¿Qué puede esconder el retraso global del desarrollo? A propósito de un caso de causa genética / What can Global Developmental Delay Conceal? Apropos of a Case with a Genetic Cause

Se presenta un niño de 6 años con antecedente de retraso del lenguaje que llevó a sus padres a realizar múltiples consultas. En un primer momento, su cuadro fue interpretado como parte de un retraso global del desarrollo. Posteriormente, el paciente presentó convulsiones y episodios de descompensación metabólica, comenzando desde entonces su seguimiento por los Servicios de neurología, genética y metabolismo. Finalmente, tras varios estudios complementarios, por medio de un exoma trío se arribó al diagnóstico de síndrome de microduplicación del cromosoma 7q11.23, lo que justifica tanto el retraso global de desarrollo del paciente como su clínica neurológica. (AU)

A six-year-old boy presents with a history of language delay that led his parents to make multiple consultations. At first, we interpreted his condition as part of a global developmental delay. Subsequently, the patient presented seizures and episodes of metabolic decompensation, and since then, he had to be followed up by neurology, genetics, and metabolism services. Finally, after several complementary studies, following a trio exome analysis, we diagnosed chromosome 7q11.23 microduplication syndrome, which explains his global developmental delay and neurological symptoms. (AU)

Williams-Beuren Syndrome: What Orthodontists Need to Know / Síndrome de Williams-Beuren: Lo que los Ortodoncistas Deben Saber

ABSTRACT: Williams-Beuren syndrome is a rare disease with manifestations such as cardiovascular changes, distinct facial features, mental retardation, and learning disabilities. Oral manifestations are not commonly described and can often be misdiagnosed. This report describes the case of a male patient diagnosed with Williams-Beuren syndrome presenting classic clinical features that affect the face as a convex profile, with maxillary protrusion and mandibular retrusion, a discreetly acute nasolabial angle, passive labial sealing, and an open mandibular angle characteristic of Class II skeletal pattern. In addition, the patient has oral manifestations such as the absence of some dental elements, a Class II of Angle 1st division, dental cross bite, and atresic arches. The periodontal condition presents with generalized gingivitis. Knowledge about the possible manifestations of Williams-Beuren syndrome is important to improve the ability of orthodontists to better serve these patients.

RESUMEN: El síndrome de Williams-Beuren es una enfermedad rara con manifestaciones tales como cambios cardiovasculares, diversas características faciales, retraso mental y problemas de aprendizaje. Las manifestaciones orales no se describen comúnmente y con frecuencia se pueden diagnosticar erróneamente. Este informe describe el caso de un paciente masculino diagnosticado con síndrome de Williams-Beuren que presentaba características clínicas clásicas que afectaban la cara como un perfil convexo, con protrusión maxilar y retrusión mandibular, un ángulo nasolabial discretamente agudo, sellado labial pasivo y un ángulo mandibular abierto característico del patrón esquelético clase II. Además, el paciente presentaba manifestaciones orales tales como, ausencia de algunos elementos dentales, una clase II de Angle 1ª división, mordida dental cruzada y arcos acrílicos. La condición periodontal se presentaba con gingivitis generalizada. El conocimiento sobre las posibles manifestaciones del síndrome de Williams-Beuren es importante ya que mejora la capacidad de los ortodoncistas para atender mejor a estos pacientes.

Cognitive and behavioral profile of Williams Syndrome toddlers / Perfil cognitivo comportamental de crianças pré-escolares com Síndrome de Williams

ABSTRACT Purpose To verify indicators of cognitive development, receptive language skills and adaptive behavioral patterns in toddlers with Williams syndrome (WS). Methods The sample comprised 8 children of both sex, aged between 48 and 72 months with WS. Instruments of data collection were Denver Developmental Screening Test II; Peabody Picture Vocabulary Test; Vineland Adaptive Behavior Scale; Child Behavior Checklist for Ages 1½-5and 6 to 18; Columbia Mental Maturity Scale (CMMS), and Behavior Problems Inventory-01. Results The major developmental impairments were associated with fine motor skills and personal care abilities. Deficits in receptive language and communication skills were reported according to the PPVT and Denver II, respectively. The caregivers reported behavioral and emotional problems associated to anxiety and depression, and attention problems scales of CBCL. Conclusion The toddlers demonstrated deficits in adaptive functioning and behavioral, motor and cognitive difficulties such as inattention and hyperactivity, stereotypies and aggressive behavior.

