RESUMO
Williams-Beuren syndrome (WBS) is a rare disorder caused by a recurrent microdeletion with hallmarks of cardiovascular manifestations, mainly supra-valvular aortic stenosis (SVAS). Unfortunately, there is currently no efficient treatment. We investigated the effect of chronic oral treatment with curcumin and verapamil on the cardiovascular phenotype of a murine model of WBS harbouring a similar deletion, CD (complete deletion) mice. We analysed systolic blood pressure in vivo and the histopathology of the ascending aorta and the left ventricular myocardium to determine the effects of treatments and their underlying mechanism. Molecular analysis showed significantly upregulated xanthine oxidoreductase (XOR) expression in the aorta and left ventricular myocardium of CD mice. This overexpression is concomitant with increased levels of nitrated proteins as a result of byproduct-mediated oxidative stress damage, indicating that XOR-generated oxidative stress impacts the pathophysiology of cardiovascular manifestations in WBS. Only the combined therapy of curcumin and verapamil resulted in a significant improvement of cardiovascular parameters via activation of the nuclear factor erythroid 2 (NRF2) and reduction of XOR and nitrated protein levels. Our data suggested that the inhibition of XOR and oxidative stress damage could help prevent the severe cardiovascular injuries of this disorder.
Assuntos
Estenose Aórtica Supravalvular , Curcumina , Síndrome de Williams , Camundongos , Animais , Síndrome de Williams/genética , Verapamil , Modelos Animais de Doenças , Estenose Aórtica Supravalvular/complicações , Estenose Aórtica Supravalvular/patologiaRESUMO
Non-traumatic neurological deterioration is a medical emergency that may arise from diverse causes, to include cerebral infarction or intracranial hemorrhage, meningoencephalitis, seizure, hypoxic-ischemic or toxic/metabolic encephalopathy, poisoning, or drug intoxication. We describe the abrupt onset of neurological deterioration in a 53-year-old man with Williams-Beuren syndrome, a sporadically occurring genetic disorder caused by chromosomal microdeletion at 7q11.23. The clinical phenotype of Williams-Beuren syndrome is suggested by distinctive elfin facies, limited intellect, unique personality features, growth abnormalities, and endocrinopathies. The causative microdeletion of chromosomal material will frequently involve loss of the elastin gene, ELN, with resulting arteriopathy, supravalvular aortic stenosis, non-ischemic cardiopathy, and atrial fibrillation. Our patient sustained acute neurological decline within one month after undergoing a cardiac ablative procedure to convert atrial fibrillation to sinus rhythm. We present our findings in the setting of a clinico-pathological correlation, in which we reveal the cause of the abrupt neurological deterioration and discuss how our patient was affected by an uncommon stroke disorder.
Assuntos
Estenose Aórtica Supravalvular , Fibrilação Atrial , Ablação por Cateter , Embolia Aérea , Síndrome de Williams , Estenose Aórtica Supravalvular/genética , Estenose Aórtica Supravalvular/patologia , Fibrilação Atrial/complicações , Ablação por Cateter/efeitos adversos , Humanos , Síndrome de Williams/complicações , Síndrome de Williams/diagnóstico , Síndrome de Williams/genéticaRESUMO
Obstructive arterial diseases, including supravalvular aortic stenosis (SVAS), atherosclerosis, and restenosis, share 2 important features: an abnormal or disrupted elastic lamellae structure and excessive smooth muscle cells (SMCs). However, the relationship between these pathological features is poorly delineated. SVAS is caused by heterozygous loss-of-function, hypomorphic, or deletion mutations in the elastin gene (ELN), and SVAS patients and elastin-mutant mice display increased arterial wall cellularity and luminal obstructions. Pharmacological treatments for SVAS are lacking, as the underlying pathobiology is inadequately defined. Herein, using human aortic vascular cells, mouse models, and aortic samples and SMCs derived from induced pluripotent stem cells of ELN-deficient patients, we demonstrated that elastin insufficiency induced epigenetic changes, upregulating the NOTCH pathway in SMCs. Specifically, reduced elastin increased levels of γ-secretase, activated NOTCH3 intracellular domain, and downstream genes. Notch3 deletion or pharmacological inhibition of γ-secretase attenuated aortic hypermuscularization and stenosis in Eln-/- mutants. Eln-/- mice expressed higher levels of NOTCH ligand JAGGED1 (JAG1) in aortic SMCs and endothelial cells (ECs). Finally, Jag1 deletion in SMCs, but not ECs, mitigated the hypermuscular and stenotic phenotype in the aorta of Eln-/- mice. Our findings reveal that NOTCH3 pathway upregulation induced pathological aortic SMC accumulation during elastin insufficiency and provide potential therapeutic targets for SVAS.
