Andes Pediatr. 2021 Apr;92(2):309-315. doi: 10.32641/andespediatr.v92i2.3716.

ABSTRACT

In the framework of the vaccination campaign against the SARS-CoV-2 virus, the Chilean Ministry of Health requested advice from the Genetics Branch of the Chilean Society of Pediatrics, to define the level of prioritization for people with Down Syndrome . A panel of geneticists worked on the development of this consensus, in which not only patients with Down syndrome were included, but the search was extended to patients with other types of disabilities, in both pediatric and adult ages in or der to contribute to the development of public health measures against the COVID-19 pandemic. The consensus concludes that, given the prevalence of comorbidities associated with Down syndrome, the higher incidence of cases with severe COVID-19 in this population group and a higher mortality, individuals with trisomy 21 should be considered as a high-risk population, and therefore, vaccina tion against SARS-CoV-2 should have a high priority for all people with Down syndrome regardless of their age (except for the age limit established by the clinical trials of each vaccine), and should be preceded only by the groups of health personnel and adults aged > 60-65 years. Likewise, this group of experts urges health authorities to include people with intellectual disabilities and related conditions as a priority population (other chromosomal abnormalities other than Down syndrome, intellectual disability, congenital anomalies and conditions that cause disability with microcephaly), as well as the caregivers of people with this type of conditions. Vaccination in children with this type of disorders should be considered as part of the first priority group, once safe vaccines against SARS-CoV-2 are available for use in children and adolescents.

PMID:34106172 | DOI:10.32641/andespediatr.v92i2.3716

Orphanet J Rare Dis. 2021 Jun 8;16(1):262. doi: 10.1186/s13023-021-01830-4.

ABSTRACT

BACKGROUND: Rare diseases are ailments which impose a heavy burden on individual patients and global society as a whole. The rare disease management landscape is not a smooth one-a rare disease is quite often hard to diagnose, treat, and investigate. In China, the country's rapid economic rise and development has brought an increased focus on rare diseases. At present, there is a growing focus placed on the importance and public health priority of rare diseases and on improving awareness, definitions, and treatments.

METHODS: In this work we utilized clinical data from the Shanghai HIE System to characterize the status of 33 rare diseases with effective treatment in Shanghai for the time period of 2013-2016.

RESULTS AND CONCLUSION: First, we describe the total number of patients, year-to-year change in new patients with diagnosis in one of the target diseases and the distribution of gender and age for the top six (by patient number) diseases of the set of 33 rare diseases. Second, we describe the hospitalization burden in terms of in-hospital ratio, length of stay, and medical expenses during hospitalization. Finally, rare disease period prevalence is calculated for the rare diseases set.

PMID:34103049 | DOI:10.1186/s13023-021-01830-4

Eur J Anaesthesiol. 2021 Jul 1;38(7):788-790. doi: 10.1097/EJA.0000000000001317.

NO ABSTRACT

PMID:34101642 | DOI:10.1097/EJA.0000000000001317

Am J Case Rep. 2021 Jun 5;22:e930384. doi: 10.12659/AJCR.930384.

ABSTRACT

BACKGROUND Ewing sarcoma and primitive neuroectodermal tumor are rare tumors grouped under the spectrum of the Ewing sarcoma family of tumors. These highly malignant tumors involve the bones and commonly occur in children. Ewing sarcoma of the skull bone accounts for only 1% of all Ewing sarcomas, with primary skull base Ewing sarcoma occurring in less than 1% of cases. We present a case of skull base Ewing sarcoma with complete symptom recovery and near-total radiological resolution. CASE REPORT A 4-year-old girl initially presented with a 2-month history of vomiting, poor oral intake, weight loss, and gradual visual deterioration followed by acute symptoms of fever, breathing difficulties, and seizure. Initial computed tomography and magnetic resonance imaging of the brain displayed a large sinonasal mass with extensive regional infiltration and bony destruction and no evidence of distant metastasis. A transnasal biopsy was taken. The histopathology result revealed features of skull base Ewing sarcoma. The child was given a combination of radiotherapy and chemotherapy, to which she responded well, with a minimal residual tumor. CONCLUSIONS Skull base Ewing sarcoma is a rare entity, presenting a challenge to the reporting radiologists. Differential diagnoses of esthesioneuroblastoma, olfactory neuroepithelioma, and, more commonly, sinonasal carcinoma can be misleading since they have similar radiological appearances to skull base Ewing sarcoma, which differs in treatment regimen and prognosis. Therefore, a combination of histopathological appearance, radiographic findings, and clinical correlation is important to determine the correct diagnosis, establish the appropriate treatment regime, and improve the patient's survival.

