What Can Really Be Considered a Syndrome? An Insight Based on 16p11.2 Microduplication.

What is the definition of Syndrome? Since the beginning of studies in genetics, certain terminologies have been created and used to define groups of diseases or alterations. With the advancement of knowledge and the emergence of new technologies, the use of basic concepts is being done in a mistaken or often confusing way. Because of this, revisiting and readjusting the old terms becomes imminent. Here, we explore these concepts and their use, through a literature compilation of an already well-defined genetic alteration (16q11.2 microduplication). We bring comparisons in clinical and molecular scope of the alteration itself and its diagnostic methods, to improve the report of cases, rescuing terminologies and their applicability nowadays.

Contemporary Trends in Cardiac Surgical Care for Trisomy 13 and 18 Patients Admitted to Hospitals in the United States.

OBJECTIVE: To assess rates of cardiac surgery and the clinical and demographic features that influence surgical vs nonsurgical treatment of congenital heart disease (CHD) in patients with trisomy 13 (T13) and trisomy 18 (T18) in the United States. STUDY DESIGN: A retrospective study was performed using the Pediatric Health Information System. All hospital admissions of children (<18 years of age) with T13 and T18 in the United States were identified from 2003 through 2022. International Classifications of Disease (ICD) codes were used to identify presence of CHD, extracardiac comorbidities/malformations, and performance of cardiac surgery. RESULTS: Seven thousand one hundred thirteen patients were identified. CHD was present in 62% (1625/2610) of patients with T13 and 73% (3288/4503) of patients with T18. The most common CHD morphologies were isolated atrial/ventricular septal defects (T13 40%, T18 42%) and aortic hypoplasia/coarctation (T13 21%, T18 23%). Single-ventricle morphologies comprised 6% (100/1625) of the T13 and 5% (167/3288) of the T18 CHD cohorts. Surgery was performed in 12% of patients with T13 plus CHD and 17% of patients with T18 plus CHD. For all cardiac diagnoses, <50% of patients received surgery. Nonsurgical patients were more likely to be born prematurely (P < .05 for T13 and T18). The number of extracardiac comorbidities was similar between surgical/nonsurgical patients with T13 (median 2 vs 2, P = .215) and greater in surgical vs nonsurgical patients with T18 (median 3 vs 2, P < .001). Hospital mortality was <10% for both surgical cohorts. CONCLUSIONS: Patients with T13 or T18 and CHD receive surgical palliation, but at a low prevalence (≤17%) nationally. Given operative mortality <10%, opportunity exists perhaps for quality improvement in the performance of cardiac surgery for these vulnerable patient populations.

Epidemiological Assessment of a Pediatric Palliative Care Clinic at a Brazilian Quaternary Hospital: 20 Years of Experience.

Background: The pediatric palliative care (PPC) sets up an interdisciplinary approach of chronic complex diseases throughout birth to adolescence. It encompasses countless contrasts in development and diagnosis scopes, which make this area a challenge to nonpediatric practitioners. Objective: We sought to assess the most prevalent diseases in follow-up of the PPC team. Methods: We analyzed the medical records of PPC clinic during the years 2001 and 2021 and the diagnosis of outpatients. We established a parallel with the world scientific literature concerning the epidemiology of PPC. Results: The most prevalent diseases were epidermolysis bullosa (36.9%), followed by neurological Inherited Errors of Metabolism (IEM) diseases (19.0%), IEM diseases (14.3%), dysmorphological and chromosomal disorders (8.5%), skeletal disorders mainly osteogenesis imperfecta (6.9%), and liver transplantation conditions (5.5%) (p < 0.001). The less frequent conditions were external causes, such as neonatal insults or traffic accidents (2.8%), cancer (1.7%), congenital cardiopathies (1.4%), congenital infectious diseases (1.1%), gastrointestinal and hepatic conditions (0.8%), and rheumatological conditions (0.3%). The patients were older at diagnosis (6.9 years) and at PPC referral (13.2 years) than patients with epidermolysis bullosa and skeletal disorders and dysmorphological and chromosomal disorders were younger on referral. Conclusion: There are a lot of complex chronic conditions which could benefit from palliative care in pediatric setting. However, epidemiological and symptomatological assessment of the health service is necessary to provide an appropriate care to the country's reality.

Avaliação e ensino de emoções com crianças e jovens adultos com autismo ou síndrome de down mediado pela família / Assessment and teaching of emotions with children and young adults with autism or down syndrome mediated by family / Evaluación y enseñanza de las emociones con niños y jóvenes con autismo o síndrome de down mediadas por la familia

Este estudo avaliou o reconhecimento (imitação, identidade e identificação) e a nomeação de estímulos emocionais de valência negativa (raiva e tristeza) e positiva (alegria e surpresa) em conjunto com a influência dos tipos de estímulos utilizados (social-feminino, social-masculino, familiar e emoji) em crianças e jovens adultos com autismo ou síndrome de Down, por meio de tarefas aplicadas pela família e mediadas por recursos tecnológicos durante a pandemia de covid-19. Participaram cinco crianças e dois jovens adultos com autismo e uma criança e dois jovens adultos com síndrome de Down. Foram implementadas tarefas de identidade, reconhecimento, nomeação e imitação, com estímulos faciais de função avaliativa (sem consequência diferencial) e de ensino (com consequência diferencial, uso de dicas e critério de aprendizagem), visando a emergência da nomeação emocional por meio do ensino das tarefas de reconhecimento. Os resultados da linha de base identificaram que, para os participantes que apresentaram menor tempo de resposta para o mesmo gênero, a diferença de tempo de resposta foi em média 57,28% menor. Em relação à valência emocional, 50% dos participantes apresentaram diferenças nos acertos, a depender da valência positiva e negativa, sendo que 66,66% apresentaram diferenças para o tempo de resposta a depender da valência emocional. Após o procedimento de ensino, os participantes mostraram maior número de acertos nas tarefas, independentemente do gênero de estímulo e valência emocional, criando ocasião para generalização da aprendizagem de reconhecimento e nomeação de emoções, além de consolidar a viabilidade de estratégias de ensino mediadas por recursos tecnológicos e aplicadas por familiares.(AU)