Assuntos
Estenose Aórtica Supravalvular , Elastina , Proteína Jagged-1/metabolismo , Secretases da Proteína Precursora do Amiloide , Animais , Aorta/metabolismo , Estenose Aórtica Supravalvular/genética , Estenose Aórtica Supravalvular/metabolismo , Estenose Aórtica Supravalvular/patologia , Constrição Patológica , Elastina/genética , Elastina/metabolismo , Células Endoteliais/metabolismo , Humanos , Camundongos , Receptor Notch3/genéticaRESUMO
Williams-Beuren syndrome (WBS) is a rare neurodevelopmental disorder characterized by supravalvular aortic stenosis (SVAS), intellectual disability, overfriendliness and dysmorphic features. It is typically caused by 1.5-1.8 Mb deletions on 7q11.23. The 22q11.21 microduplication syndrome has a variable phenotype and is frequently associated with congenital heart disease. Here we present a unique patient, carrying aberrations within both of the above syndrome regions, referred for possible diagnosis of WBS because of SVAS. The patient was a boy who died suddenly 47 days after birth, possibly due to cardiac complications. Genetic testing was carried out, including array Comparative Genomic Hybridization (aCGH), Fluorescence In situ Hybridization (FISH) and Multiplex Ligation-Dependent Probe Amplification (MLPA) showing that the proband was heterozygous for a novel and atypical 0.3 Mb deletion in WBS region (7q11.23) encompassing the ELN gene. In addition, he was found heterozygous for a 22q11.21 microduplication. Parental studies revealed that the 7q11.23 deletion was inherited from the mother who also exhibited a cardiovascular phenotype, however very mild. The same maternally inherited deletion was detected in one of the proband's siblings, born two years later with a less severe SVAS. The 22q11.2 microduplication was de novo in origin. Detection and investigation of atypical deletions within known syndrome regions are crucial for better genotype-phenotype correlations and more accurate characterization of critical regions. The combined effect of two different genetic defects - one in a known syndrome region and one with variable clinical significance, is valuable for revealing gene interactions and enabling more accurate predictions, especially in prenatal diagnosis.
Assuntos
Anormalidades Múltiplas/genética , Estenose Aórtica Supravalvular/genética , Duplicação Cromossômica/genética , Síndrome de DiGeorge/genética , Síndrome de Williams/genética , Anormalidades Múltiplas/patologia , Adulto , Estenose Aórtica Supravalvular/patologia , Cromossomos Humanos Par 22/genética , Síndrome de DiGeorge/patologia , Feminino , Humanos , Lactente , Padrões de Herança , Masculino , Síndrome de Williams/patologiaRESUMO
Williams-Beuren syndrome (WBS) affects young infants and children. The underlying etiopathogenesis of this rare disease is due to the mutation of the elastin gene that is responsible for the elasticity of the arterial wall. As a result of inadequate elastin production, the major systemic arteries become abnormally rigid and can be manifested by an impediment to the blood flow. The most common cardiovascular abnormalities encountered in WBS are supravalvular aortic stenosis, pulmonary arterial stenosis, and mitral valve prolapse. Less frequently observed cardiovascular abnormalities include coarctation of the aorta, ventricular septal defect, patent ductus, subaortic stenosis, and hypertrophic cardiomyopathy. Coronary artery stenosis and severe impediment to the bi-ventricular outflow as a result of supravalvular aortic and pulmonary artery stenosis predispose patients to sudden death. Patients with progressed arterial stenosis and severe stenosis are likely to require intervention to prevent serious complications. Rarely, imaging findings may precede clinical presentation, which allows the radiologist to participate in the patient care. However, to be more prudent, the radiologist must be accustomed to the imaging characteristics of WBS as well as the patient's clinical information, which could raise the suspicion of WBS. We performed a retrospective analysis of all the available images from patients diagnosed with WBS in last 4 years at our institution, and present key imaging findings along with a review of the literature to summarize the clinically relevant features as demonstrated by multidetector computed tomography in WBS. Cross-sectional imaging plays a vital role in the diagnosis of WBS cases with equivocal clinical features. MDCT evaluation of complex cardiovascular abnormalities of WBS including coronary artery disease is feasible with modern MDCT scanners and in the future, this approach could provide accurate information for planning, navigation, and noninvasive assessment of the secondary arterial changes in WBS and thus reducing the dependence upon invasive contrast catherization techniques.
