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1.
Nucleic Acids Res ; 49(D1): D1207-D1217, 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33264411

RESUMO

The Human Phenotype Ontology (HPO, https://hpo.jax.org) was launched in 2008 to provide a comprehensive logical standard to describe and computationally analyze phenotypic abnormalities found in human disease. The HPO is now a worldwide standard for phenotype exchange. The HPO has grown steadily since its inception due to considerable contributions from clinical experts and researchers from a diverse range of disciplines. Here, we present recent major extensions of the HPO for neurology, nephrology, immunology, pulmonology, newborn screening, and other areas. For example, the seizure subontology now reflects the International League Against Epilepsy (ILAE) guidelines and these enhancements have already shown clinical validity. We present new efforts to harmonize computational definitions of phenotypic abnormalities across the HPO and multiple phenotype ontologies used for animal models of disease. These efforts will benefit software such as Exomiser by improving the accuracy and scope of cross-species phenotype matching. The computational modeling strategy used by the HPO to define disease entities and phenotypic features and distinguish between them is explained in detail.We also report on recent efforts to translate the HPO into indigenous languages. Finally, we summarize recent advances in the use of HPO in electronic health record systems.

2.
J Pediatr Gastroenterol Nutr ; 72(2): 276-281, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32925557

RESUMO

OBJECTIVES: Advances in genetic technologies provide opportunities for patient care and ethical challenges. Clinical care of patients with rare Mendelian disorders is often at the forefront of those developments. Whereas in classical polygenic inflammatory bowel disease (IBD), the predictive value of genetic variants is very low, predictive prenatal genetic diagnosis can inform families at high risk of severe genetic disorders. Patients with IL-10 signalling defects because of pathogenic variants in IL10RA, Il10RB, and IL10 develop severe infantile onset inflammatory bowel disease that is completely penetrant and has a high morbidity and substantial mortality despite treatment. METHODS: We performed a survey among tertiary specialist paediatric centers of 10 countries on the utilization of predictive prenatal genetic diagnosis in IL-10 signalling defects. We retrospectively report prenatal genetics in a series of 8 families. RESULTS: International variation in legislation, guidelines, expert opinion, as well as cultural and religious background of families and clinicians results in variable utilization of preimplantation and prenatal genetic testing for IL-10 signalling defects. Eleven referrals for prenatal diagnosis for IL-10 signalling defects were identified across 4 countries. We report on 8 families who underwent prenatal preimplantation monogenic testing after in vitro fertilization (n = 2) and/or by amniocentesis/chorion villus sampling (n = 6). A genetic diagnosis was established in 1 foetus and excluded in 7 foetuses (all IL10RA variants). CONCLUSIONS: Prenatal genetic testing for IL10R-defects is feasible, yet the legal and ethical considerations are complex and controversial. In some countries, predictive genetics for IL-10-related signalling defects is entering clinical practice.

3.
J Pediatr Gastroenterol Nutr ; Publish Ahead of Print2020 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-33346580

RESUMO

BACKGROUND: It is important to identify patients with monogenic IBD since management may differ from classical IBD. In this position statement we formulate recommendations for the use of genomics in evaluating potential monogenic causes of IBD across age groups. METHODS: The consensus included paediatric IBD specialists from the Paediatric IBD Porto group of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and specialists from several monogenic IBD research consortia. We defined key topics and performed a systematic literature review to cover indications, technologies (targeted panel, exome and genome sequencing), gene panel setup, cost-effectiveness of genetic screening, and requirements for the clinical care setting. We developed recommendations that were voted upon by all authors and Porto group members (32 voting specialists). RESULTS: We recommend next-generation DNA sequencing technologies to diagnose monogenic causes of IBD in routine clinical practice embedded in a setting of multidisciplinary patient care. Routine genetic screening is not recommended for all IBD patients. Genetic testing should be considered depending on age of IBD onset (infantile IBD, very early onset IBD, paediatric or young adult IBD) and further criteria such as family history, relevant comorbidities and extraintestinal manifestations. Genetic testing is also recommended in advance of hematopoietic stem cell transplantation. We develop a diagnostic algorithm that includes a gene panel of seventy-five monogenic IBD genes. Considerations are provided also for low resource countries. SUMMARY: Genomic technologies should be considered an integral part of patient care to investigate patients at risk for monogenic forms of IBD.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33263366

