Cerebral hemispheric glioblastoma with PNET-like morphology and histone H3.3 G34 mutation in younger patients: Report of three rare cases and diagnostic pitfalls.

Indian J Pathol Microbiol. 2020 Apr-Jun;63(2):262-266

Authors: Cheng Y, Bao W, Wu Q

Abstract
Recurrent mutations in H3F3A that encodes the histone 3 variant H3.3, lead to amino acid substitutions including K27M and G34R/V-which are observed in high-grade gliomas (HGGs) of children and young adults. Previous studies have focused on gliomas with K27M mutation, whereas gliomas with G34R/V mutation have received little attention. Herein, we report three rare cases of glioblastoma (GBM) with H3.3 G34 mutation arising from a cerebral hemisphere in two children and one young adult. All three cases showed microscopic characteristics of central nervous system primitive neuroectodermal tumor (CNS-PNET, called CNS embryonal tumors in WHO 2016 Revised 4th Edition) and presented H3.3 G34 mutation. H3.3 G34-mutant brain tumors were formerly a group of histopathologically distinct neoplasms, involved in GBM, CNS-PNET, and astroblastoma. However, recent studies have demonstrated that different CNS tumors with H3.3 G34 mutation display coherent epigenetic signatures, implying a single biological origin. Correspondingly, our three cases showed high consistency in tumor location, histological morphology, and molecular phenotype. Their immunophenotypes are similar to astrocytoma, with ATRX loss and TP53 mutation. Therefore it suggests that these H3.3 G34-mutant brain tumors may be a rare entity of HGG.

PMID: 32317528 [PubMed - indexed for MEDLINE]

Two cases of rare subglottic MALT lymphoma of the larynx.

Am J Otolaryngol. 2020 Nov - Dec;41(6):102736

Authors: Johnson AO, Stevens BP, Lam JT, Schweinfurth JM

Abstract
BACKGROUND: Primary MALT lymphoma of the larynx is a rare condition first described in 1990. There have been only 43 reported cases as of 2015. The disease appears to be indolent in nature and responds well to radiation therapy. Symptoms are non-specific and may be limited to a combination of hoarseness, sore throat, shortness of breath, or cough.
METHODS: We describe two cases of subglottic laryngeal MALT lymphoma identified from one academic medical center within five years of each other. Though identical in pathology, the presentation of the two cases were distinct in both patient demographic and tumor appearance. One patient required dilation of a subglottic stenosis caused by tumor, and the other required surgical debulking of a ball-valve-like mass. Neither patient presented with B-symptoms (fever, night sweats, weight loss) that often characterize other lymphomas.
RESULTS: In both cases, histopathological exam revealed extensive infiltration of mucosa with atypical monomorphous lymphocytes, consistent with MALT lymphoma.
CONCLUSION: MALT lymphoma of the larynx may present with non-specific symptoms such as cough and/or hoarseness. Thorough evaluation including flexible laryngoscopy should be performed should these symptoms persist without a known cause. Surgical biopsy and histopathological exam are crucial to determine the etiology of unknown subglottic masses.

PMID: 33198051 [PubMed - indexed for MEDLINE]

Development of a Social Network for People Without a Diagnosis (RarePairs): Evaluation Study.

J Med Internet Res. 2020 09 29;22(9):e21849

Authors: Kühnle L, Mücke U, Lechner WM, Klawonn F, Grigull L

Abstract
BACKGROUND: Diagnostic delay in rare disease (RD) is common, occasionally lasting up to more than 20 years. In attempting to reduce it, diagnostic support tools have been studied extensively. However, social platforms have not yet been used for systematic diagnostic support. This paper illustrates the development and prototypic application of a social network using scientifically developed questions to match individuals without a diagnosis.
OBJECTIVE: The study aimed to outline, create, and evaluate a prototype tool (a social network platform named RarePairs), helping patients with undiagnosed RDs to find individuals with similar symptoms. The prototype includes a matching algorithm, bringing together individuals with similar disease burden in the lead-up to diagnosis.
METHODS: We divided our project into 4 phases. In phase 1, we used known data and findings in the literature to understand and specify the context of use. In phase 2, we specified the user requirements. In phase 3, we designed a prototype based on the results of phases 1 and 2, as well as incorporating a state-of-the-art questionnaire with 53 items for recognizing an RD. Lastly, we evaluated this prototype with a data set of 973 questionnaires from individuals suffering from different RDs using 24 distance calculating methods.
RESULTS: Based on a step-by-step construction process, the digital patient platform prototype, RarePairs, was developed. In order to match individuals with similar experiences, it uses answer patterns generated by a specifically designed questionnaire (Q53). A total of 973 questionnaires answered by patients with RDs were used to construct and test an artificial intelligence (AI) algorithm like the k-nearest neighbor search. With this, we found matches for every single one of the 973 records. The cross-validation of those matches showed that the algorithm outperforms random matching significantly. Statistically, for every data set the algorithm found at least one other record (match) with the same diagnosis.
CONCLUSIONS: Diagnostic delay is torturous for patients without a diagnosis. Shortening the delay is important for both doctors and patients. Diagnostic support using AI can be promoted differently. The prototype of the social media platform RarePairs might be a low-threshold patient platform, and proved suitable to match and connect different individuals with comparable symptoms. This exchange promoted through RarePairs might be used to speed up the diagnostic process. Further studies include its evaluation in a prospective setting and implementation of RarePairs as a mobile phone app.