Assuntos
Estenose Aórtica Supravalvular/diagnóstico por imagem , Doença da Artéria Coronariana/diagnóstico por imagem , Tomografia Computadorizada Multidetectores/métodos , Estenose da Valva Pulmonar/diagnóstico por imagem , Síndrome de Williams/diagnóstico por imagem , Síndrome de Williams/patologia , Adolescente , Estenose Aórtica Supravalvular/patologia , Criança , Pré-Escolar , Doença da Artéria Coronariana/patologia , Feminino , Humanos , Lactente , Masculino , Estenose da Valva Pulmonar/patologiaRESUMO
A estenose aórtica supravalvar é uma rara cardiopatia congênita, bastante incomum em adultos. Apresentamos um caso de estenose aórtica supravalvar em adulto com anomalia de vasos do arco aórtico, já com presença de insuficiência aórtica importante, tratado com êxito por meio de plastia da aorta ascendente e troca valvar aórtica.
The supravalvular aortic stenosis is a rare congenital heart defect being very uncommon in adults. We present a case of supravalvular aortic stenosis in adult associated with anomalies of the aortic arch vessels and aortic regurgitation, which was submitted to aortic valve replacement and arterioplasty of the ascending aorta with a good postoperative course.
Assuntos
Adulto , Humanos , Masculino , Aorta Torácica/cirurgia , Estenose Aórtica Supravalvular/cirurgia , Insuficiência da Valva Aórtica/cirurgia , Aorta Torácica/patologia , Estenose Aórtica Supravalvular/patologia , Insuficiência da Valva Aórtica/patologia , Tronco Braquiocefálico/patologia , Tronco Braquiocefálico/cirurgia , Angiografia Coronária , Próteses Valvulares Cardíacas , Artéria Subclávia/patologia , Artéria Subclávia/cirurgia , Resultado do TratamentoRESUMO
Supravalvar aortic stenosis (SVAS) is a congenital anomaly characterized by a discrete or diffuse narrowing of the ascending aorta. It may also be associated with right-ventricular outflow tract obstruction, aortic valve pathology and coronary ostial stenosis. While present in both familial and sporadic forms, it demonstrates a strong association with William-Beuren syndrome, both being anomalies associated with defects in the elastin gene. In this article, the authors have discussed the etiology, morphology, clinical presentation and genetic basis of SVAS. Various surgical approaches, both conventional and recent, have been discussed and demonstrated with the aid of diagrams. Single-, two- and three-sinus methods have been presented, along with a comparative analysis of early results, associated procedures, late mortality and reoperation. In conclusion, the authors have described their institutional experience of more than 40 years in the surgical management of SVAS.
