, to the full WBS
  phenotype. DNA sequence analysis showed that the breakpoint on
  chromosome 7 was within intron 5 of the ELN gene and on chromosome 16
  within intron 1 of the GPR56 gene (604110). In the course of the
  rearrangement, no basepair was lost from either the chromosome 7 or
  chromosome 16 sequences. The chromosomal breakpoints in the 5
  translocation carriers were identical, and FISH analysis of the WBS
  critical region indicated that no predisposing inversion of the WBS
  region had occurred prior to the translocation. Duba et al. (2002)
  speculated that the expected phenotype in the reported family would be
  SVAS, not WBS, and proposed a long-range position effect caused by the
  translocation event as the most likely explanation.
  
  Kara-Mostefa et al. (1999) reported an instance of recurrent WBS in 2
  sibs with deletions on the maternally inherited haploidentical
  chromosome. The authors interpreted this as suggesting a premeiotic
  intrachromosomal event leading to gonadal mosaicism in the mother.
  
  Valero et al. (2000) found that 3 large region-specific segmental
  duplication or low copy repeat elements (centromeric, medial, and
  telomeric LCRs), each composed of 3 differentiated blocks designated A,
  B, and C, flank the WBS common deletion region. Bayes et al. (2003)
  determined the exact deletion size and LCR copy number in 74 patients
  with WBS, as well as precisely defined deletion breakpoints in 30 of
  them, using LCR-specific nucleotide differences. Most patients (95%)
  exhibited a 1.55-Mb deletion caused by recombination between centromeric
  and medial block B copies, which share approximately 99.6% sequence
  identity along 105 to 143 kb. In these cases, deletion breakpoints were
  mapped at several sites within the recombinant block B, with a cluster
  (more than 27%) occurring at a 12-kb region within the GTF2I gene
  (601679). Almost one-third (28%) of the transmitting progenitors were
  found to be heterozygous for an inversion between centromeric and
  telomeric LCRs. All deletion breakpoints in the patients with the
  inversion occurred in the distal 38-kb block B region only present in
  the telomeric and medial copies. Only 4 patients (5%) displayed a large
  deletion (approximately 1.84 Mb) caused by recombination between
  centromeric and medial block A copies. Bayes et al. (2003) proposed
  models for the specific pairing and precise aberrant recombination
  leading to each of the different germline rearrangements that occur in
  this region, including inversions and deletions associated with WBS.
  Chromosomal instability at 7q11.23 is directly related to the genomic
  structure of the region.
  
  GENOTYPE/PHENOTYPE CORRELATIONS
  
  Wang et al. (1999) analyzed 85 confirmed cases of 7q11.23 deletion and
  Williams-Beuren syndrome. Deletion of this region is responsible for 90
  to 95% of all clinically typical cases. No statistically significant
  associations were found between clinical features and deletion size,
  inherited ELN and LIMK1 alleles, gender, and parental origin of the
  deletion. The data did not support the presence of imprinted genes in
  the WBS common deletion, despite a nonsignificant excess of maternal
  over paternal deletions. Maternal deletion cases were more likely to
  have a large head circumference. Pairwise comparisons between individual
  WBS clinical features showed significant association between (1) low
  birth weight and poor postnatal weight gain and (2) transient infantile
  hypercalcemia and a stellate iris pattern. The latter association was
  thought possibly to indicate a common underlying etiology.
  
  Tassabehji (2003) reviewed genotype-phenotype correlations in Williams
  syndrome.
  
  The WBS locus is prone to recurrent chromosomal rearrangements,
  including the microdeletion that causes WBS. Reciprocal duplications of
  the WBS interval should also occur, and Somerville et al. (2005)
  described such a case. The most striking phenotype was a severe delay in
  expressive speech, in contrast to the normal articulation and fluent
  expressive language observed in persons with WBS. The results suggested
  that specific genes at 7q11.23 are exquisitely sensitive to dosage
  alterations that can influence human language and visuospatial
  capabilities. See 609757 for a discussion of the WBS duplication
  syndrome, which is the reciprocal of the microdeletion that underlies
  the Williams-Beuren syndrome.
  
