scholarly journals Novel Pathogenic Variant in TGFBR2 Confirmed by Molecular Modeling Is a Rare Cause of Loeys-Dietz Syndrome

2017 ◽  
Vol 2017 ◽  
pp. 1-4
Author(s):  
Michael T. Zimmermann ◽  
Raul A. Urrutia ◽  
Patrick R. Blackburn ◽  
Margot A. Cousin ◽  
Nicole J. Boczek ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Connective Tissue Disorder ◽  
Pathogenic Variant ◽  
Molecular Testing ◽  
Commercial Laboratory ◽  
Local Protein Structure ◽  
Abdominal Arteries ◽  
The Right ◽  
Skeletal Findings ◽  
Local Protein

Loeys-Dietz syndrome (LDS) is a connective tissue disorder characterized by vascular findings of aneurysm and/or dissection of cerebral, thoracic, or abdominal arteries and skeletal findings. We report a case of a novel pathogenic variant in TGFBR2 and phenotype consistent with classic LDS. The proband was a 10-year-old presenting to the genetics clinic with an enlarged aortic root (Z-scores 5-6), pectus excavatum, and congenital contractures of the right 2nd and 3rd digit. Molecular testing of TGFBR2 was sent to a commercial laboratory and demonstrated a novel, likely pathogenic, variant in exon 4, c.1061T>C, p.(L354P). Molecular modeling reveals alteration of local protein structure as a result of this pathogenic variant. This pathogenic variant has not been previously reported in LDS and thus expands the pathogenic variant spectrum of this condition.

scholarly journals The contribution of epigenetics to the pathogenesis and gender dimorphism of systemic sclerosis: a comprehensive overview

2020 ◽  
Vol 12 ◽  
pp. 1759720X2091845 ◽  
Author(s):  
Bianca Saveria Fioretto ◽  
Irene Rosa ◽  
Eloisa Romano ◽  
Yukai Wang ◽  
Serena Guiducci ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
X Chromosome ◽  
Clinical Manifestations ◽  
Connective Tissue Disorder ◽  
Epigenetic Modifications ◽  
Unknown Etiology ◽  
Comprehensive Overview ◽  
Gender Dimorphism ◽  
Immune Related Genes ◽  
The Right

Systemic sclerosis (SSc) is a life-threatening connective tissue disorder of unknown etiology characterized by widespread vascular injury and dysfunction, impaired angiogenesis, immune dysregulation and progressive fibrosis of the skin and internal organs. Over the past few years, a new trend of investigations is increasingly reporting aberrant epigenetic modifications in genes related to the pathogenesis of SSc, suggesting that, besides genetics, epigenetics may play a pivotal role in disease development and clinical manifestations. Like many other autoimmune diseases, SSc presents a striking female predominance, and even if the reason for this gender imbalance has yet to be completely understood, it appears that the X chromosome, which contains many gender and immune-related genes, could play a role in such gender-biased prevalence. Besides a short summary of the genetic background of SSc, in this review we provide a comprehensive overview of the most recent insights into the epigenetic modifications which underlie the pathophysiology of SSc. A particular focus is given to genetic variations in genes located on the X chromosome as well as to the main X-linked epigenetic modifications that can influence SSc susceptibility and clinical phenotype. On the basis of the most recent advances, there is realistic hope that integrating epigenetic data with genomic, transcriptomic, proteomic and metabolomic analyses may provide in the future a better picture of their functional implications in SSc, paving the right way for a better understanding of disease pathogenesis and the development of innovative therapeutic approaches.

Clinical Diagnosis of Classical Cornelia de Lange Syndrome Made From Postmortem Examination of Second Trimester Fetus With Novel NIPBL Pathogenic Variant

2019 ◽  
Vol 22 (5) ◽  
pp. 475-479 ◽  
Author(s):  
Jennifer Hague ◽  
Philip Twiss ◽  
Zoe Mead ◽  
Soo-Mi Park
Keyword(s):  
Clinical Diagnosis ◽  
Upper Limb ◽  
Growth Retardation ◽  
Postmortem Examination ◽  
Pathogenic Variant ◽  
Cornelia De Lange Syndrome ◽  
Molecular Testing ◽  
Intrauterine Death ◽  
Second Trimester ◽  
Cornelia De Lange