This study evaluated the recognition (imitation, identity, and identification) and naming of negative (anger and sadness) and positive (joy and surprise) emotional stimuli alongside the influence of the types of stimuli (social-female, social-male, family, and emoji) in children and young adults with autism and Down syndrome, via tasks applied by the family and mediated by technological resources, during the COVID-19 pandemic. Five children and two young adults with autism and one child and two young adults with Down syndrome participated. Identity, recognition, naming, and imitation tasks were planned and implemented using facial stimuli with evaluative (without differential consequence) and teaching (with differential consequence, tips, and learning criteria) functions, aiming at the emergence of emotional naming from the recognition teaching tasks. The baseline results showed that, for participants who had a shorter response time for the same gender, the response time difference was on average 57.28% lower. Regarding the emotional valence, 50% of the participants showed differences in the correct answers, depending on the positive and negative valence, and 66.66% showed differences in the response time depending on the emotional valence. After the teaching procedure, the participants showed a greater number of correct answers in the tasks, regardless of the stimulus type and emotional valence, creating an opportunity for generalizing learning of emotion recognition and naming, in addition to consolidating the feasibility of teaching strategies mediated by technological resources and applied by family members.(AU)

Este estudio evaluó el reconocimiento (imitación, identidad e identificación) y la denominación de estímulos emocionales negativos (enfado y tristeza) y positivos (alegría y sorpresa) y la influencia de los tipos de estímulos utilizados (social-femenino, social-masculino, familiar y emoji ) de niños y jóvenes con autismo o síndrome de Down, a través de tareas aplicadas por la familia, mediadas por recursos tecnológicos durante la pandemia de la covid-19. Participaron cinco niños y dos adultos jóvenes con autismo, y un niño y dos adultos jóvenes con síndrome de Down. Se planificaron e implementaron tareas de identidad, reconocimiento, nombramiento e imitación con estímulos faciales con función evaluativa (sin consecuencia diferencial) y enseñanza (con consecuencia diferencial, uso de ayudas y criterios de aprendizaje), buscando la emergencia del nombramiento emocional después de la enseñanza de tareas de reconocimiento. Los resultados de la línea de base identificaron que para los participantes que tenían un tiempo de respuesta más corto para el mismo género, la diferencia en el tiempo de respuesta fue un 57,28% menor. En cuanto a la valencia emocional, el 50% de los participantes mostraron diferencias en las respuestas correctas, en función de la valencia positiva y negativa, y el 66,66% tuvieron diferencias en el tiempo de respuesta, en función de la valencia emocional. Después del procedimiento de enseñanza, los participantes mostraron mayor número de aciertos en las tareas evaluadas, independientemente del tipo de estímulo o valencia emocional, lo que genera una oportunidad para la generalización del aprendizaje de reconocimiento y denominación de emociones, además de consolidar la viabilidad de estrategias de enseñanza mediadas por recursos tecnológicos y aplicadas por la familia.(AU)

Patau and Edwards Syndromes in a University Hospital: beyond palliative care.

OBJECTIVE: To describe the newborn population with Patau (T13) and Edwards Syndrome (T18) with congenital heart diseases that stayed in the Intensive Care Unit (ICU) of a quaternary care hospital complex, regarding surgical and non-surgical medical procedures, palliative care, and outcomes. METHODS: Descriptive case series conducted from January/2014 to December/2018 through analysis of records of patients with positive karyotype for T13 or T18 who stayed in the ICU of a quaternary hospital. Descriptive statistics analysis was applied. RESULTS: 33 records of eligible patients were identified: 27 with T18 (82%), and 6 T13 (18%); 64% female and 36% male. Eight were preterm infants with gestational age between 30-36 weeks (24%), and only 4 among the 33 infants had a birth weight >2500 g (12%). Four patients underwent heart surgery and one of them died. Intrahospital mortality was 83% for T13, and 59% for T18. The majority had other malformations and underwent other surgical procedures. Palliative care was offered to 54% of the patients. The median hospitalization time for T18 and T13 was 29 days (range: 2-304) and 25 days (13-58), respectively. CONCLUSIONS: Patients with T13 and T18 have high morbidity and mortality, and long hospital and ICU stays. Multicentric studies are needed to allow the analysis of important aspects for creating protocols that, seeking therapeutic proportionality, may bring better quality of life for patients and their families.

Identification of 17q12 microdeletion syndrome in a Latin American patient with maturity-onset diabetes of the young subtype 5: a case report.