RESUMO

Surgical ventricular reconstruction is a proven option for treating patients who have heart failure due to a postinfarction scar or an aneurysm of the left ventricle. The BioVentrix Revivent TC System offers a reliable alternative to the conventional, more invasive surgical ventricular restoration. The system requires no sternotomy, no heart-lung machine, and no cardioplegic arrest.  In this video tutorial, we present our technique for using the Revivent TC System to reconstruct the normal left ventricular shape and volume in a patient with a postinfarction, anteroapical scar.

5.
Front Psychiatry ; 11: 505800, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33132925

RESUMO

Increased Intra-Subject Variability (ISV) is a candidate endophenotype of ADHD. ISV's relationship with response speed is highly relevant for ADHD as patients are highly variable but typically no slower than controls. This brief report addresses the relationship between variability and speed by employing dimensional analyses for differentiated performance measures, with a particular focus on the ex-Gaussian measures, across relevant ADHD studies and in young healthy adults (N = 70). For both patients with ADHD and healthy adults, we found that reaction time standard deviation and mean reaction time were strongly correlated, thus failing to dissociate, but ex-Gaussian tau (τ) shared only little variance with Gaussian mu (µ), thus dissociating slow responses (τ) from response speed or-if given-slow responding (µ). Our results highlight the utility of employing the ex-Gaussian measures to disentangle ISV and speed, particularly for ADHD data as patients make more slow responses but are not overall slower than typical controls.

6.
Artigo em Inglês | MEDLINE | ID: mdl-33236094

RESUMO

OBJECTIVES: The present study sought to develop a reliable calcium score (Ca-score) to predict paravalvular leak (PVL) in patients undergoing transcatheter aortic valve (AV) implantation. METHODS: A total of 965 patients were prospectively included from 2012 to 2019. Preprocedural contrast-media-enhanced computed tomography scans were analysed regarding the amount of AV cusp calcification and the presence of upper and lower left ventricular outflow tract calcification. The calcium volume threshold of each AV cusp [non-coronary cusp (NCC); left coronary cusp (LCC); right coronary cusp (RCC)] with optimal PVL prediction was defined using the Youden index value derived from receiver operating characteristic analysis. The final score was developed based on the multivariable regression analysis, while individual variables were weighted based on their corresponding odds ratio. RESULTS: The AV calcium volume threshold with optimal PVL prediction was 733.6, 296.0 and 131.2 mm3 for the NCC, RCC and LCC respectively. Overall, calcification of the upper left ventricular outflow tract was present in 233 (23%), 111 (12%) and 304 (32%) of patients below the NCC, RCC and LCC respectively, while 260 (27%), 44 (5%) and 217 (23%) patients suffered from calcification under the NCC, RCC and LCC, respectively. A total Ca-score of ≥4 was present in 356 (37%) of patients and was independently associated with ≥ mild PVL [odds ratio 3.662; 95% confidence interval (2.740-4.911); P < 0.001]. The area under the curve of the Ca-score was 0.713 [95% confidence interval (0.678-0.748); P < 0.001]. CONCLUSION: The provided Ca-score independently correlates with the development of PVL and improves risk stratification in patients undergoing transcatheter AV implantation.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33188394

RESUMO

Down syndrome (DS) predisposes to severe immunologic reaction secondary to infectious triggers. Here we report a paediatric DS patient with COVID-19 who developed a hyperinflammatory syndrome, severe ARDS and secondary HLH requiring PICU admission and treatment with steroids, IVIG and Remdesivir. Investigations into genetic susceptibilities for COVID-19 and SARS-CoV-2-associated complications warrants systematic clinical and scientific studies.