PMID: 32990634 [PubMed - indexed for MEDLINE]

Endoscopy for a fourth branchial cleft cyst.

Am J Otolaryngol. 2020 Nov - Dec;41(6):102623

Authors: Saadoun A

PMID: 32623228 [PubMed - indexed for MEDLINE]

Central diabetes insipidus: A rare unreported side effect of temozolomide in pediatrics.

Pediatr Blood Cancer. 2020 12;67(12):e28516

Authors: Kuo C, Foon D, Waters K, Cheung C, Margol AS

PMID: 32573959 [PubMed - indexed for MEDLINE]

Ascending Aortic Aneurysm in a Case of Arterial Tortuosity Syndrome: A Rare Tortuous Disorder.

World J Pediatr Congenit Heart Surg. 2020 Jul;11(4):NP53-NP56

Authors: Siddiqui S, Rana Y, Patel H, Malhotra A, Mishra A

Abstract
Aortic aneurysms are a common entity among adults but very rare in the pediatric age-group. Association with autosomal inheritance is well established. We describe the unusual clinical presentation of a large ascending aortic aneurysm in a young child who was ultimately found to have severe diffuse arterial tortuosity.

PMID: 28825384 [PubMed - indexed for MEDLINE]

Inactivating PTH/PTHrP signaling disorders (iPPSDs): evaluation of the new classification in a multicenter large series of 544 molecularly characterized patients.

Eur J Endocrinol. 2021 Feb;184(2):311-320

Authors: Pereda A, Elli FM, Thiele S, de Sanctis L, Rothenbuhler A, Hanna P, Francou B, Ertl DA, Perez de Nanclares G, Linglart A, Mantovani G

Abstract
Objective: Pseudohypoparathyroidism and related disorders belong to a group of heterogeneous rare diseases that share an impaired signaling downstream of Gsα-protein-coupled receptors. Affected patients may present with various combination of symptoms including resistance to PTH and/or to other hormones, ectopic ossifications, brachydactyly type E, early onset obesity, short stature and cognitive difficulties. Several years ago we proposed a novel nomenclature under the term of inactivating PTH/PTHrP signaling disorders (iPPSD). It is now of utmost importance to validate these criteria and/or improve the basis of this new classification.
Design: Retrospective study of a large international series of 459 probands and 85 relatives molecularly characterized.
Methods: Information on major and minor criteria associated with iPPSD and genetic results were retrieved from patient files. We compared the presence of each criteria according to the iPPSD subtype, age and gender of the patients.
Results: More than 98% of the probands met the proposed criteria for iPPSD classification. Noteworthy, most patients (85%) presented a combination of symptoms rather than a single sign suggestive of iPPSD and the overlap among the different genetic forms of iPPSD was confirmed. The clinical and molecular characterization of relatives identified familial history as an additional important criterion predictive of the disease.
Conclusions: The phenotypic analysis of this large cohort confirmed the utility of the major and minor criteria and their combination to diagnose iPPSD. This report shows the importance of having simple and easily recognizable signs to diagnose with confidence these rare disorders and supports a better management of patients.

PMID: 33270042 [PubMed - indexed for MEDLINE]

ENSAT registry-based randomized clinical trials for adrenocortical carcinoma.

