General, verbal, and non-verbal cognitive functioning of children and adolescents with 22q11-2 deletion syndrome / Funcionamento cognitivo geral, verbal e não verbal de crianças e adolescentes com síndrome de deleção 22q11-2

BACKGROUND: Cognitive dysfunctions are frequently found in the 22q11.2 Deletion Syndrome, being an aggravating factor in the impairment of social relationships and communication, strongly impacting the functionality of the individual. Increasing the knowledge regarding cognitive skills may provide contributions to the diagnostic process and the intervention planning. OBJECTIVES: To estimate the general, verbal, and non-verbal cognitive functioning of children and adolescents with 22q11.2 Deletion Syndrome. METHODS: This is a cross-sectional, descriptive, and case series study regarding 15 individuals between 7-18 years-old diagnosed with 22q11.2 Deletion Syndrome. An assessment of the cognitive functions was performed using the Wechsler Abbreviated Scale of Intelligence (WASI). For data analysis we used a descriptive statistics analysis, having absolute frequencies for variables, and mean, median, standard deviation, minimum and maximum values for numerical variables. RESULTS: In the group analysis, we observed an important cognitive impairment degree. Most of the sampling (n=8; 53.33%) presented a considerably low total intelligence quotient score. Cases showing lower performances also presented greater difficulties regarding Visual Motor and Visuospatial coordination. Regarding the intelligence quotient representative punctuation in the WASI scale, the sample showed a large variability in the results (between 40 and 92 points), with the median total of 83. CONCLUSIONS: We observed important dysfunctions, cognitive difficulties, and intellectual, verbal, and non-verbal disabilities in the population studied. These findings indicate the need for an early intervention to assist not only the cognitive aspect, but also the socio-emotional development of children with the 22q11.2 Deletion Syndrome, aiming at their participation in society.

FUNDAMENTO: Disfunções cognitivas são frequentemente encontradas na Síndrome de Deleção 22q11.2, sendo um agravante no comprometimento das relações sociais e da comunicação, impactando fortemente na funcionalidade do indivíduo. O aumento do conhecimento sobre as habilidades cognitivas pode trazer contribuições no processo diagnóstico e no planejamento da intervenção. OBJETIVO: Estimar o funcionamento cognitivo geral, verbal e não verbal de crianças e adolescentes com Síndrome de Deleção 22q11.2. MÉTODOS: Estudo transversal, descritivo, tipo série de casos, com 15 indivíduos entre 7-18 anos com diagnóstico da Síndrome de Deleção 22q11.2. A avaliação das habilidades cognitivas foi realizada com a Escala Wechsler Abreviada de Inteligência (WASI). Para análise dos dados, foi utilizada análise estatística descritiva, com frequências absolutas para variáveis, e média, mediana, desvio padrão, mínima e máximo para variáveis numéricas. RESULTADOS: Na análise do grupo, observou-se um importante grau de comprometimento cognitivo. A maior parte da amostra (n=8; 53,33%) mostrou quociente de inteligência total extremamente baixo. Os casos com desempenhos mais baixos apresentaram maiores dificuldades em relação às habilidades de coordenação visuomotora e visuoespacial. Em relação à pontuação representativa do quociente de inteligência na escala WASI, a amostra apresentou uma grande variabilidade de resultados (entre 40 a 92 pontos), com mediana total de 83 pontos. CONCLUSÕES: As dificuldades cognitivas encontradas indicam a necessidade de uma intervenção precoce para auxiliar não só no desenvolvimento cognitivo, mas socioemocional de crianças com a Síndrome de Deleção 22q11.2 visando sua participação na sociedade.

Síndrome de DiGeorge/velocardiofacial: reporte de un caso / DiGeorge/velocardiofacial syndrome: a case report

El síndrome de DiGeorge, también conocido como síndrome velocardiofacial o síndrome de deleción 22q11, se caracteriza por la ausencia congénita del timo y la glándula paratiroides. La tríada clásica de este trastorno es cardiopatía congénita, endocrinopatía con hipocalcemia e inmunodeficiencia primaria. Sin embargo, el síndrome puede exhibir múltiples alteraciones y manifestaciones clínicas pleiotrópicas que, a menudo, resultan en dismorfismo facial y alteraciones en el paladar. Clínicamente se evidencia mayor susceptibilidad a infecciones respiratorias o gastrointestinales recurrentes y, en los casos de aplasia tímica, se requiere tratamiento con antibióticos profilácticos y trasplante tímico, mientras que en los demás se hace manejo expectante. En este manuscrito se presenta el caso de un paciente masculino de 18 meses de edad, remitido al servicio de genética por presentar diversas alteraciones fenotípicas. Se describe el proceso mediante el cual se llegó al diagnóstico de síndrome de DiGeorge, a su manejo y pronóstico, y se hace una breve revisión de la literatura