BACKGROUND: Maturity-onset diabetes of the young comprises a large group of autosomal inherited gene mutations. Maturity-onset diabetes of the young subtype 5 is caused by mutations in the HNF1B gene. This gene is expressed in the early phase of embryonic development in the pancreas, kidneys, liver, and genital tract; therefore, kidney or urinary tract malformations are associated with diabetes mellitus. The 17q12 deletion syndrome is a cause of maturity-onset diabetes of the young subtype 5 that should be considered. CASE PRESENTATION: We present the case of a 35-year-old Hispanic female patient with a history of bicornuate uterus and polycystic renal disease that required kidney transplant. She had insulin-dependent diabetes, with her mother, maternal grandmother, and great-grandmother showing a similar clinical manifestation. Molecular analysis showed a deletion in chromosome 17q12 involving 15 genes, including HNF1B. Therefore, a diagnosis of deletion syndrome was made. CONCLUSIONS: The 17q12 deletion syndrome represents a rare genetic syndrome that involves different genes, including HNF1B. Principally, it is characterized by the combination of genitourinary tract malformations and diabetes mellitus, similar to our patient.

Behavior of the Genetic Markers at Screening during the First Trimester of Pregnancy in Euploid Fetuses.

OBJECTIVE: This study aims to describe the behavior of chromosomopathy screenings in euploid fetuses. METHODS: This is a prospective descriptive study with 566 patients at 11 to 14 weeks of gestation. The associations between ultrasound scans and serological variables were studied. For the quantitative variables we used the Spearman test; for the qualitative with quantitative variables the of Mann-Whitney U-test; and for qualitative variables, the X2 test was applied. Significance was set at p ≤ 0.05. RESULTS: We have found that gestational age has correlation with ductus venosus, nuchal translucency, free fraction of ß subunit of human chorionic gonadotropin, pregnancy-associated plasma protein-A and placental growth factor; there is also a correlation between history of miscarriages and nasal bone. Furthermore, we correlated body mass index with nuchal translucency, free fraction of ß subunit of human chorionic gonadotropin, and pregnancy-associated plasma protein-A. Maternal age was associated with free fraction of ß subunit of human chorionic gonadotropin and pregnancy-associated plasma protein-A. CONCLUSION: Our study demonstrates for the first time the behavior of the biochemical and ultrasonographic markers of chromosomopathy screenings during the first trimester in euploid fetuses in Colombia. Our information is consistent with international reference values. Moreover, we have shown the correlation of different variables with maternal characteristics to determine the variables that could help with development of a screening process during the first trimester with high detection rates.

OBJETIVO: Este estudo tem como objetivo descrever o comportamento do rastreamento de cromossomopatias em fetos euploides. MéTODOS: Trata-se de um estudo prospectivo descritivo com 566 pacientes, entre 11 e 14 semanas de gestação. A associação entre a ultrassonografia e as variáveis sorológicas foi estudada. Para as variáveis quantitativas foi utilizado o teste de Spearman; para as qualitativas com variáveis quantitativas foi utilizado o teste U de Mann-Whitney e para as variáveis qualitativas foi aplicado o teste X2. A significância foi fixada em p ≤ 0,05. RESULTADOS: Constatou-se que a idade gestacional tem correlação com o ducto venoso, translucência nucal, fração livre da subunidade ß da gonadotrofina coriônica humana, proteína plasmática A associada à gravidez e fator de crescimento placentário; há também correlação entre a história de abortos e o osso nasal. Além disso, correlacionamos o índice de massa corporal com translucência nucal, fração livre da subunidade ß da gonadotrofina coriônica humana e proteína plasmática A associada à gravidez. A idade materna foi relacionada com fração livre da subunidade ß da gonadotrofina coriônica humana e proteína plasmática A associada à gravidez. CONCLUSãO: Nosso estudo demonstra pela primeira vez o comportamento dos marcadores bioquímicos e ultrassonográficos de triagem de cromossomas durante o primeiro trimestre em fetos euploides na Colômbia. Nossa informação é consistente com a referência de valores internacionais. Além disso, mostram-se as relações das diferentes variáveis com as características maternas para determinar as variáveis capazes de ajudar no desenvolvimento de um processo de rastreamento durante o primeiro trimestre com alta taxa de detecção.

Clinical and Genetic Aspects of Phelan-McDermid Syndrome: An Interdisciplinary Approach to Management.

Phelan-McDermid syndrome (PMS) is a rare, heterogeneous, and complex neurodevelopmental disorder. It is generally caused by a heterozygous microdeletion of contiguous genes located in the distal portion of the long arm of chromosome 22, including the SHANK3 gene. Sequence variants of SHANK3, including frameshift, nonsense mutations, small indels and splice site mutations also result in PMS. Furthermore, haploinsufficiency in SHANK3 has been suggested as the main cause of PMS. SHANK3 is also associated with intellectual disability, autism spectrum disorder and schizophrenia. The phenotype of PMS is variable, and lacks a distinctive phenotypic characteristic, so the clinical diagnosis should be confirmed by genetic analysis. PMS is a multi-system disorder, and clinical care must encompass various specialties and therapists. The role of risperidone, intranasal insulin, insulin growth factor 1, and oxytocin as potential therapeutic options in PMS will be discussed in this review. The diagnosis of PMS is important to provide an appropriate clinical evaluation, treatment, and genetic counseling.