8.
Front Psychiatry ; 11: 545567, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33192661

RESUMO

Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) represent two common neurodevelopmental disorders with considerable co-occurrence. Their comorbidity (ASD + ADHD) has been included in the latest diagnostic guidelines (DSM-V, 2013). The present study focuses on social visual attention that i) is a main aspect of social attention reflecting social cognition and ii) its atypicalities have been suggested as a potential biomarker for ASD. Considering the possible shared background of both disorders and their comorbidity, it is important to compare such traits directly. Here, 73 children and adolescents paired for age and IQ diagnosed with ASD (N = 12), ADHD (N = 21), comorbid ASD + ADHD (N = 15), and "typically developing" (TD) controls (N = 25), were shown static real-life social scenes while their gaze movements were recorded with eye-tracking. Scenes with two levels of social complexity were presented: low complexity (one person depicted) and high (four interacting individuals). Gaze fixation variables were investigated. Fixation duration on faces was significantly reduced only in ASD + ADHD which also required longer time to fixate all faces at least once. Fixation duration on faces in ASD was reduced, compared to TD, only when looking at scenes with high versus low social complexity. ADHD individuals did not differ from TD. Concluding, the observed alterations of social visual attention support the existence of possible dysfunctional particularities differentiating ASD, ADHD, and ASD + ADHD, which can be revealed with the new method of eye-tracking technique. The objective gaze measurements provided contribute to the development of biomarkers enabling early diagnosis, amelioration of care and further interventions specified for each group.

9.
Sci Rep ; 10(1): 16157, 2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-32999327

RESUMO

Sensory processing deficits and altered long-range connectivity putatively underlie Multisensory Integration (MSI) deficits in Autism Spectrum Disorder (ASD). The present study set out to investigate non-social MSI stimuli and their electrophysiological correlates in young neurotypical adolescents and adolescents with ASD. We report robust MSI effects at behavioural and electrophysiological levels. Both groups demonstrated normal behavioural MSI. However, at the neurophysiological level, the ASD group showed less MSI-related reduction of the visual P100 latency, greater MSI-related slowing of the auditory P200 and an overall temporally delayed and spatially constrained onset of MSI. Given the task design and patient sample, and the age of our participants, we argue that electro-cortical indices of MSI deficits in ASD: (a) can be detected in early-adolescent ASD, (b) occur at early stages of perceptual processing, (c) can possibly be compensated by later attentional processes, (d) thus leading to normal MSI at the behavioural level.


Assuntos
Atenção/fisiologia , Percepção Auditiva/fisiologia , Transtorno do Espectro Autista/fisiopatologia , Encéfalo/fisiopatologia , Potenciais Evocados/fisiologia , Percepção Visual/fisiologia , Estimulação Acústica , Adolescente , Transtorno do Espectro Autista/psicologia , Criança , Eletroencefalografia , Feminino , Humanos , Masculino , Estimulação Luminosa , Tempo de Reação/fisiologia
10.
Blood ; 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33094319

