scholarly journals Congenital Afibrinogenemia and Hypofibrinogenemia: Laboratory and Genetic Testing in Rare Bleeding Disorders with Life-Threatening Clinical Manifestations and Challenging Management

Diagnostics ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 2140
Author(s):  
Tomas Simurda ◽  
Rosanna Asselta ◽  
Jana Zolkova ◽  
Monika Brunclikova ◽  
Miroslava Dobrotova ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Clinical Phenotype ◽  
Clinical Manifestations ◽  
Compound Heterozygous ◽  
Genes Encoding ◽  
Life Threatening ◽  
Congenital Afibrinogenemia ◽  
Thrombotic Complications ◽  
Based Medicine ◽  
Processing Stability

Congenital fibrinogen disorders are rare pathologies of the hemostasis, comprising quantitative (afibrinogenemia, hypofibrinogenemia) and qualitative (dysfibrinogenemia and hypodysfibrinogenemia) disorders. The clinical phenotype is highly heterogeneous, being associated with bleeding, thrombosis, or absence of symptoms. Afibrinogenemia and hypofibrinogenemia are the consequence of mutations in the homozygous, heterozygous, or compound heterozygous state in one of three genes encoding the fibrinogen chains, which can affect the synthesis, assembly, intracellular processing, stability, or secretion of fibrinogen. In addition to standard coagulation tests depending on the formation of fibrin, diagnostics also includes global coagulation assays, which are effective in monitoring the management of replacement therapy. Genetic testing is a key point for confirming the clinical diagnosis. The identification of the precise genetic mutations of congenital fibrinogen disorders is of value to permit early testing of other at risk persons and better understand the correlation between clinical phenotype and genotype. Management of patients with afibrinogenemia is particularly challenging since there are no data from evidence-based medicine studies. Fibrinogen concentrate is used to treat bleeding, whereas for the treatment of thrombotic complications, administered low-molecular-weight heparin is most often. This review deals with updated information about afibrinogenemia and hypofibrinogenemia, contributing to the early diagnosis and effective treatment of these disorders.

scholarly journals Analyses of Leishmania-LRV Co-Phylogenetic Patterns and Evolutionary Variability of Viral Proteins

Viruses ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2305
Author(s):  
Alexei Y. Kostygov ◽  
Danyil Grybchuk ◽  
Yulia Kleschenko ◽  
Daniil S. Chistyakov ◽  
Alexander N. Lukashev ◽  
...  
Keyword(s):  
Rna Virus ◽  
Clinical Manifestations ◽  
Purifying Selection ◽  
Viral Proteins ◽  
Small Scale ◽  
Self Healing ◽  
Genes Encoding ◽  
Leishmania Spp ◽  
Life Threatening ◽  
Vector Borne

Leishmania spp. are important pathogens causing a vector-borne disease with a broad range of clinical manifestations from self-healing ulcers to the life-threatening visceral forms. Presence of Leishmania RNA virus (LRV) confers survival advantage to these parasites by suppressing anti-leishmanial immunity in the vertebrate host. The two viral species, LRV1 and LRV2 infect species of the subgenera Viannia and Leishmania, respectively. In this work we investigated co-phylogenetic patterns of leishmaniae and their viruses on a small scale (LRV2 in L. major) and demonstrated their predominant coevolution, occasionally broken by intraspecific host switches. Our analysis of the two viral genes, encoding the capsid and RNA-dependent RNA polymerase (RDRP), revealed them to be under the pressure of purifying selection, which was considerably stronger for the former gene across the whole tree. The selective pressure also differs between the LRV clades and correlates with the frequency of interspecific host switches. In addition, using experimental (capsid) and predicted (RDRP) models we demonstrated that the evolutionary variability across the structure is strikingly different in these two viral proteins.

scholarly journals A Twins Case of Lissencephaly With GPR56 Compound Heterozygous Mutations and Literatures Review

2021 ◽  
Author(s):  
Wenxin Lin ◽  
Yingying Chai ◽  
Xia Zhang ◽  
Tingting Huang ◽  
Guo Zheng ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Clinical Manifestations ◽  
Compound Heterozygous ◽  
The Novel ◽  
Chain Reaction ◽  
Causative Gene ◽  
Whole Exome ◽  
Malformation Of Cortical Development ◽  
Hypothalamic Pituitary Axis ◽  
Polymerase Chain

