Williams Syndrome - Supravalvular Aortic Stenosis

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J Med Genet. 2002 Aug;39(8):554-8.
Cardiovascular manifestations in 75 patients with Williams syndrome.
Eronen M, Peippo M, Hiippala A, Raatikka M, Arvio M, Johansson R, Kahkonen M.
The Hospital for Children and Adolescents, Division of Paediatric Cardiology, University of Helsinki, Finland. Marianne.eronen@dlc.fi

OBJECTIVE: The prevalence and types of various cardiovascular diseases in different age groups as well as the outcomes of cardiac surgery and other interventions were assessed in a population of 75 Williams syndrome (WS) patients aged 4 months to 76 years (median 22.7 years). STUDY DESIGN: The diagnosis of WS was in each case confirmed by the clinical phenotype and by a FISH test showing elastin hemizygosity. Clinical and operative data were collected from all hospitals where the patients had been treated. RESULTS: Cardiovascular symptoms were evident in 35 of 75 (47%) WS children at birth. During follow up, 44 of 75 (53%) WS patients were found to have cardiovascular defects. Among them, the definitive diagnosis was made before 1 year of age in 23 (52%) infants, between 1 year and 15 years of age in 14 (32%) children, and older than 15 years of age in 7 (16%) adults. Multiple obstructive cardiovascular diseases were found in six infants. Supravalvular aortic stenosis (SVAS) was diagnosed in 32/44 (73%), pulmonary arterial stenosis (PAS) in 18/44 (41%), aortic or mitral valve defect in 5/44 (11 %) of cases, and tetralogy of Fallot in one (2%) case. Altogether, 17/44 (39 %) underwent surgery or intervention. Surgery was most frequently performed in the infant group (6% v 21% v 0%, p=0.004). After 1 year of age, seven patients underwent SVAS relief and two cases PAS relief. Postoperatively there was no mortality (median follow up time 6.9 years). Arterial hypertension was found in 55% of adults. In three adults, arterial vasculopathy was not diagnosed until necropsy. CONCLUSIONS: Our data indicate the following in WS. Cardiac symptoms are common in neonates. Heart disease diagnosed in infancy frequently requires operation. After 1 year of age, PAS tends to improve and SVAS to progress. Life long cardiac follow up is necessary because of the risks of developing vasculopathy or arterial hypertension.

J Cardiol. 2002 Jul;40(1):25-30. Related Articles, Links
Intractable infective endocarditis associated with supraaortic stenosis in Williams syndrome: a case report
Maruyoshi H, Nakatani S, Yasumura Y, Nakajima H, Niwaya K, Sasako Y, Ando M, Miyatake K, Yamagishi M.
Divisions of Cardiology, National Cardiovascular Center, Osaka.

A 17-year-old man with supravalvular aortic stenosis associated with Williams syndrome was admitted to our hospital for intensive treatment for intractable infective endocarditis. The patient had a history of percutaneous balloon valvuloplasty for aortic stenosis in 1992. He was well until late in 1999, when he had a high temperature after dental work-up. The diagnosis was infective endocarditis but antibiotic therapy was not effective. He was transferred to our clinic. Transthoracic echocardiography demonstrated bicuspid aortic valve, supraaortic stenosis, mitral valve prolapse with severe regurgitation and scattered vegetations on the anterior mitral and aortic valves. In addition, transesophageal echocardiography showed innumerable mobile vegetations located from Valsalva's sinus to the descending aorta. Aortic root and arch replacement with a homograft and mitral valve replacement with an artificial valve were successfully performed to eliminate the infective endocarditis. In the present patient, the flow jet across the supraaortic stenosis seemed to cause a predisposition to severe endocarditis.

Clin Pediatr (Phila). 1999 Apr;38(4):189-208.
Williams-Beuren syndrome: an update and review for the primary physician.
Lashkari A, Smith AK, Graham JM Jr.
Steven Spielberg Pediatric Research Center, Ahmanson Pediatric Center, UCLA School of Medicine.

Williams-Beuren syndrome is an autosomal dominant disorder resulting from a submicroscopic deletion of contiguous genes on the long arm of chromosome 7. It consists of a variety of hallmark physical features, which include distinctive facial characteristics, cardiac anomalies (of which the most common is supravalvular aortic stenosis), and occasional idiopathic hypercalcemia. The condition also includes a unique cognitive profile, with relative sparing of language and facial recognition skills against a background of mental retardation. This paper reviews the early history and clinical experience with this syndrome, how it unfolds from infancy through adulthood, and how it manifests in different organ systems. Evidence-based recommendations are then offered for the treatment of the specific developmental and medical issues that arise in patients with Williams syndrome.