RESUMO

Emerging immunotherapies such as chimeric antigen receptor T cells have advanced the treatment of acute lymphoblastic leukemia. In contrast, long-term control of acute myeloid leukemia (AML) cannot be achieved by single lineage-specific targeting while sparing benign hematopoiesis. In addition, heterogeneity of AML warrants combinatorial targeting and several suitable immunotargets (HAVCR2/CD33 or HAVCR2/CLEC12A) were identified in adult AML. However, clinical and biologic characteristics differ between children and the elderly. Here, we analyzed 36 bone marrow (BM) samples of pediatric AML patients and 13 age-matched healthy donors using whole RNA-sequencing of sorted CD45dim and CD34+CD38-CD45dim BM populations and flow cytometry for surface expression of putative target antigens. Pediatric AML clusters apart from healthy myeloid BM precursors in principle component analysis. Immunotargets known from adult AML such as IL3RA were not overexpressed in pediatric AML compared to healthy precursors by RNA-sequencing. CD33 and CLEC12A were the most upregulated immunotargets on RNA level and showed the highest surface expression on AML detected by flow cytometry. KMT2A mutated infant AML cluster separately by RNA-sequencing, overexpress FLT3 and hence CD33/FLT3 co-targeting is an additional specific option for this subgroup. CLEC12A and CD33/CLEC12Adouble-positive expression was absent in CD34+CD38-CD45RA-CD90+ hematopoietic stem cells (HSC) and both are restricted to healthy hematopoietic tissue, while CD33 and FLT3 is expressed on HSC. In summary, we show that expression of immunotargets in pediatric AML differs from known expression profiles in adult AML. We identify CLEC12A/CD33 as preferential generic combinatorial immunotargets in pediatric AML and CD33/FLT3 as immunotargets specific for KMT2A mutated infant AML.

11.
Front Psychiatry ; 11: 585149, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33101094

RESUMO

Social interaction in individuals with Autism Spectrum Disorder (ASD) is characterized by qualitative impairments that highly impact quality of life. Bayesian theories in ASD frame an understanding of underlying mechanisms suggesting atypicalities in the evaluation of probabilistic links within the perceptual environment of the affected individual. To address these theories, the present study explores the applicability of an innovative Bayesian framework on social visual perception in ASD and demonstrates the use of gaze transitions between different parts of social scenes. We applied advanced analyses with Bayesian Hidden Markov Modeling (BHMM) to track gaze movements while presenting real-life scenes to typically developing (TD) children and adolescents (N = 25) and participants with ASD and Attention-Deficit/Hyperactivity Disorder (ASD+ADHD, N = 15) and ASD without comorbidity (ASD, N = 12). Regions of interest (ROIs) were generated by BHMM based both on spatial and temporal gaze behavior. Social visual perception was compared between groups using transition and fixation variables for social (faces, bodies) and non-social ROIs. Transition variables between faces, namely gaze transitions between faces and likelihood of linking faces, were reduced in the ASD+ADHD compared to TD participants. Fixation count to faces was also reduced in this group. The ASD group showed similar performance to TD in the studied variables. There was no difference between groups for non-social ROIs. Our study provides an innovative, interpretable example of applying Bayesian theories of social visual perception in ASD. BHMM analyses and gaze transitions have the potential to reveal fundamental social perception components in ASD, contributing thus to amelioration of social-skill interventions.

12.
Artigo em Inglês | MEDLINE | ID: mdl-33122583

RESUMO

OBJECTIVE: Mutations in IKZF1, which encodes Ikaros family zinc finger 1 (IKAROS) transcription factor, are associated with recurrent infections, cytopenia, autoimmune diseases, and hematological malignancies. Diverse clinical phenotypes resulting from IKZF1 mutations include pulmonary fungal infections, cytopenia, autoimmune hemolytic anemia (AIHA), and malignancies. In this study, we aimed to assess the DNA-binding ability and pericentromeric (PC) localization of a variant of IKZF discovered in a patient. MATERIALS AND METHODS: DNA-binding ability of a pathogenic IKZF variant was tested using electrophoretic mobility shift assay and PC localization of the variant was assessed by immunofluorescent microscopy in NIH3T3 cells. RESULTS: Clinical features of a 3-month-old male infant who underwent hematopoietic stem cell transplantation because of an IKZF1 mutation-associated common variable immunodeficiency, AIHA, and pancytopenia are described. DNA studies revealed a heterozygous missense variant (IKZF1 NM_006060 c.427C>T; p.R143W). Cotransfection studies revealed that mutant R143W has a partial dominant-negative effect over PC targeting and DNA binding. CONCLUSIONS: IKZF1 mutation must be kept in mind if neonatal AIHA, common variable immunodeficiency, and pancytopenia are observed.

