Form Of Syndrome Research Articles

Mermaid baby or sirenomelia: a lethal congenital anomaly

Mermaid syndrome is a very rare, lethal congenital anomaly. It is associated with other congenital anomalies and is incompatible with life. Typical clinical features are fused lower limb from perineum to ankle and single umbilical artery. Etiology is multifactorial and is extreme form of caudal regression syndrome. When diagnosed in early gestation, termination of pregnancy may be considered.

Development of Erf-Mediated Craniosynostosis and Pharmacological Amelioration.

ETS2 repressor factor (ERF) insufficiency causes craniosynostosis (CRS4) in humans and mice. ERF is an ETS domain transcriptional repressor regulated by Erk1/2 phosphorylation via nucleo-cytoplasmic shuttling. Here, we analyze the onset and development of the craniosynostosis phenotype in an Erf-insufficient mouse model and evaluate the potential of the residual Erf activity augmented by pharmacological compounds to ameliorate the disease. Erf insufficiency appears to cause an initially compromised frontal bone formation and subsequent multisuture synostosis, reflecting distinct roles of Erf on the cells that give rise to skull and facial bones. We treated animals with Mek1/2 and nuclear export inhibitors, U0126 and KPT-330, respectively, to increase Erf activity by two independent pathways. We implemented both a low dosage locally over the calvaria and a systemic drug administration scheme to evaluate the possible indirect effects from other systems and minimize toxicity. The treatment of mice with either the inhibitors or the administration scheme alleviated the synostosis phenotype with minimal adverse effects. Our data suggest that the ERF level is an important regulator of cranial bone development and that pharmacological modulation of its activity may represent a valid intervention approach both in CRS4 and in other syndromic forms of craniosynostosis mediated by the FGFR-RAS-ERK-ERF pathway.

The hereditary nephrotic syndrome in children: features of clinical phenotype and genotype, pathogenesis, renal prognosis of isolated and syndromic forms

The review of the literature presents the clinical phenotype and genotype pathogenesis, renal prognosis of isolated and extra-renal manifestation form of hereditary nephrotic syndrome in children. The clinical and genetic features of hereditary steroid-sensitive and steroid-resistant nephrotic syndrome in children caused by mutations of genes encoding the main components of the slit diaphragm, glomerular basement membrane, structural and functional proteins of the podocyte are highlighted. Literature data demonstrate an unfavorable renal prognosis in children with hereditary steroid-resistant nephrotic syndrome with focal segmental glomerulosclerosis and diffuse mesangial sclerosis with clinical manifestation at the age of 0–17 years with progression to terminal renal failure at the age of 0.4–18 years. Renal replacement therapy with dialysis and kidney transplantation improves the prognosis, survival, and quality of life of children with hereditary nephrotic syndrome.

A Targeted, Low-Throughput Compound Screen in a Drosophila Model of Neurofibromatosis Type 1 Identifies Simvastatin and BMS-204352 as Potential Therapies for Autism Spectrum Disorder (ASD).

Autism spectrum disorder (ASD) is a common neurodevelopmental condition for which there are no pharmacological therapies that effectively target its core symptomatology. Animal models of syndromic forms of ASD, such as neurofibromatosis type 1, may be of use in screening for such treatments. Drosophila larvae lacking Nf1 expression exhibit tactile hypersensitivity following mechanical stimulation, proposed to mirror the sensory sensitivity issues comprising part of the ASD diagnostic criteria. Such behavior is associated with synaptic dysfunction at the neuromuscular junction (NMJ). Both phenotypes may thus provide tractable outputs with which to screen for potential ASD therapies. In this study, we demonstrate that, while loss of Nf1 expression within the embryo is sufficient to impair NMJ synaptic transmission in the larva, constitutive Nf1 knock-down is required to induce tactile hypersensitivity, suggesting that a compound must be administered throughout development to rescue this behavior. With such a feeding regime, we identify two compounds from a targeted, low-throughput screen that significantly and consistently reduce, but do not fully rescue, tactile hypersensitivity in Nf1P1 larvae. These are the HMG CoA-reductase inhibitor simvastatin, and the BKCa channel activator BMS-204352. At the NMJ, both compounds induce a significant reduction in the enhanced spontaneous transmission frequency of Nf1P1 larvae, though again not to the level of vehicle-treated controls. However, both compounds fully rescue the increased quantal size of Nf1P1 mutants, with simvastatin also fully rescuing their reduced quantal content. Thus, the further study of both compounds as potential ASD interventions is warranted.