Classical Cornelia de Lange syndrome (CdLS) is a rare genetic disorder which is associated with distinctive facial features, growth retardation, significant intellectual disability and global developmental delay, hirsutism, and upper-limb reduction defects. Classical CdLS is associated with pathogenic variants in NIPBL. We present a clinical diagnosis of classical CdLS made in a second trimester male fetus with advanced maceration who had undergone intrauterine death at 15 + 6 weeks gestation. The diagnosis was suspected after multiple congenital anomalies were identified on fetal postmortem examination. These included intrauterine growth retardation, upper limb anomalies, ventricular septal defect and diaphragmatic hernia, and skeletal and genitourinary abnormalities. Related prenatal screening findings included a raised nuchal translucency and low maternal serum pregnancy-associated plasma protein-A. Targeted molecular sequencing of genes associated with CdLS identified a novel de novo frameshift pathogenic variant in NIPBL, which confirmed the diagnosis. This report describes our case and reviews the current literature on prenatal diagnosis of CdLS. In summary, we demonstrate that clinical diagnosis of CdLS in a second trimester fetus, through postmortem examination findings, is possible, with confirmation through molecular testing.

scholarly journals Mycobacterium intracellulare Infection Mimicking Progression of Scleroderma

2017 ◽  
Vol 2017 ◽  
pp. 1-3
Author(s):  
Simon Krabbe ◽  
Merete Engelhart ◽  
Sören Thybo ◽  
Søren Jacobsen
Keyword(s):  
Case Report ◽  
Listeria Monocytogenes ◽  
Interstitial Lung Disease ◽  
Connective Tissue ◽  
Connective Tissue Disorder ◽  
High Dose ◽  
Esophageal Dysmotility ◽  
Mycobacterium Intracellulare ◽  
The Right ◽  
Inflammatory Changes

This case report describes a patient with scleroderma who developed Mycobacterium intracellulare infection, which for more than a year mimicked worsening of her connective tissue disorder. The patient was diagnosed with scleroderma based on puffy fingers that developed into sclerodactyly, abnormal nail fold capillaries, interstitial lung disease, Raynaud’s phenomenon, esophageal dysmotility, and positivity for rheumatoid factor and anti-SSA antibodies. She developed massive inflammatory changes of the cutis, the subcutis, and the muscle fasciae of the right leg, that after several failed attempts of immunosuppressive treatments were found to be caused by Mycobacterium intracellulare. While she was receiving high-dose prednisolone, as worsening of her connective tissue disease was suspected to be the cause of the inflammatory changes, she had Listeria monocytogenes meningitis and was hospitalized for several weeks, but she recovered from this without sequelae. After Mycobacterium intracellulare infection was diagnosed, she was treated with clarithromycin and rifampicin. Her skin manifestations, arthralgias, and fatigue improved considerably, and the wounds of the right leg healed, unfortunately with significant scarring. Immunodeficiency testing was unremarkable. In summary, an infection with Mycobacterium intracellulare was mistaken for an unusually severe progression of scleroderma.

Personalized molecular testing for therapeutic guidance in Taiwan.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e22067-e22067
Author(s):  
Kang-Yi Su ◽  
Sung-Liang Yu
Keyword(s):  
Target Therapy ◽  
Cost Effective ◽  
Personalized Therapy ◽  
Identification System ◽  
Molecular Testing ◽  
Reference Laboratory ◽  
Technical Limitation ◽  
Targeting Therapy ◽  
Therapeutic Decisions ◽  
The Right

e22067 Background: Personalized cancer therapy is based on the precept that detail molecular characterization of tumors as well as tumor microenvironment will enable tailored therapies to improve outcomes and decrease toxicity. The goal of personalized therapy is to target aberrations driving tumor growth and prolongs survival, by administering the right drug combination for the right person. However, several practical and technological challenges including tumor heterogeneity, molecular evolution, costs and morbidity of biopsies as well as technical limitation critical for molecular testing. In addition, development of biomarkers should be considered all aspects of drug development, from discovery through to clinical trials. Methods: In Taiwan, we have established a well-qualified reference laboratory with ISO15189 certification for molecular testing of personalized therapy in clinical practice. Based on our innovation, we utilized DNA mass spectrometry platform to develop high sensitive EGFR mutation identification system. Recently, KRAS, BRAF, HER2 together with EGFR were also combined into multiplex gene testing for biomarker-assessed therapeutic decision. To this end, the National Science Council of Taiwan government had supported this project through NRPB (National Research Program of Biopharmaceutical) at the middle of 2011. This facility performed selected molecular tests for cancer patients from medical centers and regional hospitals. Results: A specific program had also been implemented to anticipate the launch of molecular targeting therapy (MTT) and reduce time-to-assess to MTT drugs and experimental therapies. From Jane 2011 to Dec 2012, more than 2,500 patients with lung cancer in Taiwan benefited from this facility. Conclusions: The Taiwan nationwide initiative for tumor molecular profiling is a tool to fight inequalities in access to molecular testing and target therapy, and demonstrates that molecular stratification of tumor for therapeutic decisions is a cost-effective strategy that can be integrated into the national health-care system.