13.
Sci Rep ; 10(1): 18648, 2020 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-33122718

RESUMO

Very early onset inflammatory bowel disease (VEOIBD) denotes children with onset of IBD before six years of age. A number of monogenic disorders are associated with VEOIBD including tetratricopeptide repeat domain 7A (TTC7A) deficiency. TTC7A-deficiency is characterized by apoptotic colitis in milder cases with severe intestinal atresia and immunodeficiency in cases with complete loss of protein. We used whole exome sequencing in a VEOIBD patient presenting with colitis characterized by colonic apoptosis and no identified known VEOIBD variants, to identify compound heterozygous deleterious variants in the Ubiquitin protein ligase E3 component N-recognin 5 (UBR5) gene. Functional studies demonstrated that UBR5 co-immunoprecipitates with the TTC7A and the UBR5 variants had reduced interaction between UBR5 and TTC7A. Together this implicates UBR5 in regulating TTC7A signaling in VEOIBD patients with apoptotic colitis.

14.
Nat Rev Cancer ; 20(11): 681-694, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33024261

RESUMO

Metastatic dissemination occurs very early in the malignant progression of a cancer but the clinical manifestation of metastases often takes years. In recent decades, 5-year survival of patients with many solid cancers has increased due to earlier detection, local disease control and adjuvant therapies. As a consequence, we are confronted with an increase in late relapses as more antiproliferative cancer therapies prolong disease courses, raising questions about how cancer cells survive, evolve or stop growing and finally expand during periods of clinical latency. I argue here that the understanding of early metastasis formation, particularly of the currently invisible phase of metastatic colonization, will be essential for the next stage in adjuvant therapy development that reliably prevents metachronous metastasis.


Assuntos
Metástase Neoplásica/fisiopatologia , Segunda Neoplasia Primária , Progressão da Doença , Humanos , Metástase Neoplásica/genética , Metástase Neoplásica/terapia , Neoplasias/fisiopatologia , Segunda Neoplasia Primária/fisiopatologia , Segunda Neoplasia Primária/prevenção & controle , Processos Neoplásicos
15.
JMIR Med Inform ; 8(10): e17420, 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33026355

RESUMO

BACKGROUND: The German Network on Primary Immunodeficiency Diseases (PID-NET) utilizes the European Society for Immunodeficiencies (ESID) registry as a platform for collecting data. In the context of PID-NET data, we show how registries based on custom software can be made interoperable for better collaborative access to precollected data. The Open Source Registry System for Rare Diseases (Open-Source-Registersystem für Seltene Erkrankungen [OSSE], in German) provides patient organizations, physicians, scientists, and other parties with open source software for the creation of patient registries. In addition, the necessary interoperability between different registries based on the OSSE, as well as existing registries, is supported, which allows those registries to be confederated at both the national and international levels. OBJECTIVE: Data from the PID-NET registry should be made available in an interoperable manner without losing data sovereignty by extending the existing custom software of the registry using the OSSE registry framework. METHODS: This paper describes the following: (1) the installation and configuration of the OSSE bridgehead, (2) an approach using a free toolchain to set up the required interfaces to connect a registry with the OSSE bridgehead, and (3) the decentralized search, which allows the formulation of inquiries that are sent to a selected set of registries of interest. RESULTS: PID-NET uses the established and highly customized ESID registry software. By setting up a so-called OSSE bridgehead, PID-NET data are made interoperable according to a federated approach, and centrally formulated inquiries for data can be received. As the first registry to use the OSSE bridgehead, the authors introduce an approach using a free toolchain to efficiently implement and maintain the required interfaces. Finally, to test and demonstrate the system, two inquiries are realized using the graphical query builder. By establishing and interconnecting an OSSE bridgehead with the underlying ESID registry, confederated queries for data can be received and, if desired, the inquirer can be contacted to further discuss any requirements for cooperation. CONCLUSIONS: The OSSE offers an infrastructure that provides the possibility of more collaborative and transparent research. The decentralized search functionality includes registries into one search application while still maintaining data sovereignty. The OSSE bridgehead enables any registry software to be integrated into the OSSE network. The proposed toolchain to set up the required interfaces consists of freely available software components that are well documented. The use of the decentralized search is uncomplicated to use and offers a well-structured, yet still improvable, graphical user interface to formulate queries.