Hum Mol Genet. 1997 Jul;6(7):1021-8.
Elastin point mutations cause an obstructive vascular disease, supravalvular aortic stenosis.
Li DY, Toland AE, Boak BB, Atkinson DL, Ensing GJ, Morris CA, Keating MT.
Cardiology Division, University of Utah Health Sciences Center, Eccles Institute of Human Genetics, Salt Lake City 84112, USA.

Supravalvular aortic stenosis (SVAS) is an inherited obstructive vascular disease that affects the aorta, carotid, coronary and pulmonary arteries. Previous molecular genetic data have led to the hypothesis that SVAS results from mutations in the elastin gene, ELN. In these studies, the disease phenotype was linked to gross DNA rearrangements (35 and 85 kb deletions and a translocation) in three SVAS families. However, gross rearrangements of ELN have not been identified in most cases of autosomal dominant SVAS. To define the spectrum of ELN mutations responsible for this disorder, we refined the genomic structure of human ELN and used this information in mutational analyses. ELN point mutations co-segregate with the disease in four familial cases and are associated with SVAS in three sporadic cases. Two of the mutations are nonsense, one is a single base pair deletion and four are splice site mutations. In one sporadic case, the mutation arose de novo. These data demonstrate that point mutations of ELN cause autosomal dominant SVAS.

J Pediatr. 1996 Dec;129(6):926-31.
Sudden death in Williams syndrome: report of ten cases.
Bird LM, Billman GF, Lacro RV, Spicer RL, Jariwala LK, Hoyme HE, Zamora-Salinas R, Morris C, Viskochil D, Frikke MJ, Jones MC.
Division of Dysmorphology, Children's Hospital, San Diego, California 92123, USA.

Williams syndrome (WS) is a recognizable pattern of malformation with mental retardation, mild growth deficiency, characteristic facies and temperament, and cardiovascular disease. Sudden death is a recognized complication of WS; however, it is thought to be rare. The clinical features of 10 children with WS who died suddenly are reported here, doubling the number of unexpected deaths reported in the literature. We suggest that sudden death is a more common complication than has been assumed previously. Pathologic findings on the seven autopsy cases implicate two anatomic abnormalities that predispose individuals with WS to sudden death: coronary artery stenosis and severe biventricular outflow tract obstruction. The mechanisms for sudden death for both anatomic subgroups include myocardial ischemia, decreased cardiac output, and arrhythmia. We believe these observations warrant the development of strategies for monitoring patients with WS in an attempt to identify those at increased risk of sudden death.

Nat Genet. 1993 Sep;5(1):11-6.
Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome.
Ewart AK, Morris CA, Atkinson D, Jin W, Sternes K, Spallone P, Stock AD, Leppert M, Keating MT.
Department of Human Genetics, University of Utah, Salt Lake City 84112.

Williams syndrome (WS) is a developmental disorder affecting connective tissue and the central nervous system. A common feature of WS, supravalvular aortic stenosis, is also a distinct autosomal dominant disorder caused by mutations in the elastin gene. In this study, we identified hemizygosity at the elastin locus using genetic analyses in four familial and five sporadic cases of WS. Fluorescent in situ hybridization and quantitative Southern analyses confirmed these findings, demonstrating inherited and de novo deletions of the elastin gene. These data indicate that deletions involving one elastin allele cause WS and implicate elastin hemizygosity in the pathogenesis of the disease.

Am J Med Genet. 1993 Mar 15;45(6):739-42.
Comment in: Am J Med Genet. 1994 Feb 15;49(4):454-5.
Concurrence of supravalvular aortic stenosis and peripheral pulmonary stenosis in three generations of a family: a form of arterial dysplasia.
Kumar A, Stalker HJ, Williams CA.
Department of Pediatrics, College of Medicine, University of Florida, Gainesville.