Assuntos
Estenose Aórtica Supravalvular/cirurgia , Elastina/genética , Síndrome de Williams/cirurgia , Animais , Estenose Aórtica Supravalvular/genética , Estenose Aórtica Supravalvular/patologia , Valva Aórtica/patologia , Valva Aórtica/cirurgia , Estenose Coronária/patologia , Estenose Coronária/cirurgia , Humanos , Reoperação , Obstrução do Fluxo Ventricular Externo/patologia , Obstrução do Fluxo Ventricular Externo/cirurgia , Síndrome de Williams/genética , Síndrome de Williams/fisiopatologiaRESUMO
Loeffler's endocarditis is a complication of diseases associated with the idiopathic hypereosinophilic syndrome, which is characterised by persistently elevated blood eosinophil counts with symptoms and signs of organ involvement especially in the heart, vascular system, nervous system and bone marrow. We report the involvements of the endocardium and aorta, without endomyocardial fibrosis and the complete resolution of the endocardial eosinophilic infiltration with steroids and anticoagulation therapy.
Assuntos
Aorta Abdominal/patologia , Estenose Aórtica Supravalvular , Síndrome Hipereosinofílica , Estenose Aórtica Supravalvular/tratamento farmacológico , Estenose Aórtica Supravalvular/etiologia , Estenose Aórtica Supravalvular/patologia , Humanos , Síndrome Hipereosinofílica/complicações , Síndrome Hipereosinofílica/tratamento farmacológico , Síndrome Hipereosinofílica/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
Occult coronary artery obstruction can be a late source of morbidity and mortality following the arterial switch operation for transposition of the great arteries. We describe a case of undiagnosed left coronary ostial obstruction in a teenager which may have contributed to perioperative ventricular dysfunction and subsequent mortality following a reoperation many years after arterial switch.
Assuntos
Estenose Aórtica Supravalvular/diagnóstico , Estenose Aórtica Supravalvular/cirurgia , Cateterismo Cardíaco , Estenose Coronária/diagnóstico , Estenose Coronária/cirurgia , Ecocardiografia , Imageamento por Ressonância Magnética , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/cirurgia , Transposição dos Grandes Vasos/cirurgia , Adolescente , Alcenos , Estenose Aórtica Supravalvular/patologia , Implante de Prótese Vascular , Estenose Coronária/patologia , Vasos Coronários/patologia , Evolução Fatal , Corpos Estranhos/patologia , Parada Cardíaca/etiologia , Parada Cardíaca/patologia , Humanos , Masculino , Complicações Pós-Operatórias/patologia , Reoperação , Suturas , Transposição dos Grandes Vasos/patologiaRESUMO
The supravalvular aortic stenosis is a rare congenital heart defect being very uncommon in adults. We present a case of supravalvular aortic stenosis in adult associated with anomalies of the aortic arch vessels and aortic regurgitation, which was submitted to aortic valve replacement and arterioplasty of the ascending aorta with a good postoperative course.
Assuntos
Aorta Torácica/cirurgia , Estenose Aórtica Supravalvular/cirurgia , Insuficiência da Valva Aórtica/cirurgia , Adulto , Aorta Torácica/patologia , Estenose Aórtica Supravalvular/patologia , Insuficiência da Valva Aórtica/patologia , Tronco Braquiocefálico/patologia , Tronco Braquiocefálico/cirurgia , Angiografia Coronária , Próteses Valvulares Cardíacas , Humanos , Masculino , Artéria Subclávia/patologia , Artéria Subclávia/cirurgia , Resultado do TratamentoRESUMO
Supravalvular aortic stenosis is a systemic elastin (ELN) arteriopathy that disproportionately affects the supravalvular aorta. ELN arteriopathy may be present in a nonsyndromic condition or in syndromic conditions such as Williams-Beuren syndrome. The anatomic findings include congenital narrowing of the lumen of the aorta and other arteries, such as branches of pulmonary or coronary arteries. Given the systemic nature of the disease, accurate evaluation is recommended to establish the degree and extent of vascular involvement and to plan appropriate interventions, which are indicated whenever hemodynamically significant stenoses occur. ELN arteriopathy is genetically heterogeneous and occurs as a consequence of haploinsufficiency of the ELN gene on chromosome 7q11.23, owing to either microdeletion of the entire chromosomal region or ELN point mutations. Interestingly, there is a prevalence of premature termination mutations resulting in null alleles among ELN point mutations. The identification of the genetic defect in patients with supravalvular aortic stenosis is essential for a definitive diagnosis, prognosis, and genetic counseling.