RESUMO Objetivo Verificar indicadores de desenvolvimento cognitivo, habilidades de linguagem receptiva e padrões comportamentais adaptativos em pré-escolares com Síndrome de Williams (SW). Método A amostra foi composta por 8 crianças de ambos os sexos, com idade entre 48 e 72 meses com SW. Os instrumentos de coleta de dados utilizados foram Denver Developmental Screening Test II; Peabody Picture Vocabulary Test; Escala de comportamento adaptativo Vineland; Child Behavior Checklist (CBCL) para as idades 1½-5 e 6 a 18; Inventário de Problemas de Comportamento (BPI-01) e Escala de Maturidade Mental Columbia. Resultados Os principais prejuízos de desenvolvimento foram associados a habilidades motoras finas e habilidades de cuidados pessoais. Os déficits em linguagem receptiva e habilidades de comunicação foram relatados de acordo com o PPVT e Denver II, respectivamente. Os cuidadores relataram problemas comportamentais e emocionais associados às escalas de ansiedade e depressão e de problemas de atenção do CBCL. Conclusão Os pré-escolares demonstraram déficits no funcionamento adaptativo e dificuldades comportamentais, motoras e cognitivas, como desatenção e hiperatividade, estereotipias e comportamento agressivo.

Oral Findings and Dental Treatment in a Child with Williams-Beuren Syndrome

Williams-Beuren syndrome (WBS), also known as Williams syndrome, is a rare congenital disorder involving cardiovascular problems, mental retardation, distinctive facial features and tooth anomalies. It is caused by the submicroscopic deletion of 1.5 to 1.8 Mb on chromosome 7q11.23. This paper reports the dental care to a 7-year-old child with WBS syndrome. The interview also revealed visual impairment, sensorineural hearing loss, hyperacusis, photophobia and hoarse voice. The intraoral clinical examination showed anterior open bite, tongue thrusting, excessive interdental spacing, enamel hypomineralization of the incisors, hypoplasia and caries lesions. The dental treatment included: modulating sessions to control aversion to noises, the photophobia, and the dental fear and anxiety because of his reduced visual acuity; oral hygiene instructions, dietary and daily use of a 0.05% sodium fluoride mouthwash; the permanent mandibular left first molar was treated endodontically, and maxillary and mandibular first molars were restored with amalgam. Due to the patient's heart defect, a prophylactic antibiotic regimen was prescribed prior to the dental procedures. This patient has been followed up for 4 years and this case report underscores the importance of early dental evaluation and counseling for parents of WBS patients.

A Síndrome de Williams-Beuren (SWB), também conhecida como síndrome de Williams, consiste em uma desordem congêntica rara a qual apresenta problemas cardiovasculares, retardo mental, alterações faciais e anomalias dentárias. É causada pela microdeleção de 1,5 a 1,8 Mb no cromossomo 7q11.23. Este trabalho relata o tratamento odontológico de uma criança de 7 anos com a síndrome. Durante a anamnese constatou-se deficiência visual, perda auditiva neurossensorial, hiperacusia, fotofobia e voz rouca. O exame clínico intra-oral revelou mordida aberta anterior, deglutição atípica, espaçamento interdental excessivo, hipomineralização dos incisivos, hipoplasia e lesões de cárie. O tratamento dentário incluiu: sessões de condicionamento comportamental afim de controlar a aversão a ruídos, a fotofobia e o medo e a ansiedade frente ao tratamento odontológico, provocadas principalmente por sua reduzida acuidade visual; instruções de higiene oral, dieta e uso diário de bochechos de fluoreto de sódio a 0,05%; endodontia do primeiro molar permanente inferior esquerdo e restaurações de amálgama nos primeiros molares superiores e inferiores. Devido ao defeito cardíaco do paciente, antibioticoterapia profilática foi realizada antes dos atendimentos odontológicos. Este paciente está em acompanhamento há 4 anos e este relato ressalta a importância da avaliação odontológica precoce e do aconselhamento aos pais dos pacientes com SWB.