  Dai et al. (2009) provided a detailed genotype/phenotype analysis of a
  7-year-old girl with WBS resulting from an atypical 7q11.2 deletion
  (Jarvinen-Pasley et al., 2008). She had some specific features of the
  disorder, including growth delay, characteristic facies, cardiovascular
  involvement with pulmonic stenosis and hypertension, delayed growth, and
  deficits in visual-spatial construction. However, in contrast to the
  usual findings in WBS, she had normal developmental milestones,
  comparatively high cognitive function, and did not have the typical
  delay in language or overly social behavior. By high-resolution
  oligonucleotide array CGH analysis, multicolor FISH analysis, and PCR
  analysis of somatic cell hybrids, they showed that the 1.26- to 1.31-Mb
  deletion included most of FKBP6, possibly NSUN5 and TRIM50 (612548), and
  all of the other genes in the interval through GTF2IRD1, but not GTF2I.
  Neuropsychologic studies showed that the patient had IQ scores 1 to 23
  standard deviations above typical WBS children. Dai et al. (2009)
  postulated that deletion of the GTF2I gene may not play a role in some
  of the physical aspects of WBS, but may play an important role in some
  aspects of cognition and social behavior seen in the disorder. Since the
  patient did demonstrate defects in visual-spatial construction, deletion
  of GTF2IRD1 may play a role in that specific dysfunction. Dai et al.
  (2009) also found no correlation between neurocognitive performance and
  social behavior among 20 patients with typical WBS, suggesting that the
  normal social behavior in the atypical patient did not result from
  better cognition.
  
  Ferrero et al. (2010) reported an 11-year-old Italian boy with a mild
  form of WBS with mild facial features, normal IQ, and only some of the
  neuropsychologic features of the disorder, including visual-spatial
  defects and performance deficits. Although he demonstrated an
  extroverted personality in infancy, this disappeared as he got older.
  FISH analysis and quantitative PCR studies identified a de novo 0.84 to
  0.94-Mb deletion in the core of the WBS critical region that partially
  included the BAZ1B gene (605681), but did not include the GTF2IRD1 or
  GTF2I genes. The findings were consistent with the hypothesis that
  hemizygosity of the GTF2IRD1 and GTF2I genes may be involved in the
  facial dysmorphism and specific motor and cognitive deficits observed in
  WBS patients, since extremes of these features were not found in the
  patient.
  
  MOLECULAR GENETICS
  
  Jones (1990) speculated that calcitonin-gene-related peptide (114130)
  may be implicated in this disorder. Using 5 restriction enzymes in the
  study of 13 families, each with at least 1 affected member, Hitman et
  al. (1989) could find no abnormality of the calcitonin-CGRP gene.
  Furthermore, no association of the Williams-Beuren syndrome with
  polymorphism of this gene or of the parathormone (168450) locus was
  found. Russo et al. (1991) found no abnormality of the calcitonin/CGRP
  gene on Southern blot analysis of white blood cell DNA in 5 patients.
  Furthermore, the possibility of small deletions or point mutations
  within the exon encoding the mature calcitonin hormone was considered
  unlikely based on the negative findings of ribonuclease protection
  assays with patient DNA amplified by PCR. Thus the calcitonin deficiency
  found in these patients may be due either to mutations elsewhere in the
  gene or to defects in the cellular machinery needed for calcitonin
  synthesis and/or secretion.
  
  As indicated, Williams-Beuren syndrome is most often caused by
  hemizygous deletion of a 1.5-Mb interval encompassing at least 17 genes
  at 7q11.23. As with many other haploinsufficiency diseases, the
  mechanism underlying the WBS deletion is thought to be unequal meiotic
  recombination, probably mediated by the highly homologous DNA that
  flanks the commonly deleted region (Baumer et al., 1998). Osborne et al.
  (2001) used interphase fluorescence in situ hybridization (FISH) and
  pulsed field gel electrophoresis to identify a genomic polymorphism in
  families with WBS, consisting of an inversion of the WBS region. They
  found that the inversion was hemizygous in 3 of 11 (27%) atypical
  affected individuals who showed a subset of the WBS phenotypic spectrum
  but did not carry the typical WBS microdeletion. Two of these
  individuals also had a parent who carried the inversion. In addition, in
  4 of 12 (33%) families with a proband carrying the WBS deletion, they
  observed the inversion exclusively in the parent transmitting the
  disease-related chromosome. These results suggested the presence of a
  genomic variant within the population that may be associated with WBS.
  The variant may result in predisposition to primarily WBS-causing
  microdeletions, but may also cause translocations and inversions.
  