Assuntos
Aorta/patologia , Estenose Aórtica Supravalvular/patologia , Elastina/metabolismo , Aorta/diagnóstico por imagem , Estenose Aórtica Supravalvular/diagnóstico , Estenose Aórtica Supravalvular/diagnóstico por imagem , Estenose Aórtica Supravalvular/etiologia , Diagnóstico Diferencial , Elastina/genética , Humanos , Síndrome , UltrassonografiaRESUMO
BACKGROUND: Supravalvular aortic stenosis (SVAS) is caused by mutations in the elastin (ELN) gene and is characterized by abnormal proliferation of vascular smooth muscle cells (SMCs) that can lead to narrowing or blockage of the ascending aorta and other arterial vessels. Having patient-specific SMCs available may facilitate the study of disease mechanisms and development of novel therapeutic interventions. METHODS AND RESULTS: Here, we report the development of a human induced pluripotent stem cell (iPSC) line from a patient with SVAS caused by the premature termination in exon 10 of the ELN gene resulting from an exon 9 four-nucleotide insertion. We showed that SVAS iPSC-derived SMCs (iPSC-SMCs) had significantly fewer organized networks of smooth muscle α-actin filament bundles, a hallmark of mature contractile SMCs, compared with control iPSC-SMCs. The addition of elastin recombinant protein or enhancement of small GTPase RhoA signaling was able to rescue the formation of smooth muscle α-actin filament bundles in SVAS iPSC-SMCs. Cell counts and BrdU analysis revealed a significantly higher proliferation rate in SVAS iPSC-SMCs than control iPSC-SMCs. Furthermore, SVAS iPSC-SMCs migrated at a markedly higher rate to the chemotactic agent platelet-derived growth factor compared with the control iPSC-SMCs. We also provided evidence that elevated activity of extracellular signal-regulated kinase 1/2 is required for hyperproliferation of SVAS iPSC-SMCs. The phenotype was confirmed in iPSC-SMCs generated from a patient with deletion of elastin owing to Williams-Beuren syndrome. CONCLUSIONS: SVAS iPSC-SMCs recapitulate key pathological features of patients with SVAS and may provide a promising strategy to study disease mechanisms and to develop novel therapies.
Assuntos
Estenose Aórtica Supravalvular/patologia , Células-Tronco Pluripotentes Induzidas/patologia , Síndrome de Williams/patologia , Adulto , Animais , Células Cultivadas , Criança , Humanos , Masculino , CamundongosRESUMO
Report of a patient with seven years old and effort intolerance progressing. The child had tachycardia, pansystolic murmur in the aortic focus. Echocardiography showed left ventricle hypertrophy and aortic narrowing at the level of sinotubular junction with sistolic gradient of 190 mmHg. Cardiac catheterization confirmed the diagnostic suggesting left coronary ostium stenosis. The surgery was performed modification the technique, described by Sousa. Immediate post-operative has presented no complications, with gradient of 23 mmHg, and good leaflets mobility.
Assuntos
Estenose Aórtica Supravalvular/cirurgia , Procedimentos Cirúrgicos Cardíacos/métodos , Pericárdio/transplante , Estenose Aórtica Supravalvular/patologia , Criança , Feminino , Humanos , Transplante AutólogoRESUMO
Relato de uma paciente de sete anos apresentando progressiva intolerância ao esforço. A criança apresentava taquicardia e sopro pansistólico de maior intensidade no foco aórtico. O ecocardiograma evidenciava hipertrofia ventricular esquerda e estenose aórtica supravalvar com gradiente sistólico de 190 mmHg. A angioressonância e o cateterismo cardíaco confirmaram o diagnóstico, sugerindo estenose do óstio da artéria coronária esquerda. A correção foi realizada modificando a técnica descrita por Sousa. A evolução pósoperatória transcorreu sem intercorrências, com gradiente pós-operatório de 23 mmHg e boa mobilidade da valva aórtica.