PMID:34089579 | DOI:10.12659/AJCR.930384

Orphanet J Rare Dis. 2021 Jun 2;16(1):251. doi: 10.1186/s13023-021-01872-8.

ABSTRACT

BACKGROUND: The European Rare Kidney Disease Reference Network (ERKNet) recently established ERKReg, a Web-based registry for all patients with rare kidney diseases. The main objectives of this core registry are to generate epidemiological information, identify current patient cohort for clinical research, explore diagnostic and therapeutic management practices, and monitor treatment performance and patient's outcomes. The registry has a modular design that allows to integrate comprehensive disease-specific registries as extensions to the core database. The diagnosis (Orphacode) and diagnostic information (clinical, imaging, histopathological, biochemical, immunological and genetic) are recorded. Anthropometric, kidney function, and disease-specific management and outcome items informing a set of 61 key performance indicators (KPIs) are obtained annually. Data quality is ensured by automated plausibility checks upon data entry and regular offline database checks prompting queries. Centre KPI statistics and benchmarking are calculated automatically.

RESULTS: Within the first 24 months since its launch, 7607 patients were enrolled to the registry at 45 pediatric and 12 specialized adult nephrology units from 21 countries. A kidney disease diagnosis had been established in 97.1% of these patients at time of enrolment. While 199 individual disease entities were reported by Orphacode, 50% of the cohort could be classified with 11, 80% with 43 and 95% with 92 codes. Two kidney diagnoses were assigned in 6.5% of patients; 5.9% suffered from syndromic disease. Whereas glomerulopathies (54.8%) and ciliopathies including autosomal dominant polycystic kidney disease (ADPKD) (31.5%) were the predominant disease groups among adults, the pediatric disease spectrum encompassed congenital anomalies of the kidney and urinary tract (CAKUT) (33.7%), glomerulopathies (30.7%), ciliopathies (14.0%), tubulopathies (9.2%), thrombotic microangiopathies (5.6%), and metabolic nephropathies (4.1%). Genetically confirmed diagnoses were reported in 24% of all pediatric and 12% adult patients, whereas glomerulopathies had been confirmed by kidney biopsy in 80.4% adult versus 38.5% pediatric glomerulopathy cases.

CONCLUSIONS: ERKReg is a rapidly growing source of epidemiological information and patient cohorts for clinical research, and an innovative tool to monitor management quality and patient outcomes.

PMID:34078418 | PMC:PMC8173879 | DOI:10.1186/s13023-021-01872-8

Int J Environ Res Public Health. 2021 May 31;18(11):5895. doi: 10.3390/ijerph18115895.

ABSTRACT

Uterine leiomyomas are a common finding in medical practice, but their frequency changes drastically when contextualized in a syndrome, as in the following case. A 50-year-old woman with a known Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome presented at our clinic with abdominal pain located in the lower quadrants and scarcely responsive to analgesic therapy. A twisted gynecological pelvic mass was diagnosed, and management for prompt resolution was adopted. Histologically the mass was described as a leiomyoma. The aim of the present study is to share our experience and to review the literature to compare different manifestation of the disease and different approach used in the various centers. The additional novelty of the paper is the immunohistochemical study we carried out on the leiomyoma that is contrasted with the current etiopathogenetic theories.

PMID:34072739 | PMC:PMC8198036 | DOI:10.3390/ijerph18115895

Int J Environ Res Public Health. 2021 May 8;18(9):4993. doi: 10.3390/ijerph18094993.