  Scherer et al. (2005) reported 2 sibs with WBS and demonstrated that the
  7q11 deletion was paternally inherited in both cases. Although DNA from
  the father was not available for study, the authors used site-specific
  nucleotide analysis and dosage comparisons to determine that the father
  carried the inverted WBS variant chromosome (WBSinv-1) reported by
  Osborne et al. (2001). The inversion of 7q11.23 on one chromosome 7
  likely caused misalignment of the WBS region between sister chromatids
  during meiosis, resulting in deletion and/or duplication of the region
  during recombination. Scherer et al. (2005) concluded that presence of
  the WBSinv-1 variant, which is estimated to occur in 5% of the
  population, confers an increased risk of WBS in the offspring of
  carriers. The findings were significant in identifying a potential
  genetic risk factor for WBS.
  
  Williams-Beuren syndrome represents a model for studying hypertension in
  a genetically determined disorder. Haploinsufficiency of the elastin
  gene is known to lead to the vascular stenoses in WBS and is also
  thought to predispose to hypertension, which is present in approximately
  50% of patients. Del Campo et al. (2006) performed detailed clinical and
  molecular characterization of 96 patients with WBS to explore
  clinical-molecular correlations. Deletion breakpoints were precisely
  defined and found to result in variability at 2 genes, NCF1 (608512) and
  GTF2IRD2 (608899). Hypertension was significantly less prevalent in
  patients with WBS who had a deletion that included NCF1 (p = 0.02), a
  gene encoding the p47(phox) subunit of NADPH oxidase. Decreased levels
  of the p47(phox) protein, decreased superoxide anion production, and
  lower protein nitrotyrosination were all observed in cell lines from
  patients hemizygous at NCF1. The results indicated that the loss of a
  functional copy of NCF1 protects a proportion of patients with WBS
  against hypertension, likely through a lifelong reduced angiotensin II
  (see 106150)-mediated oxidative stress. Del Campo et al. (2006)
  speculated that antioxidant therapy that reduces NADPH oxidase activity
  might have a benefit in identifiable patients with WBS in whom serious
  complications related to hypertension have been reported, as well as in
  forms of essential hypertension mediated by a similar pathogenic
  mechanism.
  
  Merla et al. (2006) measured the relative expression level of genes that
  map within the microdeletion that causes WBS and within its flanking
  regions. They found, unexpectedly, that not only hemizygous genes but
  also normal-copy neighboring genes showed decreased relative levels of
  expression. The results suggested that not only the aneuploid genes but
  also the flanking genes that map several megabases away from a genomic
  rearrangement should be considered possible contributors to the
  phenotypic variation in genomic disorders.
  
  Marshall et al. (2008) found that the MAGI2 gene (606382), which is
  telomeric to the WBS gene region, was hemizygously disrupted in 10
  patients with a severe form of WBS that included infantile spasms and
  mental retardation. The disruption was part of a larger deletion at
  7q11.23-q21.11 in all of these patients. In contrast, 9 WBS patients
  with deletions at 7q11.23 that did not disrupt the MAGI2 gene did not
  have infantile spasms. One WBS patient with spasms did not have
  disruption of the MAGI2 gene. Marshall et al. (2008) also reported 5
  patients without WBS but with infantile seizures, developmental delay,
  and other variable clinical features who had contiguous gene deletions
  in this region including the MAGI2 gene. The findings suggested the
  MAGI2 gene may be a locus for infantile spasms and that its disruption
  may be responsible for infantile spasms in some WBS patients.
  
  DIAGNOSIS
  
  Del Rio et al. (1998) reported a gene-dosage octaplex PCR assay using
  DNA from buccal smears for the rapid detection of elastin gene deletions
  in Williams syndrome patients. A domain within the promoter region of
  the elastin gene spanning exons 20-21, and part of exon 36, were
  amplified. The disomic reference gene chosen was the lysyl oxidase gene
  (LOX; 153455), and a domain of LOX was used in preparation of the
  internal standard.
  