Eur J Endocrinol. 2021 Feb;184(2):R51-R59

Authors: Crona J, Baudin E, Terzolo M, Chrisoulidou A, Angelousi A, Ronchi CL, Oliveira CL, Nieveen van Dijkum EJM, Ceccato F, Borson-Chazot F, Reimondo G, Tiberi GAM, Ettaieb H, Kiriakopoulos A, Letizia C, Kastelan D, Osher E, Yiannakopoulou E, Arnaldi G, Assié G, Paiva I, Bourdeau I, Newell-Price J, Nowak KM, Romero MT, De Martino MC, Bugalho MJ, Sherlock M, Vantyghem MC, Dennedy MC, Loli P, Rodien P, Feelders R, de Krijger R, Van Slycke S, Aylwin S, Morelli V, Vroonen L, Shafigullina Z, Bancos I, Trofimiuk-Müldner M, Quinkler M, Luconi M, Kroiss M, Naruse M, Igaz P, Mihai R, Della Casa S, Berruti A, Fassnacht M, Beuschlein F

Abstract
Adrenocortical carcinoma (ACC) is an orphan disease lacking effective systemic treatment options. The low incidence of the disease and high cost of clinical trials are major obstacles in the search for improved treatment strategies. As a novel approach, registry-based clinical trials have been introduced in clinical research, so allowing for significant cost reduction, but without compromising scientific benefit. Herein, we describe how the European Network for the Study of Adrenal Tumours (ENSAT) could transform its current registry into one fit for a clinical trial infrastructure. The rationale to perform randomized registry-based trials in ACC is outlined including an analysis of relevant limitations and challenges. We summarize a survey on this concept among ENSAT members who expressed a strong interest in the concept and rated its scientific potential as high. Legal aspects, including ethical approval of registry-based randomization were identified as potential obstacles. Finally, we describe three potential randomized registry-based clinical trials in an adjuvant setting and for advanced disease with a high potential to be executed within the framework of an advanced ENSAT registry. Thus we, therefore, provide the basis for future registry-based trials for ACC patients. This could ultimately provide proof-of-principle of how to perform more effective randomized trials for an orphan disease.

PMID: 33166271 [PubMed - indexed for MEDLINE]

Mesenchymal stromal cells for systemic sclerosis treatment.

Autoimmun Rev. 2021 Jan 18;:102755

Authors: Farge D, Loisel S, Lansiaux P, Tarte K

Abstract
Systemic sclerosis (SSc) is a rare chronic autoimmune disease characterized by vasculopathy, dysregulation of innate and adaptive immune responses, and progressive fibrosis. SSc remains an orphan disease, with high morbity and mortality in SSC patients. The mesenchymal stromal cells (MSC) demonstrate in vitro and in vivo pro-angiogenic, immuno-suppressive, and anti-fibrotic properties and appear as a promising stem cell therapy type, that may target the key pathological features of SSc disease. This review aims to summarize acquired knowledge in the field of :1) MSC definition and in vitro and in vivo functional properties, which vary according to the donor type (allogeneic or autologous), the tissue sources (bone marrow, adipose tissue or umbilical cord) or inflammatory micro-environment in the recipient; 2) preclinical studies in various SSc animal models , which showed reduction in skin and lung fibrosis after MSC infusion; 3) first clinical trials in human, with safety and early efficacy results reported in SSc patients or currently tested in several ongoing clinical trials.

PMID: 33476823 [PubMed - as supplied by publisher]

Into the gray-zone: update on the diagnosis and classification of a rare lymphoma.

Expert Rev Hematol. 2020 01;13(1):1-3

Authors: Egan C, Pittaluga S

PMID: 31755790 [PubMed - indexed for MEDLINE]

A Platform for Experimental Precision Medicine: The Extended BXD Mouse Family.

Cell Syst. 2021 Jan 13;:

Authors: Ashbrook DG, Arends D, Prins P, Mulligan MK, Roy S, Williams EG, Lutz CM, Valenzuela A, Bohl CJ, Ingels JF, McCarty MS, Centeno AG, Hager R, Auwerx J, Lu L, Williams RW

Abstract
The challenge of precision medicine is to model complex interactions among DNA variants, phenotypes, development, environments, and treatments. We address this challenge by expanding the BXD family of mice to 140 fully isogenic strains, creating a uniquely powerful model for precision medicine. This family segregates for 6 million common DNA variants-a level that exceeds many human populations. Because each member can be replicated, heritable traits can be mapped with high power and precision. Current BXD phenomes are unsurpassed in coverage and include much omics data and thousands of quantitative traits. BXDs can be extended by a single-generation cross to as many as 19,460 isogenic F1 progeny, and this extended BXD family is an effective platform for testing causal modeling and for predictive validation. BXDs are a unique core resource for the field of experimental precision medicine.

PMID: 33472028 [PubMed - as supplied by publisher]

Idiopathic chylopericardium. A case report from Saudi Arabia.

