Supravalvular Aortic Stenosis Research Articles

A novel 2.43 Mb deletion of 7q11.22–q11.23

We present a patient with a novel heterozygous deletion of 7q11.22-q11.23. Standard cytogenetic analysis using the ELN cosmid 82C and the ELN/ LIMK1 cosmid 34B FISH probes suggested a diagnosis of Williams syndrome. Although he has supravalvular aortic stenosis and peripheral pulmonary artery stenosis, which are common in this condition, he does not have the clinical gestalt of Williams syndrome. 44k oligo array CGH analysis showed a 2.43 Mb deletion, encompassing the proximal 1.43 kb of the Williams syndrome critical region and extending approximately 1 Mb beyond it. The deletion of further genes outside the Williams syndrome critical region does not appear to be having a phenotypic effect at present.

Abstract 5717: Cardiovascular Abnormalities and Outcomes in a Large Williams Syndrome Cohort

Background: Williams syndrome (WS) is a congenital developmental disorder caused by microdeletion of approximately 28 genes on chromosome 7q11.23, affecting the vascular, connective tissue, and central nervous systems of 1 in 8,000 live births. Previous reports have reported high frequencies of cardiovascular abnormalities (CVA) in small cohorts of patients with WS. Methods: A retrospective review was undertaken of patients (pts) with WS evaluated at the Children’s Hospital of Philadelphia from 1/1/1980 through 12/31/2007. WS was diagnosed by the clinical phenotype assessed by an experienced medical geneticist and/or by fluorescence in situ hybridization. Congenital CVA were diagnosed by echocardiography and/or cardiac catheterization. Freedom from intervention was determined using Kaplan-Meier analysis. Results: Two hundred and seventy two pts were identified and constituted the study group. Pts presented to our center at 5.2 ± 8.2 yrs with an average length of follow-up of 8.2 ± 7.8 yrs (0 – 43 yrs). Congenital CVA were present in 220/272 (81%) pts. The commonest lesions were supravalvar (SV) aortic stenosis (AS) in 120/272 (44%) and branch pulmonary stenosis (PS) in 84/272 (31%); 44/272 (16%) had both. Other common lesions included mitral valve prolapse and regurgitation in 32/272 (12%), VSD in 30/272 (11%), and SVPS in 29/272 (11%). A number of other CVA occurred with frequencies less than 10%. Surgical or catheter-based interventions were performed in 55/220 (25%) pts with CVA. SVAS most commonly required intervention (28/120 pts, 23%). Branch PS was second with 13/84 (15%). Freedom from intervention in all pts with CVA was 91, 78, 75, 69, and 66% at 1, 5, 10, 20, and 40 years, respectively. Death occurred in 7 pts with an average of 1 death per 345 pt-yrs. Conclusion: Though CVA are common in WS, in this, the largest cohort ever reported analyzing CVA and outcomes, SVAS and branch PS occur less frequently than previously reported. In WS pts with CVA, interventions are commonly required and usually occur by 5 years of age. Most WS pts do not require intervention on long-term follow-up and overall mortality in these pts is low.

Elastin insufficiency predisposes to elevated pulmonary circulatory pressures through changes in elastic artery structure

Elastin is a major structural component of large elastic arteries and a principal determinant of arterial biomechanical properties. Elastin loss-of-function mutations in humans have been linked to the autosomal-dominant disease supravalvular aortic stenosis, which is characterized by stenotic lesions in both the systemic and pulmonary circulations. To better understand how elastin insufficiency influences the pulmonary circulation, we evaluated pulmonary cardiovascular physiology in a unique set of transgenic and knockout mice with graded vascular elastin dosage (range 45-120% of wild type). The central pulmonary arteries of elastin-insufficient mice had smaller internal diameters (P < 0.0001), thinner walls (P = 0.002), and increased opening angles (P = 0.002) compared with wild-type controls. Pulmonary circulatory pressures, measured by right ventricular catheterization, were significantly elevated in elastin-insufficient mice (P < 0.0001) and showed an inverse correlation with elastin level. Although elastin-insufficient animals exhibited mild to moderate right ventricular hypertrophy (P = 0.0001) and intrapulmonary vascular remodeling, the changes were less than expected, given the high right ventricular pressures, and were attenuated compared with those seen in hypoxia-induced models of pulmonary arterial hypertension. The absence of extensive pathological cardiac remodeling at the high pressures in these animals suggests a developmental adaptation designed to maintain right-sided cardiac output in a vascular system with altered elastin content.