Abstract Background: Lissencephaly (LIS) is a malformation of cortical development characterized by developmental delay and seizure in combination with wide gyrus, superficial sulcus, and thickened cortex. Up to date, 20 genes have been implicated in LIS. However, GRP56-related LIS has never been reported, which was considered one causative gene for bilateral frontoparietal polymicrogyria(BFPP). Methods: Genetic testing of the proband was performed by whole exome sequencing and mainly analyzed 662 genes related to brain hypoplasia, white matter abnormalities, and hypothalamic-pituitary axis abnormalities such us AAAS, AARS2, ABAT, ABCC8, etc.. And the candidate mutations were further confirmed by polymerase chain reaction (PCR) and Sanger sequencing. Though we did genetic testing on the twin sisters and their parents, we could only obtain the clinical data of the older sister.Results: We reported a case of LIS twins, form a nonconsanguineous family, both carried the novel compound heterozygous GPR56 mutations, p.F76fs and p.H607fs.The older sister manifested lissencephaly, seizures, and flathead deformity and the younger sister had lissencephaly. We summarized their clinical characteristics and reviewed all the literatures of LIS and GPR56 to further clarify the correlation between genotype and phenotype.Conclusion: The LIS twins with GPR56 mutations were the first reported. By reviewing the clinical manifestations of LIS and GPR56 mutations, we validated the association between them, and broaden the clinical manifestations of GPR56 related phenotypes, indicating the importance of GPR56 screening in LIS patients.

scholarly journals Genetic Variants in the FGB and FGG Genes Mapping in the Beta and Gamma Nodules of the Fibrinogen Molecule in Congenital Quantitative Fibrinogen Disorders Associated with a Thrombotic Phenotype

2020 ◽  
Vol 21 (13) ◽  
pp. 4616
Author(s):  
Tomas Simurda ◽  
Monika Brunclikova ◽  
Rosanna Asselta ◽  
Sonia Caccia ◽  
Jana Zolkova ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Clinical Manifestations ◽  
Cell Interaction ◽  
Fibrin Clot ◽  
Congenital Defects ◽  
Blood Clots ◽  
Life Threatening ◽  
Congenital Afibrinogenemia ◽  
Insoluble Polymer ◽  
Fibrinogen Molecule

Fibrinogen is a hexameric plasmatic glycoprotein composed of pairs of three chains (Aα, Bβ, and γ), which play an essential role in hemostasis. Conversion of fibrinogen to insoluble polymer fibrin gives structural stability, strength, and adhesive surfaces for growing blood clots. Equally important, the exposure of its non-substrate thrombin-binding sites after fibrin clot formation promotes antithrombotic properties. Fibrinogen and fibrin have a major role in multiple biological processes in addition to hemostasis and thrombosis, i.e., fibrinolysis (during which the fibrin clot is broken down), matrix physiology (by interacting with factor XIII, plasminogen, vitronectin, and fibronectin), wound healing, inflammation, infection, cell interaction, angiogenesis, tumour growth, and metastasis. Congenital fibrinogen deficiencies are rare bleeding disorders, characterized by extensive genetic heterogeneity in all the three genes: FGA, FGB, and FGG (enconding the Aα, Bβ, and γ chain, respectively). Depending on the type and site of mutations, congenital defects of fibrinogen can result in variable clinical manifestations, which range from asymptomatic conditions to the life-threatening bleeds or even thromboembolic events. In this manuscript, we will briefly review the main pathogenic mechanisms and risk factors leading to thrombosis, and we will specifically focus on molecular mechanisms associated with mutations in the C-terminal end of the beta and gamma chains, which are often responsible for cases of congenital afibrinogenemia and hypofibrinogenemia associated with thrombotic manifestations.

scholarly journals Double Trouble: Co-Occurrence of Aromatase Deficiency and Non-Classic CAH in Three Siblings

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A127-A127
Author(s):  
Maja Marinkovic ◽  
Marcela Vargas Trujillo
Keyword(s):  
Genetic Testing ◽  
Gh Deficiency ◽  
Oral Contraceptive Pill ◽  
Clinical Manifestations ◽  
Compound Heterozygous ◽  
Aromatase Activity ◽  
Tall Stature ◽  
Androgen Excess ◽  
Classic Cah

