Genetic Testing for Supravalvar Aortic Stenosis: What to Do When It Is Not Williams Syndrome.

BACKGROUND: We aimed to describe the frequency and yield of genetic testing in supravalvar aortic stenosis (SVAS) following negative evaluation for Williams-Beuren syndrome (WS). METHODS AND RESULTS: This retrospective cohort study included patients with SVAS at our institution who had a negative evaluation for WS from May 1991 to September 2021. SVAS was defined as (1) peak supravalvar velocity of ≥2 meters/second, (2) sinotubular junction or ascending aortic Z score <-2.0, or (3) sinotubular junction Z score <-1.5 with family history of SVAS. Patients with complex congenital heart disease, aortic valve disease as the primary condition, or only postoperative SVAS were excluded. Genetic testing and diagnoses were reported. Of 162 patients who were WS negative meeting inclusion criteria, 61 had genetic testing results available (38%). Chromosomal microarray had been performed in 44 of 61 and was nondiagnostic for non-WS causes of SVAS. Sequencing of 1 or more genes was performed in 47 of 61. Of these, 39 of 47 underwent ELN sequencing, 20 of 39 (51%) of whom had a diagnostic variant. Other diagnoses made by gene sequencing were Noonan syndrome (3 PTPN11, 1 RIT1), Alagille syndrome (3 JAG1), neurofibromatosis (1 NF1), and homozygous familial hypercholesterolemia (1 LDLR1). Overall, sequencing was diagnostic in 29 of 47 (62%). CONCLUSIONS: When WS is excluded, gene sequencing for SVAS is high yield, with the highest yield for the ELN gene. Therefore, we recommend gene sequencing using a multigene panel or exome analysis. Hypercholesterolemia can also be considered in individuals bearing the stigmata of this disease.

Electrocardiograms Do Not Detect Myocardial Ischemia in Patients With Williams Syndrome and Nonsyndromic Elastin Arteriopathy With Coronary Artery Stenosis.

Coronary artery stenosis (CAS) may affect up to 27% of patients with Williams syndrome (WS), which may lead to myocardial ischemia. Patients with WS face a 25- to 100-fold greater risk of sudden cardiac death, frequently linked to anesthesia. Assessing CAS requires either imaging while under general anesthesia or intraoperative assessment, with the latter considered the gold standard. Our study aimed to identify electrocardiogram (ECG) markers of myocardial ischemia in patients with WS or nonsyndromic elastin arteriopathy and documented CAS. We retrospectively reviewed patients with WS/elastin arteriopathy who underwent supravalvar aortic stenosis surgery and CAS assessment from January 1, 2006 to April 30, 2021. A pediatric electrophysiologist, not aware of the patients' CAS status, reviewed their preoperative ECGs for markers of ischemia. We assessed associations of study parameters using Wilcoxon rank-sum and Fisher's exact tests. Of 34 patients, 62% were male, with a median age of 20 months (interquartile range: 8 to 34). CAS was present in 62% (21 of 34), 76% of whom (16 of 21) were male. There were no ECG indicators of myocardial ischemia in patients with CAS. In conclusion, CAS was present in >1/2 the children with WS/elastin arteriopathy who underwent repair of supravalvar aortic stenosis. CAS in WS/nonsyndromic elastin arteriopathy does not appear to exhibit typical ECG-detectable myocardial ischemia. ECGs are not a useful screening tool for CAS in WS/elastin arteriopathy. Given the high anesthesia-related cardiac arrest risk, other noninvasive indicators of CAS are needed.

Novel mutation in ELN gene causes cardiac abnormalities and inguinal hernia: case report.

BACKGROUND: Elastin-driven genetic diseases are a group of complex diseases driven by elastin protein insufficiency and dominant-negative production of aberrant protein, including supravalvular aortic stenosis (SVAS) and autosomal dominant cutis laxa. Here, a Chinese boy with a novel nonsense mutation in the ELN gene is reported. CASE PRESENTATION: We report a 1-year-old boy who presented with exercise intolerance, weight growth restriction with age, a 1-year history of heart murmur, and inguinal hernia. Gene sequencing revealed a novel nonsense mutation in the ELN gene (c.757 C > T (p.Gln253Ter), NM_000501.4). Due to severe branch pulmonary artery stenosis, the reconstruction of the branch pulmonary artery with autologous pericardium was performed. The inguinal hernia repair was performed 3 months postoperatively. After six months of outpatient follow-up, the child recovered well, gained weight with age, and had no special clinical symptoms. CONCLUSION: We identified a de novo nonsense mutation in the ELN gene leading to mild SVAS and severe branch pulmonary artery stenosis. A new phenotype of inguinal hernia was also needed to be considered for possible association with the ELN gene. Still, further confirmation will be necessary.