Periodontal conditions in Williams Beuren Syndrome: A series of 8 cases

Williams Beuren syndrome (WBS) is an unusual hereditary connective tissue disease caused by a microdeletion at position 7q11-23 and a haploinsufficiency at the elastin gene. The most frequent specific features are elf-like face, alteration of cognitive functions and cardiovascular diseases including isolated supravalvular aortic stenosis. A number of clinical findings have been reported, but none of the studies evaluating this syndrome consider the oral cavity. It is equally surprising that the gingival tissue, which carries a perfectly structured elastic fibre network, has not yet been investigated. It is important to verify whether subjects affected by WBS are more susceptible to periodontal disease than healthy subjects who are not that much affected, for periodontal disease may have deleterious effects on the cardiovascular system. In an attempt to address this issue, the oral manifestations of 8 patients (ages from 5 to 12 years) with WBS have been investigated: dental examination, periodontal examination (gingival phenotype, plaque control record, gingival index, bone quality). All patients had oral parafunction, tooth number abnormalities and malocclusions. Average gingival height and width were greater than normal. Plaque index was always very high except for one patient, but the gingival inflammation was not linked to the quantity of clinical plaque index. There was no obvious loss of attachment. As with collagen, elastin is a structural macromolecule of the gingiva. These components play an important role in gingival function and in the resistance of the periodontium to daily aggressions. Unlike genetic diseases characterized by impairment of collagen macrofibrils, it is suggested that the hemizygous gene encoding elastin does not result in periodontal disease. In addition there is an existence of a possible concordance between the elastin gene haploinsufficiency and the periodontal phenotype. There might be some adaptive process to this deficiency.

Acquired supravalvular aortic stenosis: a late complication of replacement of the ascending aorta

Aortic syndromes are an increasing cause of morbidity and mortality. Ascending aortic dissection is a clinical emergency with most patients requiring open surgery to replace the ascending aorta. Detection through clinical suspicion, improved non-invasive imaging and refined surgical techniques have resulted in an improved survival rate. Acquired supravalvular aortic stenosis is an extremely rare complication of cardiac surgery. We present the case of a patient who, 15 years after undergoing elective replacement of the ascending aorta for aortic dissection, required repeat surgery for symptomatic supravalvular aortic stenosis. This case elegantly highlights the need for a detailed focused assessment in patients where the clinical presentation does not correlate with initial investigations. To our knowledge this is the first reported case of late symptomatic supravalvular aortic stenosis following replacement of the ascending aorta.

Supravalvular aortic stenosis and peripheral pulmonary stenosis in family with balanced translocation t(7;14) and break point within the elastin gene region

We present a family form of balanced translocation t(7;14) found in a mother and her two sons. The mother had an aortic cardiac murmur, without hemo-dynamic repercussions and the children had almost identical clinical findings, significant supravalvular aortic stenosis, left ventricle intracavitary stenosis and multiple peripheral pulmonary stenosis but with no other clinical manifestations of Williams-Beuren syndrome, except, perhaps, a deep, metallic voice. The conventional chromosome analysis unexpectedly revealed a balanced translocation between chromosomes 7 and 14, the same translocation was found in the mother and both children. Subsequent fluorescent in situ hybridization analysis with WSCR probe showed that the break point was within the elastin gene region in the mother and both children. The proband karyotype was interpreted, according to ISCN (2005) as 46,XY,t(7;14) (q11.23;p12).ish t(7;14)(D7Z1+,ELNsp;D14Z1/D22Z1+,ELNsp+)mat, in other words, translocation had disrupted the elastin region and may have contributed to the developmental defects in Williams-Beuren syndrome. When going through the references on genetic examination of supravalvular aortic stenosis, Williams-Beuren syndrome and some other conditions that could not be placed in any of these two terminal categories because of the various phenotype characteristics, we found that such a result has not yet been published.