Teste citogenético por Hibridização in Situ por Fluorescência (FISH) para detecção de alterações citogenéticas de alto risco em pacientes com mieloma múltiplo / Cytogenetic test by Hybridization in Situ by Fluorescence (FISH) for detection of alterations High-risk cytogenetics in patients with multiple myeloma

INTRODUÇÃO: O mieloma múltiplo é uma neoplasia dos plasmócitos. Essas células neoplásicas proliferam na medula óssea impedindo o funcionamento das demais células hematológicas. As células neoplásicas produzem uma imunoglobulina monoclonal (proteína M) que é importante na fisiopatologia e no diagnóstico dessa doença. O mieloma múltiplo geralmente acomete adultos acima de 60 anos e estima-se que no Brasil a sua incidência anual esteja próximo à 1,2 indivíduos para cada 100.000 habitantes, com elevada letalidade. As manifestações clínicas mais comuns são dores ósseas, anemia e infecções recorrentes. As alterações mais comuns em exames de imagem e de laboratório incluem lesões líticas nos ossos, exames associados com insuficiência renal, hipercalcemia e anemia, além do achado da proteína M. Determinadas alterações citogenéticas estão associadas com o tratamento que deve ser instituído para o paciente e com o seu prognóstico. As alterações cromossômicas estudadas foram: t(4;14), del(17p13) e t(14;16). TECNOLOGIA: Citogenética por Hibridização in Situ por Fluorescência (FISH). PERGUNTA: Deve-se utilizar a citogenética por Hibridização In Situ por Fluorescência (FISH) versus citogenética convencional para detectar as alterações t(4:14), del(17p13) e t(14:16) em pacientes com mieloma múltiplo? EVIDÊNCIAS CLÍNICAS: Foi realizada busca de estudos que avaliassem a tecnologia nas bases de dados Embase, Medline (via Pubmed), Cochrane Library e LILACS. Após a triagem de 1346 relatos, 11 estudos observacionais foram selecionados. Nos domínios do QUADAS-2, a maioria dos estudos apresentou risco de viés incerto, exceto para o domínio Fluxo e Temporalidade, em que 81,8% dos estudos apresentaram baixo risco de viés. Os estudos incluídos analisaram uma amostra de 781 pacientes com mieloma múltiplo. Destes, 653 foram avaliadas pelo FISH e 719 pela citogenética convencional. A t(4;14) foi detectada em 11,3% (58/518) das amostras por FISH e 0,17% (1/607) por citogenética convencional. Os resultados da meta-análise mostraram que o FISH aumentou em 12% a detecção da t(4;14) quando comparado a citogenética convencional (RD: 0,12 [IC 95%: 0,06-0,19]; p < 0,0001; I2 : 52%). Em relação à del(17p13), esta foi detectada em 12,2% (80/653) das amostras por FISH e 1,6% (10/607) por citogenética convencional. O FISH aumentou em 12% a detecção da del(17p13) em comparação à citogenética convencional (RD: 0,12 [IC 95%: 0,04-0,20]; p < 0,0001; I 2 : 77%). Por fim, a t(14;16) foi detectada em 0,42% (2/478) das amostras por FISH e 0,17% (1/607) por citogenética convencional. Não houve diferença entre o FISH e a citogenética convencional para detecção da t(14;16) (RD: 0,00 [IC 95%: -0,01-0,02]; p = 0,41; I2 : 0%). A qualidade da evidência, avaliada pelo GRADE, foi considerada muito baixa para todos os desfechos avaliados. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: Foram elaborados dois cenários, proposto e alternativo, considerando as estratégias de estadiamento incluindo FISH e citogenética convencional, variando a porcentagem de pacientes submetidos ao teste citogenético por FISH. A incorporação do FISH para o estadiamento dos pacientes com mieloma múltiplo pode provocar um incremento orçamentário em R$239.206,38 para o primeiro ano (2022), atingindo R$1.246.915,77 no quinto ano (2026), quando inicialmente 5% dos pacientes são submetidos ao FISH e ocorre aumento progressivo de 5% ao ano. O impacto em cinco anos seria de R$ 3.691.966,50. Quando inicialmente 10% dos pacientes diagnosticados com mieloma múltiplo são estadiados por meio do FISH, com o aumento progressivo de 10% ao ano, mantendo-se porcentagem constante para a citogenética convencional, o impacto orçamentário incremental seria de R$478.412,76 para o primeiro ano (2022), atingindo R$2.493.831,54 no quinto ano de incorporação (2026), sendo o valor acumulado em cinco anos de R$ 7.383.933,00. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: As pesquisas nas bases de dados para monitoramento do horizonte tecnológico identificaram três modelos de sonda para o painel FISH em pacientes com mieloma múltiplo no FDA. No Clinical Trials nenhuma nova tecnologia para avaliação citogenética foi identificada. Em relação ao depósito de patentes, foi encontrado um depósito patentário chinês do ano de 2019. PERSPECTIVA DO PACIENTE: Foi aberta chamada pública conjunta para Perspectiva do Paciente durante o período de 18/10/2021 a 24/10/2021, que contou com quinze inscrições, sendo o representante definido por consenso do grupo. No relato, o participante descreveu aspectos da sua vivência como paciente com mieloma múltiplo, destacando a rapidez na obtenção de diagnóstico, a realização do transplante de medula óssea e o uso de diferentes tecnologias durante o tratamento.  Além disso, informou ter tido boa resposta terapêutica à lenalidomida durante cinco anos, em virtude da progressão da doença depois desse intervalo temporal, passou a utilizar protocolo com daratumumabe, apresentando melhora geral do quadro clínico. CONSIDERAÇÕES FINAIS: O teste FISH já é realizado pelo Sistema Único de Saúde (SUS) no diagnóstico de outras doenças. Neste Relatório, foi analisado a ampliação de uso deste exame para o diagnóstico de mieloma múltiplo. Pelos achados desta revisão, o teste FISH foi superior à citogenética convencional no diagnóstico das alterações citogenéticas t(4;14) e del(17p13), que são alterações relativamente frequentes e relevantes para o tratamento e o prognóstico dos pacientes com esse tipo de câncer. A alteração t(14;16), por ter baixa prevalência nos pacientes com esse tipo de câncer, demanda que ela seja analisada em uma amostra maior de indivíduos para que seja evidenciada uma diferença significativa entre os dois métodos. No Brasil, os laboratórios de referência para doenças raras possuem a infraestrutura necessária para a realização dos exames e seria necessária a ampliação do uso por meio do SUS. Do ponto de vista da implementação, a capacitação de recursos humanos é um fator de extrema importância, uma vez que a maioria destes laboratórios, atualmente, não possui pessoal capacitado especificamente para analisar amostras de pacientes com mieloma múltiplo. As agências internacionais NICE e CADTH recomendam a realização do FISH como parte dos exames diagnósticos necessários para o estadiamento citogenético e a tomada de decisão quanto a estratégia terapêutica a ser empregada diante da classificação de risco dos pacientes com mieloma múltiplo. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros do Plenário presentes na 104ª Reunião da Conitec, no dia 08 de dezembro de 2021, deliberaram, por unanimidade, sem nenhum conflito de interesses, que a matéria fosse disponibilizada em consulta pública com recomendação preliminar favorável à ampliação de uso do teste citogenético por Hibridização in Situ por Fluorescência (FISH) na detecção de alterações citogenéticas de alto risco em pacientes com mieloma múltiplo. CONSULTA PÚBLICA: Por meio da Consulta Pública nº 116/2021, realizada entre os dias 27/12/2021 e 17/01/2022, foram recebidas 73 contribuições, todas favoráveis à ampliação do uso do FISH para detecção de alterações moleculares de alto risco em pacientes com mieloma múltiplo. As evidências científicas apresentadas reforçaram a importância do FISH enquanto método de identificação destas alterações moleculares, para as quais a citogenética convencional possui baixa sensibilidade. Na avaliação econômica e de impacto orçamentário, foram apontadas possibilidades de redução do custo do exame com a utilização de menor número de sondas de hibridização, dependendo do nível de treinamento dos profissionais. Pacientes e associações enfatizaram a necessidade de garantir o acesso ao exame pelo SUS e, como pontos negativos, o alto custo do exame na rede privada e a indisponibilidade atual do exame no sistema público de saúde. RECOMENDAÇÃO FINAL DA CONITEC: Os membros do Plenário presentes na 105ª Reunião da Conitec, no dia 09/02/2022, deliberaram, por unanimidade, sem nenhuma declaração de conflito de interesses, recomendar a ampliação de uso do teste citogenético por Hibridização in Situ por Fluorescência (FISH) na detecção de alterações citogenéticas de alto risco em pacientes com mieloma múltiplo. Foi assinado o Registro de Deliberação nº 695/2022. DECISÃO: Ampliar o uso do teste citogenético por Hibridização in Situ por Fluorescência (FISH) na detecção de alterações citogenéticas de alto risco em pacientes com mieloma múltiplo, no âmbito do Sistema Único de Saúde ­ SUS, conforme a Portaria nº 20, publicada no Diário Oficial da União nº 49, seção 1, página 95, em 14 de março de 2022.