Abstract Introduction: Aromatase deficiency (AD), an exceedingly rare autosomal recessive condition, causes virilization in females and tall stature with metabolic derangements in males. Clinical manifestations result from decreased estrogen production and androgen excess, but presentation varies based on residual aromatase activity. Non-classic CAH (NCCAH) is a relatively common disorder. Males are often asymptomatic or present with premature adrenarche (PA). Females are typically diagnosed during childhood/adolescence with PA, acne, hirsutism, or menstrual irregularities. We present three siblings with both conditions and describe their long-term follow-up. Cases: Identical twin sisters presented at birth with virilized genitalia. Evaluation revealed 46XX karyotype, transiently elevated testosterone (unchanged with hCG stimulation), normal 17OHP and normal ovarian tissue on gonadal biopsy. Due to sporadic follow-up, their diagnosis and care were delayed until age 15y when AD was confirmed with genetic testing (compound heterozygous: whole gene deletion on one allele and c.242A>G (p.tyr81cys) mutation on the other). Both girls had acne, hirsutism and clitoromegaly, but reached spontaneous menarche at 11y and height within mid-parental height (MPH). Given the genetic nature of AD, younger brother was assessed and diagnosed with AD with the same mutation in CYP19A1. He had normal height-corrected BMD, lipids and glucose. His testosterone level was high-normal with undetectable estradiol. He had height below MPH with slow growth velocity, low IGF-1 and bone age (BA) within 2SD for age (BA 14y at CA 15y). GH stimulation test with estrogen priming revealed GH peak of 4.1 ng/ml, consistent with GH deficiency. All three siblings had high baseline and stimulated 17OHP which prompted genetic testing for CAH and confirmed NCCAH due to homozygous pVal282Leu substitution in CYP21A2. Treatment for both AD and NCCAH in females is combined estrogen+progesterone (usually given as an oral contraceptive pill), to replace estrogen and suppress androgen overproduction. The twin sisters elected clitoral reduction at age 19y with a satisfactory outcome. Their brother is not on any treatment at this time. At age 18y, his BA is still 14y-14.5y, as expected in AD, but atypical for NCCAH. Conclusion: Virilized genitalia in the newborn period prompted extensive evaluation of twin sisters that led to diagnosis of AD but also prompted assessment and diagnosis of their asymptomatic brother. Elevation of 17OHP, previously not described in AD patients, prompted testing for CAH and confirmed the unique finding of both AD and NCCAH in these three siblings. We postulate that the combined AD/NCCAH caused exacerbation of androgen excess in all three siblings. The short stature in our male patient is presumably due to GH deficiency.

Major Hereditary Gastrointestinal Cancer Syndromes: a Narrative Review

2017 ◽  
Vol 26 (2) ◽  
pp. 157-163 ◽  
Author(s):  
Lakshmi Manogna Chintalacheruvu ◽  
Trudy Shaw ◽  
Avanija Buddam ◽  
Osama Diab ◽  
Thamer Kassim ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Genetic Testing ◽  
Gastrointestinal Cancer ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Clinical Manifestations ◽  
Micro Rna ◽  
Diffuse Gastric Cancer ◽  
Adenomatous Polyposis ◽  
Cancer Syndromes

Gastrointestinal cancer is one of the major causes of death worldwide. Hereditary gastrointestinal cancer syndromes constitute about 5-10% of all cancers. About 20-25% of undiagnosed cases have a possible hereditary component, which is not yet established. In the last few decades, the advance in genomics has led to the discovery of multiple cancer predisposition genes in gastrointestinal cancer. Physicians should be aware of these syndromes to identify high-risk patients and offer genetic testing to prevent cancer death. In this review, we describe clinical manifestations, genetic testing and its challenges, diagnosis and management of the major hereditary gastrointestinal cancer syndromes.Key words:  −  −  −  − .Abbreviations: ACG: American College of Gastroenterology; AFAP: attenuated FAP; APC: adenomatous polyposis coli; CDH1: E-cadherin; CHRPE: congenital hypertrophy of the retinal pigment epithelium; CRC: colorectal cancer; FAMMM: Familial atypical multiple mole melanoma; FAP: Familial adenomatous polyposis; GC: gastric cancer; HDGC: Hereditary diffuse gastric cancer; IHC: immunohistochemical; IPAA: ileal pouch–anal anastomosis; IRA: ileorectal anastomosis; MSI: microsatellite instability; MMR: mismatch repair; miRNA: micro RNA.

scholarly journals Progress in Diagnosing Primary Ciliary Dyskinesia: The North American Perspective

Diagnostics ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1278
Author(s):  
Michael Glenn O’Connor ◽  
Amjad Horani ◽  
Adam J. Shapiro
Keyword(s):  
Genetic Testing ◽  
North America ◽  
North American ◽  
Primary Ciliary Dyskinesia ◽  
Clinical Phenotype ◽  
The United States ◽  
Diagnostic Process ◽  
The North ◽  
Diagnostic Guideline ◽  
Ciliary Dyskinesia