Saudi Med J. 2020 Mar;41(3):304-308

Authors: Kawthar AM

Abstract
Chylopericardium is a rare clinical condition in which chyle leaks into the pericardial space owing to lymphatic system derangement. It can be idiopathic or occur secondarily to another clinical condition. Optimal management is accomplished through surgical intervention to impede leaks and drain fluid. In this report, we discuss an initially asymptomatic patient with a pre-employment chest radiograph that revealed cardiomegaly. An echocardiogram revealed pericardial effusion. Medical workup was unable to determine secondary causes for effusion. Pericardiocentesis revealed milky-colored fluid with a high lymphocyte count, and a lymphoscintigraphy lymphangiogram revealed a leak into the pericardium and decreased flow through left iliac and left periaortic lymph nodes. Since the patient was asymptomatic, she was treated conservatively with diet changes, pericardial drainage, and a pericardial window procedure. This type of case risks being misdiagnosed as tuberculosis, especially in countries where tuberculosis is endemic. In such cases, assessing pericardial fluid for chyle is crucial.

PMID: 32114604 [PubMed - indexed for MEDLINE]

Leiomyosarcoma of the colon. A very uncommon condition with poor prognosis.

Gastroenterol Hepatol. 2020 Apr;43(4):200-201

Authors: Merichal Resina M, Cerdan Santacruz C, Sierra Grañón E, Tarragona Foradada JA, Olsina Kissler JJ

PMID: 31864684 [PubMed - indexed for MEDLINE]

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"Rare Diseases"[Mesh] OR "orphan disease"

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Prenatal Diagnosis of a Ventral Abdominal Wall Defect.

Neoreviews. 2020 04;21(4):e286-e292

Authors: Beam K, Wojcik MH, Agrawal PB, Smithers C, Estroff J

PMID: 32238493 [PubMed - indexed for MEDLINE]

Somatic copy number variants in neuropsychiatric disorders.

Curr Opin Genet Dev. 2021 Jan 11;68:9-17

Authors: Maury EA, Walsh CA

Abstract
Copy number variants (CNVs) have been implicated in neuropsychiatric disorders, with rare-inherited and de novo CNVs (dnCNVs) having large effects on disease liability. Recent studies started exploring a class of dnCNVs that occur post-zygotically, and are therefore present in some but not all cells of the body. Analogous to conditional mutations in animal models, the presence of risk mutations in a fraction of cells has the potential to enlighten how damaging mutations affect cell-type/cell-circuit specific pathologies leading to neuropsychiatric manifestations. Although mosaic CNVs appear to contribute to a modest fraction of risk (0.3-0.5%), expanding our insights about them with more sensitive experimental and statistical methods, has the potential to help clarify mechanisms of neuropsychiatric disease.

PMID: 33444936 [PubMed - as supplied by publisher]

Syringomyelia and Chiari Syndrome Registry: advances in epidemiology, clinical phenotypes and natural history based on a North Western Italy cohort.

Ann Ist Super Sanita. 2020 Jan-Mar;56(1):48-58

Authors: Ciaramitaro P, Garbossa D, Peretta P, Piatelli G, Massimi L, Valentini L, Migliaretti G, Baldovino S, Roccatello D, Kodra Y, Taruscio D, Interregional Chiari and Syringomyelia Consortium, on behalf of the Interregional Chiari and Syringomyelia Consortium

Abstract
BACKGROUND: Syringomyelia and Chiari Syndrome are classified as rare diseases, but current known occurrence in Europe is missing. The increased ability to diagnose these pathologies by magnetic resonance imaging and its widespread availability has led to an increase of reported cases, often asymptomatic, with the need to standardize definitions, diagnostic criteria and treatments.
AIMS: We present shared Interregional Recommendations developed with the primary aim to estimate Syringomyelia and Chiari Syndrome prevalence and incidence in North Western Italy, with special reference to symptomatic forms.
METHODS: An agreement for the standardization of definitions, classifications, diagnostic criteria and surgical Recommendations was reached by the multidisciplinary Interregional Piemonte and Valle d'Aosta Chiari-Syringomyelia Consortium (Delphi method); next, in 2011 a census for Syringomyelia and Chiari Malformation was performed through the Interregional Piemonte and Valle d'Aosta Rare Disease Registry, integrated by a dedicated form in order to estimate prevalence and incidence.
RESULTS: 436 patients, 292 females, met shared interregional diagnostic criteria. Syringomyelia prevalence was estimated in 4.84:100 000; Chiari Malformation prevalence was 7.74:100 000; incidence was 0.82:100 000 and 3.08:100 000 respectively. Demographics, neuroradiological parameters and aetiology were reported (in symptomatic and asymptomatic forms). Finally, symptoms and signs, familiar and natural history were analyzed.
CONCLUSIONS: First Italian epidemiological data (prevalence, incidence) on Chiari and syringomyelia was collected, according to shared diagnostic Recommendations. Future perspectives include the adoption of these Recommendations at national level to standardize the access to diagnosis and care process and promote multicenter clinical trials.