  ANIMAL MODEL
  
  To investigate why a loss-of-function mutation in 1 elastin allele
  causes an obstructive arterial disease, supravalvular aortic stenosis,
  Li et al. (1998) generated mice hemizygous for the elastin gene (ELN
  +/-). ELN +/- mice have an expected reduction in ELN mRNA and protein of
  50% but nearly normal arterial compliance at physiologic pressures. This
  discrepancy was explained by a paradoxical increase of 35% in the number
  of elastic lamellae and smooth muscle in ELN +/- arteries. Examination
  of humans with ELN hemizygosity revealed a 2.5-fold increase in elastic
  lamellae and smooth muscle. Thus, ELN hemizygosity in mice and humans
  induces a compensatory increase in the number of rings of elastic
  lamellae and smooth muscle during arterial development. Humans are
  exquisitely sensitive to reduced ELN expression, developing profound
  arterial thickening and markedly increased risk of obstructive vascular
  disease. Other factors may contribute to the risk of obstructive
  arterial disease by reducing ELN expression during development.
  Hypervitaminosis D, for example, reduces ELN expression in both in vitro
  and in vivo systems (Vijayakumar and Kurup, 1974; Hinek et al., 1991).
  Animal models exposed to hypervitaminosis D gave birth to offspring that
  developed SVAS (Friedman and Roberts, 1966; Chan et al., 1979). These
  findings supported the model of Li et al. (1998) of reduced gestational
  ELN expression resulting in abnormal vascular development and
  obstructive vascular disease.
  
  Faury et al. (2003) reported that mice with haploinsufficiency for
  elastin were stably hypertensive from birth. They discussed the
  mechanism by which decreased elastin in vessel walls leads to
  hypertension. In a commentary, D'Armiento (2003) provided an
  illustration of how hemodynamic forces resulting from altered matrix
  structure influence vascular development.
  
  HISTORY
  
  Miles and Michalski (1983) found duplication of 15q11.2-q13.1 in a boy
  judged to satisfy the clinical criteria for Williams syndrome. The
  father, who had the same duplication, had postnatal growth retardation,
  height at the 2% level at age 12, and bone age consistent with the
  chronologic age of 12. Kaplan et al. (1987) reported apparent deletion
  in 15q11-q12 in a child with typical Williams syndrome.
  
  Jefferson et al. (1986) described a terminal deletion of the long arm of
  chromosome 4, 46,XX,del(4)(q33), in a female infant with peripheral
  pulmonary artery stenosis, growth retardation, and physiognomic features
  consistent with Williams syndrome.
  
  Bzduch and Lukacova (1989) found features of Williams syndrome in a boy
  with an interstitial deletion of the long arm of chromosome 6 involving
  band q22.2-q23. The boy had supravalvular aortic stenosis and also
  coarctation of the aorta which was repaired surgically. He was short of
  stature and had microcephaly, long philtrum, and dental anomalies.
  
  In a 2.5-year-old girl thought to have Williams syndrome, Colley et al.
  (1992) described a de novo 13;18 unbalanced translocation.
  
  Tupler et al. (1992) described a girl with severe abnormalities, many of
  which were consistent with Williams syndrome, in association with an
  unbalanced complex chromosome rearrangement involving 10 breakpoints and
  resulting in 4 derivative chromosomes, nos. 1, 2, 4, and 11. The patient
  was monosomic for the region 4q33-q35.1. Tupler et al. (1992) suggested
  that the gene for Williams syndrome is located in this region.
  