DiGeorge syndrome, also known as velocardiofacial syndrome or 22q11 deletion syndrome, is characterized by the congenital absence of the thymus and the parathyroid gland. The classic triad of this disorder is congenital heart disease, endocrinopathy with hypocalcemia and primary immunodeficiency. However, the syndrome may exhibit multiple pleotropic abnormalities and clinical manifestations that often result in facial dysmorphism and changes in the palate. Clinically, a high susceptibility to recurrent respiratory or gastrointestinal infections is observed. In cases of thymic aplasia, treatment with prophylactic antibiotics and thymic transplantation is necessary, while in others, expectant management is used. This manuscript presents the case of an 18-month old male patient, referred to the genetics service due to several phenotypic alterations. The process by which the Di- George syndrome diagnosis, management and prognosis was reached, as well as a brief review of the literature, are presented.

Aplicación de Hibridación In Situ Fluorescente (FISH) en pacientes con sospecha clínica de Síndrome de Deleción 22q11. 2 (SD22q11. 2) / Applying Fluorescent in situ hy-bridiza on (FISH) in patients with suspected clinical signs of 22q11. 2 dele on syndrome (DS22q11. 2)

El SD22q11.2 está asociado a síndromes de DiGeorge, velocardiofacial, facioconotruncal y Cayler, reconocidos con la misma etiología: microdeleción 22q11.2. El fenotipo es variable y presenta cardiopatía conotruncal (CC), dismorfias faciales, anomalías palatinas, inmunodeficiencias y trastornos del neurodesarrollo. Las manifestaciones endocrinológicas que predominan son talla baja, hipocalcemia neonatal asociada a hipoparatiroidismo y disfunción tiroidea. El 90% de los afectados presenta una deleción típica de 3-Mb, mientras que el resto tiene deleciones de menor tamaño o deleción localizada más distal a la región crítica . El objetivo del trabajo es identificar en una cohorte de 63 pacientes con sospecha clínica de SD22q11.2, la presencia de la microdeleción 22q11.2 empleando como método diagnóstico la técnica de FISH y describir brevemente las características clínicas más prevalentes que presentan los pacientes con resultado de FISH positivo y negativo. La microdeleción 22q11.2 se identificó en el 38% (24/63) de los pacientes estudiados. Las características clínicas más prevalentes en este grupo fueron las cardiopatías congénitas conotruncales (95,6%), microcefalia (50%), inmunodeficiencias (50%), hipocalcemia (48,8%), anomalías del paladar (45,8%), retraso del desarrollo y déficit cognitivo (41,5%). En nuestro hospital, el algoritmo diagnóstico para la detección de la microdeleción 22q11.2 es el cariotipo de alta resolución y el estudio por la técnica de FISH.

DS22q11.2 is associated with a wide spectrum of clinical disorders (DiGeorge, velocardiofacial, facioconotrunal and Cayler syndromes) known to arise from the same etiology 22q11.2 microdeletion The phenotype is variable and includes conotruncal cardiac defect (CCD), facial phenotype, palate anomalies, inmunodeficiency and developmental disorders. The endocrine manifestations are short stature (ST), neonatal hypocalcemia due to hypoparathyroidism, and thyroid dysfunction. In 90% of patients with 22q11.1 deletion a common 3-Mb deletion has been found, whereas the rest of cases share a smaller deletion or more distal atypical deletions. The aim of the present study was to identify the 22q11.2 microdeletion by FISH in 63 patients from the Genetic and Endocrinology Division between 2002 and 2017 who had more than one clinical feature of DS22q11. 2. High resolution karyotype and fluorescent in situ hybridization (FISH) were performed with different commercial probes. The 22q11.2 microdeletion was demonstrated in 24/63 patients (38%). The more relevant clinical features in this group were: conotruncal cardiac defect (95.6%), microcephaly (50%), immunodeficiency (50%), hypocalcaemia (48.8%) palate anomalies (45.8%), development delay and cognitive deficit (41.5%). In our hospital, the diagnostic algorithm for the detection of the 22q11.2 microdeletion is the high resolution karyotype and the study by the FISH technique.