An infant with suspected missed diagnosis of Williams syndrome failed weaning off CPB after surgical correction of pulmonary stenosis: a case report and literature review.

Williams syndrome (WS) is a rare congenital developmental disorder caused by the deletion of between 26 and 28 genes on chromosome 7q11.23. For patients with WS, in view of the particularity of the supravalvular aortic stenosis, choosing appropriate arterial cannula, maintaining higher perfusion pressure as well as strengthening myocardial protection during cardiopulmonary bypass (CPB) is essential to the clinical outcome. Here, we report a child with pulmonary artery valvular stenosis who failed to wean off CPB because of malignant arrhythmias and cardiac insufficiency after surgical correction of pulmonary valvular stenosis. With the assistance of extracorporeal membrane oxygenation (ECMO), emergency cardiac catheterization revealed supravalvular aortic stenosis (SVAS), which suggests a suspected missed diagnosis of WS. Finally, under the support of ECMO, the cardiac function gradually returned to normal, and the child was discharged 23 days after surgery.

Cardiovascular findings in Williams-Beuren Syndrome: Experience of a single center with 127 cases.

Williams-Beuren syndrome (WBS) is a rare, microdeletion syndrome characterized by facial dysmorphisms, intellectual disability, a friendly personality, cardiovascular and other abnormalities. Cardiovascular defects (CVD) are among the most prevalent characteristics in WBS, being supravalvular aortic stenosis (SVAS) the most frequent, followed by peripheral pulmonary stenosis (PPS). A comprehensive retrospective review of medical records of 127 patients with molecular diagnosis of WBS, in a period of 20 years, was done to evaluate the incidence, the natural history of cardiovascular disease, and the need for surgical intervention, including heart transplantation (HT). A total of 94/127 patients presented with CVD. Of these 94 patients, 50% presented with SVAS and 22.3% needed heart surgery and/or cardiac catheterization including one that required HT due to severe SVAS-related heart failure at 19 years of age. The patient died in the postoperative period due to infectious complications. Cardiovascular problems are the major cause of sudden death in patients with WBS, who have a significantly higher mortality risk associated with surgical interventions. There is a higher risk for anesthesia-related adverse events and for major adverse cardiac events following surgery. End-stage heart failure due to myocardial ischemia has been described in WBS patients and it is important to consider that HT can become their only viable option. To our knowledge, the case mentioned here is the first HT reported in an adolescent with WBS. HT can be a viable therapeutic option in WBS patients with adequate evaluation, planning, and a multidisciplinary team to provide the required perioperative care and follow-up.

Sliding Aortoplasty for Severe Supravalvular Aortic Stenosis After the Lecompte Procedure.

This report describes the case of a 3-year-old boy with supravalvular aortic stenosis after an arterial switch operation in whom the stenosis was successfully repaired using an ascending sliding arch aortoplasty without using a patch. Because patches were avoided, growth of the surgical site is expected. Ascending sliding arch aortoplasty and longitudinal expansion of the pulmonary bifurcation are useful for relieving stenosis and preventing supravalvular aortic stenosis recurrence after an arterial switch operation.

Aspergillus Infection in an Immunocompetent Host With Supravalvular Aortic Stenosis.

Supravalvular aortic stenosis is the rarest form of left ventricular outflow tract obstruction. Aspergillus endocarditis is also rare and generally reported in immunocompromised hosts. Here we present a case of an immunocompetent patient with supravalvular aortic stenosis complicated by aortic mycotic pseudoaneurysm due to invasive aspergillosis.

Un caso de muerte súbita por estenosis aórtica subvalvular / Subvalvular aortic stenosis and sudden death. Presentation of a case

La estenosis subaórtica, aunque patología infrecuente, es susceptible de cursar con muerte súbita por un mecanismo arritmogénico. Si bien su etiología no está aún aclarada, dado el presumible componente genético subyacente, el examen autópsico se convierte en instrumento esencial para el diagnóstico posmortem y trasmitir el pertinente consejo médico a los familiares. Se presenta el estudio médico forense de una mujer de 39 años, que fallece de forma súbita a causa de esta etiología, se discuten los principales hallazgos y los antecedentes familiares conocidos

Subaortic stenosis, although an infrequent pathology, is prone to cause a sudden death through an arrhythmogenic mechanism. Although its aetiology is still unclear, and given an assumed underlying genetic component, the autopsy becomes an essential tool for post-mortem diagnosis of the disease and to give relevant medical advice to family members. A case of sudden death of a 39 year-old woman involving this aetiology is presented, and the medico-legal findings, as well as a discussion on the known family's medical background

Atrial septal defects, supravalvular aortic stenosis and syndromes predisposing to aneurysm of large vessels.