16.
Nat Commun ; 11(1): 4977, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-33020483

RESUMO

Although thousands of breast cancer cells disseminate and home to bone marrow until primary surgery, usually less than a handful will succeed in establishing manifest metastases months to years later. To identify signals that support survival or outgrowth in patients, we profile rare bone marrow-derived disseminated cancer cells (DCCs) long before manifestation of metastasis and identify IL6/PI3K-signaling as candidate pathway for DCC activation. Surprisingly, and similar to mammary epithelial cells, DCCs lack membranous IL6 receptor expression and mechanistic dissection reveals IL6 trans-signaling to regulate a stem-like state of mammary epithelial cells via gp130. Responsiveness to IL6 trans-signals is found to be niche-dependent as bone marrow stromal and endosteal cells down-regulate gp130 in premalignant mammary epithelial cells as opposed to vascular niche cells. PIK3CA activation renders cells independent from IL6 trans-signaling. Consistent with a bottleneck function of microenvironmental DCC control, we find PIK3CA mutations highly associated with late-stage metastatic cells while being extremely rare in early DCCs. Our data suggest that the initial steps of metastasis formation are often not cancer cell-autonomous, but also depend on microenvironmental signals.


Assuntos
Interleucina-6/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Transdução de Sinais , Medula Óssea/patologia , Mama/citologia , Neoplasias da Mama/patologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Receptor gp130 de Citocina/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Humanos , Interleucina-6/genética , Mutação , Metástase Neoplásica/genética , Receptores de Interleucina-6/deficiência , Receptores de Interleucina-6/metabolismo , Células Estromais/metabolismo , Microambiente Tumoral
17.
Artigo em Inglês | MEDLINE | ID: mdl-32941296

RESUMO

Type 1 plasminogen deficiency is a rare genetic disorder. Type 1 plasminogen deficiency is characterized by fibrin-rich pseudomembrane formation on mucosal surfaces, particularly the conjunctiva. Tracheobronchial tree involvement is a less common reported manifestation of type 1 plasminogen deficiency. Pseudomembranes in the tracheobronchial tree may result in respiratory compromise and ultimately fail if not recognized and treated. Currently, there is no specific replacement therapy approved for the treatment of congenital plasminogen deficiency. In the present paper, we report that type 1 plasminogen deficiency with novel frameshift mutation and pulmonary involvement was treated initially with systemic fresh frozen plasma followed by pulmonary lavage with fresh frozen plasma and tissue plasminogen activator.

18.
J Card Surg ; 35(9): 2185-2193, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32652711

RESUMO

BACKGROUND: The aim of this study was to evaluate the impact of transcatheter aortic valve implantation (TAVI) on mitral valve geometry and function. METHODS: Eighty-four patients underwent TAVI. Forty-four (52%) patients received a balloon-expandable valve and 40 (48%) were implanted with a self-expandable valve. All patients underwent three-dimensional-volumetric transesophageal echocardiography of the mitral valve before and immediately after TAVI. A dedicated software was used for assisted semiautomatic measurement of mitral annular geometry. RESULTS: During systole, the anterior to posterior (AP) diameter was significantly reduced after the procedure (3.4 ± 0.5 cm vs 3.2 ± 0.5 cm; P < .05). The mitral annular area (10.8 ± 2.8cm2 vs 9.9 ± 2.6cm2 ; P < .05) as well as the tenting area (1.6 ± 0.7 cm2 vs 1.2 ± 0.6 cm2 ; P < .001) measured at mid-systole were reduced after TAVI. Diastolic measures were similar. Patients treated with balloon-expandable valves showed a significantly larger reduction in the AP diameter compared to self-expandable valves (-0.25 cm vs -0.11 cm; P < .05). The reduction of the annular area was higher in the balloon-expandable group (-1.2 ± 1.59 vs -0.22 ± 1.41; P < .05). Grade of mitral regurgitation did improve or remained stable after TAVI. CONCLUSION: TAVI significantly impacts the mitral valve and mitral annular geometry and morphology. The choice of the prosthesis (balloon- vs self-expandable) may be relevant for those changes.