ABSTRACT

Parents caring for children with rare diseases fear the long-term progression of the child's disease. The current study aims to systematically investigate the quality of life (QoL) in parents of children with different rare diseases. We performed a systematic literature search including quantitative studies on QoL of parents caring for children and adolescents with rare diseases in five databases (APA PsycArticles, APA PsycInfo, MEDLINE, PSYNDEXplus, and PubMed) published between 2000-2020. Of the 3985 titles identified, 31 studies met the inclusion criteria and were selected for narrative review. Studies were included if they investigated predictors of parental QoL or reported QoL compared to normative samples, parents of healthy children, or children with other chronic diseases. We used the Newcastle-Ottawa Scale to assess methodological quality. The systematic review revealed that parents of children with rare diseases experience reduced QoL compared to parents with healthy children and norm values. Psychosocial factors, beyond disease-specific predictors, were shown to influence parental QoL substantially and may thus present an essential aspect within interventions for this highly burdened group. Health care professionals should consider and address the impairment of parental QoL due to the child's rare disease. We discuss insights into existing research gaps and improvements for subsequent work.

PMID:34066738 | PMC:PMC8125857 | DOI:10.3390/ijerph18094993

Int J Mol Sci. 2021 May 27;22(11):5732. doi: 10.3390/ijms22115732.

ABSTRACT

Mutations in striated preferentially expressed protein kinase (SPEG), a member of the myosin light chain kinase protein family, are associated with centronuclear myopathy (CNM), cardiomyopathy, or a combination of both. Burgeoning evidence suggests that SPEG plays critical roles in the development, maintenance, and function of skeletal and cardiac muscles. Here we review the genotype-phenotype relationships and the molecular mechanisms of SPEG-related diseases. This review will focus on the progress made toward characterizing SPEG and its interacting partners, and its multifaceted functions in muscle regeneration, triad development and maintenance, and excitation-contraction coupling. We will also discuss future directions that are yet to be investigated including understanding of its tissue-specific roles, finding additional interacting proteins and their relationships. Understanding the basic mechanisms by which SPEG regulates muscle development and function will provide critical insights into these essential processes and help identify therapeutic targets in SPEG-related disorders.

PMID:34072258 | DOI:10.3390/ijms22115732

Int J Mol Sci. 2021 May 25;22(11):5569. doi: 10.3390/ijms22115569.

ABSTRACT

The high mortality rate together with an ever-growing number of annual cases have defined neoplastic disorders as "the real 21st-century disease". Its dubious distinction also results from conventional therapy failure, which has made cancer an orphan disease. Therefore, innovative and alternative therapeutic strategies are mandatory. The ability to leverage human naturally occurring anti-tumor defenses has always represented a fascinating perspective, and the immuno blockage approval in cancer treatment represents in timeline the latest success. As a multifunctional organ, adipose tissue releases a large amount of adipokines having both carcinogenic and antitumor properties. The negative correlation between serum levels and risk for developing malignancies, as well as the huge number of existing preclinical studies, have identified adiponectin as a potential anticancer adipokine. Nevertheless, its usage in clinical has constantly clashed with the inability to reproduce a mimic synthetic compound. Between 2011 and 2013, two distinct adiponectin receptor agonists were recognized, opening new scenarios even in cancer. Here, we review the first orally active adiponectin receptor agonists AdipoRon, from the discovery to the anticancer evidence. Including our latest findings in osteosarcoma models, we summarize AdipoRon and other existing agonists state-of-art, questioning about the feasibility assessment of this strategy in cancer treatment.

PMID:34070338 | DOI:10.3390/ijms22115569

J Pak Med Assoc. 2021 Mar;71(3):1007-1010. doi: 10.47391/JPMA.045.

ABSTRACT

Dyskeratosis congenita is a very rare inherited haematological disorder characterised by a classical clinical triad of leukoplakia, skin pigmentation and dystrophied nails. Here is a case of a young patient who presented with brittle nails, lacy hyperpigmentation of the skin and leukoplakia along with pancytopenia. Haematopoietic stem cell transplantation is the only cure for this disease but due to financial constraints of the family it was not possible. The patient was placed on androgen therapy and showed favourable response but later was lost to follow-up.

PMID:34057965 | DOI:10.47391/JPMA.045

Stud Health Technol Inform. 2021 May 24;278:49-57. doi: 10.3233/SHTI210050.