Report of a patient with seven years old and effort intolerance progressing. The child had tachycardia, pansystolic murmur in the aortic focus. Echocardiography showed left ventricle hypertrophy and aortic narrowing at the level of sinotubular junction with sistolic gradient of 190 mmHg. Cardiac catheterization confirmed the diagnostic suggesting left coronary ostium stenosis. The surgery was performed modification the technique, described by Sousa. Immediate post-operative has presented no complications, with gradient of 23 mmHg, and good leaflets mobility.
Assuntos
Criança , Feminino , Humanos , Estenose Aórtica Supravalvular/cirurgia , Procedimentos Cirúrgicos Cardíacos/métodos , Pericárdio/transplante , Estenose Aórtica Supravalvular/patologia , Transplante AutólogoRESUMO
The left main trunk stenosis with Williams syndrome and supravalvular stenosis is a cause of sudden death and a serious disease. We performed modified Myers procedure with patch aortoplasty concomitant with coronary artery bypass grafting (CABG) using a free right internal thoracic artery (ITA) graft for a 2-year-old patient with this disease. The proximal cuff of the free right ITA graft was implanted in the posterior wall of the reconstructed aorta. The postoperative clinical course was uneventful, and aortic regurgitation and ischemic signs were not detected. CABG using this technique is useful for coronary artery stenosis in infants and young children, and favorable long-term outcomes are expected.
Assuntos
Estenose Aórtica Supravalvular/diagnóstico , Estenose Aórtica Supravalvular/cirurgia , Anomalias dos Vasos Coronários/diagnóstico , Anomalias dos Vasos Coronários/cirurgia , Síndrome de Williams , Estenose Aórtica Supravalvular/patologia , Procedimentos Cirúrgicos Cardíacos/métodos , Pré-Escolar , Ponte de Artéria Coronária/métodos , Anomalias dos Vasos Coronários/patologia , Diagnóstico Diferencial , Humanos , Artéria Torácica Interna/transplanteRESUMO
Familial homozygous hypercholesterolemia is a rare disease with diverse clinical presentations. Patients often present with cutaneous xanthomas, particularly in the Achilles' tendon. They may have significant cardiovascular involvement, including premature atherosclerotic coronary artery disease and valvar and supravalvar aortic stenosis. Standard therapy includes diet modulation, pharmacotherapy, and lipid apheresis. Rarely, patients require surgical intervention for coronary artery bypass grafting and/or relief of the aortic stenosis. We present the case of a patient with severe progressive supravalvar aortic stenosis that ultimately required surgical resection despite aggressive medical therapy.
Assuntos
Estenose Aórtica Supravalvular/etiologia , Aterosclerose/etiologia , Hiperlipoproteinemia Tipo II/complicações , Estenose Aórtica Supravalvular/patologia , Estenose Aórtica Supravalvular/cirurgia , Aterosclerose/patologia , Aterosclerose/cirurgia , Pré-Escolar , Progressão da Doença , Ecocardiografia , Humanos , Hiperlipoproteinemia Tipo II/terapia , MasculinoRESUMO
Supravalvular aortic stenosis (SVAS) and Williams Beuren syndrome (WBS) can be considered as inherited diseases affecting the whole arterial tree and causing narrowing of the vessels. It has been reported that abnormal deposition of elastin in arterial walls of patients with SVAS and WBS leads to increased proliferation of arterial smooth muscle cells (SMC), which result in the formation of hyperplastic intimal lesions. In this work, we conducted morphological and morphometrical analysis with stenotic aortas from patients suffering from SVAS and WBS and from healthy control subjects and demonstrated that the amount of elastic fibers and the loss of integrity of vascular elastic fibers in the aortas reflect similar changes in the skin of patients with SVAS or WBS, as reported in our previous work conducted on skin in these pathological states. On the other hand, we conducted investigations on metalloproteinases (MMP2, MMP9, MMP7) and their specific tissue inhibitors TIMP1 and TIMP2 to verify their possible involvement in the etiopathogeny of SVAS and WBS. We particularly evidenced an altered MMP9/TIMP1 balance in favor of matrix degradation which could facilitate SMC migration and neointimal hyperplasia. Our findings suggest that elastinolytic enzymes secreted by arterial SMC, possibly including matrilysin 1, are critical for the development of arterial lesions in SVAS and WBS and contribute to perpetuate arterial stenosis in either SVAS or WBS.
