A Pilot Study about Clinical Features of Aberrations Chromosome 22q

Abstract Objective A significant number of genetic variations have been identified in chromosome 22, using molecular genetic techniques. Various genomic disorders on chromosome 22, including cat's eye syndrome caused by extra copies of the proximal region of the 22q chromosome, are now well-defined.Our aim in the study was to show phenotypic variability associated with rearrangements of the 22q chromosomal region. Methods We focused our study on clinical aspects of these disorders, including genetic testing, genotype-phenotype correlation, and potential treatments. A total of 998 patients were referred for genetic analysis (Karyotyping, MLPA, array-CGH) during January 2015 to February 2020 because of intellectual deficiency, behavior issues, and/or multiple congenital abnormalities in several genetics departments. Informed consent was obtained from all the patients and/or their parents. Results 22q11.21 or 22q13.33 microdeletions and 22q11.22-q11.23 microduplication were identified in 31 patients out of referrals. The 22q aberrations were detected in 31/998 patients, giving a prevalence of 3.1%. In this study, 18 patients with 22q11.2 (LCR22A-H) deletion, three patients with 22q13.31 deletion, 9 patients with 22q11.2 duplication and one patient with 22q13.31 duplication were identified. We report on the clinical and molecular characterization of 31 individuals with distal deletions and duplications of chromosome 22q. Conclusions The current study demonstrated in the largest postnatal case series reporting the whole spectrum of atypical phenotypic and genotypic variations at 22q. We believe that when all the phenotypic differences are taken into account, various anomalies including developmental delay and intellectual disability might be considered as an indication to search for aberrations of 22q along with congenital heart diseases.

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Two Novel Mutations in the JAG1 Gene in Pediatric Patients with Alagille Syndrome: The First Case Series in Czech Republic

Diagnostics ◽

10.3390/diagnostics11060983 ◽

2021 ◽

Vol 11 (6) ◽

pp. 983

Author(s):

Dagmar Prochazková ◽

Romana Borská ◽

Lenka Fajkusová ◽

Petra Konečná ◽

Eliška Hloušková ◽

...

Keyword(s):

De Novo ◽

Phenotypic Variability ◽

Molecular Genetic ◽

Case Series ◽

Alagille Syndrome ◽

Pathogenic Mutation ◽

Novel Mutations ◽

Multisystem Disorder ◽

Targeted Next Generation Sequencing ◽

First Case

Background: Alagille syndrome (ALGS) is a highly variable multisystem disorder inherited in an autosomal dominant pattern with incomplete penetration. The disorder is caused by mutations in the JAG1 gene, only rarely in the NOTCH2 gene, which gives rise to malformations in multiple organs. Bile duct paucity is the main characteristic feature of the disease. Methods: Molecular-genetic examination of genes JAG1 and NOTCH2 in four probands of Czech origin who complied with the diagnostic criteria of ALGS was performed using targeted next-generation sequencing of genes JAG1 and NOTCH2. Segregation of variants in a family was assessed by Sanger sequencing of parental DNA. Results: Mutations in the JAG1 gene were confirmed in all four probands. We identified two novel mutations: c.3189dupG and c.1913delG. Only in one case, the identified JAG1 mutation was de novo. None of the parents carrying JAG1 pathogenic mutation was diagnosed with ALGS. Conclusion: Diagnosis of the ALGS is complicated due to the absence of clear genotype-phenotype correlations and the extreme phenotypic variability in the patients even within the same family. This fact is of particular importance in connection to genetic counselling and prenatal genetic testing.

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Molecular Basis and Clinical Aspects of Hereditary Megakaryocyte and Platelet Membrane Glycoprotein Disorders

Hämostaseologie ◽

10.1055/s-0038-1656647 ◽

1996 ◽

Vol 16 (02) ◽

pp. 114-138 ◽

Cited By ~ 6

Author(s):

R. E. Scharf

Keyword(s):