PMID: 32242535 [PubMed - indexed for MEDLINE]

Anti-synthetase syndrome: a rare and challenging diagnosis for bilateral ground-glass opacities-a case report with literature review.

BMC Pulm Med. 2021 Jan 06;21(1):11

Authors: Alfraji N, Mazahir U, Chaudhri M, Miskoff J

Abstract
BACKGROUND: Anti-synthetase syndrome (ASS) is an uncommon immune-mediated entity characterized by myositis, interstitial lung disease (ILD), non-erosive arthritis, and less common features such as fever, Raynaud's phenomenon, and skin changes in association with anti-aminoacyl-transfer-RNA antibodies, most commonly anti-Jo-1 antibodies.
CASE PRESENTATION: We present a challenging and rare case of ASS-associated ILD presenting with unexplained respiratory symptoms and bilateral infiltrates on chest imaging during the COVID-19 pandemic. High clinical suspicion for ASS with early appropriate therapy with corticosteroids and immunosuppressive agents led to marked clinical improvement.
CONCLUSION: High index of suspicion for ASS is mandated in patients with unexplained ILD. A comprehensive autoimmune work-up is important as an early treatment with corticosteroids with or without immunomodulators improves patient outcomes and survival in an otherwise poor prognostic disease.

PMID: 33407281 [PubMed - indexed for MEDLINE]

The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing.

Nat Neurosci. 2021 Jan 11;:

Authors: Rodin RE, Dou Y, Kwon M, Sherman MA, D'Gama AM, Doan RN, Rento LM, Girskis KM, Bohrson CL, Kim SN, Nadig A, Luquette LJ, Gulhan DC, Brain Somatic Mosaicism Network, Park PJ, Walsh CA

Abstract
We characterize the landscape of somatic mutations-mutations occurring after fertilization-in the human brain using ultra-deep (~250×) whole-genome sequencing of prefrontal cortex from 59 donors with autism spectrum disorder (ASD) and 15 control donors. We observe a mean of 26 somatic single-nucleotide variants per brain present in ≥4% of cells, with enrichment of mutations in coding and putative regulatory regions. Our analysis reveals that the first cell division after fertilization produces ~3.4 mutations, followed by 2-3 mutations in subsequent generations. This suggests that a typical individual possesses ~80 somatic single-nucleotide variants present in ≥2% of cells-comparable to the number of de novo germline mutations per generation-with about half of individuals having at least one potentially function-altering somatic mutation somewhere in the cortex. ASD brains show an excess of somatic mutations in neural enhancer sequences compared with controls, suggesting that mosaic enhancer mutations may contribute to ASD risk.

PMID: 33432195 [PubMed - as supplied by publisher]

Large mosaic copy number variations confer autism risk.

Nat Neurosci. 2021 Jan 11;:

Authors: Sherman MA, Rodin RE, Genovese G, Dias C, Barton AR, Mukamel RE, Berger B, Park PJ, Walsh CA, Loh PR

Abstract
Although germline de novo copy number variants (CNVs) are known causes of autism spectrum disorder (ASD), the contribution of mosaic (early-developmental) copy number variants (mCNVs) has not been explored. In this study, we assessed the contribution of mCNVs to ASD by ascertaining mCNVs in genotype array intensity data from 12,077 probands with ASD and 5,500 unaffected siblings. We detected 46 mCNVs in probands and 19 mCNVs in siblings, affecting 2.8-73.8% of cells. Probands carried a significant burden of large (>4-Mb) mCNVs, which were detected in 25 probands but only one sibling (odds ratio = 11.4, 95% confidence interval = 1.5-84.2, P = 7.4 × 10-4). Event size positively correlated with severity of ASD symptoms (P = 0.016). Surprisingly, we did not observe mosaic analogues of the short de novo CNVs recurrently observed in ASD (eg, 16p11.2). We further experimentally validated two mCNVs in postmortem brain tissue from 59 additional probands. These results indicate that mCNVs contribute a previously unexplained component of ASD risk.

PMID: 33432194 [PubMed - as supplied by publisher]