Atrial septal defect is a persistent interatrial communication. It is the second most common congenital heart defect and is detected in 1:1500 live births. Clinical course is variable and depends on the size of the malformation. Clinical diagnosis is based on patient history, physical and instrumental examination. Atrial septal defect is frequently sporadic, but familial cases have been reported. The disease has autosomal dominant inheritance with reduced penetrance, variable expressivity and genetic heterogeneity. Supravalvular aortic stenosis is a congenital narrowing of the lumen of the ascending aorta. It has an incidence of 1:20000 newborns and a prevalence of 1:7500. Clinical diagnosis is based on patient history, physical and instrumental examination. Supravalvular aortic stenosis is either sporadic or familial and has autosomal dominant inheritance with reduced penetrance and variable expressivity. It is associated with mutations in the ELN gene. Syndromes predisposing to aneurysm of large vessels is a group of inherited disorders that may affect different segments of the aorta. They may occur in isolation or associated with other genetic syndromes. Clinical symptoms are highly variable. Familial thoracic aortic aneurysm and dissection accounts for ~20% of all cases of aneurysms. The exact prevalence is unknown. Clinical diagnosis is based on medical history, physical and instrumental examination. Genetic testing is useful for confirming diagnosis of these syndromes and for differential diagnosis, recurrence risk evaluation and prenatal diagnosis in families with a known mutation. Most syndromes predisposing to aneurysm of large vessels have autosomal dominant inheritance with reduced penetrance and variable expressivity.

Frequent intragenic microdeletions of elastin in familial supravalvular aortic stenosis.

BACKGROUND: Supravalvular aortic stenosis (SVAS) is a congenital heart disease affecting approximately 1:25,000 live births. SVAS may occur sporadically, be inherited in an autosomal dominant manner, or be associated with Williams-Beuren syndrome, a complex developmental disorder caused by a microdeletion of chromosome 7q11.23. ELN on 7q11.23, which encodes elastin, is the only known gene to be recurrently mutated in less than half of SVAS patients. METHODS: Whole-exome sequencing (WES) was performed for seven familial SVAS families to identify other causative gene mutations of SVAS. RESULTS: Three truncating mutations and three intragenic deletions affecting ELN were identified, yielding a diagnostic efficiency of 6/7 (85%). The deletions, which explained 3/7 of the present cohort, spanned 1-29 exons, which might be missed in the course of mutational analysis targeting point mutations. The presence of such deletions was validated by both WES-based copy number estimation and multiplex ligation-dependent probe amplification analyses, and their pathogenicity was reinforced by co-segregation with clinical presentations. CONCLUSIONS: The majority of familial SVAS patients appear to carry ELN mutations, which strongly indicates that elastin is the most important causative gene for SVAS. The frequency of intragenic deletions highlights the need for quantitative tests to analyze ELN for efficient genetic diagnosis of SVAS.

Familial hypercholesterolemia supravalvular aortic stenosis and extensive atherosclerosis.

Familial hypercholesterolemia is an autosomally dominant disorder caused by various mutations in low-density lipoprotein receptor genes. This can lead to premature coronary atherosclerosis and cardiac-related death. The symptoms are more severe in the homozygous type of the disease. Premature malignant atherogenesis leading to aortic root abnormalities causing supravalvular aortic stenosis is rare. Our case demonstrates the diagnostic imaging findings of the phenotype of patients who have severe elevated LDL with familial hypercolesterolemia.

Two Cases of Surgical Management of Supravalvular Aortic Stenosis in Familial Hypercholesterolemia.

Homozygous familial hypercholesterolemia is a rare autosomal dominant disorder caused by gene mutations of the low-density lipoprotein receptor, generally characterized by three major signs-hyper low-density lipoprotein cholesterolemia, tendon/skin xanthomas, and premature atherosclerosis disease-beginning in childhood and including supravalvular aortic stenosis. To the best of our knowledge, only a few successful surgical cases for supravalvular aortic stenosis in these patients have been reported. We report two cases of homozygous familial hypercholesterolemia with severe supravalvular aortic stenosis and coronary artery disease associated with very small aortic root, managed by aortic root replacement concomitant with coronary artery bypass graft surgery, which resulted in excellent postoperative outcomes.

Isolated Supravalular Aortic Stenosis with Infective Endocarditis presenting as Pyrexia of Unknown Origin.

