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BACKGROUND: Mesomelia-Synostoses Syndrome (MSS)(OMIM 600,383) is a rare autosomal dominant disorder characterized by mesomelic limb shortening, acral synostoses and multiple congenital malformations which is described as a contiguous deletion syndrome involving the two genes SULF1 and SLCO5A1. The study of apparently balanced chromosomal rearrangements (BCRs) is a cytogenetic strategy used to identify candidate genes associated with Mendelian diseases or abnormal phenotypes. With the improved development of genomic technologies, new methods refine this search, allowing better delineation of breakpoints as well as more accurate genotype-phenotype correlation. CASE PRESENTATION: We present a boy with a global development deficit, delayed speech development and an ASD (Asperger) family history, with an apparently balanced "de novo" reciprocal translocation [t(1;8)(p32.2;q13)dn]. The cytogenetic molecular study identified a likely pathogenic deletion of 21 kb in the 15q12 region, while mate pair sequencing identified gene-truncations at both the 1p32.2 and 8q13 translocation breakpoints. CONCLUSIONS: The identification of a pathogenic alteration on 15q12 involving GABRA5 was likely the main cause of the ASD-phenotype. Importantly, the chr8 translocation breakpoint truncating SLCO5A1 exclude SLCO5A1 as a candidate for MSS, leaving SULF1 as the primary candidate. However, the deletions observed in MSS remove a topological associated domain (TAD) boundary separating SULF1 and SLCO5A1. Hence, Mesomelia-Synostoses syndrome is either caused by haploinsufficiency of SULF1 or ectopic enhancer effects where skeletal/chrondrogenic SULF1 enhancers drive excopic expression of developmental genes in adjacent TADs including PRDM14, NCOA2 and/or EYA1.

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Introdução: A Síndrome de Cornelia de Lange (CdLS) (OMIM: 122470) é uma doença genética rara com quadro clínico e fenótipo variáveis, compreendendo um grupo de doenças denominado coesinopatias. Entre suas principais características: deficiência intelectual (DI), baixa estatura, doença do refluxo gastroesofágico (DRGE), hipertricose, dismorfismos faciais e anomalias em membros superiores. O diagnóstico pode ser dificultado nos quadros atenuados. O objetivo do estudo foi determinar os principais achados clínicos e moleculares em uma série de pacientes com o diagnóstico clínico de CdLS.Métodos: Foram avaliados 33 pacientes com diagnóstico clínico e/ou molecular de CdLS (18 sexo feminino e 15 masculino) com idades entre 1 mês e 43 anos. Aplicou-se um escore clínico visando a categorização dos pacientes baseado em Kline et al. (2018). Esta ferramenta utiliza sinais clínicos para determinar as formas clássicas (n: 23), não clássicas (n: 6) e os casos que, apesar de não se enquadrarem nestas categoriais, também deveriam ser testados molecularmente para a síndrome (n: 4).Resultados: Atraso do desenvolvimento/DI, distúrbios de comportamento, déficit de crescimento e DRGE foram as comorbidades mais prevalentes. Entre as dismorfias: sinofris, micrognatia, narinas antevertidas e comissura labial desviada para baixo. Os achados moleculares nos pacientes submetidos ao sequenciamento completo do exoma revelaram 6 variantes em NIPBL (46%), 2 variantes em SMC1A (15%), 1 variante em SMC3, 1 variante em HDAC8, 1 variante em AHDC1 e 2 resultados negativos.Conclusões: Os dados obtidos revelaram uma grande heterogeneidade de apresentação da síndrome. A utilização de escores clínicos podem auxiliar no diagnóstico de CdLS.

Introduction: Cornelia de Lange syndrome (CdLS) (OMIM: 122470) is a rare genetic disease with variable clinical presentation and phenotype, part of a group of disorders termed cohesinopathies. Intellectual disability, growth retardation, gastroesophageal reflux disease, hypertrichosis, facial dysmorphisms, and anomalies of the upper limbs are the most common clinical characteristics. Diagnosis may be difficult, especially in attenuated presentations. The aim of this study was to determine the main clinical and molecular findings in a series of patients with clinical diagnosis of CdLS.Methods: Thirty-three patients with typical clinical and/or molecular diagnosis of CdLS (18 female and 15 male) aged between 1 month and 43 years were evaluated. A clinical score was applied to categorize patients. This tool uses clinical signs to determine the classic (n: 23) and nonclassic (n: 6) forms, in addition to a category to suggest which cases should be molecularly tested for the syndrome (n: 4).Results: Developmental delay/intellectual disability, behavioral disorders, growth retardation, and gastroesophageal reflux disease were the most prevalent comorbidities. Dysmorphic features included synophrys micrognathia, anteverted nostrils, and labial commissure turning downwards. Molecular findings in those who underwent whole exome sequencing revealed 6 variants in NIPBL (46%), 2 variants in SMC1A (15%), 1 variant in SMC3, 1 variant in HDAC8, 1 variant in AHDC1, and 2 negative results.Conclusions: The data revealed a great heterogeneity in the presentation of the syndrome. The use of clinical scores can help in the diagnosis of CdLS.