Distinct Etiologies of RANBP2-negative Acute Necrotizing Encephalopathy of Childhood (P10-9.008)

<h3>Objective:</h3> We sought to determine the etiology of <i>RANBP2</i>-negative pediatric patients presenting with acute necrotizing encephalopathy of childhood (ANEC). <h3>Background:</h3> ANEC is a rare childhood syndrome associated with fulminant encephalopathy and characteristic neuroimaging typically precipitated by acute infection and often associated with heterozygous mutation in <i>RANBP2</i>. Additional genes implicated in ANEC include <i>CPT2, MC1DN1</i> and <i>ILAE4</i>, yet many patients who meet clinical criteria for ANEC do not have mutations in any known genes and the cause of these cases has remained cryptic. <h3>Design/Methods:</h3> We performed a multicenter trio-based whole exome analysis of 12 <i>RANBP2</i>-negative pediatric patients diagnosed with ANEC using our established pipeline and filtering criteria. Whole exome sequencing was performed using a TruSeq exome capture kit and run on an Illumina NovaSeq 6000. Fastq files were analyzed using our established GATK-based pipeline and filtered for rare variants using our published approach. We prioritized rare candidate genes to determine plausible candidates based on the existing literature. <h3>Results:</h3> 32 candidate genes survived filtering and were considered in our analysis. We identified three high-confidence candidate genes. The first was <i>SCN1A</i>, segregating a heterozygous <i>de novo</i> (p.F1765Cfs*28). SCN1A encodes a voltage-gated sodium channel subunit. Mutations in SCN1A are well-known causes of Dravet Syndrome and other forms of epilepsy, but have also been associated with a fulminant encephalopathy phenotype independent of seizure burden. The second was <i>TNFAIP3</i> (heterozygous <i>de novo</i> p.R728C), previously shown to lead to an autoinflammatory Behcet-like syndrome. The third was <i>PRF1</i> (homozygous p.R225W), associated with a hemophagocytic lymphocystiocytosis-like phenotype with encephalopathy, ataxia, deep white matter lesions, and increased intracranial pressure. <h3>Conclusions:</h3> Our study indicates that ANEC is genetically heterogeneous and highlights three additional genes that should be considered in individuals presenting with ANEC. Our results also showcase how monogenic conditions can impact immune system regulation and lead to neuroimmunologic disorders. <b>Disclosure:</b> Dr. Vaidyanathan has nothing to disclose. Somayeh Bakhtiari has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Xilis Inc. Somayeh Bakhtiari has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant (Bioinformatics) with Phoenix Childrens Hospital. Dr. Appavu has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Natus. The institution of Dr. Appavu has received research support from American Heart Association. The institution of Dr. Appavu has received research support from United States Department of Defense. Derek Neilson has nothing to disclose. The institution of Dr. Kruer has received research support from NIH NINDs. Dr. Kruer has received research support from Cure CP. Dr. Kruer has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant with NHRSA.