22q11.2 deletion detected by in situ hybridization in Mexican patients with velocardiofacial syndrome-like features / Deleción 22q11.2 detectada por hibridación in situ en pacientes mexicanos con características clínicas similares al síndrome velocardiofacial

Abstract Introduction: Deletion 22q11.2 occurs in 1:4,000-1:6,000 live births while 10p13p14 deletion is found in 1:200,000 newborns. Both deletions have similar clinical features such as congenital heart disease and immunological anomalies. Objective: We looked for a 22q11.2 deletion in Mexican patients with craniofacial dysmorphisms suggestive of DiGeorge or velocardiofacial syndromes and at least one major phenotypic feature (cardiac anomaly, immune deficiency, palatal defects or development delay). Methods: A prospective study of 39 patients recruited in 2012-2015 at the Instituto Mexicano del Seguro Social at Guadalajara, Mexico. The patients with velocardiofacial syndrome-like features or a confirmed tetralogy of Fallot (TOF) or complex cardiopathy were studied by G-banding and fluorescence in situ hybridization (FISH) with a dual TUPLE1(HIRA)/ARSA or TUPLE1(22q11)/22q13(SHANK3) probe, six patients without the 22q11.2 deletion (arbitrarily selected) were tested with the dual DiGeorge II (10p14)/D10Z1 probe. Results: Twenty-two patients (7 males and 15 females) had the 22q11.2 deletion and 17/39 did not have it; no patient had a 10p loss. Among the 22 deleted patients, 19 had congenital heart disease (mostly TOF). Twelve patients without deletion had heart defects such as TOF (4/12), isolate ventricular septal defect (2/12) or other disorders (6/12). Conclusion: In our small sample about ~56% of the patients, regardless of the clinical diagnosis, had the expected 22q11.2 deletion. We remark the importance of early cytogenetic diagnosis in order to achieve a proper integral management of the patients and their families.

Resumen Introducción: La deleción 22q11.2 ocurre con una frecuencia de 1:4,000-1:6,000 nacidos vivos, mientras que la deleción 10p13p14 es detectada en 1:200,000 recién nacidos. Ambas deleciones comparten características clínicas similares tales como defectos cardiacos congénitos y anomalías inmunológicas. Objetivo: Identificar la deleción 22q11.2 en pacientes mexicanos con dismorfismo craneofacial sugestivo de síndrome DiGeorge o velocardiofacial y por lo menos con una característica clínica mayor (anomalía cardiaca, deficiencia inmunológica, defectos en paladar o retardo en el desarrollo) Métodos: Estudio prospectivo de 39 pacientes captados entre 2012-2015 en el Instituto Mexicano del Seguro Social en Guadalajara, México. Los pacientes con características clínicas sugerentes de síndrome velocardiofacial o diagnostico confirmado de tetralogía de Fallot (TOF) o cardiopatía compleja fueron estudiados por bandas G y por hibridación in situ fluorescente (FISH) con una sonda dual TUPLE1(HIRA)/ARSA o TUPLE1(22q11)/22q13(SHANK3), seis pacientes sin la deleción 22q11.2 (seleccionados arbitrariamente) fueron estudiados con la sonda dual DiGeorge II (10p14)/D10Z1. Resultados: Veintidós pacientes (7 hombres y 15 mujeres) tuvieron la deleción 22q11.2 y 17/39 no la tuvieron, ningún paciente tuvo la pérdida de 10p. Entre los 22 pacientes delecionados, 19 tuvieron defecto cardiaco congénito (principalmente TOF). Doce pacientes sin la deleción tuvieron defectos cardiacos congénitos como TOF (4/12), defecto del septo ventricular aislado (2/12) y otros trastornos cardiacos (6/12). Conclusión: En nuestra pequeña muestra, alrededor de ~56% de los pacientes, independientemente de su diagnostico clínico, tuvieron la deleción 22q11.2 esperada. Resaltamos la importancia del diagnóstico citogenético temprano para determinar un apropiado manejo integral para el paciente y sus familiares.