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OBJECTIVE: to discuss strategic challenges in complex health organizations sustained by an analysis in a Medical Genetics Center at a National Health Research Institute in Brazil. METHOD: Démarche Stratégique adapted for use with research institutes, including the policy formulation function. The study used institution's databases and workshops with key actors between Dec/2014 and Jun/2015. RESULTS: Were defined the segments: clinical diagnosis, lysosomal diseases, osteogenesis imperfecta, genetic counseling, cytogenetics, biochemistry, and genomics. The findings reveal that the segments are aligned with the Institute's mission when it comes to referral care, although investment is required in strategic areas. The clinical diagnosis, lysosomal diseases, and genomics segments stood out in the scientific output portfolio. The findings show that progress needs to be made with policy implementation and planning to improve access to new technologies, together with investment in training and development, and the strengthening of coordination and collaboration between research institutes and referral services and between the wider healthcare network and research, care, and teaching. The inclusion of the policy formulation dimension was essential to highlight the unique role medical genetics plays in Brazil's public health system and the importance of developing action plans in the field of public health.

O objetivo deste artigo é discutir os desafios estratégicos em organizações complexas de saúde apoiado na análise da posição estratégica em um centro de genética médica em um instituto nacional de pesquisa em saúde brasileiro. Utilizou-se a démarche stratégique adaptada para institutos de pesquisa, incorporando a função formulação de políticas com apoio de bancos de dados institucionais, livros de registros, reuniões com atores-chave e oficinas de trabalho de dezembro de 2014 a junho de 2015. Foram definidos os segmentos diagnóstico clínico, doenças lisossômicas, osteogênese imperfeita, aconselhamento genético, citogenética, bioquímica e genômica. Estes mostraram-se adequados à missão institucional no que se refere à atenção de referência, necessitando investimentos em pontos estratégicos. Na produção científica destacaram-se os segmentos diagnóstico clínico, doenças lisossômicas e genômica. Os resultados mostraram que é preciso avançar na implementação de políticas e no planejamento para ampliar o acesso da população às novas tecnologias, investindo em formação e na articulação assistência/pesquisa/ensino. A incorporação da dimensão formulação de política foi fundamental para indicar o papel diferencial da genética médica no SUS.

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Prader-Willi (PWS) and Angelman (AS) syndromes are two clinically distinct imprinted disorders characterized by genetic abnormalities at 15q11-q13. Early diagnosis of both syndromes provides improved treatment and accurate genetic counseling. Whole blood (WB) is the most common DNA source of many methodologies to detect PWS and AS, however, the need of WB makes a massive screening difficult in newborns due to economic and technical limitations. The aim of this study was to adapt a Methylation-sensitive High-Resolution Melting (MS-HRM) approach from dried blood spot (DBS) samples, assessing the different DNA isolation techniques and diagnostic performance. Over a 1-year period, we collected 125 DBS cards, of which 45 had already been diagnosed by MS-HRM (20 PWS, 1 AS, and 24 healthy individuals). We tested three different DBS-DNA extraction techniques assessing the DNA concentration and quality, followed by MS-HRM and statistical comparison. Each DBS-DNA extraction method was capable of accuracy in detecting all PWS and AS individuals. However, the efficiency to detect healthy individuals varied according to methodology. In our experience, DNA extracted from DBS analyzed by the MS-HRM methodology provides an accurate approach for genetic screening of imprinting related disorders in newborns, offering several benefits compared to traditional whole blood methods.