Surgical Results of Anomalous Origin of the Right Pulmonary Artery From the Ascending Aorta Including Reoperation for Infrequent Complications

We evaluated the results of surgery for an anomalous origin of the right pulmonary artery from the ascending aorta. From August 1986 to December 2005, 8 children (6 neonates) aged 7 to 180 days (mean, 35 +/- 59 days) with anomalous origin of the right pulmonary artery from the ascending aorta underwent surgical repair at our institute. All except one child, who had the distal form, had the proximal form. Cardiac catheterization showed that the left pulmonary artery to systemic pressure ratio was 1.0 or more. Surgery was performed by direct anastomosis in 7 patients and by graft interposition in 1. There were no operative or late deaths. All patients postoperatively underwent cardiac catheterization that showed decreased left pulmonary artery to systemic pressure ratio ranging from 0.2 to 0.6. Follow-up periods ranged from 2 months to 13 years. We undertook reoperations for two infrequent postoperative causes. One patient exhibited significant supravalvar aortic stenosis and required patch enlargement of the ascending aorta 3 years after operation. The other patient (with the distal form) needed a reoperation after 1 month because of progressive stenosis at the anatomic site. Graft interposition was performed, and histopathologic examination showed that the tissue from the stenotic region looked like that of a ductus. We undertook surgical repair for anomalous origin of the right pulmonary artery from the ascending aorta. Pulmonary hypertension was improved in all patients. Careful follow-up was necessary to detect supravalvar aortic and anastomotic stenosis early and late after operation.

Heart Failure Due to Severe Supravalvular Aortic Stenosis in Painless Type A Aortic Dissection

Severe supravalvular aortic stenosis is a rare complication of aortic dissection. Painless aortic dissection is also relatively rare. We report the case of a 67-year-old man who had New York Heart Association class III heart failure without chest pain and was found to have supravalvular aortic stenosis secondary to chronic type A aortic dissection. The patient underwent ascending aorta and hemiarch replacement with selective antegrade cerebral perfusion under deep hypothermic circulatory arrest. The patient was discharged to home with complete resolution of heart failure and has been carefully followed up for 1 year, during which he has experienced no symptoms.

Sudden Death of a 17-Year-Old Boy Due to Suspected Williams Syndrome

In this article, we present a case of sudden death of a 17-year-old boy, in which diagnosis of Williams syndrome was firstly suspected after medicolegal autopsy, on the basis of typical macroscopical changes (facial appearance, dental status, supravalvular aortic stenosis with mild enlargement of the heart and significant thickening of the left ventricular myocardium) as well as heteroanamnestic data (slight mental retardation and nervousness). All other causes of sudden death were excluded. The definite diagnosis of this syndrome could not be corroborated as specific genetic analysis (fluorescent in situ hybridization test) could not be performed because of the lack of appropriate technical facilities.