Clinical and functional heterogeneity associated with the disruption of retinoic acid receptor beta

PurposeDominant variants in the retinoic acid receptor beta (RARB) gene underlie a syndromic form of microphthalmia, known as MCOPS12, which is associated with other birth anomalies and global developmental delay with spasticity and/or dystonia. Here, we report 25 affected individuals with 17 novel pathogenic or likely pathogenic variants in RARB. This study aims to characterize the functional impact of these variants and describe the clinical spectrum of MCOPS12. MethodsWe used in vitro transcriptional assays and in silico structural analysis to assess the functional relevance of RARB variants in affecting the normal response to retinoids. ResultsWe found that all RARB variants tested in our assays exhibited either a gain-of-function or a loss-of-function activity. Loss-of-function variants disrupted RARB function through a dominant-negative effect, possibly by disrupting ligand binding and/or coactivators’ recruitment. By reviewing clinical data from 52 affected individuals, we found that disruption of RARB is associated with a more variable phenotype than initially suspected, with the absence in some individuals of cardinal features of MCOPS12, such as developmental eye anomaly or motor impairment. ConclusionOur study indicates that pathogenic variants in RARB are functionally heterogeneous and associated with extensive clinical heterogeneity.

Selected Serum Biomarkers (Leptin, Chromogranin A, CA19-9, CEA) in Patients with Pancreatic Neuroendocrine Neoplasm and Associations with Metabolic Syndrome

Metabolic abnormalities are well-known risk factors for many cancers, even though no clearly established link with pancreatic neuroendocrine neoplasms (PanNENs) has yet been investigated. This research aimed to assess the serum levels of leptin, chromogranin A (CgA), carbohydrate antigen 19-9 (CA19-9), and carcinoembryonic antigen (CEA) in patients with PanNENs and to search for associations between PanNENs, these selected serum biomarkers, and metabolic abnormalities in the form of metabolic syndrome (MS). Second, we aimed to investigate whether MS increases the risk of PanNENs. The serum concentrations of biomarkers, metabolic parameters (glucose, cholesterol, triglycerides), and anthropometric measurements (weight, height, BMI) were assessed in 106 patients with PanNENs and 40 healthy volunteers. Patients with PanNENs showed higher serum concentrations of CA19-9, CEA, and CgA in comparison to controls (p < 0.001, p = 0.042, and p = 0.025, respectively). Statistically significant differences in CEA levels were found in PanNENs patients with MS (p = 0.043). PanNENs patients with a BMI ≥ 25 kg/m2 and who were female exhibited significantly higher leptin levels (p < 0.001 and p = 0.013, respectively). Additionally, this study reflects the importance of determining markers. Future research should focus on understanding the impact of metabolic disturbances on PanNENs and accounting for the relationship between PanNENs and MS, such as other malignancies.

Comparative Study Between the First and Second Wave of COVID-19 Deaths in India: A Single Center Study.

Introduction The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is continuously evolving, and many mutant variants of the virus are circulating in the world. Recurrent waves of COVID-19 have caused enormous mortality all across the globe. Considering the novelty of the virus, it becomes crucial for healthcare experts and policymakers to understand the demographic and clinical attributes of inpatient deaths in the first and second waves of COVID-19. Methods This hospital record-based comparative study was conducted at a tertiary care hospital in Uttarakhand, India. The study included all COVID-19 RT PCR-positive patients admitted to the hospital during the first wave, from 1stApril2020to 31stJanuary2021, and the second wavefrom 1stMarch2021to 30thJune2021. Comparisons were made with respect to demographic, clinical, laboratory parameters, and course of hospital stay. Results The study exhibited 11.34% more casualties in the second wave, with the number of deaths being 424 and 475 for the first and second waves, respectively. A male preponderance of mortality was evident in both waves with significant differences(p=0.004). There was no significant difference in age between the two waves(p=0.809). The significantly different comorbidities were hypertension (p=0.003) and coronary artery disease (p=0.014). The clinical manifestations demonstrating a significant difference were cough (p=0.000), sore throat (p=0.002), altered mental status (p=0.002), headache (p=0.025), loss of taste and smell (p=0.001), and tachypnea (p=0.000). The lab parameters with a significant difference across both waves were lymphopenia (p=0.000), elevated aspartate aminotransferase (p=0.004), leukocytosis (p=0.008), and thrombocytopenia (p=0.004). During the hospital course of the second wave, in terms of intensive care unit stay, the need for non-invasive ventilation and inotrope support was higher. The complications manifesting in the form of acute respiratory distress syndrome and sepsis were observed more in the second wave. A significant difference was discerned in the median duration of hospital stay in both waves (p=0.000). Conclusion Despite being of shorter duration, the second wave of COVID-19 culminated in more deaths. The study demonstrated that most of the baseline demographic and clinical characteristics attributed to mortality were more common during the second wave of COVID-19, including lab parameters, complications, and duration of hospital stays. The unpredictable nature of COVID-19 waves calls for instituting a well-planned surveillance mechanism in place to identify the surge in cases at the earliest possible time and prompt response, along with developing infrastructure and capacity to manage complications.