Genetic Basis ◽

Molecular Mechanisms ◽

Molecular Genetic ◽

Platelet Membrane ◽

Clinical Aspects ◽

Membrane Glycoprotein ◽

Membrane Glycoproteins ◽

Membrane Expression ◽

Receptor Complexes ◽

Platelet Membrane Glycoprotein

SummarySpecific membrane glycoproteins (GP) expressed by the megakaryocyte-platelet system, including GPIa-lla, GPIb-V-IX, GPIIb-llla, and GPIV are involved in mediat-ing platelet adhesion to the subendothelial matrix. Among these glycoproteins, GPIIb-llla plays a pivotal role since platelet aggregation is exclusively mediated by this receptor and its interaction with soluble macromolecular proteins. Inherited defects of the GPIIb-llla or GPIb-V-IX receptor complexes are associated with bleeding disorders, known as Glanzmann's thrombasthenia, Bernard-Soulier syndrome, or platelet-type von Willebrand's disease, respectively. Using immuno-chemical and molecular biology techniques, rapid advances in our understanding of the molecular genetic basis of these disorders have been made during the last few years. Moreover, analyses of patients with congenital platelet membrane glycoprotein abnormalities have provided valuable insights into molecular mechanisms that are required for structural and functional integrity, normal biosynthesis of the glycoprotein complexes and coordinated membrane expression of their constituents. The present article reviews the current state of knowledge of the major membrane glycoproteins in health and disease. The spectrum of clinical bleeding manifestations and established diagnostic criteria for each of these dis-orders are summarized. In particular, the variety of molecular defects that have been identified so far and their genetic basis will be discussed.

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Cartilage Regeneration with Cell-free Type 1 Collagen Matrix – Past, Present and Future (Part 1 – Clinical Aspects)

Zeitschrift für Orthopädie und Unfallchirurgie ◽

10.1055/a-1200-2765 ◽

2020 ◽

Author(s):

Philip Peter Roessler ◽

Turgay Efe ◽

Dieter Christian Wirtz ◽

Frank Alexander Schildberg

Keyword(s):

Type I Collagen ◽

Case Series ◽

Cartilage Regeneration ◽

Collagen Matrix ◽

Treatment Method ◽

Collagen Type I ◽

Legal Framework ◽

Clinical Aspects ◽

Type I ◽

Collagen Hydrogel

AbstractCartilage regeneration with cell-free matrices has developed from matrix-associated autologous cartilage cell transplantation (MACT) over ten years ago. Adjustments to the legal framework and higher hurdles for cell therapy have led to the procedures being established as an independent alternative to MACT. These procedures, which can be classified as matrix-induced autologous cartilage regeneration (MACR), all rely on the chemotactic stimulus of a cross-linked matrix, which mostly consists of collagens. Given the example of a commercially available type I collagen hydrogel, the state of clinical experience with MACR shall be summarized and an outlook on the development of the method shall be provided. It has been demonstrated in the clinical case series summarized here over the past few years that the use of the matrix is not only safe but also yields good clinical-functional and MR-tomographic results for both small (~ 10 mm) and large (> 10 mm) focal cartilage lesions. Depending on the size of the defect, MACR with a collagen type I matrix plays an important role as an alternative treatment method, in direct competition with both: microfracture and MACT.

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Oral Squamous Cell Carcinoma on Gingiva, Edentulous Ridge, and Retromolar Pad: A Case Series

Oral ◽

10.3390/oral1020016 ◽

2021 ◽

Vol 1 (2) ◽

pp. 159-167

Author(s):

Lucio Lo Russo ◽

Eleonora Lo Muzio ◽

Giuseppe Colella ◽

Maria Eleonora Bizzoca ◽

Vera Panzarella ◽

...

Keyword(s):