Elastin Haploinsufficiency Induces Alternative Aging Processes in the Aorta

Elastin, the main component of elastic fibers, is synthesized only in early life and provides the blood vessels with their elastic properties. With aging, elastin is progressively degraded, leading to arterial enlargement, stiffening, and dysfunction. Also, elastin is a key regulator of vascular smooth muscle cell proliferation and migration during development since heterozygous mutations in its gene (Eln) are responsible for a severe obstructive vascular disease, supravalvular aortic stenosis, isolated or associated to Williams syndrome. Here, we have studied whether early elastin synthesis could also influence the aging processes, by comparing the structure and function of ascending aorta from 6- and 24-month-old Eln+/- and Eln+/+ mice. Eln+/- animals have high blood pressure and arteries with smaller diameters and more rigid walls containing additional although thinner elastic lamellas. Nevertheless, longevity of these animals is unaffected. In young adult Eln+/- mice, some features resemble vascular aging of wild-type animals: cardiac hypertrophy, loss of elasticity of the arterial wall through enhanced fragmentation of the elastic fibers, and extracellular matrix accumulation in the aortic wall, in particular in the intima. In Eln+/- animals, we also observed an age-dependent alteration of endothelial vasorelaxant function. On the contrary, Eln+/- mice were protected from several classical consequences of aging visible in aged Eln+/+ mice, such as arterial wall thickening and alteration of alpha(1)-adrenoceptor-mediated vasoconstriction. Our results suggest that early elastin expression and organization modify arterial aging through their impact on both vascular cell physiology and structure and mechanics of blood vessels.

An investigation of voice quality in individuals with inherited elastin gene abnormalities

The human elastin gene (ELN) is responsible for the generation of elastic fibres in the extracellular matrix of connective tissue throughout the body, including the vocal folds. Individuals with Supravalvular aortic stenosis (SVAS) and Williams syndrome (WS) lack one normal ELN allele due to heterozygous ELN abnormalities, resulting in a haploinsufficiency. We measured perceptual and acoustic characteristics of voice quality in individuals with SVAS and WS to investigate the consequences to vocal function secondary to ELN haploinsufficiency. Results indicated that the voice quality of individuals with SVAS/WS was rated as significantly more abnormal, rough, and hoarse compared to normal controls, and that adults with SVAS/WS were rated as significantly lower in pitch. Acoustic measures indicated that individuals with SVAS/WS produced greater instability of fundamental frequency during phonation (as reflected via increased pitch sigma and increased jitter). These findings support the possibility that heterozygous ELN abnormalities negatively influence vocal fold biomechanics and the resulting sound produced by the vibrating glottis.

左冠動脈入口部狭窄を伴う大動脈弁および弁上狭窄症の幼児に対する手術経験

冠動脈入口部狭窄を伴う先天性大動脈弁上狭窄症は稀であるが，Williams症候群以外での治験報告はさらに少ない．症例はWilliams症候群ではない3歳の男児．生後3カ月時から先天性大動脈弁および弁上狭窄症と診断されていた．3歳時の心臓カテーテル検査において，90mmHgの左室-大動脈間圧較差に加え新たに高度の左冠動脈入口部狭窄と左室心尖部の虚血性壁運動異常を認め，手術適応となった．大動脈弁上狭窄部の右頭側から大動脈斜切開を入れ，左冠動脈入口部に向かって左後方にこれを延長した．肥厚した大動脈2尖弁に交連切開を加えた後，1枚のglutaraldehyde処理自己心膜片を用いて左冠動脈入口部と弁上狭窄部のパッチ拡大を行った．冠動脈狭窄の解除と左室-大動脈間圧較差の改善が得られ，左室壁運動異常は解消された．

Surgery for supravalvular aortic stenosis - the three-patch technique

The objective of this paper is to describe the three-patch technique for repair of supravalvular aortic stenosis (SVAS). Supravalvular aortic stenosis is a rare malformation as a result of an abnormal thickening of the aortic wall. SVAS may present in two forms: a localized form (affecting only the aortic sinotubular junction) and a diffuse form, where the aortic arch and its side branches are also affected. Since 1960, multiple surgical techniques have been described with the aim of relieving the aortic narrowing and restoring the aortic root. We present the three-patch technique as originally developed by Brom. After transection of the aorta at the sinotubular junction, three longitudinal incisions are made into the three sinuses. The aortic root geometry is then restored by placement of three separate patches of autologous pericardium in the opened sinuses. Brom's technique provides a complete and symmetric restoration of the aortic anatomy. The technique is illustrated by angiographies, surgical drawings, videos and a review of the literature. The results of the three-patch technique are good and our long-term experience will be described.