Molecular cytogenetic evaluation of chromosomal microdeletions: the experience of a public hospital in Southern Brazil

Introduction: During the past few decades, the number of diseases identified to be caused by chromosomal microdeletions has increased quickly, bringing a new and crucial role for cytogenetics on the diagnosis of these conditions. The purpose of this study was to identify and characterize chromosomal microdeletions associated with malformation syndromes and intellectual disability. Methods: We retrospectively evaluated a consecutive series of samples from a cohort of 598 subjects with clinical symptoms of a microdeletion syndrome, including the deletion of chromosomes 4p16.3, 5p15.2, 5q35, 7q11.23, 8q24.12, 15q11.2, 16p13.3, 17p13.3, 17p11.2,2, and 22q11.2, as investigated by fluorescence in situ hybridization (FISH). Array-based comparative genomic hybridization (array-CGH) was performed on 25 samples with microdeletions. Results: A total of 598 samples were evaluated from patients whose clinical phenotypes were most indicative of 22q11.2 deletion syndrome (29.10%), Prader-Willi syndrome (23.41%), Angelman syndrome (16.89%), and Williams-Beuren syndrome (14.72%). In 142 of the samples (23.75%), a chromosomal imbalance associated with phenotypic abnormalities was found. The deletion of 7q11.23 was the most frequent (8.03%), followed by del22q11.2 (5.68%) and del15q11.2 (5%). Conclusion: Our study reinforces the idea that the effort to improve the capacity to perform molecular cytogenetic investigations associated with a qualified clinical evaluation is crucial for the detection and precise characterization of submicroscopic chromosome deletions, bringing benefits to patients, relatives, and genetic counselors. It also contributes to the continuing education of cytogeneticists and to the knowledge of chromosomal rearrangements associated with genomic disorders.

Detección de un caso de síndrome de Williams-Beuren por MLPA / Detection of a Williams Beuren syndrome case by MLPA

El síndrome de Williams-Beuren (WBS) es un trastorno del desarrollo neurológico que incluye diferentes manifestaciones clínicas como estenosis aórtica supravalvular, lesiones cerebrovasculares, retraso en el crecimiento, rasgos faciales "élficos" y retraso mental. Es causado por una microdeleción heterocigótica de genes contiguos en la banda cromosómica 7q11.23, generando un cambio en el número de copias (CNV) de esta región crítica. Los pacientes presentan una amplia manifestación clínica y variada expresión fenotípica. La confirmación de la sospecha clínica es esencial para el seguimiento clínico del paciente y el asesoramiento genético de la familia. La técnica estándar para la detección de WBS es la hibridización fluorescente in situ. En los últimos años la metodología MLPA (Multiplex Ligation dependent Probe Amplification) ha sido incorporada a los laboratorios diagnósticos para la detección de CNV relacionados con distintas enfermedades, incluyendo WBS. El objetivo de este trabajo fue confirmar el diagnóstico clínico de WBS en un niño, utilizando la técnica de MLPA. Los ensayos por MLPA permitieron detectar la deleción de los genes CYLN2, FZD9, STX1A, ELN, LIMK1y RFC2. En regiones geográficas donde la determinación por FISH (Fluorescence In Situ Hybridization) no está disponible para esta enfermedad, la metodología MLPA ha permitido confirmar el diagnóstico clínico y detectar los genes involucrados en la alteración. Hasta nuestro conocimiento no hay otros casos publicados sobre síndrome de WB detectado por la técnica MLPA en la Argentina.

Williams-Beuren syndrome (WBS) is a rare developmental disorder characterized by distinctive facial, neurobehavioral, and cardiovascular features. WBS is caused by a heterozygous contiguous gene microdeletion of the WBS crítical region on chromosome 7q11.23. Confirmation of clinical suspicion is essential for clinical monitoring of the patient and genetic counseling of the family. Fluorescence in situ hybridization (FISH) is considered the gold standard technique for detecting WBS. Multiplex ligation-dependent probe amplification (MLPA) has been introduced into DNA diagnostic laboratories for the detection of copy number variations in several diseases including WBS. The objective of this study was to confirm, by MLPA, the clinical diagnosis of WBS in a pediatric patient. This technique allowed to detect the deletion of CYLN2, FZD9, STX1A, ELN, LIMK1 and RFC2 genes. In geographic regions were the detection by F ISH is not available for this disease, the MLPA methodology allowed to confirm the clinic diagnostic of WBS. To our knowledge this is the first report demonstrating the confirmation of WBS by MLPA in Argentina.