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BACKGROUND: Myelodysplastic syndrome (MDS) is rare in the pediatric age group and it may be associated with inheritable bone marrow failure (BMF) such as Fanconi anemia (FA). FA is a rare multi-system genetic disorder, characterized by congenital malformations and progressive BMF. Patients with FA usually present chromosomal aberrations when evolving to MDS or acute myeloid leukemia (AML). Thus, the cytogenetic studies in the bone marrow (BM) of these patients have an important role in the therapeutic decision, mainly in the indication for hematopoietic stem cell transplantation (HSCT). The most frequent chromosomal alterations in the BM of FA patients are gains of the chromosomal regions 1q and 3q, and partial or complete loss of chromosome 7. However, the significance and the predictive value of such clonal alterations, with respect to malignant progress, are not fully understood and data from molecular cytogenetic studies are very limited. CASE PRESENTATION: A five-year-old boy presented recurrent infections and persistent anemia. The BM biopsy revealed hypocellularity. G-banding was performed on BM cells and showed a normal karyotype. The physical examination showed to be characteristic of FA, being the diagnosis confirmed by DEB test. Five years later, even with supportive treatment, the patient presented severe hypocellularity and BM evolution revealing megakaryocyte dysplasia, intense dyserythropoiesis, and 11% myeloblasts. G-banded analysis showed an abnormal karyotype involving a der(9)t(9;11)(p24;q?22). The FISH analysis showed the monoallelic loss of ATM and KMT2A genes. At this moment the diagnosis was MDS, refractory anemia with excess of blasts (RAEB). Allogeneic HSCT was indicated early in the diagnosis, but no donor was found. Decitabine treatment was initiated and well tolerated, although progression to AML occurred 3 months later. Chemotherapy induction was initiated, but there was no response. The patient died due to disease progression and infection complications. CONCLUSIONS: Molecular cytogenetic analysis showed a yet unreported der(9)t(9;11)(p24;q?22),der(11)t(9;11)(p24;q?22) during the evolution from FA to MDS/AML. The FISH technique was important allowing the identification at the molecular level of the monoallelic deletion involving the KMT2A and ATM genes. Our results suggest that this chromosomal alteration conferred a poor prognosis, being associated with a rapid leukemic transformation and a poor treatment response.

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Abstract The clinical management and decision-making in pregnancies in which there is suspicion of lethal fetal malformations during the prenatal period, such as lethal skeletal dysplasia (SD), demand a multidisciplinary approach coordinated by an experienced physician. Based on the presentation of a case of osteogenesis imperfecta type IIA, we offer and discuss recommendations with the intention of organizing clinical and laboratory investigations aiming toward the clinical management, prognosis, and etiological diagnosis of these malformations, as well as genetic counselling to patients who wish to become pregnant.

Resumo O manejo clínico e a tomada de decisões médicas em gestantes com suspeita de malformação letal em um feto no período pré-natal, tal qual uma displasia esquelética letal, demandam uma abordagem multidisciplinar coordenada por um médico experiente. Baseado na apresentação de um caso de osteogênese imperfeita tipo IIA, recomendações são apresentadas e discutidas com a intenção de organizar as investigações clínicas e laboratoriais visando o manejo clínico, o prognóstico, e o diagnóstico etiológico dessas malformações, e o aconselhamento genético para as pacientes que desejam engravidar.

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The clinical management and decision-making in pregnancies in which there is suspicion of lethal fetal malformations during the prenatal period, such as lethal skeletal dysplasia (SD), demand a multidisciplinary approach coordinated by an experienced physician. Based on the presentation of a case of osteogenesis imperfecta type IIA, we offer and discuss recommendations with the intention of organizing clinical and laboratory investigations aiming toward the clinical management, prognosis, and etiological diagnosis of these malformations, as well as genetic counselling to patients who wish to become pregnant.

O manejo clínico e a tomada de decisões médicas em gestantes com suspeita de malformação letal em um feto no período pré-natal, tal qual uma displasia esquelética letal, demandam uma abordagem multidisciplinar coordenada por um médico experiente. Baseado na apresentação de um caso de osteogênese imperfeita tipo IIA, recomendações são apresentadas e discutidas com a intenção de organizar as investigações clínicas e laboratoriais visando o manejo clínico, o prognóstico, e o diagnóstico etiológico dessas malformações, e o aconselhamento genético para as pacientes que desejam engravidar.