Surgical Repair of Congenital Supravalvular Aortic Stenosis in Adult

Supravalvular aortic stenosis is a rare congenital cardiac anomaly occurring mainly as a part of Williams-Beuren syndrome. Aortic narrowing above the level of the aortic valve causes obstruction of the left ventricular outflow tract, and a pressure gradient between the left ventricle and the aorta causes left ventricle hypertrophy. We report here a case of a 22-year-old man who underwent extended patch aortoplasty because of supravalvular aortic stenosis accompanying Williams-Beuren syndrome. He was in New York Heart Association functional class III with localized hourglass type supravalvular aortic stenosis. Related to arterial hypertension he was in a cardiac decompensation. Mean pressure gradient was 73 mm Hg and maximum gradient 104 mm Hg. Electrocardiography indicated left ventricle hypertrophy, which was also seen in x-ray, as heart enlargement. We successfully treated this patient with extended patch aortoplasty and immediate postoperative echocardiography showed reduction of gradient. Good surgical outcome of congenital supravalvular aortic stenosis in adults can be achieved with this treatment. This technique provides symmetric reconstruction of the aorta with good postoperative results and no gradient across aortic valve and aortic valve insufficiency remains, providing excellent long-term relief of localized supravalvular gradients and preservation of aortic valve competence.

Demonstration of peripheral pulmonary stenosis and supravalvular aortic stenosis by different cardiac imaging modalities in a patient with Williams syndrome — usefulness of noninvasive imaging studies

With technical improvement, noninvasive cardiac imaging modalities, including multislice computed tomography and magnetic resonance imaging, can offer sufficient imaging quality to differentiate cardiac anatomies. These noninvasive modalities also can identify aortic and pulmonary vascular abnormalities clearly in the same study. We report a case with severe pulmonary hypertension associated with peripheral pulmonary stenosis and supravalvular aortic stenosis in a 29-year-old woman with Williams syndrome, which was identified similarly with both invasive and noninvasive imaging modalities. The need for invasive tests can be reduced with appropriate improvement and validation of these noninvasive tests.

Diffuse Supravalvular Aortic Stenosis with Multiple Stenoses of the Branches of Arcus Aorta in a Child

We give details of a sporadic case with congenital supravalvular aortic stenosis associated with critical stenosis of the left carotid artery, and severe stenosis of the innominate artery at their origins as well as excessive dilatations of both the right and the left coronary arteries.

General anesthesia for dental treatment in a Williams syndrome patient with severe aortic and pulmonary valve stenosis: suspected episode of postoperatively malignant hyperthermia

A 28-month-old boy (height, 76 cm; weight, 9.4 kg) diagnosed as having Williams syndrome presented for dental care. We report a case of postoperatively suspected malignant hyperthermia after the administration of general anesthesia for dental treatment in this patient with severe supravalvular aortic stenosis and pulmonary artery hypoplasia. Anesthesia was maintained through the inhalation of nitrous oxide and sevoflurane with oxygen. The patient was hemodynamically stable and no other abnormalities were observed. After the completion of the dental treatment, he was transferred to the pediatric ward. On arrival at the ward, the patient's core temperature increased to 39.5 degrees C and tachypnea (RR, 30 breaths/min) was observed. The SPO2 during inhalation was slightly low (92%-93%). Serum biochemistry revealed an elevated CK level (1345 U/L) but no other abnormal findings. Twelve hours after the dental treatment, the patient's core temperature fell to 37.4 degrees C. After hospitalization for 4 days, the patient was discharged in good condition. In the present case, general anesthesia was employed for dental treatment despite severe supravalvular aortic stenosis and peripheral pulmonary artery hypoplasia, because conventional dental therapy was very difficult as a result of the patient's mental retardation and hyperkinesia. The present case suggests that the use of volatile agents that could trigger malignant hyperthermia should be avoided wherever possible.