Síndrome de Williams: características clínicas de tres casos / Williams syndrome: clinical characteristics of three cases

El Síndrome de Williams (SW) es un síndrome genético generado por la deleción del gen de la Elastina y genes contiguos del cromosoma 7q11.23. Tiene una incidencia de 1:7500-20.000 recién nacidos vivos. Se caracteriza por un conjunto de síntomas y signos con compromiso multiorgánico y un fenotipo conductual distintivo. Objetivo: Describir la clínica del SW en relación a tres casos clínicos. Método: Estudio descriptivo retrospectivo de fichas clínicas de pacientes estudiados y tratados entre el 2006 y 2012. Resultados: Tres varones con rango de edad entre 4 y 6 años. Todos presentaron dismorfias características y se asociaron a cardiopatía congénita: estenosis aórtica supravalvular. En los rasgos de personalidad destacaron alta sociabilidad y habilidades en lenguaje expresivo, RM leve a moderado y mala coordinación motora. Conclusión: Todos nuestros pacientes presentaron características concordantes con las descritas para SW. Existen alteraciones funcionales cerebrales en pacientes con SW que tienen relación con el perfil cognitivo observado.

Williams Syndrome (WS) is a genetic disorder caused by deletion of elastine gene and contiguous genes of chromosome 7q11.2. It has an incidence of 1:7.500-20.000 newly born. It is characterized by a group of symptoms and signs with multiorganic involvement and a distinctive behavioural phenotype. Objective: To describe the clinical manifestations of WS in relation to three case reports. Method: review of clinical reports of patients diagnosed and treated between 2006 and 2012. Results: Three boys aged 5-9 years, all of them presented distinctive appearance, associated to congenital heart disease: aortic supravalvular stenosis. Behavioral features included high sociability and expressive language skills, mental retardation and poor motor coordination. Conclusions: All of our patients had clinical characteristics corresponding to the ones described for WS in the literature. The peculiar cognitive profile is presumed to be related to functional brain alterations described in WS.

Detection of deletions at 7q11.23 in Williams-Beuren syndrome by polymorphic markers

INTRODUCTION: Williams-Beuren syndrome (WBS; OMIM 194050) is caused by a hemizygous contiguous gene microdeletion at 7q11.23. Supravalvular aortic stenosis, mental retardation, overfriendliness, and ocular and renal abnormalities comprise typical symptoms in WBS. Although fluorescence in situ hybridization is widely used for diagnostic confirmation, microsatellite DNA markers are considered highly informative and easily manageable. OBJECTIVES: This study aimed to test the microsatellite markers for the diagnosis of Williams-Beuren syndrome, to determine the size and parental origin of microdeletion, compare the clinical characteristics between patients with different sizes of the deletion and parental origin. METHODS: We studied 97 patients with clinical diagnosis of Williams-Beuren syndrome using five microsatellite markers: D7S1870, D7S489, D7S613, D7S2476 and D7S489_A. RESULTS AND DISCUSSION: Using five markers together, the result was informative in all patients. The most informative marker was D7S1870 (78.4 percent), followed by D7S613 (75.3 percent), D7S489 (70.1 percent) and D7S2476 (62.9 percent). The microdeletion was present in 84 (86.6 percent) patients and absent in 13 (13.4 percent) patients. Maternal deletions were found in 52.4 percent of patients and paternal deletions in 47.6 percent of patients. The observed size of deletions was 1.55 Mb in 76/ 84 patients (90.5 percent) and 1.84 Mb in 8/84 patients (9.5 percent). SVAS as well as ocular and urinary abnormalities were more frequent in the patients with a deletion. There were no clinical differences in relation to either the size or parental origin of the deletion. CONCLUSION: Using these five selected microsatellite markers was informative in all patients, thus can be considered an alternative method for molecular diagnosis in Williams-Beuren syndrome.

Comparing Two Diagnostic Laboratory Tests for Several Microdeletions Causing Mental Retardation Syndromes: Multiplex Ligation-Dependent Amplification vs Fluorescent In Situ Hybridization / 대한진단검사의학회지