Early onset intellectual disability in chromosome 22q11.2 deletion syndrome / Inicio temprano de discapacidad intelectual en el Síndrome de deleción del cromosoma 22q11.2

Chromosome 22q11.2 deletion syndrome, or DiGeorge syndrome, or velocardiofacial syndrome, is one of the most common multiple anomaly syndromes in humans. This syndrome is commonly caused by a microdelection from chromosome 22 at band q11.2. Although this genetic disorder may reflect several clinical abnormalities and different degrees of organ commitment, the clinical features that have driven the greatest amount of attention are behavioral and developmental features, because individuals with 22q11.2 deletion syndrome have a 30-fold risk of developing schizophrenia. There are differing opinions about the cognitive development, and commonly a cognitive decline rather than an early onset intellectual disability has been observed. We report a case of 22q11.2 deletion syndrome with both early assessment of mild intellectual disabilities and tetralogy of Fallot as the only physic manifestation.

El síndrome del cromosoma 22q11.2, también conocido como supresión o síndrome de DiGeorge o síndrome velocardiofacial, es uno de los síndromes más comunes de anomalías múltiples en los seres humanos. Este síndrome es comúnmente causado por una microdeleción del cromosoma 22 en q11.2 banda. Aunque este trastorno genético muestra varias anomalías clínicas y diferentes grados de compromiso orgánico, las características clínicas que han atraído la mayor atención son el comportamiento y el desarrollo, porque las personas con síndrome de deleción 22q11.2 tienen un riesgo 30 veces mayor de desarrollar esquizofrenia. Hay diferentes opiniones sobre el desarrollo cognitivo, y comúnmente se se ha observado un deterioro cognitivo en lugar de un inicio temprano de discapacidad intelectual. Presentamos un caso de síndrome de deleción 22q11.2 tanto con la evaluación temprana de discapacidades intelectuales leves como con la tetralogía de Fallot como única manifestación física.

Alta prevalencia de hernias abdominales en pacientes con síndrome velocardiofacial / High incidence of abdominal wall hernias in patients with velocardiofacial syndrome

Velocardiofacial syndrome (VCFS) is due to a microdeletion on chromosome region 22q11.2. Clinically, it is characterized by congenital anomalies and psychiatric and cognitive manifestations. The most common structural defects are congenital heart disease and palatal anomalies, both due to abnormal development of the pharyngeal pouches. Another less studied manifestation is abdominal wall hernias. Objective: To characterize the frequency and types of hernias in patients with VCFS, and their association with congenital cardiopathies and palatine abnormalities. Patients and Methods: 202 patients were evaluated by direct clinical examination and questionnaire about their phenotypic characteristics. Results were compared to those found in the literature. Results: Age range was 0.5 to 48.4 years old (mean 11.9 years), 50.4 percent were females. Twenty two percent of patients had abdominal wall hernias. Of these, 49.1 percent were inguinal and 40.3 percent, umbilical. Conclusion: Patients with VCFS have a higher incidence of abdominal hernias than general population, described as approximately 5 percent. This is another common manifestation of the syndrome, not attributable to defects in development of pharyngeal pouches and with unknown pathogenesis.

El síndrome velocardiofacial (SVCF) se debe a una microdeleción en la región cromosómica 22q11.2. Clínicamente, se caracteriza por anomalías congénitas y manifestaciones siquiátricas y cognitivas. Entre las malformaciones más comunes, están las cardiopatías congénitas y anomalías palatinas, por defectos en el desarrollo de las bolsas faríngeas. Otra manifestación menos estudiada son las hernias de la pared abdominal. Objetivo: Caracterizar la frecuencia y tipos de hernias en pacientes con SVCF y su asociación con cardiopatías congénitas y anomalías del paladar. Pacientes y Método: Evaluamos 202 pacientes mediante un examen clínico directo y un cuestionario sobre sus características fenotípicas. Comparamos los resultados con la información de la literatura. Resultados: El rango de edad fue de 0,5 a 48,4 años (media de 11,9 años), 50,4 por ciento de sexo femenino. El 22 por ciento de los pacientes presentó hernias de la pared abdominal. De estas, el 49,1 por ciento fueron inguinales y el 40,3 por ciento, umbilicales. La frecuencia de hernias en los pacientes con SVCF es significativamente mayor que la descrita para la población general, aproximadamente un 5 por ciento. Esta es una manifestación común del síndrome, que no es atribuible a defectos del desarrollo de las bolsas faríngeas y cuya patogenia no ha sido definida.