Diagnosis and management of medical problems in adults with Williams–Beuren syndrome

Williams-Beuren syndrome (WBS) is a multi-system disorder that requires ongoing management by a primary care physician familiar with the natural history and common medical problems associated with the condition. Some abnormalities are unique to WBS, such as the elastin arteriopathy that often manifests as supravalvar aortic stenosis and hypertension. Still other features, such as diverticulosis, are seen in the general population but tend to present earlier in WBS. Life long monitoring of the cardiovascular and endocrine systems is essential to the clinical management of individuals with Williams-Beuren syndrome. Constipation should be aggressively managed, and symptoms of abdominal pain should prompt an evaluation for diverticulosis/diverticulitis. While the mean IQ of WBS is in the mild mental retardation range, difficulties with attention and anxiety are more likely to negatively impact independent functioning in the adult with WBS. There is no evidence for decline in cognitive ability over time, but adaptive functioning may be improved with treatment of anxiety by both behavior and medical modalities.

Functional Rescue of Elastin Insufficiency in Mice by the Human Elastin Gene

Diseases linked to the elastin gene arise from loss-of-function mutations leading to protein insufficiency (supravalvular aortic stenosis) or from missense mutations that alter the properties of the elastin protein (dominant cutis laxa). Modeling these diseases in mice is problematic because of structural differences between the human and mouse genes. To address this problem, we developed a humanized elastin mouse with elastin production being controlled by the human elastin gene in a bacterial artificial chromosome. The temporal and spatial expression pattern of the human transgene mirrors the endogenous murine gene, and the human gene accurately recapitulates the alternative-splicing pattern found in humans. Human elastin protein interacts with mouse elastin to form functional elastic fibers and when expressed in the elastin haploinsufficient background reverses the hypertension and cardiovascular changes associated with that phenotype. Elastin from the human transgene also rescues the perinatal lethality associated with the null phenotype. The results of this study confirm that reestablishing normal elastin levels is a logical objective for treating diseases of elastin insufficiency such as supravalvular aortic stenosis. This study also illustrates how differences in gene structure and alternative splicing present unique problems for modeling human diseases in mice.

Presenting phenotype and clinical evaluation in a cohort of 22 Williams–Beuren syndrome patients

Williams–Beuren syndrome (WS) is a rare multi-system genomic disorder, caused by 7q11.23 microdeletion with a prevalence of 1/7500–1/20,000 live births. Clinical phenotype includes typical facial dysmorphism (elfin face), mental retardation associated with a peculiar neuropsychological profile and congenital heart defects. We investigated 22 WS patients (mean age of 9.7 years, range 1 day to 39 years) with a multi-specialist follow-up protocol comprehensive of neuropsychological, cardiologic, nephrologic, ophthalmologic, endocrinologic, gastroenterologic, odontostomatologic and orthopaedic evaluations. The mean age at diagnosis was 5.38 years, being 1.02 years when genetic evaluation was requested for congenital heart defects (CHD) and 10.68 years in case of mental retardation and/or abnormal neuropsychological profile without an evident CHD. All patients showed facial dysmorphisms, with supravalvular aortic stenosis (SVAS) as the most common cardiovascular anomaly (12/22), followed by peripheral pulmonary stenosis (9/22); interestingly, in one patient we detected a total anomalous pulmonary venous return (TAPVR), confirming the possible association of this rare CHD with WS. Hypertension was detected by 24-h ambulatory blood pressure monitoring in 7/22 cases. A cognitive assessment was performed in 13 patients older than 6 years, showing various degrees of mental retardation in 12 and a normal intelligence quotient (IQ) in a single patient; evaluation of developmental milestones revealed various grades of developmental delay in all the patients younger than 6 years. Chiari malformation type 1 was found in 3 patients. Our study underlines a remarkable diagnostic delay in patients who present to genetic evaluation because of mental retardation and/or peculiar neuropsychological profile lacking an evident cardiopathy and confirms the multi-systemic nature of WS leading to a high clinical presentation's variability and complex follow-up strategies.