BACKGROUND: Microdeletion syndromes not detectable by conventional cytogenetic analysis have been reported to occur in approximately 5% of patients with unexplained mental retardation (MR). Therefore, it is essential to ensure that patients with MR are screened for these microdeletion syndromes. Mental retardation syndrome multiplex ligation-dependent probe amplification (MRS-MLPA) is a new technique for measuring sequence dosages that allows for the detection of copy number changes of several microdeletion syndromes (1p36 deletion syndrome, Williams syndrome, Smith-Magenis syndrome, Miller-Dieker syndrome, DiGeorge syndrome, Prader-Willi/Angelman syndrome, Alagille syndrome, Saethre-Chotzen syndrome, and Sotos syndrome) to be processed simultaneously, thus significantly reducing the amount of laboratory work. METHODS: We assessed the performance of MLPA (MRC-Holland, The Netherlands) for the detection of microdeletion syndromes by comparing the results with those generated using FISH assays. MLPA analysis was carried out on 12 patients with microdeletion confirmed by FISH (three DiGeorge syndrome, four Williams syndrome, four Prader-Willi syndrome, and one Miller-Dieker syndrome). RESULTS: The results of MLPA analysis showed a complete concordance with FISH in 12 patients with microdeletion syndromes. CONCLUSIONS: On the basis of these results, we conclude that MLPA is an accurate, reliable, and cost-effective alternative to FISH in the screening for microdeletion syndromes.

Williams Syndrome: development of a new scoring system for clinical diagnosis

OBJECTIVE: To develop a scoring system based on clinical findings to assist pediatricians in the diagnosis of William syndrome and to delineate when the fluorescent in-situ hybridization test to detect the microdeletion at 7q11.23 may be needed. METHODS: The fluorescent in-situ hybridization test was performed on 20 patients presenting William syndrome suggestive clinical features. Eleven studies were selected from the literature in which there were 2 groups: patients with positive or negative fluorescent in-situ hybridization tests. Forty-two clinical characteristics were compared to those reported in the literature to determine which ones were associated with the affected patients (ie, bearing deletions) using meta-analysis. The 2-tailed Fisher exact test were used so that the frequency of findings observed in fluorescent in-situ hybridization positive and fluorescent in-situ hybridization negative patients could be compared in the present study together with the patients from the literature. We developed a scoring system based on clinical findings and their significant associations with patients with positive fluorescent in-situ hybridization tests. From themean and standard-deviation values of the data from our patients, we determined the cut-off score that that indicated the need for a fluorescent in-situ hybridization test to confirm diagnosis. RESULTS: Seventeen patients were fluorescent in-situ hybridization positive, and 3 were fluorescent in-situ hybridization negative. The more discriminative findings among fluorescent in-situ hybridization positive patients were the following: typical facies, low birth weight, feeding difficulties, constipation, supravalvar aortic stenosis, mental retardation, and friendly personality. The distribution of the points among the 20 patients ranged from 19 to 28 points with a mean value of 23.3 out of a possible total of 31 points. The cut-off score that indicated the need for a fluorescent in-situ...

OBJETIVOS: Desenvolver um sistema de pontuação (Score) baseado nos achados clínicos para auxiliar os pediatras no diagnóstico clínico da Síndrome de Williams-Beuren e na indicação do teste de hibridização in situ por fluorescência para detectar a microdeleção em 7q11.23. MÉTODOS: O teste de hibridização in situ por fluorescência foi feito em 20 acometidos pela Síndrome de Williams-Beuren, nos quais 42 achados clínicos foram estudados. Para estabelecer quais desses achados estariam associados ao teste de hibridização in situ por fluorescência positivo, realizou-se uma metanálise com 11 trabalhos da literatura em que havia dois grupos, hibridização in situ por fluorescência positivo e negativo. As freqüências dos achados presentes nos indivíduos fluorescência positivo e fluorescência negativo neste estudo foram comparadas em conjunto com os pacientes da literatura através do teste exato de Fisher. Elaboramos um sistema de pontuação (score) baseado nos achados que mostraram correlação significante (p<0,001) para os pacientes hibridização in situ por fluorescência positivo. Determinamos os valores correspondentes aos percentis baseados na média e desvio-padrão, calculados a partir dos 20 pacientes do presente trabalho. RESULTADOS: Dezessete pacientes foram hibridização in situ por fluorescência positivo e três, negativo. Os achados mais discriminativos nos hibridização in situ por fluorescência positivo (3 pontos no score) foram: fáceis típico, baixo peso ao nascimento, dificuldades alimentares, obstipação, estenose aórtica supravalvar, deficiência mental e personalidade amigável.A distribuição dos valores entre os 20 pacientes variou de 19 a 28 pontos com uma média de 23,3 pontos. CONCLUSÕES: O score elaborado permitiu propor o valor de 20 pontos para a indicação do teste de hibridização in situ por fluorescência nos pacientes com suspeita clínica de Síndrome de Williams-Beuren.