ABSTRACT

The diagnosis of patients with rare diseases is often delayed. A Clinical Decision Support System using similarity analysis of patient-based data may have the potential to support the diagnosis of patients with rare diseases. This qualitative study has the objective to investigate how the result of a patient similarity analysis should be presented to a physician to enable diagnosis support. We conducted a focus group with physicians practicing in rare diseases as well as medical informatics researchers. To prepare the focus group, a literature search was performed to check the current state of research regarding visualization of similar patients. We then created software-mockups for the presentation of these visualization methods for the discussion within the focus group. Two persons took independently field notes for data collection of the focus group. A questionnaire was distributed to the participants to rate the visualization methods. The results show that four visualization methods are promising for the visualization of similar patients: "Patient on demand table", "Criteria selection", "Time-Series chart" and "Patient timeline. "Patient on demand table" shows a direct comparison of patient characteristics, whereas "Criteria selection" allows the selection of different patient criteria to get deeper insights into the data. The "Time-Series chart" shows the time course of clinical parameters (e.g. blood pressure) whereas a "Patient timeline" indicates which time events exist for a patient (e.g. several symptoms on different dates). In the future, we will develop a software-prototype of the Clinical Decision Support System to include the visualization methods and evaluate the clinical usage.

PMID:34042875 | DOI:10.3233/SHTI210050

Stud Health Technol Inform. 2021 May 24;278:41-48. doi: 10.3233/SHTI210049.

ABSTRACT

Rare lung diseases affect 1.5-3 million people in Europe while causing bad prognosis or early deaths for patients. The European Reference Network for Respiratory Diseases (ERN-Lung) is a patient centric network, funded by the European Union (EU). The aims of ERN-LUNG is to increase healthcare and research regarding rare respiratory diseases. An initial need for cross-border healthcare and research is the use of registries and databases. A typical problem in registries for RDs is the data exchange, since the registries use different kind of data with different types or descriptions. Therefore, ERN-Lung decided to create a new Registry Data-Warehouse (RDW) where different existing registries are connected to enable cross-border healthcare within ERN-Lung. This work facilitates the aims, conception and implementation for the RDW, while considering a semantic interoperability approach. We created a common dataset (CDS) to have a common descriptions of respiratory diseases patients within the ERN registries. We further developed the RDW based on Open Source Registry System for Rare Diseases (OSSE), which includes a Metadata Repository with the Samply.MDR to unique describe data for the minimal dataset. Within the RDW, data from existing registries is not stored in a central database. The RDW uses the approach of the "Decentral Search" and can send requests to the connected registries, whereas only aggregated data is returned about how many patients with specific characteristics are available. However, further work is needed to connect the different existing registries to the RDW and to perform first studies.

PMID:34042874 | DOI:10.3233/SHTI210049

Stud Health Technol Inform. 2021 May 27;281:1085-1086. doi: 10.3233/SHTI210356.

ABSTRACT

Web-based patient registries support clinicians by providing a way to effectively store and process data. Here, we present a new feature for the open-source registry software OSSE: medical reports generated with R Markdown. As part of a rare disease research project, we describe the process from requirements assessment to the current state of technical implementation. The feature offers clinicians the possibility to download customised as well as generic reports from an OSSE rare disease registry.

PMID:34042849 | DOI:10.3233/SHTI210356

Stud Health Technol Inform. 2021 May 27;281:138-142. doi: 10.3233/SHTI210136.

ABSTRACT

The OMOP Common Data Model (OMOP CDM) is an option to store patient data and to use these in an international context. Up to now, rare diseases can only be partly described in OMOP CDM. Therefore, it is necessary to investigate which special features in the context of rare diseases (e.g. terminologies) have to be considered, how these can be included in OMOP CDM and how physicians can use the data. An interdisciplinary team developed (1) a Transition Database for Rare Diseases by mapping Orpha Code, Alpha ID, SNOMED, ICD-10-GM, ICD-10-WHO and OMOP-conform concepts; and (2) a Rare Diseases Dashboard for physicians of a German Center of Rare Diseases by using methods of user-centered design. This demonstrated how OMOP CDM can be flexibly extended for different medical issues by using independent tools for mappings and visualization. Thereby, the adaption of OMOP CDM allows for international collaboration, enables (distributed) analysis of patient data and thus it can improve the care of people with rare diseases.

PMID:34042721 | DOI:10.3233/SHTI210136

Stud Health Technol Inform. 2021 May 27;281:600-604. doi: 10.3233/SHTI210241.