Case Series ◽

Medical Consultation ◽

Clinical Aspects ◽

University Hospitals ◽

Clinical Appearance ◽

Oral Cancers ◽

Presenting Symptoms ◽

Medical Evaluation ◽

Significant Incidence ◽

Advanced Stages

(1) Background: Gingival cancer has a significant incidence and is often diagnosed at advanced stages. The aim of this paper is to highlight its clinical aspects on the basis of a case series analysis in order to promote awareness and improve the diagnosis process. (2) Methods: Oral cancers diagnosed and treated at three Italian University Hospitals over ten years were retrospectively investigated. Cancer location on the gingiva, edentulous ridge, and retromolar pad was addressed. Data regarding clinical features, stage at the diagnosis, and time from presenting symptoms to first medical consultation were retrieved. (3) Results: Thirty-three cancers located on the gingiva, edentulous ridge, and retromolar pad were retrieved from 276 total oral cancer cases (11.9%). A median of 50 days (range 2–300) passed for the patient to seek for a medical evaluation. At the time of diagnosis, 63.3% were advanced stage cancers, mainly located at the mandible (91%), especially in the retromolar pad (48.5%) and the edentulous alveolar ridge (24.2%). Lesions were red (45.5%), red and white (45.4%), or white (9.1%), appearing as an ulcer (69.7%), exophytic mass (12.1%) or flat lesion (12.1%). Sixty-six percent of cancers were completely asymptomatic, regardless their clinical appearance. A statistically significant association between the time from the presentation of symptoms to the first medical consultation and the cancers stage was found. (4) Conclusions: The clinical appearance of gingival cancer is very polymorphous; its understanding may be significant to improve patient education and early medical consultation.

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Aggressive Ciliary Body Adenocarcinoma with Bilateral Lung Metastases: Histological, Molecular, Genetic and Clinical Aspects

Ocular Oncology and Pathology ◽

10.1159/000487805 ◽

2018 ◽

Vol 5 (2) ◽

pp. 79-84

Author(s):

Konstantinos Kopsidas ◽

Hardeep Mudhar ◽

Karen Sisley ◽

David W. Hammond ◽

L. Worthington ◽

...

Keyword(s):

Ciliary Body ◽

Lung Metastases ◽

Molecular Genetic ◽

Clinical Aspects ◽

Bilateral Lung

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AB1027 EFFECTIVENESS OF SUBCUTANEOUS ANTI-INTERLEUCINE 6 TREATMENT IN PATIENTS WITH ACTIVE MODERATE-SEVERE GRAVES’ ORBITOPATHY REFRACTORY TO CONVENTIONAL THERAPY.

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.6201 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1806.2-1806

Author(s):

L. Fernández de la Fuente Bursón ◽

F. J. Toyos Sáenz de Miera ◽

D. Ruiz-Montesinos ◽

M. Gessa Sorroche ◽

M. C. Díaz Ruiz ◽

...

Keyword(s):

Demographic Data ◽

Case Series ◽

Multicenter Trial ◽

Smoking History ◽

Clinical Aspects ◽

Clinical Activity ◽

Nonsurgical Management ◽

Usual Clinical Practice ◽

Antithyroid Treatment ◽

Graves Orbitopathy

Background:Graves’ Orbitopathy (OG) is the main extrathyroid manifestation of Graves’ disease (GD). Up to 25% of patients have moderate-severe inflammatory activity with a risk of major sequelae. Intravenous (i.v.) glucocorticoids (GC) pulses are the standard therapy. In refractory cases, several classic and some biological immunosuppressantsare used, obtaining variable responses. Interleukin 6 (IL6) is involved in the pathogenesis of OG, which has justified the off-label treatment with Tocilizumab (TCZ)1, whose use by route i.v. has shown favorable results in published small case series and a single multicenter trial2.Objectives:To analyse the ocular effectiveness of anti-IL6 therapy used subcutaneously (s.c.) in patients with moderate-severe active refractory OG in usual clinical practice.Methods:Retrospective descriptive observational study of a series of cases of moderate-severe OG patients treated with anti-IL6 s.c. The patient medical records of those who had received at least 1 cycle of anti-IL6 treatment were reviewed (December 2013-December 2019). The primary effectiveness outcome was the change of the Clinical Activity Score (CAS). Favorable response was considered: reduction of CAS≥2 points together with obtaining inactivity (CAS <3). Demographic data, personal medical history, clinical aspects of GD, previous therapies and data on the use and safety of anti-IL6 were collected. The SPSS11 package was used for statistical analysis, using non-parametric tests for quantitative variables. The study was approved by the local Ethical Committee.Results:12 of the 15 patients (80%) were women with a mean of 50.27 years (21-72). 60% (n=9) had smoking history, 40% (n=6) active. 26.7% (n=4) were diabetic, all without retinopathy. 100% of patients received imidazole antithyroid treatment. 46.7% (n=7) required β-blockers and 20% (n=3) diuretics. 66.7% thyroidectomy (n=10) and 20% (n=3) decompressive eye surgery and/or blepharoplasty were performed. Thyroid and ocular radiotherapy were used in 2 patients. 3 patients received botox. 80% (n=12) of them had previously received GC. 93.3% (n=14) were naïve to biological therapy, only 1 patient previously used Rituximab. All except one patient who was treated with SRL received TCZ as IL6 therapy. A significant favorable response was obtained in 100% of the patients (p=0.008), decreasing CAS average from 4.9 (2-7) to 1.7 (0-2) at the end of the therapy [Figure 1]. The severity of the OG changed from being moderate in 72.7% of the patients to mild in 66.7% of the total. The median time to inactivity was 8 months (2-15). 73.3% (n=11) of the patients finished the treatment reaching inactive OG, the rest (although inactive) maintained therapy. After 6 months, 100% of those who completed the treatment remained inactive with average CAS of 1.3 (0-2). Smoking did not influence the response, nor any other variable collected. Adverse events appeared in 26.7% (n=4) of the cases, all of them mild and without widrawal.Conclusion:Treatment with anti-IL6 s.c. steadily decreases the clinical activity measured by CAS in patients with moderate-severe refractory OG, despite poor prognosis factors (such as smoking), with a good safety profile.References:[1]Taylor PN, Zhang L, Lee RWJ, Muller I, Ezra DG, Dayan CM, et al. New insights into the pathogenesis and nonsurgical management of Graves’ orbitopathy. Nat Rev Endocrinol. 2020 Feb;16(2):104-116.[2]Perez-Moreiras JV, Gomez-Reino JJ, Maneiro JR, Perez-Pampin E, Romo Lopez A, Rodríguez Álvarez FM, et al. Efficacy of Tocilizumab in Patients With Moderate-to-Severe Corticosteroid-Resistant Gravesˊ Orbitopathy: A Randomized Clinical Trial. Am J Ophthalmol. 2018;195:181–90.Disclosure of Interests:None declared