See Also:
  Feigl et al. (1980); Hoogenraad et al. (2002); Ino et al. (1985);
  Martin et al. (1984); Monaco  (1996); Preus  (1984); Reiss et al.
  (1985); Rowe  (1963); Vogt et al. (1980); Wesselhoeft et al. (1980);
  Williams et al. (1961)
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Clinical Synopsis:
  INHERITANCE:
     Autosomal dominant
  
  GROWTH:
     Short stature;
     [Other];
     Intrauterine growth retardation
  
  HEAD AND NECK:
     [Face];
     Medial eyebrow flare;
     Flat midface;
     Periorbital fullness (puffy eyes);
     Epicanthal folds;
     Long philtrum;
     [Ears];
     Sensorineural hearing loss, mild to moderate;
     Hyperacusis;
     Phonophobia;
     Abnormal brain auditory evoked responses (BAER);
     Decreased or absent ipsilateral acoustic reflex response to maximum
     stimulation;
     [Eyes];
     Stellate pattern of iris;
     [Nose];
     Depressed nasal bridge;
     Anteverted nares;
     [Mouth];
     Thick lips;
     [Teeth];
     Hypodontia;
     Microdontia
  
  CARDIOVASCULAR:
     [Heart];
     Supravalvular aortic stenosis;
     Valvular aortic stenosis;
     Bicuspid aortic valve;
     Mitral valve prolapse;
     Mitral regurgitation;
     Coronary artery stenosis;
     Pulmonary valve stenosis;
     Atrial septal defect;
     Ventricular septal defect;
     [Vascular];
     Peripheral pulmonary artery stenosis;
     Systemic hypertension
  
  RESPIRATORY:
     [Larynx];
     Vocal cord paralysis
  
  CHEST:
     [Ribs, sternum, clavicles, and scapulae];
     Pectus excavatum
  
  ABDOMEN:
     [External features];
     Inguinal hernia;
     [Gastrointestinal];
     Chronic constipation;
     Diverticulosis
  
  GENITOURINARY:
     [Kidneys];
     Small kidneys;
     Solitary kidney;
     Pelvic kidney;
     Nephrocalcinosis;
     Renal insufficiency;
     Renal artery stenosis;
     [Ureters];
     Vesicoureteral reflux;
     [Bladder];
     Bladder diverticula;
     Urethral stenosis;
     Recurrent urinary tract infections
  
  SKELETAL:
     [Spine];
     Kyphoscoliosis;
     [Limbs];
     Joint limitation;
     [Feet];
     Hallux valgus
  
  NEUROLOGIC:
     [Central nervous system];
     Mental retardation (average IQ 56);
     Relative sparing of language;
     Poor visual-motor integration (Range 41-80);
     Poor visual-spatial construction;
     Hypersensitivity to sound;
     [Behavioral/psychiatric manifestations];
     Attention deficit disorder;
     Friendly personality;
     Gregarious;
     Cocktail party personality;
     Strong attraction to music
  
  SKIN, NAILS, HAIR:
     [Nails];
     Hypoplastic nails
  
  VOICE:
     Harsh, brassy, or hoarse voice
  
  ENDOCRINE FEATURES:
     Hypercalcemia
  
  LABORATORY ABNORMALITIES:
     Hemizygous deletion at 7q11.23
  
  MISCELLANEOUS:
     Incidence 1 in 8,000 live births;
     Main aspects of phenotype attributed to defects in GTF2IRD1 (604318)
     and GTF2I (601679)
  
  MOLECULAR:
     Contiguous gene syndrome involving mutation of genes on 7q11.2
  
Contributors: 
  Cassandra L. Kniffin - updated: 4/6/2006
  Michael J. Wright  - revised: 6/22/1999
  Ada Hamosh - revised: 6/22/1999
  
Creation Date: 
  John F. Jackson: 6/15/1995
  
Edit Dates: 
  ckniffin: 02/04/2010
  joanna: 9/12/2006
  ckniffin: 4/6/2006
  ckniffin: 11/3/2003
  joanna: 5/6/2002
  root: 6/24/1999
  kayiaros: 6/22/1999
  