ABSTRACT

To identify patients with similar clinical profiles and derive insights from the records and outcomes of similar patients can help fast and precise diagnosis and other clinical decisions for rare diseases. Similarity methods are required to take into account the semantic relations between medical concepts and also the different relevance of all medical concepts presented in patients' medical records. In this paper, we introduce the methods developed in the context of rare disease screening/diagnosis from clinical data warehouse using medical concept embedding and adjusted aggregations. Our methods provided better preliminary results than baseline methods, with a significant improvement of precision among the top ranked similar patients, which is encouraging for further fine-tuning and application on a large-scale dataset for new/candidate patient identification.

PMID:34042646 | DOI:10.3233/SHTI210241

BMC Anesthesiol. 2021 May 26;21(1):162. doi: 10.1186/s12871-021-01380-z.

ABSTRACT

BACKGROUND: Nicolaides-Baraitser syndrome (NCBRS) is a rare disease caused by mutations in the SMRCA2 gene, which affects chromatin remodelling and leads to a wide range of symptoms including microcephaly, distinct facial features, recurrent seizures, and severe mental retardation. Until now, less than 100 cases have been reported.

CASE PRESENTATION: A 22-month old male infant with NCBRS underwent elective cleft palate surgery. The anaesthetists were challenged by the physiological condition of the patient: narrow face, very small mouth, mild tachypnea, slight sternal retractions, physical signs of partial monosomy 9p, and plagiocephalus, midface hypoplasia, V-shaped cleft palate, enhanced muscular hypotension, dysplastic kidneys (bilateral, estimated GFR: approx. 40 ml/m2), nocturnal oxygen demand, and combined apnea. In addition, little information was available about interaction of the NCBRS displayed by the patient and anaesthesia medications.

CONCLUSIONS: The cleft palate was successfully closed using the bridge flap technique. Overall, we recommend to perform a trial video assisted laryngoscopy in the setting of spontaneous breathing with deep inhalative anaesthesia before administration of muscle relaxation to detect any airway difficulties while remaining spontaneoues breathing and protective reflexes.

PMID:34039274 | DOI:10.1186/s12871-021-01380-z

Bull Cancer. 2021 Jul-Aug;108(7-8):771-778. doi: 10.1016/j.bulcan.2021.03.011. Epub 2021 May 20.

ABSTRACT

Hairy cell leukemia is a rare form of leukemia: three hundred new cases are diagnosed each year in France. The diagnosis is based on: (1) morphological examination of the blood and bone marrow smear, (2) analysis by flow cytometry of hairy cells, which express three or the four following markers: CD11c, CD25, CD103 and CD123, (3) identification of the BRAFV600E mutation, a true molecular marker of the disease. The management of treatment has evolved considerably in recent years. As of today, the purine analogues remain the standard treatment in the first line. Relapses are however observed in about 40% of cases. In the event of a first relapse, the preferred option is treatment with immunochemotherapy i.e. a combination of cladribine plus rituximab. Subsequent relapses are treated with moxetumomab pasudotox or BRAF inhibitors which provide indisputable benefits if third-line treatment is required. We will discuss in patients with relapsed/refractory hairy cell leukemia the needs for personalized medicine and the advantages and disadvantages of each treatment modality. The good prognosis for LT requires treatments that are not immunosuppressive, non-myelotoxic, and do not increase the risk of secondary cancers.

PMID:34023063 | DOI:10.1016/j.bulcan.2021.03.011

Nucleic Acids Res. 2021 Jul 2;49(W1):W93-W103. doi: 10.1093/nar/gkab347.