High-level mosaic monosomy 21 in a 13-year-old girl: Case report and review of the literature.

Monosomy 21 is an exceedingly rare and fatal chromosomal anomaly. Mosaic monosomy 21, however, can be observed in living patients. There have been discussions on whether there are liveborn cases with true mosaic full monosomy 21. Here, we report the case of a 13-year-old patient with mosaic full monosomy 21 who presented with postnatal microcephaly, low weight, facial dysmorphisms, developmental delay, and severe intellectual disability. To the best of our knowledge, this is the oldest patient with mosaic full monosomy 21 described so far and the first reported in Brazil.

Reporte de malformaciones fetales diagnosticadas en comité ecográfico del Hospital Regional de Talca, entre junio 2020 y junio 2021 / Report of fetal malformations diagnosed in the ultrasound committee of the regional hospital of Talca, between june 2020 and june 2021

Introduction: Obstetric ultrasound is part of the screening to select the population at high risk of having a congenital malformation. Considering that fetal defects occur in approximately 2-4 out of every 100 live newborns, and are the cause of 35-40% of perinatal mortality in Chile, it is therefore justified to perform the second trimester ultrasound, which presents a high index prenatal screening (56%), with few false positives. Methods: A retrospective, cross-sectional and descriptive study was carried out, by reviewing 6,385 ultrasound scans, which were performed during one year (June 2020-June 2021), at the Regional Hospital of Talca, where 126 fetuses with suspected malformation were detected. Results: Of the total number of patients evaluated, a congenital malformation rate of 1.9% was detected, with cardiac malformations the most frequent, and diabetes mellitus the main risk factor. Conclusions: Antenatal ultrasound study is essential in the first and second trimesters of pregnancy, followed by a referral to an ultrasound committee, emphasizing early and interdisciplinary management. The frequencies found are similar to those reported in the international bibliography

Uleritema ofriógenes como entidad asociada al síndrome 18p- en un paciente pediátrico / Ulerythema ophryogenes as an entity associated with 18p- syndrome in a pediatric patient

El uleritema ofriógenes es un trastorno cutáneo benigno y poco frecuente que se presenta habitualmente en la infancia. Se caracteriza por pápulas foliculares eritematosas y queratósicas en el lateral de las cejas, que con el tiempo suelen evolucionar a alopecia cicatricial. Dicha entidad puede aparecer como manifestación clínica aislada o asociada a varios síndromes congénitos (18p-, Cornelia de Lange, Noonan y Rubinstein- Taybi, entre otros). Presentamos el caso de un paciente de 13 años con síndrome 18p- que consultó por lesiones puntiformes rugosas al tacto y pérdida de pelo en ambas cejas (uleritema ofriógenes), así como por hiperqueratosis pilar en brazos. Esta tríada, conocida como síndrome de Zouboulis, ha sido poco descrita en la literatura. Se considera que el reconocimiento del uleritema ofriógenes es de crucial importancia ya que, ante su presencia, debería realizarse una anamnesis y una exploración física exhaustivas en búsqueda de otras alteraciones que pudieran orientar a la existencia de un trastorno genético subyacente.