Genética e linguagem na síndrome de Williams-Beuren: uma condição neuro-cognitiva peculiar / Genetics and language in Williams-Beuren syndrome: a distinct neurobehavioral disorder

TEMA: aspectos genéticos, cognitivos e de linguagem na Síndrome de Williams-Beuren (SWB). OBJETIVO: revisar a literatura sobre a SWB, destacando aspectos genéticos, cognitivos e de linguagem. CONCLUSÕES: a literatura mostrou que a etiologia da SWB é conhecida, embora o diagnóstico precoce pode ser difícil pela variabilidade de manifestações clínicas dessa condição. O fenótipo variável tem sido atribuído a deleção de vários genes na região 7q11.23. que inclui o gene da elastina. A deleção desse gene é identificada pelo estudo citogenético molecular denominado Hibridização in situ por Fluorescência (FISH). A freqüência populacional desta síndrome é de 1 em 20,000 nascimentos e é resultante de uma alteração genética "de novo". O quadro da SWB é caracterizado principalmente por fácies típica conhecida como face de duende, alterações cardíacas, prejuízos cognitivos e aspectos comportamentais que incluem a linguagem. A característica falante e sociável associada as dificuldades viso-construtivas conferem a esta síndrome um quadro neuro-cognitivo peculiar. A deficiência mental é variável e pode ou não estar presente. Estudos que descreveram as habilidades de linguagem nesta síndrome destacaram que a habilidade sintática pode estar íntegra ou parcialmente íntegra, a produção verbal pode ser precisa e inteligível, mostrando a integridade do sistema fonológico. O vocabulário receptivo-auditivo é citado em alguns estudos como adequado e em outros como prejudicado para a idade mental. Pesquisas na área têm produzido, resultados incongruentes com respeito ao perfil de habilidades cognitivas e lingüísticas nos portadores dessa condição. A correlação entre as habilidades de linguagem e a cognição e a divergência de achados na literatura serão abordadas neste artigo.

BACKGROUND: genetic, cognitive and language aspects of the Williams-Beuren Syndorme (WBS). AIM: to present a review of the literature about WBS, highlighting its genetic, cognitive and language characteristics. CONCLUSION: the literature indicates that although the etiology of WBS is known, early diagnosis is difficult due to the great variability of its clinical characteristics. This great phenotypic variability has been associated to a deletion of several genes in region 7q11.23 which includes the elastin gene. The deletion of this gene is identified by the Fluorecent in situ Hibridization test (FISH). The incidence of this syndrome is 1 in every 20,000 birth and is the result of a "de novo" genetic alteration. The syndrome is characterized by an elfin type face, cardiac alterations, cognitive deficits and behavioral aspects that include language. A peculiar cognitive profile has often been described as consisting of outstanding social and verbal skills associated to visuo-spatial impairments. Cognitive deficits are variable and may not be present. Studies that describe language abilities indicate that syntax might be intact or partially intact; speech can be precise and intelligible indicating that the phonological system is preserved. The receptive vocabulary is mentioned in a few studies as being adequate and in others as being impaired according to mental age. Researches have produced incongruent findings regarding the cognitive and linguistic abilities. The correlation between the language and cognitive abilities and the divergent findings presented in the literature will be discussed in this article.

Síndrome de Williams-Beuren: anomalias cardiovasculares em 20 pacientes diagnosticados pela hibridazação in situ por fluorescência / Williams-Beuren syndrome: cardiovascular abnormalities in 20 patients diagnosed with fluorescence in situ hybridization

OBJECTIVE: To evaluate the cardiovascular findings and clinical follow-up of patients with Williams-Beuren syndrome. METHODS: We studied 20 patients (11 males, mean age at diagnosis: 5.9 years old), assessed for cardiovascular abnormalities with electrocardiography and Doppler echocardiography. Fluorescence in situ hybridization (FISH) was used to confirm the diagnosis of the syndrome. RESULTS: Elastin gene locus microdeletion was detected in 17 patients (85 percent) (positive FISH), and in 3 patients deletion was not detected (negative FISH). Sixteen patients with a positive FISH (94 percent) had congenital cardiovascular disease (mean age at diagnosis: 2,3 years old). We observed isolated (2/16) supravalvular aortic stenosis and supravalvular aortic stenosis associated (11/16) with pulmonary artery stenosis (4/11); mitral valve prolapse (3/11); bicuspid aortic valve (3/11); aortic coarctation (2/11), thickened pulmonary valve (2/11); pulmonary valvular stenosis (1/11); supravalvular pulmonary stenosis (1/11); valvular aortic stenosis (1/11); fixed subaortic stenosis (1/11); pulmonary artery stenosis (2/16) associated with pulmonary valvar stenosis (1/2) and with mitral valve prolapse (1/2); and isolated mitral valve prolapse (1/16). Four patients with severe supravalvular aortic stenosis underwent surgery (mean age: 5.7 years old), and 2 patients had normal pressure gradients (mean follow-up: 8.4 years). CONCLUSION: A detailed cardiac evaluation must be performed in all patients with Williams-Beuren syndrome due to the high frequency of cardiovascular abnormalities