ABSTRACT

Copy Number Variants (CNVs) are an important cause of rare diseases. Array-based Comparative Genomic Hybridization tests yield a ∼12% diagnostic rate, with ∼8% of patients presenting CNVs of unknown significance. CNVs interpretation is particularly challenging on genomic regions outside of those overlapping with previously reported structural variants or disease-associated genes. Recent studies showed that a more comprehensive evaluation of CNV features, leveraging both coding and non-coding impacts, can significantly improve diagnostic rates. However, currently available CNV interpretation tools are mostly gene-centric or provide only non-interactive annotations difficult to assess in the clinical practice. Here, we present CNVxplorer, a web server suited for the functional assessment of CNVs in a clinical diagnostic setting. CNVxplorer mines a comprehensive set of clinical, genomic, and epigenomic features associated with CNVs. It provides sequence constraint metrics, impact on regulatory elements and topologically associating domains, as well as expression patterns. Analyses offered cover (a) agreement with patient phenotypes; (b) visualizations of associations among genes, regulatory elements and transcription factors; (c) enrichment on functional and pathway annotations and (d) co-occurrence of terms across PubMed publications related to the query CNVs. A flexible evaluation workflow allows dynamic re-interrogation in clinical sessions. CNVxplorer is publicly available at http://cnvxplorer.com.

PMID:34019647 | PMC:PMC8262689 | DOI:10.1093/nar/gkab347

J Inflamm (Lond). 2021 May 19;18(1):17. doi: 10.1186/s12950-021-00284-6.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is an orphan disease characterized by progressive loss of lung function resulting in shortness of breath and often death within 3-4 years of diagnosis. Repetitive lung injury in susceptible individuals is believed to promote chronic oxidative stress, inflammation, and uncontrolled collagen deposition. Several preclinical and retrospective clinical studies in IPF have reported beneficial outcomes associated with the use of proton pump inhibitors (PPIs) such as esomeprazole. Accordingly, we sought to investigate molecular mechanism(s) by which PPIs favorably regulate the disease process.

METHODS: We stimulated oxidative stress, pro-inflammatory and profibrotic phenotypes in primary human lung epithelial cells and fibroblasts upon treatment with bleomycin or transforming growth factor β (TGFβ) and assessed the effect of a prototype PPI, esomeprazole, in regulating these processes.

RESULTS: Our study shows that esomeprazole controls pro-inflammatory and profibrotic molecules through nuclear translocation of the transcription factor nuclear factor-like 2 (Nrf2) and induction of the cytoprotective molecule heme oxygenase 1 (HO1). Genetic deletion of Nrf2 or pharmacological inhibition of HO1 impaired esomeprazole-mediated regulation of proinflammatory and profibrotic molecules. Additional studies indicate that activation of Mitogen Activated Protein Kinase (MAPK) pathway is involved in the process. Our experimental data was corroborated by bioinformatics studies of an NIH chemical library which hosts gene expression profiles of IPF lung fibroblasts treated with over 20,000 compounds including esomeprazole. Intriguingly, we found 45 genes that are upregulated in IPF but downregulated by esomeprazole. Pathway analysis showed that these genes are enriched for profibrotic processes. Unbiased high throughput RNA-seq study supported antifibrotic effect of esomeprazole and revealed several novel targets.

CONCLUSIONS: Taken together, PPIs may play antifibrotic role in IPF through direct regulation of the MAPK/Nrf2/HO1 pathway to favorably influence the disease process in IPF.

PMID:34011367 | DOI:10.1186/s12950-021-00284-6

Nat Commun. 2021 May 18;12(1):2897. doi: 10.1038/s41467-021-23113-z.

ABSTRACT

Reciprocal copy number variations (CNVs) of 16p11.2 are associated with a wide spectrum of neuropsychiatric and neurodevelopmental disorders. Here, we use human induced pluripotent stem cells (iPSCs)-derived dopaminergic (DA) neurons carrying CNVs of 16p11.2 duplication (16pdup) and 16p11.2 deletion (16pdel), engineered using CRISPR-Cas9. We show that 16pdel iPSC-derived DA neurons have increased soma size and synaptic marker expression compared to isogenic control lines, while 16pdup iPSC-derived DA neurons show deficits in neuronal differentiation and reduced synaptic marker expression. The 16pdel iPSC-derived DA neurons have impaired neurophysiological properties. The 16pdel iPSC-derived DA neuronal networks are hyperactive and have increased bursting in culture compared to controls. We also show that the expression of RHOA is increased in the 16pdel iPSC-derived DA neurons and that treatment with a specific RHOA-inhibitor, Rhosin, rescues the network activity of the 16pdel iPSC-derived DA neurons. Our data suggest that 16p11.2 deletion-associated iPSC-derived DA neuron hyperactivation can be rescued by RHOA inhibition.

PMID:34006844 | DOI:10.1038/s41467-021-23113-z