Ulerythema ophryogenes is a benign and rare skin disorder commonly presenting in childhood. It is characterized by erythematous and keratotic follicular papules located on the side of the eyebrows, and which over time tends to evolve into scarred alopecia. This entity may appear as an isolated clinical manifestation or associated with several congenital syndromes (18p-, Cornelia de Lange, Noonan, Rubinstein-Taybi, among others). We present a 13-year-old male with 18p- syndrome who consults for rough lesions and hair loss in both eyebrows (ulerythema ophryogenes), as well as for hyperkeatosis pilaris in both arms. This triad, known as Zouboulis syndrome, has been rarely reported in the literature. We consider that the recognition of ulerythema ophryogenes is of crucial importance since, in view of its presence, comprehensive anamnesis and physical examination should be performed in search of other alterations that could guide the existence of an underlying genetic disord

[Ulerythema ophryogenes as an entity associated with 18p- syndrome in a pediatric patient]. / Uleritema ofriógenes como entidad asociada al síndrome 18pen un paciente pediátrico.

Ulerythema ophryogenes is a benign and rare skin disorder commonly presenting in childhood. It is characterized by erythematous and keratotic follicular papules located on the side of the eyebrows, and which over time tends to evolve into scarred alopecia. This entity may appear as an isolated clinical manifestation or associated with several congenital syndromes (18p-, Cornelia de Lange, Noonan, Rubinstein- Taybi, among others). Uleritema ofriógenes como entidad asociada al síndrome 18pen un paciente pediátrico Ulerythema ophryogenes as an entity associated with 18p- syndrome in a pediatric patient We present a 13-year-old male with 18p- syndrome who consults for rough lesions and hair loss in both eyebrows (ulerythema ophryogenes), as well as for hyperkeatosis pilaris in both arms. This triad, known as Zouboulis syndrome, has been rarely reported in the literature. We consider that the recognition of ulerythema ophryogenes is of crucial importance since, in view of its presence, comprehensive anamnesis and physical examination should be performed in search of other alterations that could guide the existence of an underlying genetic disorder.

El uleritema ofriógenes es un trastorno cutáneo benigno y poco frecuente que se presenta habitualmente en la infancia. Se caracteriza por pápulas foliculares eritematosas y queratósicas en el lateral de las cejas, que con el tiempo suelen evolucionar a alopecia cicatricial. Dicha entidad puede aparecer como manifestación clínica aislada o asociada a varios síndromes congénitos (18p-, Cornelia de Lange, Noonan y Rubinstein- Taybi, entre otros). Presentamos el caso de un paciente de 13 años con síndrome 18p- que consultó por lesiones puntiformes rugosas al tacto y pérdida de pelo en ambas cejas (uleritema ofriógenes), así como por hiperqueratosis pilar en brazos. Esta tríada, conocida como síndrome de Zouboulis, ha sido poco descrita en la literatura. Se considera que el reconocimiento del uleritema ofriógenes es de crucial importancia ya que, ante su presencia, debería realizarse una anamnesis y una exploración física exhaustivas en búsqueda de otras alteraciones que pudieran orientar a la existencia de un trastorno genético subyacente.

A child with cat-eye syndrome and oculo-auriculo-vertebral spectrum phenotype: A discussion around molecular cytogenetic findings.

Cat eye syndrome (CES) is a rare chromosomal disorder that may be evident at birth. A small supernumerary chromosome is present, frequently has 2 centromeres, is bisatellited, and represents an inv dup(22)(q11) in those affected. It's known that the 22q11 region is associated with disorders involving higher and lower gene dosages. Conditions such as CES, 22q11 microduplication syndrome (Dup22q11) and oculoauriculovertebral spectrum phenotype (OAVS) may share genes belonging to this same region, which is known to have a predisposition to chromosomal rearrangements. The conditions, besides being related to chromosome 22, also share similar phenotypes. Here we have added a molecular evaluation update and results found of the first patient described with CES and OAVS phenotype, trying to explain the potential mechanism involved in the occurrence of this association.

Síndrome de Rubinstein ­ Taybi: características fenotípicas, reporte de caso / Rubinstein - Taybi syndrome: phenotypic characteristics, case report / Síndrome de Rubinstein - Taybi: características fenotípicas, relato de caso