Hipertensäo arterial em criança portadora de síndrome de Williams-Beuren (deleçao cromossômica 7q11.23) / Arterial hypertension in a child with Williams-Beuren syndrome (7q11.23 chromosomal deletion)

We report the case of a 7-year-old male child diagnosed with Williams-Beuren syndrome and arterial hypertension refractory to clinical treatment. The diagnosis was confirmed by genetic study. Narrowing of the descending aorta and stenosis of the renal arteries were also diagnosed. Systemic vascular alterations caused by deletion of the elastin gene may occur early in individuals with Williams-Beuren syndrome, leading to the clinical manifestation of systemic arterial hypertension refractory to drug treatment

Síndrome de Williams: estudio clínico, citogenético, neurofisiológico y neuroanatómico / Williams syndrome: clinical, cytogenetic, neurophysiological and neuroanatomic features in 44 patients

Background: Williams syndrome (WS) is a genetically based disorder caused by deletion of elastin and contiguous genes on chromosome 7q11.23. This syndrome is characterized by multiorganic involvement with dysmorphic facial features and a distinctive cognitive profile. It is an interesting model for elucidation of relationships between brain, cognition and genes. Patients have a visual-spatial cognition impaired with relative strengths in social and language abilities. Aim: To report clinical, cytogenetic, neurophysiological and neuroanatomic features in 44 patients referred as WS. Patients and methods: Forty four patients, aged 2 to 17 years, with the clinical diagnosis of Williams syndrome were studied with fluorescence in situ hybridization (FISH). In three cases, electrophysiological and neuroimaging studies were performed. Result: The deletion was confirmed in 23 patients. In three patients with neurophysiological studies, event related potentials suggested a cognitive difficulty in detecting and processing visual stimuli. Magnetic resonance imaging showed normal brain morphology. SPECT showed hypoperfusion of the right frontal lobe and bilateral anterior cingulum hyperperfusion. Conclusions: There are functional alterations in the brains of patients with Williams, which may be related to the cognitive deficits

Genetics and cardiac anomalies: the heart of the matter.

The recent exponential increase in knowledge in genetics has revolutionized all aspects of medicine. The completion of the first draft of the human genome project has provided for clinicians a range and depth of information never before imagined. Over the last 25 years understanding the anatomical and physiological basis of a number of congenital cardiac anomalies has led to better care and outcome for the patients born with congenital cardiac defects. In the last decade the role of genes, their critical timing of expression, and understanding of important downstream pathways for optimizing normal development and control of the left right asymmetry have emerged. The progress in cardiac genetics has been supplemented by advances in cardiac imaging modalities leading to improvements in diagnosis of the cardiac anomalies. About 30% of all congenital heart diseases are associated with extra- cardiac malformations. Chromosomal anomalies are more common in patients with cardiac anomalies than the general population. Presence of facial dysmorphic features and associated extra-cardiac anomalies should alert the pediatricians to an underlying syndrome diagnosis. Newer molecular cytogenetics techniques such as fluorescence in situ hybridization (FISH) and molecular tests are now routinely utilized for confirming clinical diagnoses. In this review we have summarized clinical features and discussed the genetic basis of several syndromes (for example, 22q11 deletion syndrome, Williams syndrome, Down Syndrome, Kabuki syndrome etc.) where specific cardiac anomalies are frequently encountered. The importance of establishing an accurate clinical diagnosis cannot be over emphasized. The families need genetic counselling with accurate information on the recurrence risks. With the advent of the Internet and rapid access to information, the clinicians and the patient families can access valuable information regarding the prognosis, natural history, and clinical interventions for the affected child, and useful support groups for the family. Detection of cardiac anomalies during antenatal period warrants a genetics assessment.