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ABSTRACT Pompe disease (PD) is a potentially lethal illness involving irreversible muscle damage resulting from glycogen storage in muscle fiber and activation of autophagic pathways. A promising therapeutic perspective for PD is enzyme replacement therapy (ERT) with the human recombinant enzyme acid alpha-glucosidase (Myozyme®). The need to organize a diagnostic flowchart, systematize clinical follow-up, and establish new therapeutic recommendations has become vital, as ERT ensures greater patient longevity. A task force of experienced clinicians outlined a protocol for diagnosis, monitoring, treatment, genetic counseling, and rehabilitation for PD patients. The study was conducted under the coordination of REBREPOM, the Brazilian Network for Studies of PD. The meeting of these experts took place in October 2013, at L’Hotel Port Bay in São Paulo, Brazil. In August 2014, the text was reassessed and updated. Given the rarity of PD and limited high-impact publications, experts submitted their views.

RESUMO A doença de Pompe (DP) é uma doença grave, potencialmente letal, devida ao depósito de glicogênio na fibra muscular e ativação de vias autofágicas. Tratamento promissor para a DP é a reposição enzimática com a enzima recombinante humana alfa-glicosidase ácida (rhAGA -Myozyme®). A necessidade de organizar uma propedêutica diagnóstica, sistematizar o seguimento clínico e sedimentar as novas recomendações terapêuticas tornaram-se vitais à medida que o tratamento permite uma maior longevidade aos pacientes. Uma força-tarefa de clínicos experientes no manejo da DP foi constituída para elaborar um protocolo para o diagnóstico, acompanhamento clínico, tratamento, aconselhamento genético, entre outras considerações voltadas ao paciente adulto. O estudo foi realizado sob a coordenação da Rede Brasileira de Estudos da Doença de Pompe (REBREPOM). Diante da raridade da DP e escassez de trabalhos de alto impacto de evidência científica, os especialistas emitiram suas opiniões.

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Pompe disease (PD) is a potentially lethal illness involving irreversible muscle damage resulting from glycogen storage in muscle fiber and activation of autophagic pathways. A promising therapeutic perspective for PD is enzyme replacement therapy (ERT) with the human recombinant enzyme acid alpha-glucosidase (Myozyme®). The need to organize a diagnostic flowchart, systematize clinical follow-up, and establish new therapeutic recommendations has become vital, as ERT ensures greater patient longevity. A task force of experienced clinicians outlined a protocol for diagnosis, monitoring, treatment, genetic counseling, and rehabilitation for PD patients. The study was conducted under the coordination of REBREPOM, the Brazilian Network for Studies of PD. The meeting of these experts took place in October 2013, at L'Hotel Port Bay in São Paulo, Brazil. In August 2014, the text was reassessed and updated. Given the rarity of PD and limited high-impact publications, experts submitted their views.

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Objetivo: A partir da perspectiva de especialistas em Osteogênese Imperfeita (OI), identificar as categorias da Classificação Internacional de Funcionalidade, Incapacidade e Saúde- versão crianças e jovens (CIF-CJ) mais relevantes para avaliação de pacientes. Métodos: Três etapas de questionários enviados por correio eletrônico para cinco especialistas em OI utilizando o método Delphi modificado. Os participantes escolheram a partir de uma lista de categorias de segundo nível da CIF-CJ, as mais relevantes para avaliação da funcionalidade em crianças e adolescentes com OI. Ao final da terceira etapa, foram selecionadas as categorias escolhidas por no mínimo 80% dos respondentes. Resultados: Todos os componentes atingiram categorias com consenso. Os componentes com maior número de categorias escolhidas foram Atividades e Participação e Fatores Ambientais. Conclusão: Uma lista de categorias da CIF-CJ relevantes para OI pôde ser elaborada a partir da perspectiva de especialistas. Esta é uma importante etapa na elucidação do que deve ser avaliado em crianças e adolescentes com OI

Objective: From the perspective of specialists in Osteogenesis Imperfecta (OI), to identify the most relevant categories of the International Classification of Functioning, Disability, and Health: children and youth version (ICF-CY) to patients. Methods: Three-stage surveys were sent by email to five OI specialists using the modified Delphi method. From a list of second-level ICFCY categories, the participants chose the most relevant categories to assess the functioning of children and adolescents with OI. At the end of the third stage, the categories considered relevant by at least 80% of the responders were selected. Results: Categorizations of all ICF-CY components were agreed upon. Activities, Participation, and Environmental Factors were the categories with the most components. Conclusion: A list of ICF-CY categories relevant to OI could be created from the perspective of specialists. This is an important step to highlight what to assess in children and adolescents with OI

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