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Molecular genetic analysis of chromosome #22 in neurogenic neoplasms

Cancer Genetics and Cytogenetics ◽

10.1016/0165-4608(92)90521-9 ◽

1992 ◽

Vol 63 (2) ◽

pp. 172

Author(s):

Juan A. Rey

Keyword(s):

Genetic Analysis ◽

Molecular Genetic ◽

Molecular Genetic Analysis ◽

Chromosome 22

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Molecular genetic investigation of the neurofibromatosis type 2 tumor suppressor gene in sporadic meningioma

Journal of Neurosurgery ◽

10.3171/jns.1996.84.5.0847 ◽

1996 ◽

Vol 84 (5) ◽

pp. 847-851 ◽

Cited By ~ 58

Author(s):

Takehiko Harada ◽

Richard M. Irving ◽

John H. Xuereb ◽

David E. Barton ◽

David G. Hardy ◽

...

Keyword(s):

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Molecular Genetic ◽

Gene Mutations ◽

Neurofibromatosis Type ◽

Suppressor Gene ◽

Neurofibromatosis Type 2 ◽

Chromosome 22 ◽

Sporadic Meningioma

✓ The authors investigated the role of somatic mutations of the neurofibromatosis type 2 (NF2) gene in sporadic meningioma. Neurofibromatosis 2 is a dominantly inherited familial tumor syndrome predisposing affected patients to a variety of central nervous system tumors including vestibular schwannoma and meningioma. Neurofibromatosis type 2 is caused by germline mutations in the NF2 tumor suppressor gene. In addition, the authors and others have reported that somatic NF2 gene mutations occur frequently in nonfamilial vestibular schwannoma. In this study, molecular genetic analysis was performed on 23 nonfamilial meningiomas. Paired DNA samples extracted from the blood and tumors of the patients were analyzed for loss of heterozygosity (LOH) in the region of the NF2 gene on chromosome 22 using closely linked DNA markers. The NF2 gene mutations were sought by single-stranded conformation polymorphism analysis and DNA sequencing. Fourteen (61%) of 23 meningiomas showed LOH in the region of the NF2 gene on chromosome 22. Somatic NF2 gene mutations were detected in eight meningiomas (35%) after screening all 17 exons. All tumors with NF2 gene mutations showed simultaneous chromosome 22 LOH. Review of the histopathological findings of the cases studied did not demonstrate any predominance of genetic abnormalities in a particular histological type of meningioma. These results are compatible with the hypothesis that the NF2 gene acts as a tumor suppressor and that its inactivation is important in the pathogenesis of sporadic meningioma.

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