Isolated supravalvular aortic stenosis (SVAS) commonly is an autosomal dominant trait; it may also occur in the Williams syndrome (WS). While peripheral pulmonary stenosis (PPS) can occur in the same individual with familial isolated SVAS, concurrence of these lesions in different relatives of a family is uncommon. We describe five affected individuals in one family; three had isolated SVAS, one had isolated PPS, and one had SVAS and PPS. Based on this family and review of literature, we suggest that SVAS is a form of arterial dysplasia encompassing PPS in its spectrum. It is developmentally distinct from other left heart obstructive lesions that are hypothesized to be related to blood flow abnormalities in the developing embryo. We also conclude that the clinical disorder in this family represents one that is distinct from WS.

G Ital Cardiol. 1990 May;20(5):435-7.
Supraventricular aortic stenosis. A different surgical approach
Brunelli F, Ghidoni I, Parenzan L.
Divisione di Cardiochirurgia, Ospedali Riuniti di Bergamo.

A 15-year old female with William's syndrome became symptomatic for congenital supravalvular aortic stenosis. Surgery was carried out using an unpublished technique which consisted in a symmetrical enlargement of the aortic root by inserting three triangular patches of autologous pericardium. This method has the advantage of restoring normal valvular competence while respecting coronary orifices .

J Pediatr. 1988 Aug;113(2):318-26.
Natural history of Williams syndrome: physical characteristics.
Morris CA, Demsey SA, Leonard CO, Dilts C, Blackburn BL.
Genetics Center, Southwest Biomedical Research Institute, Scottsdale, AZ 85251.

The natural history of Williams syndrome, including medical complications, growth patterns, and problems in adulthood, was investigated. A growth pattern characterized by delay in the first 4 years of life, catch-up growth in childhood, and low ultimate adult height was found. 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. 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. Independent living and competitive employment were limited less by the individual's physical problems than by the psychologic and adaptive limitations. Williams syndrome is a progressive disorder with multisystem involvement.

Am J Cardiol. 1983 Jan 15;51(2):256-60.
Supravalvular aortic stenosis. A 20-year clinical perspective and experience with patch aortoplasty.
Flaker G, Teske D, Kilman J, Hosier D, Wooley C.

Supravalvular aortic stenosis has a wide range of clinical and morphologic expression. Since 1961, 25 patients (aged 1 to 49 years) with documented supravalvular aortic stenosis have been evaluated. Seven (28%) had Williams' syndrome, 5 (20%) had a familial form of supravalvular aortic stenosis, and 13 (52%) had a sporadic form. A blood pressure difference of greater than 10 mm Hg between the arms was noted in 65% of the patients. Angiographically, 19 (76%) had segmental supravalvular narrowing; 6 (24%) had diffuse narrowing of the ascending aorta. Sixteen patients underwent patch aortoplasty. At surgery, portions of the aortic valve cusps were frequently attached to supravalvular tissue. This "cusp tuck" resulted in distinctive angiographic features and influenced the results of corrective surgery. Three surgical deaths occurred in the early 1960s-2 with diffuse narrowing of the aorta. Of the remaining 12 patients, followed for 1 to 12 years, 10 are asymptomatic, 1 has angina, and 1 died from cancer. All 8 patients who underwent postoperative catheterization had a thick band between the left and right coronary sinus which represented persistent attachment of portions of the aortic valve cusps to residual supravalvular tissue (cusp tuck). This resulted in aortic valvular gradients (23 to 48 mm Hg) in 4 patients and aortic valvular insufficiency in 2 patients. No significant supravalvular gradient was noted. The 20-year experience with supravalvular aortic stenosis reported herein emphasizes a wide range of clinical and morphologic expression, the benefits and limitations of patch aortoplasty, and the importance of postoperative cardiac catheterization, and furthers the understanding of a complex clinical syndrome.

Z Kardiol. 1980 Mar;69(3):168-72.
The genetic aspects of Williams-Beuren syndrome and the isolated form of the supravalvular aortic stenosis. Investigation of 128 families (author's transl)
Grimm T, Wesselhoeft H.

Supravalvular aortic stenosis (SVAS) was seen in 128 families. In 23 families several members had SVAS. In 4 families the Williams-Beuren Syndrome (WBS) was present whereas members of 8 families had some features of the syndrome in addition to their cardiac lesion. In conclusion, no distinct separation can be made between WBS and SVAS. The genetic pattern is autosomal dominant with variable expressivity. The gene frequency is estimated at 10(-4) and the mutation rate at 2.5 . 10(-5).

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