Assuntos
Aorta/fisiopatologia , Estenose Aórtica Supravalvular/fisiopatologia , Síndrome de Williams/fisiopatologia , Adulto , Aorta/patologia , Estenose Aórtica Supravalvular/patologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Humanos , Processamento de Imagem Assistida por Computador , Técnicas Imunológicas , Metaloproteases/metabolismo , Distribuição Tecidual , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Síndrome de Williams/patologiaRESUMO
An infant with normal facies and none of the extracardiac anomalies usually associated with Williams syndrome presented at birth with an echocardiographic pattern of supravalvular pulmonary stenosis and displastic pulmonary valve. A clinical reappraisal was planned at 3 months of age, but the girl died suddenly at home at 2 months of age. At autopsy, both ventricles were hypertrophic, and the valves showed mild dysplasia. The walls of the great arteries were thick, with a "washed leather" consistency, but there was no gross evidence of discrete stenosis. The histologic mosaic appearance of the media of the great arteries, due to elastosis and extreme disarray of the elastic lamellae, prompted a postmortem diagnosis of supravalvar aortic stenosis and suggested a diagnosis of Williams syndrome, which was subsequently confirmed by fluorescence in situ hybridization. Pediatricians and pathologists should be alerted that Williams syndrome in the newborn may present as an isolated supravalvular pulmonary stenosis, whereas supravalvular aortic stenosis becomes clinically significant only a few months later.
Assuntos
Estenose da Valva Pulmonar/etiologia , Síndrome de Williams/complicações , Estenose Aórtica Supravalvular/etiologia , Estenose Aórtica Supravalvular/patologia , Deleção Cromossômica , Cromossomos Humanos Par 7/genética , Diagnóstico Diferencial , Evolução Fatal , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Recém-Nascido , Estenose da Valva Pulmonar/patologia , Síndrome de Williams/genética , Síndrome de Williams/patologiaRESUMO
To elucidate the pathomechanism leading to obstructive vascular disease in patients with elastin deficiency, we compared both elastogenesis and proliferation rate of cultured aortic smooth-muscle cells (SMCs) and skin fibroblasts from five healthy control subjects, four patients with isolated supravalvular aortic stenosis (SVAS), and five patients with Williams-Beuren syndrome (WBS). Mutations were determined in each patient with SVAS and in each patient with WBS. Three mutations found in patients with SVAS were shown to result in null alleles. RNA blot hybridization, immunostaining, and metabolic labeling experiments demonstrated that SVAS cells and WBS cells have reduced elastin mRNA levels and that they consequently deposit low amounts of insoluble elastin. Although SVAS cells laid down approximately 50% of the elastin made by normal cells, WBS cells deposited only 15% of the elastin made by normal cells. The observed difference in elastin-gene expression was not caused by a difference in the stability of elastin mRNA in SVAS cells compared with WBS cells, but it did indicate that gene-interaction effects may contribute to the complex phenotype observed in patients with WBS. Abnormally low levels of elastin deposition in SVAS cells and in WBS cells were found to coincide with an increase in proliferation rate, which could be reversed by addition of exogenous insoluble elastin. We conclude that insoluble elastin is an important regulator of cellular proliferation. Thus, the reduced net deposition of insoluble elastin in arterial walls of patients with either SVAS or WBS leads to the increased proliferation of arterial SMCs. This results in the formation of multilayer thickening of the tunica media of large arteries and, consequently, in the development of hyperplastic intimal lesions leading to segmental arterial occlusion.