Establishment of iPSC lines and zebrafish with loss-of-function AHDC1 variants: Models for Xia-Gibbs syndrome

Xia-Gibbs syndrome (XGS) is a syndromic form of intellectual disability caused by heterozygous AHDC1 variants, but the pathophysiological mechanisms underlying this syndrome are still unclear. In this manuscript, we describe the development of two different functional models: three induced pluripotent stem cell (iPSC) lines with different loss-of-function (LoF) AHDC1 variants, derived by reprogramming peripheral blood mononuclear cells from XGS patients, and a zebrafish strain with a LoF variant in the ortholog gene (ahdc1) obtained through CRISPR/Cas9-mediated editing. The three iPSC lines showed expression of pluripotency factors (SOX2, SSEA-4, OCT3/4, and NANOG). To verify the capacity of iPSC to differentiate into the three germ layers, we obtained embryoid bodies (EBs), induced their differentiation, and confirmed the mRNA expression of ectodermal, mesodermal, and endodermal markers using the TaqMan hPSC Scorecard. The iPSC lines were also approved for the following quality tests: chromosomal microarray analysis (CMA), mycoplasma testing, and short tandem repeat (STR) DNA profiling. The zebrafish model has an insertion of four base pairs in the ahdc1 gene, is fertile, and breeding between heterozygous and wild-type (WT) animals generated offspring in a genotypic proportion in agreement with Mendelian law. The established iPSC and zebrafish lines were deposited on the hpscreg.eu and zfin.org platforms, respectively. These biological models are the first for XGS and will be used in future studies that investigate the pathophysiology of this syndrome, unraveling its underlying molecular mechanisms.

The Role of Anamnesis in Modern Ophthalmic Practice: a Clinical Case

Eyes’ dryness continues to be the most frequent complication after LASIK. As a rule, it disappear in the vast majority of patients during the first year after surgery. The conducted studies indicate that complaints of eyes’ dryness in the preoperative period significantly increase the risk of developing a severe form of dry eye syndrome in the postoperative period, especially in middle-aged women (45–59 years) and older. The clinical case presented in this article indicates the development of a severe form of dry eye syndrome after LASIK in a middle-aged patient receiving hormone replacement therapy for menopause, complaining of a feeling of dryness and discomfort in the eyes in the preoperative period, with intolerance to contact lenses and taking antidepressants in the absence of signs of severe dry eye in the preoperative period. Consequently, surgical intervention led to the development of the mentioned above condition. It is confirmed by the literature data indicating that the above factors can cause the development of a severe form of dry eye syndrome after LASIK. Taking into account the fact that tear production tests do not always correlate with the intensity of complaints of dryness, burning sensation, pain in the eyes, the most important component at the stage of deciding on the feasibility of refractive surgery in a particular patient is the collection of anamnesis and clinical picture. When preparing patients with a history of dry eye syndrome for refractive surgery, it is necessary to inform them that they have a significantly increased risk of developing dry eye syndrome. It may persist in the long-term postoperative period, and possibly go into a chronic form. Candidates for refractive surgery in the presence of complaints characteristic of dry eye syndrome can only be those patients who respond well to therapy aimed at relieving these symptoms in the preoperative period. Taking into account the multicomponent nature of pain in dry eye syndrome — nociceptive pain, which is formed at the stage of receptor irritation in the corneal tissue, and neuropathic pain that occurs with the participation of the peripheral and central nervous system, a comprehensive approach is needed in the treatment of dry eye syndrome.