19.
Immunol Invest ; : 1-15, 2020 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-32633164

RESUMO

We describe a cohort of 25 Iranian patients with infantile inflammatory bowel disease (IBD), 14 (56%) of whom had monogenic defects. After proper screening, patients were referred for whole exome sequencing (WES). Four patients had missense mutations in the IL10 RA, and one had a large deletion in the IL10 RB. Four patients had mutations in genes implicated in host:microbiome homeostasis, including TTC7A deficiency, and two patients with novel mutations in the TTC37 and NOX1. We found a novel homozygous mutation in the SRP54 in a deceased patient and the heterozygous variant in his sibling with a milder phenotype. Three patients had combined immunodeficiency: one with ZAP-70 deficiency (T+B+NK-), and two with atypical SCID due to mutations in RAG1 and LIG4. One patient had a G6PC3 mutation without neutropenia. Eleven of the 14 patients with monogenic defects were results of consanguinity and only 4 of them were alive to this date.

20.
BMC Med Genet ; 21(1): 140, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32605629

RESUMO

BACKGROUND: Cohen syndrome, an autosomal recessive syndrome, is a rare syndrome with diverse clinical manifestations including failure to thrive, hypotonia, hypermobile joints, microcephaly, intellectual disabilities, craniofacial and limb anomalies, neutropenia and a friendly character. It is associated with mutations of the vacuolar protein sorting 13 homolog B (VPS13B) gene, which is involved in the development of the ocular, hematological and central nervous systems. This gene encodes a transmembrane protein playing a crucial role in preserving the integrity of the Golgi complex. To date, more than 150 mutations of VPS13B have been reported in over 200 Cohen syndrome patients. Missense or nonsense mutations are the most common mutations. CASE PRESENTATION: A 4-year-old girl, born to consanguineous parents, was referred to the pediatric clinical immunology outpatient clinic for investigation of recurrent neutropenia with a history of recurrent infections in the past year. On physical examination, she had the characteristic facial features of Cohen syndrome, developmental delay and speech disorder. She had a cheerful disposition, and her mother gave a history of feeding difficulties in her first months of life. She did not present any ophthalmologic or cardiac abnormalities. Her lab results revealed moderate neutropenia. Serum IgG, IgM, IgA and IgE levels were normal. She fulfilled the clinical diagnostic criteria for Cohen syndrome. WES revealed a novel homozygous frameshift variant in VPS13B (LRG_351t1: c.7095del; p.Ser2366AlafsTer49). Currently, she is not experiencing any severe problem, and she undergoes irregular medical treatment once her neutrophil count decreases under the normal limit. Her verbal and motor abilities have improved as a result of speech and occupational therapies. CONCLUSION: We reported a novel homozygous frameshift variant in VPS13B (LRG_351t1: c.7095del; p.Ser2366AlafsTer49) in a 4-year-old girl with Cohen syndrome. Cohen syndrome should be considered in differential diagnosis of any child with intellectual disability and neutropenia.


Assuntos
Dedos/anormalidades , Deficiência Intelectual/genética , Microcefalia/genética , Hipotonia Muscular/genética , Mutação/genética , Miopia/genética , Obesidade/genética , Degeneração Retiniana/genética , Proteínas de Transporte Vesicular/genética , Pré-Escolar , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Fenótipo
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