Primary Ciliary Dyskinesia (PCD) is a rare, under-recognized disease that affects respiratory ciliary function, resulting in chronic oto-sino-pulmonary disease. The PCD clinical phenotype overlaps with other common respiratory conditions and no single diagnostic test detects all forms of PCD. In 2018, PCD experts collaborated with the American Thoracic Society (ATS) to create a clinical diagnostic guideline for patients across North America, specifically considering the local resources and limitations for PCD diagnosis in the United States and Canada. Nasal nitric oxide (nNO) testing is recommended for first-line testing in patients ≥5 years old with a compatible clinical phenotype; however, all low nNO values require confirmation with genetic testing or ciliary electron micrograph (EM) analysis. Furthermore, these guidelines recognize that not all North American patients have access to nNO testing and isolated genetic testing is appropriate in cases with strong clinical PCD phenotypes. For unresolved diagnostic cases, referral to a PCD Foundation accredited center is recommended. The purpose of this narrative review is to provide insight on the North American PCD diagnostic process, to enhance the understanding of and adherence to current guidelines, and to promote collaboration with diagnostic pathways used outside of North America.

scholarly journals X-linked congenital adrenal hypoplasia: a case presentation

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Hong Ouyang ◽  
Bo Chen ◽  
Na Wu ◽  
Ling Li ◽  
Runyu Du ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Hormone Replacement ◽  
Slipped Capital Femoral Epiphysis ◽  
Clinical Manifestations ◽  
Addison’S Disease ◽  
Addison's Disease ◽  
Case Presentation ◽  
Early Symptoms ◽  
Congenital Adrenal Hypoplasia ◽  
Adrenal Hypoplasia

Abstract Background Most patients with congenital adrenal hypoplasia (AHC) develop symptoms during infantile and juvenile periods, with varying clinical manifestations. AHC is a disease that is easily misdiagnosed as Addison’s disease or congenital adrenal hyperplasia (CAH). There was also a significant time difference between the age at which patients developed symptoms and the age at which they were diagnosed with AHC. Most patients showed early symptoms during infantile and juvenile periods, but were diagnosed with AHC many years later. Case presentation We are currently reporting a male patient who developed systemic pigmentation at age 2 and was initially diagnosed with Addison’s disease. At 22 years of age, he experienced a slipped capital femoral epiphysis (SCFE), a disease mostly seen in adolescents aged 8–15 years, an important cause of which is endocrine disorder. Testes evaluated using color Doppler Ultrasonography suggested microcalcifications. Further genetic testing and auxiliary examinations revealed that the patient had hypogonadotropic hypogonadism (HH) and DAX-1 gene disorders, at which time he was diagnosed with AHC complicated by HH. He was given hormone replacement therapy, followed by regular outpatient review to adjust the medication. Conclusions The typical early symptoms of AHC are hyperpigmentation and ion disturbance during infantile and juvenile periods, while few patients with AHC develop puberty disorders as early symptoms. AHC is prone to being misdiagnosed as Addison’s disease, and then gradually develops the symptoms of HH in adolescence. The definitive diagnosis of AHC ultimately is based on the patient’s clinical presentation, laboratory results and genetic testing results.

Molecular basis of ciliary defects caused by compound heterozygous IFT144/WDR19 mutations found in cranioectodermal dysplasia

2021 ◽  
Author(s):  
Yamato Ishida ◽  
Takuya Kobayashi ◽  
Shuhei Chiba ◽  
Yohei Katoh ◽  
Kazuhisa Nakayama
Keyword(s):  
Protein Trafficking ◽  
Primary Cilia ◽  
Intraflagellar Transport ◽  
Missense Variant ◽  
Cellular Level ◽  
Compound Heterozygous ◽  
Hypomorphic Allele ◽  
Genes Encoding ◽  
Specific Proteins ◽  
Compound Heterozygous Mutations

Abstract Primary cilia contain specific proteins to achieve their functions as cellular antennae. Ciliary protein trafficking is mediated by the intraflagellar transport (IFT) machinery containing the IFT-A and IFT-B complexes. Mutations in genes encoding the IFT-A subunits (IFT43, IFT121/WDR35, IFT122, IFT139/TTC21B, IFT140, and IFT144/WDR19) often result in skeletal ciliopathies, including cranioectodermal dysplasia (CED). We here characterized the molecular and cellular defects of CED caused by compound heterozygous mutations in IFT144 [the missense variant IFT144(L710S) and the nonsense variant IFT144(R1103*)]. These two variants were distinct with regard to their interactions with other IFT-A subunits and with the IFT-B complex. When exogenously expressed in IFT144-knockout (KO) cells, IFT144(L710S) as well as IFT144(WT) rescued both moderately compromised ciliogenesis and the abnormal localization of ciliary proteins. As the homozygous IFT144(L710S) mutation was found to cause autosomal recessive retinitis pigmentosa, IFT144(L710S) is likely to be hypomorphic at the cellular level. In striking contrast, the exogenous expression of IFT144(R1103*) in IFT144-KO cells exacerbated the ciliogenesis defects. The expression of IFT144(R1103*) together with IFT144(WT) restored the abnormal phenotypes of IFT144-KO cells. However, the coexpression of IFT144(R1103*) with the hypomorphic IFT144(L710S) variant in IFT144-KO cells, which mimics the genotype of compound heterozygous CED patients, resulted in severe ciliogenesis defects. Taken together, these observations demonstrate that compound heterozygous mutations in IFT144 cause severe ciliary defects via a complicated mechanism, where one allele can cause severe ciliary defects when combined with a hypomorphic allele.