Contributors: 
  Cassandra L. Kniffin - updated: 4/15/2010
  Cassandra L. Kniffin - updated: 3/9/2010
  Cassandra L. Kniffin - updated: 2/4/2010
  Marla J. F. O'Neill - updated: 1/22/2010
  Marla J. F. O'Neill - updated: 12/29/2009
  Cassandra L. Kniffin - updated: 12/15/2008
  Cassandra L. Kniffin - updated: 8/11/2008
  Cassandra L. Kniffin - updated: 3/13/2008
  Cassandra L. Kniffin - updated: 2/27/2007
  Victor A. McKusick - updated: 7/10/2006
  Victor A. McKusick - updated: 6/5/2006
  Siobhan M. Dolan - updated: 4/20/2006
  Cassandra L. Kniffin - updated: 4/6/2006
  Victor A. McKusick - updated: 3/15/2006
  Victor A. McKusick - updated: 12/5/2005
  Cassandra L. Kniffin - updated: 10/4/2005
  George E. Tiller - updated: 9/30/2005
  Cassandra L. Kniffin - updated: 9/7/2005
  Marla J. F. O'Neill - updated: 7/28/2005
  Cassandra L. Kniffin - updated: 4/1/2005
  Cassandra L. Kniffin - updated: 3/1/2005
  Victor A. McKusick - updated: 1/3/2005
  Natalie E. Krasikov - updated: 7/6/2004
  Victor A. McKusick - updated: 5/10/2004
  Cassandra L. Kniffin - updated: 11/3/2003
  Victor A. McKusick - updated: 6/26/2003
  Victor A. McKusick - updated: 6/25/2003
  Michael B. Petersen - updated: 2/11/2003
  Michael J. Wright - updated: 10/22/2002
  Victor A. McKusick - updated: 8/29/2002
  Cassandra L. Kniffin - updated: 6/3/2002
  Ada Hamosh - updated: 1/30/2002
  Ada Hamosh - updated: 1/25/2002
  Victor A. McKusick - updated: 12/21/2001
  Victor A. McKusick - updated: 11/1/2001
  Sonja A. Rasmussen - updated: 3/13/2001
  Michael J. Wright - updated: 5/5/2000
  Victor A. McKusick - updated: 2/1/2000
  Sonja A. Rasmussen - updated: 12/1/1999
  Victor A. McKusick - updated: 11/16/1999
  Victor A. McKusick - updated: 9/1/1999
  Orest Hurko - updated: 7/1/1999
  Michael J. Wright - updated: 6/18/1999
  Victor A. McKusick - updated: 4/22/1999
  Ada Hamosh - updated: 2/18/1999
  Victor A. McKusick - updated: 1/20/1999
  Sheryl A. Jankowski - updated: 1/15/1999
  Victor A. McKusick - updated: 12/10/1998
  Victor A. McKusick - updated: 12/1/1998
  Victor A. McKusick - updated: 9/8/1998
  Victor A. McKusick - updated: 2/20/1998
  Michael J. Wright - updated: 12/18/1997
  Victor A. McKusick - updated: 5/16/1997
  Victor A. McKusick - updated: 3/6/1997
  Victor A. McKusick - updated: 2/6/1997
  Moyra Smith - updated: 1/24/1997
  Moyra Smith - updated: 1/3/1997
  Moyra Smith - updated: 10/21/1996
  Iosif W. Lurie - updated: 9/19/1996
  Iosif W. Lurie - updated: 9/14/1996
  Iosif W. Lurie - updated: 9/12/1996
  Iosif W. Lurie - updated: 8/20/1996
  Iosif W. Lurie - updated: 8/10/1996
  Orest Hurko - updated: 4/1/1996
  