Descripción de características clínicas del síndrome velocardiofacial / Velo-cardio-facial syndrome: a description of its clinical characteristics

Uno de los síndromes más frecuentes asociados a fisura palatina es el síndrome Velocardiofacial. Sus características involucran aspectos faciales, cardiológicos, psicológicos, ligüísticos y de aprendizaje, que deben ser abordados por equipos multiprofesionales. Internacionalmente el estudio de este síndrome se ha hizo masificando en forma progresiva. En nuestro país son escasos los grupos que manejan e intervienen en esta población. En este contexto es que se hace necesaria una revisión bibliográfica actualizada, que resuma los hallazgos clínicos y algunos aspectos de manejo multiprofesional, desde una perspectiva fonoaudiológica.

Velo-cardio-facial syndrome (VCFS) is one of the most frecuently associated syndromes to cleft palate. It comprises facial, cardiological, psychological, and linguistic disorders as well as learning difficulties which all must be addressed by a multi-professional team. The study of this syndrome has been systematically carried out around the world. In Chile, however, there are only few health-related professionals who work with this patient population. The present article aims at providing an up-to-date review, from a speech pathology point of view, on the clinical finding and on some aspects involved in the clinical management of VCFS.

Síndrome de deleção 22q11.2: compreendendo o CATCH22: [revisão] / 22q11.2 deletion syndrome: catching the CATCH22: [review]

OBJETIVO:Realizar uma revisão dos aspectos históricos, epidemiológicos, clínicos, etiológicos e laboratoriais da síndrome de deleção 22q11.2, salientando-se a importância e as dificuldades do seu diagnóstico. FONTES DE DADOS: Pesquisa nas bases de dados Medline, Lilacs e SciELO, além da Internet e capítulos de livros em inglês, acerca de publicações feitas entre 1980 e 2008. Para isso, utilizaram-se os descritores "22q11", "DiGeorge", "Velocardiofacial" e "CATCH22". SÍNTESE DOS DADOS: A síndrome de deleção 22q11.2, também conhecida como síndrome de DiGeorge ou velocardiofacial, foi identificada no começo da década de 1990. A microdeleção 22q11.2 é considerada uma das síndromes de microdeleção genética mais frequentes em seres humanos. Caracteriza-se por um espectro fenotípico bastante amplo, com mais de 180 achados clínicos já descritos do ponto de vista físico e comportamental. Contudo, nenhum achado é patognomônico ou mesmo obrigatório. A maioria dos pacientes apresenta uma deleção pequena, detectada somente por técnicas de genética molecular, como a hibridização in situ fluorescente. Apresenta padrão de herança autossômico dominante, ou seja, indivíduos acometidos apresentam um risco de 50 por cento de transmiti-la a seus filhos. CONCLUSÕES: Pacientes com a síndrome de deleção 22q11.2 frequentemente necessitam, ao longo de suas vidas, de um grande número de intervenções médicas e hospitalizações. O diagnóstico precoce é fundamental para a adequada avaliação e manejo clínico dos indivíduos e seus familiares.

OBJECTIVE:To review historical, epidemiological, clinical, etiological and laboratorial aspects of the 22q11.2 deletion syndrome, highlighting the importance of the diagnosis and its difficulties. DATA SOURCES: MedLine, Lilacs e SciELO databases, as well as internet and book chapters written in English, were searched for the period of 1980-2008, with the following descriptors "22q11", "DiGeorge", "Velocardiofacial" and "CATCH22". DATA SYNTHESIS: 22q11.2 deletion syndrome, also known as DiGeorge or velocardiofacial syndrome, was identified in the beginning of the 1990 decade. The 22q11.2 microdeletion is one of the most common human genetic microdeletion syndromes. It is characterized by a very broad phenotypic spectrum. More than 180 physical and behavioral clinical findings have already been described. However, none of them is characteristic or essential to diagnosis. The majority of the patients present a small deletion only detected by molecular genetic techniques as the fluorescent in situ hybridization. The deletion segregates in the families with an autosomal dominant pattern of inheritance, so the recurrence risk in the families is 50 percent. CONCLUSIONS: Individuals with 22q11.2 deletion syndrome have a great possibility to undergo medical interventions and hospitalizations throughout their lives. Early diagnosis is essential for the evaluation and clinical management of the patients and their families.