Utilization of liquid biopsy in a large community oncology practice.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e19150-e19150
Author(s):  
Dipen Patel ◽  
Thuy Le ◽  
Harry Staszewski
Keyword(s):  
Solid Tumors ◽  
Liquid Biopsy ◽  
Molecular Testing ◽  
Minimal Risk ◽  
Liquid Biopsies ◽  
Treatment Regimens ◽  
Large Community ◽  
Commercial Laboratory ◽  
Community Oncology ◽  
Oncology Practice

e19150 Background: Analysis of tumor cell free DNA, or liquid biopsy, is emerging as a useful adjunct to tissue biopsies in advanced solid tumors. These tests may reduce the need for repeating invasive biopsies, and may be performed serially with minimal risk to patients.The purpose of our study is to document how liquid biopsies are being used in a large, diverse community based practice in Long Island, NY and how often the results lead to changes in treatment. The aim is to derive guidelines within the practice for appropriate use of liquid biopsies going forward. Methods: The practice electronic medical record (EMR) was retrospectively examined for the first 100 patients with solid tumors who had a specimen sent to a commercial laboratory for a liquid biopsy. The EMR was also reviewed to establish the treatment regimens each patient was receiving prior to the liquid biopsy, as well as any changes to the regimen based on liquid biopsy results. Results: This analysis was based on 100 patients: 11 out of 100 patients (11%) were excluded due to loss of follow up and 89 out of 100 (89%) patients were included, 59% female and 41% male. 11 out of 100 patients (11%) were not found to have any tumor alterations on liquid biopsy. The most prevalent cancers were lung (40.4%), ovarian (17.0%), breast (6.4%), colon (5.3%) and prostate (5.3%). Treatment was changed 43% of the time after liquid biopsy results were obtained and there was no change in 57% of the time see Table. This change was irrespective of type of cancer, gender, or types of current regimen. Conclusions: Liquid biopsy has proven to be a useful adjunct to molecular testing of tumor tissue in a large community oncology practice, but ongoing examination of our results should better define its optimal use. [Table: see text]

scholarly journals Longitudinal deficiency of upper limb: similar case presentation of two subjects with unilateral ulnar hemimelia, carpal and metacarpal deficiency, and severe oligodactyly

2014 ◽  
Vol 8 (4) ◽  
pp. 569-575
Author(s):  
Muhammad Afzal ◽  
Sajid Malik
Keyword(s):  
Limb Development ◽  
Risk Estimation ◽  
Lower Limbs ◽  
Molecular Testing ◽  
Type I ◽  
Limb Anomalies ◽  
Type D ◽  
Radiographic Measurements ◽  
Severe Deficiency ◽  
The Right

Abstract Background: Longitudinal deficiency of upper limbs with oligodactyly is a very rare congenital malformation. It manifests itself as preaxial or postaxial hypoplasia/aplasia of long bones accompanied by reduction of palm and phalanges. Objective: To report two cases with essentially similar phenotypic presentation characterized by unilateral mesomelic shortening of limb, ulnar hypoplasia, and severe deficiency of skeletal elements of hand that were found in unrelated individuals. Methods: Review of clinical and family history, phenotypic examination, physical and radiological investigations, and literature review. Results: In both individuals, the right arm was short, the size of the middle arm and hand being dramatically reduced in size, and the hand comprising only two functional digits. Roentgenograms revealed hemimelia/ dysmelia of the ulna, hypoplasia of radius, dysplastic distal radial head, and several missing carpals. Only two phalangeal rays were witnessed in the hand. Radiographic measurements showed a normal contralateral arm and lower limbs, and no other associated symptoms. These phenotypes were classified as type I and type D according to the schemes proposed by Swanson et al., and Ogino and Kato, respectively. Both individuals were the product of third degree consanguineous unions (F = 0.0625). Conclusion: Consistent phenotypic pattern of longitudinal limb anomalies evident in two independent subjects suggest a common underlying genetic etiology. There is currently no known genetic factor to allow molecular testing and risk estimation for family members. Isolated limb anomalies may provide important clues to understand pathomorphogenetic mechanisms that lead to the disruption of normal limb development.

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