scholarly journals Prevalence and clinical phenotype of the triplicated α-globin genes and its ethnic and geographical distribution in Guizhou of China

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Xi Luo ◽  
Xiang-mei Zhang ◽  
Liu-song Wu ◽  
Jindong Chen ◽  
Yan Chen
Keyword(s):  
Genetic Counseling ◽  
Peripheral Blood ◽  
Clinical Phenotype ◽  
Globin Gene ◽  
Clinical Manifestations ◽  
Gene Mutations ◽  
Guizhou Province ◽  
Globin Genes ◽  
Phenotype Correlation ◽  
Chi Square

Abstract Background α-thalassemia is relatively endemic in Guizhou province of southwestern China. To predict the clinical manifestations of α-globin gene aberration for genetic counseling, we examined the prevalence of the α-globin triplication and the genotype–phenotype correlation in this subpopulation Methods A cohort of 7644 subjects was selected from nine ethnicities covering four regions in Guizhou province of China. Peripheral blood was collected from each participant for routine blood testing and hemoglobin electrophoresis. PCR-DNA sequencing and Gap-PCR were used to identify the thalassemia gene mutations. Chi-square tests and one-way analysis of variance (ANOVA) were used to statistically analyze the data. Results We found that the frequency of α-globin triplication in Guizhou province was 0.772% (59/7644). Genotypically, the αααanti4.2/αα accounted for 0.523% (40/7644), the αααanti3.7/αα for 0.235% (18/7644), and the αααanti3.7/–SEA for 0.013% (1/7644). The αααanti4.2/αα is more prevalent than the αααanti3.7/αα in Guizhou. In addition, the frequency of the HKαα/αα (that by GAP-PCR is like αααanti4.2/-α3.7) was 0.235% (18/7644). Ethnically, the Tujia group presented the highest prevalence (2.47%) of α-globin triplication. Geographically, the highest frequency of the α-globin triplication was identified in Qiannan region (2.23%). Of the triplicated α-globin cases, 5 coinherited with heterozygote β-thalassemia and presented various clinical manifestations of anemia. Conclusions These data will be used to update the Chinese triplicated α-globin thalassemia database and provide insights into the pathogenesis of thalassemia. These findings will be helpful for the diagnosis of thalassemia and future genetic counseling in those regions.

scholarly journals Current concepts in the diagnosis and management of antiphospholipid syndrome and ocular manifestations

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Gunay Uludag ◽  
Neil Onghanseng ◽  
Anh N. T. Tran ◽  
Muhammad Hassan ◽  
Muhammad Sohail Halim ◽  
...  
Keyword(s):  
Antiphospholipid Syndrome ◽  
Antiphospholipid Antibodies ◽  
Clinical Manifestations ◽  
Autoimmune Disorder ◽  
Ocular Involvement ◽  
Ocular Manifestations ◽  
Different Types ◽  
Thrombotic Complications ◽  
Specific Factors ◽  
Arteries And Veins

AbstractAntiphospholipid syndrome (APS) is an autoimmune disorder associated with obstetrical complications, thrombotic complications involving both arteries and veins, and non-thrombotic manifestations affecting multiple other systems presenting in various clinical forms. Diagnosis requires the presence of antiphospholipid antibodies. The exact pathogenesis of APS is not fully known. However, it has recently been shown that activation of different types of cells by antiphospholipid antibodies plays an important role in thrombosis formation. Ocular involvement is one of the important clinical manifestations of APS and can vary in presentations. Therefore, as an ophthalmologist, it is crucial to be familiar with the ocular findings of APS to prevent further complications that can develop. Furthermore, the ongoing identification of new and specific factors contributing to the pathogenesis of APS may provide new therapeutic options in the management of the disease in the future.

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