Supravalvular aortic stenosis is a less common form of left ventricular outflow tract obstruction (LVOTO); commonest being the valvular aortic stenosis followed by valvular and subvalvular forms respectively. Most of the supravalvular aortic stenosis is associated with Williams syndrome; isolated supravalvular aortic stenosis is further rarer. We present a case of isolated SVAS with infective endocarditis (1.6) as the cause of pyrexia of unknown origin (PUO).

Evaluation of the congenital supravalvular aortic stenosis by different imaging modalities.

A 36-year-old female was admitted to hospital exhibiting chest pain, dyspnea, and a heart murmur on the right upper sternal border, radiating to both carotid arteries. The blood pressure of the patient's right arm exceeded the pressure in the left by 25 mm Hg (Coanda effect). In spite of laboratory results that did not fall outside the expected range, the left ventricle was revealed to be hypertrophic following electrocardiography. Transthoracic echocardiography revealed a severe supravalvular aortic stenosis (SVAS) with a peak Doppler velocity of 6.04 cm/s and an estimated mean pressure gradient of 89 mm Hg, with moderate aortic and mitral regurgitation. Contrast-enhanced computed tomography (CCT) indicated a partial hourglass-shaped narrowing of the ascending aorta. Lesions associated with supravalvular stenosis of the pulmonary artery, patent ductus arteriosus, and aortic coarctation were ruled out by the CCT. Congenital SVAS is a rare heart condition, and three anatomically distinct forms have been described. The most common type is the "hourglass," which produces a marked thickening and disorganization of the aortic tissue, producing a constricting annular ridge at the superior margin of the sinuses of Valsalva.

High-resolution single nucleotide polymorphism arrays identified an atypical microdeletion of the Williams-Beuren syndrome interval in a patient presenting with a different phenotype.

The present study aimed to identify the mutation causing an atypical syndrome. High-resolution single nucleotide polymorphism (SNP) arrays are considered to be a major detection method for submicroscopic chromosomal rearrangements smaller than 5 Mb in size. Genomic DNA samples of the patient and his parents were converted to a final concentration of 50 ng/ml. The Illumina BeadScan genotyping system and the HumanOmni1­Quad Chip were employed to obtain the signal intensities of SNP probes. The patient presented with congenital heart disease, autism, mental retardation, growth retardation, hypercalcemia, nephroliths and cleft palate. The karyotypes of the patient and his parents were normal. The present study employed high­resolution SNP arrays to analyze the whole genome for copy number variations (CNVs). A total of 309 CNVs were discovered. A de novo 1.5 Mb gain of chromosome 7q11.23 (Chr7: 72,357,322­73,856,472) was identified following exclusion of CNVs presented in the Database of Genomic Variants. In conclusion, to the best of our knowledge, the current study describes the first case of a patient presenting with Williams­Beuren syndrome alongside supravalvular aortic stenosis, autism and cleft palate, and identifies an atypical deletion at 7q11.23.

Recurrent pulseless electrical activity in a patient with coronary vasospasm and supravalvular aortic stenosis: a case report.

BACKGROUND: Pulseless electrical activity cardiac arrest is associated with poor outcomes and the identification of potentially reversible reasons for cardiac arrest is fundamental. CASE PRESENTATION: We describe the case of a 46-year-old male with the rare coincidental finding of supravalvular aortic stenosis and coronary vasospasm leading to recurrent pulseless electrical activity cardiac arrest. Extracorporeal life support was successfully applied for hemodynamic stabilization. Supravalvular aorticstenosis underwent surgical repair. The patient survived five time resuscitation and was discharged after full neurological recovery. CONCLUSIONS: Coronary vasospasm and supravalvular aortic stenosis are rare but potentially reversible causes of pulseless electrical activity cardiac arrest. Extracorporeal life support allows accurate diagnostic and possibly therapy even of uncommon reasons for cardiac arrest.

Novel three-sinus enlargement technique for supravalvular aortic stenosis without aortic transection.

BACKGROUND: Although repair of a supravalvular aortic stenosis (SVAS) can be performed with low mortality rates, surgery for the complex form of SVAS continues to be associated with a high incidence of residual stenosis. CASE PRESENTATION: The patient was referred to our hospital at 1 month of age and was diagnosed with aortic valve stenosis (AS) by using echocardiography. Cardiac catheterization revealed moderate AS, and subsequent left ventriculography revealed discrete stenosis of the sino-tubular junction and a narrowed proximal ascending aorta. We performed a reconstructive operation for such heart defects involving novel three-sinus and ascending aorta enlargement without aortic root transection in a 6-month-old boy. CONCLUSION: Our novel three-sinus enlargement technique is suitable for treating each type of SVAS and is a useful method for a baby particularly less than 10 kg without disturbing the growth of the ascending aorta.