Creation Date: 
  Victor A. McKusick: 6/2/1986
  
Edit Dates: 
  alopez: 06/10/2010
  terry: 5/12/2010
  wwang: 4/29/2010
  ckniffin: 4/15/2010
  wwang: 4/7/2010
  ckniffin: 3/9/2010
  wwang: 2/18/2010
  ckniffin: 2/4/2010
  wwang: 1/25/2010
  terry: 1/22/2010
  wwang: 1/15/2010
  terry: 12/29/2009
  terry: 4/9/2009
  wwang: 3/31/2009
  carol: 2/10/2009
  carol: 1/13/2009
  wwang: 12/22/2008
  ckniffin: 12/15/2008
  terry: 9/25/2008
  wwang: 8/21/2008
  ckniffin: 8/11/2008
  carol: 6/5/2008
  wwang: 5/15/2008
  ckniffin: 3/13/2008
  terry: 12/17/2007
  ckniffin: 9/10/2007
  carol: 8/31/2007
  wwang: 3/2/2007
  ckniffin: 2/27/2007
  terry: 11/3/2006
  alopez: 7/18/2006
  terry: 7/10/2006
  alopez: 6/8/2006
  terry: 6/5/2006
  carol: 4/24/2006
  terry: 4/20/2006
  wwang: 4/11/2006
  ckniffin: 4/6/2006
  alopez: 3/20/2006
  terry: 3/15/2006
  alopez: 1/31/2006
  alopez: 12/7/2005
  terry: 12/5/2005
  wwang: 11/17/2005
  wwang: 10/6/2005
  carol: 10/6/2005
  ckniffin: 10/4/2005
  alopez: 9/30/2005
  wwang: 9/28/2005
  ckniffin: 9/7/2005
  terry: 7/28/2005
  wwang: 4/18/2005
  ckniffin: 4/1/2005
  wwang: 3/8/2005
  ckniffin: 3/1/2005
  tkritzer: 1/13/2005
  terry: 1/3/2005
  carol: 7/7/2004
  terry: 7/6/2004
  carol: 6/15/2004
  ckniffin: 6/15/2004
  tkritzer: 5/26/2004
  terry: 5/10/2004
  tkritzer: 11/18/2003
  ckniffin: 11/3/2003
  mgross: 9/18/2003
  tkritzer: 8/1/2003
  tkritzer: 7/17/2003
  terry: 6/26/2003
  carol: 6/26/2003
  terry: 6/25/2003
  cwells: 2/11/2003
  tkritzer: 10/30/2002
  tkritzer: 10/23/2002
  terry: 10/22/2002
  alopez: 10/2/2002
  tkritzer: 9/5/2002
  tkritzer: 9/3/2002
  terry: 8/29/2002
  carol: 6/3/2002
  ckniffin: 6/3/2002
  terry: 3/5/2002
  alopez: 1/31/2002
  terry: 1/30/2002
  terry: 1/25/2002
  cwells: 1/10/2002
  cwells: 1/2/2002
  terry: 12/21/2001
  alopez: 11/5/2001
  alopez: 11/2/2001
  terry: 11/1/2001
  carol: 4/12/2001
  mcapotos: 3/15/2001
  mcapotos: 3/13/2001
  alopez: 5/5/2000
  carol: 2/14/2000
  carol: 2/1/2000
  terry: 2/1/2000
  mgross: 12/1/1999
  mgross: 11/18/1999
  terry: 11/16/1999
  jlewis: 9/23/1999
  terry: 9/1/1999
  mgross: 7/7/1999
  mgross: 7/2/1999
  kayiaros: 7/1/1999
  terry: 6/18/1999
  alopez: 5/3/1999
  terry: 4/22/1999
  alopez: 2/18/1999
  carol: 1/20/1999
  psherman: 1/15/1999
  terry: 12/10/1998
  carol: 12/2/1998
  terry: 12/1/1998
  alopez: 9/9/1998
  carol: 9/8/1998
  carol: 4/21/1998
  alopez: 2/26/1998
  alopez: 2/20/1998
  terry: 2/20/1998
  alopez: 1/15/1998
  terry: 12/18/1997
  mark: 9/11/1997
  mark: 7/8/1997
  mark: 5/16/1997
  terry: 5/12/1997
  jenny: 3/6/1997
  terry: 2/12/1997
  terry: 2/6/1997
  terry: 2/3/1997
  mark: 1/25/1997
  terry: 1/24/1997
  mark: 1/24/1997
  mark: 1/3/1997
  terry: 1/2/1997
  mark: 10/21/1996
  terry: 10/7/1996
  carol: 9/19/1996
  carol: 9/14/1996
  carol: 9/12/1996
  carol: 8/23/1996
  carol: 8/20/1996
  carol: 8/10/1996
  mark: 6/27/1996
  terry: 6/25/1996
  terry: 6/20/1996
  mark: 4/19/1996
  terry: 4/11/1996
  mark: 4/2/1996
  mark: 4/1/1996
  terry: 4/1/1996
  terry: 3/23/1996
  mark: 10/22/1995
  terry: 10/6/1995
  mimadm: 6/7/1995
  carol: 2/27/1995
  warfield: 3/29/1994
  carol: 11/29/1993
  
OMIM

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