Introducción: El síndrome de Rubinstein ­ Taybi es una patología de origen genético que afecta a 1 de cada 100.000 a 125.000 nacidos vivos, se caracteriza por presentar: retraso en el crecimiento, retraso en el desarrollo psicomotriz y anomalías morfológicas que incluyen: rasgos faciales peculiares (cejas arqueadas y gruesas, fisuras palpebrales inclinadas hacia abajo, puente nasal convexo con punta de la nariz por debajo de las alas), pulgares y hallux anchos. Su origen epigenético en el 60% de los casos se debe a una alteración en el gen CREBBP (codificador de la proteína CPB), en el 10% a un cambio en el gen EP300 (codificador de la proteína p300) y en el 30% no se han logrado identificar su causa. Caso clínico: Niño de 8 años de edad con retardo en el desarrollo psicomotriz, con dificultades para la adaptación escolar. Al examen físico con rasgos faciales: cejas superpobladas y arqueadas, hirsutismo en frente y región de labio superior, fisuras palpebrales inclinadas hacia abajo, hipertelorismo con estrabismo convergente, puente nasal ancho, nariz achatada, la punta se extiende levemente por debajo de las alas nasales. Con hirsutismo en región cervical e interescapular. En las manos se identifica dedos pulgares anchos, en el resto de dedos se evidencian falanges distales ensanchadas, de igual forma en la región de los pies se identifican hallux anchos y falanges distales ensanchadas. Evolución: El paciente sigue en observación por consulta externa, fue enviado a programas de terapia de lenguaje, lectura y psicomotriz. No ha desarrollado infecciones pulmonares hasta el cierre del seguimiento, 6 meses posteriores al diagnóstico. Conclusión: En presente caso reporta las alteraciones fenotípicas características faciales y de extremidades de un niño con síndrome de Rubinstein-Taybi, las cuales ayudaron al diagnóstico clínico.

Introduction: Rubinstein-Taybi syndrome is a pathology of genetic origin that affects 1 out of every 100,000 to 125,000 live births, it is characterized by: growth retardation, delay in psy-chomotor development and morphological abnormalities that include: peculiar facial features (thick arched eyebrows, downward sloping palpebral fissures, convex nasal bridge with tip of nose below wings), broad thumbs and hallux. Its epigenetic origin in 60% of cases is due to an alteration in the CREBBP gene (coding for CPB protein), in 10% to a change in the EP300 gene (coding for p300 protein) and in the 30% have not been able to identify its cause. Clinical case: 8-year-old boy with a delay in psychomotor development, with difficulties in adapting to school. On physical examination with facial features: overpopulated and arched eyebrows, hirsutism in the forehead and upper lip region, downward sloping palpebral fissures, hypertelorism with convergent strabismus, wide nasal bridge, flattened nose, the tip extends slightly below the nasal wings. With hirsutism in the cervical and interscapular region. In the hands, broad thumbs are identified, in the rest of the fingers there are widened distal phalanges, in the same way in the region of the feet, wide hallux and widened distal phalanges are identified. Evolution: The patient continues to be observed by outpatient consultation, he was sent to speech, reading and psychomotor therapy programs. He has not developed pulmonary infections until the close of follow-up, 6 months after diagnosis. Conclusion: In this case, it reports the phenotypic alterations of the facial and limb characteristics of a child with Rubinstein-Taybi syndrome, which helped the clinical diagnosis.

Introdução: A síndrome de Rubinstein-Taybi é uma patologia de origem genética que afeta 1 em cada 100.000 a 125.000 nascidos vivos, é caracterizada por: retardo de crescimento, atraso no desenvolvimento psicomotor e anormalidades morfológicas que incluem: características faciais peculiares (sobrancelhas arqueadas e grossas, descendente fissuras palpebrais, ponte nasal convexa com a ponta do nariz abaixo das asas), polegares largos e hálux. Sua origem epigenética em 60% dos casos deve-se a uma alteração no gene CREBBP (que codifica a proteína CPB), em 10% a uma alteração no gene EP300 (que codifica a proteína p300) e em 30% sua causa não foi identificada . Caso clínico: Menino de 8 anos com atraso no desenvolvimento psicomotor, com dificuldade de adaptação à escola. No exame físico com características faciais: sobrancelhas superpovoadas e arqueadas, hirsutismo na testa e região do lábio superior, fissuras palpebrais inclinadas para baixo, hipertelorismo com estrabismo convergente, ponte nasal larga, nariz achatado, a ponta se estende ligeiramente abaixo das asas nasais. Com hirsutismo na região cervical e interescapular. Nas mãos identificam-se os polegares largos, nos restantes dedos são identificadas falanges distais alargadas, da mesma forma que na região dos pés, hálux largo e falanges distais alargadas. Evolução: O paciente ainda está em acompanhamento ambulatorial, foi encaminhado para programas de fonoaudiologia. Ele não desenvolveu infecções pulmonares até o fechamento do acompanhamento, 6 meses após o diagnóstico. Conclusão: Nesse caso, relata as alterações fenotípicas das características faciais e de membros de uma criança com síndrome de Rubinstein-Taybi, o que auxiliou no diagnóstico clínico.

Importance of determining variations in the number of copies in newborns with autosomal aneuploidies / [Importancia de la determinación de variantes en el número de copias en neonatos con aneuploidías autosómicas].

Introduction: Aneuploidies are frequent genetic disorders in clinical practice. However, little is known about other genetic variants that may influence the final phenotype. Objective: To determine the variations in the number of copies and regions with homozygosity greater than 0.5% or larger than 10 Mb in newborns with autosomal aneuploidies. Materials and methods: We performed a chromosomal microarray analysis on newborns with autosomal aneuploidies (n=7), trisomy 21 (n=5), and trisomy 18 (n=2) evaluated at the Hospital Antonio Lorena and Hospital Regional of Cusco, Perú, during 2018. Results: We found pathogenic and probably pathogenic variants in the number of copies in other genomic regions different to chromosomes 21 or 18 in two neonates. Additionally, we found two variants bigger than 500 kpb of unknown pathogenicity. Conclusions: Although the number of analyzed individuals was small, it is important to highlight that we found other variants in the number of copies that have been described in association with neurodevelopmental disorders, congenital anomalies, deafness, and short/tall stature, among others, in almost half of them, which will probably impact the phenotype negatively in patients with aneuploidies.

Introducción. Las aneuploidías son trastornos genéticos frecuentes en la práctica clínica; sin embargo, se conoce poco sobre las otras variantes genéticas que modifican el fenotipo final. Objetivo. Determinar las variantes en el número de copias y las regiones con pérdida de heterocigosidad autosómica mayor de 0,5 % o de regiones mayores de 10 Mb en neonatos con aneuploidías autosómicas. Materiales y métodos. Se hizo el análisis cromosómico por micromatrices a los neonatos con aneuploidías autosómicas (n=7), trisomía 21 (n=5) y trisomía 18 (n=2) evaluados en los hospitales Antonio Lorena y Regional de Cusco, Perú, en el 2018. Resultados. En dos neonatos se encontraron variantes en el número de copias, patogénicas o probablemente patogénicas, en regiones diferentes al cromosoma 21 o al 18. Además, se observaron dos variantes del número de copias con más de 500 kpb de patogenia desconocida. Conclusiones. Si bien el número de pacientes era muy reducido, es importante resaltar que se encontraron otras variantes en el número de copias que se han descrito asociadas con trastornos del neurodesarrollo, varias anomalías congénitas, hipoacusia y talla baja o alta, entre otras, lo que probablemente influye negativamente en el fenotipo de este grupo de pacientes.

Clinical Features of de novo Pure 16q21q24.1 Chromosome Duplication.

Pure partial duplications of the long arm of chromosome 16 are rare and few cases are described with delineation by chromosomal microarray. Data about clinical abnormalities of pure partial 16q duplications are incomplete because many individuals die during the perinatal period. We describe the clinical features of a 47-month-old Brazilian girl with 16q21q24.1 duplication. To the best of our knowledge, she is the first person with this specific chromosome segment duplication, and we compare her phenotype with the only reported individual alive with intermediate-distal pure 16q duplication.

Congenital chromoanagenesis in the routine postnatal chromosomal microarray analyses.

Chromosomal microarray analyses (CMA) have greatly increased both the yield and diagnostic accuracy of postnatal analysis; it has been used as a first-tier cytogenetic test in patients with intellectual disability, autism spectrum disorder, and multiple congenital abnormalities. During the last 15 years, we performed CMA in approximately 8,000 patients with neurodevelopmental and/or congenital disorders, of which 13 (0.16%) genetically catastrophic complex chromosomal rearrangements were identified. These ultrarare rearrangements showed clustering of breakpoints, characteristic of chromoanagenesis events. Al1 13 complex events display underlying formation mechanisms, originating either by a synchronization of the shattering of clustered chromosome regions in which regional asynchrony of DNA replication may be one of the main causes of disruption. We provide an overview of the copy number profiling in these patients. Although several previous studies have suggested that chromoanagenesis is often a genetic disease source in postnatal diagnostic screening, due to either the challenge of clinical interpretation of these complex rearrangements or the limitation of microarray resolution relative to the small size and complexity of chromogenic induced chromosome abnormalities, bringing further attention and to study its occurrence in the clinical setting is extremely important.

Shared Neurodevelopmental Perturbations Can Lead to Intellectual Disability in Individuals with Distinct Rare Chromosome Duplications.

Chromosomal duplications are associated with a large group of human diseases that arise mainly from dosage imbalance of genes within the rearrangements. Phenotypes range widely but are often associated with global development delay, intellectual disability, autism spectrum disorders, and multiple congenital abnormalities. How different contiguous genes from a duplicated genomic region interact and dynamically affect the expression of each other remains unclear in most cases. Here, we report a genomic comparative delineation of genes located in duplicated chromosomal regions 8q24.13q24.3, 18p11.32p11.21, and Xq22.3q27.2 in three patients followed up at our genetics service who has the intellectual disability (ID) as a common phenotype. We integrated several genomic data levels by identification of gene content within the duplications, protein-protein interactions, and functional analysis on specific tissues. We found functional relationships among genes from three different duplicated chromosomal regions, reflecting interactions of protein-coding genes and their involvement in common cellular subnetworks. Furthermore, the sharing of common significant biological processes associated with ID has been demonstrated between proteins from the different chromosomal regions. Finally, we elaborated a shared model of pathways directly or indirectly related to the central nervous system (CNS), which could perturb cognitive function and lead to ID in the three duplication conditions.

Spread of X-chromosome inactivation into autosomal regions in patients with unbalanced X-autosome translocations and its phenotypic effects.

Patients with unbalanced X-autosome translocations are rare and usually present a skewed X-chromosome inactivation (XCI) pattern, with the derivative chromosome being preferentially inactivated, and with a possible spread of XCI into the autosomal regions attached to it, which can inactivate autosomal genes and affect the patients' phenotype. We describe three patients carrying different unbalanced X-autosome translocations, confirmed by G-banding karyotype and array techniques. We analyzed their XCI pattern and inactivation spread into autosomal regions, through HUMARA, ZDHHC15 gene assay and the novel 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay, and identified an extremely skewed XCI pattern toward the derivative chromosomes for all the patients, and a variable pattern of late-replication on the autosomal regions of the derivative chromosomes. All patients showed phenotypical overlap with patients presenting deletions of the autosomal late-replicating regions, suggesting that the inactivation of autosomal segments may be responsible for their phenotype. Our data highlight the importance of the XCI spread into autosomal regions for establishing the clinical picture in patients carrying unbalanced X-autosome translocations, and the incorporation of EdU as a novel and precise tool to evaluate the inactivation status in such patients.