Lung Expression of Macrophage Markers CD68 and CD163, Angiotensin Converting Enzyme 2 (ACE2), and Caspase-3 in COVID-19.

Background and Objectives: The coronavirus (SARS-CoV-2) damages all systems and organs. Yet, to a greater extent, the lungs are particularly involved, due to the formation of diffuse exudative inflammation in the form of acute respiratory distress syndrome (ARDS) with next progression to pulmonary fibrosis. SARS-associated lung damage is accompanied by the pronounced activation of mononuclear cells, damage of the alveoli and microvessels, and the development of organized pneumonia. To study the expression of macrophage markers (CD68 and CD163), angiotensin-converting enzyme-2 (ACE2), and caspase-3 on the results of two fatal clinical observations of COVID-19. Materials and Methods: In both clinical cases, the female patients died from complications of confirmed COVID-19. Conventional morphological and immunohistochemical methods were used. Results: There was an acute exudative hemorrhagic pneumonia with the formation of hyaline membranes, focal organization of fibrin, stromal sclerosis, stasis, and thrombus formation in the lung vessels. Signs such as the formation of hyaline membranes, organization, and fibrosis were more pronounced in severe disease activity. The activation of CD68+/CD163+ macrophages could cause cell damage at an early stage of pneumonia development, and subsequently cause fibrotic changes in lung tissue. ACE2 expression in lung tissue was not detected in severe pneumonia, while in moderate pneumonia, weak expression was noted in individual cells of the alveolar epithelium and vascular endothelium. Conclusions: This finding could show the dependence of ACE2 expression on the severity of the inflammatory process in the lungs. The expression of caspase-3 was more pronounced in severe pneumonia.

Identification of GLI1 and KIAA0825 Variants in Two Families with Postaxial Polydactyly.

Polydactyly is a rare autosomal dominant or recessive appendicular patterning defect of the hands and feet, phenotypically characterized by the duplication of digits. Postaxial polydactyly (PAP) is the most common form and includes two main types: PAP type A (PAPA) and PAP type B (PAPB). Type A involves a well-established extra digit articulated with the fifth or sixth metacarpal, while type B presents a rudimentary or poorly developed superfluous digit. Pathogenic variants in several genes have been identified in isolated and syndromic forms of polydactyly. The current study presents two Pakistani families with autosomal recessive PAPA with intra- and inter-familial phenotype variability. Whole-exome sequencing and Sanger analysis revealed a novel missense variant in KIAA0825 (c.3572C>T: p.Pro1191Leu) in family A and a known nonsense variant in GLI1 (c.337C>T: p.Arg113*) in family B. In silico studies of mutant KIAA0825 and GLI1 proteins revealed considerable structural and interactional modifications that suggest an abnormal function of the proteins leading to the disease phenotype. The present study broadens the mutational spectrum of KIAA0825 and demonstrates the second case of a previously identified GLI1 variant with variable phenotypes. These findings facilitate genetic counseling in Pakistani families with a polydactyly-related phenotype.

Syndromic ichthyoses.

Inherited ichthyoses are classified as Mendelian disorders of cornification (MEDOC), which are further defined on the basis of clinical and genetic features and can be divided into non-syndromic and syndromic forms. To date, mutations in more than 30 genes are known to result in various types of syndromic ichthyoses, which, in addition to mostly generalised scaling and hyperkeratosis of the skin, also show additional organ involvement. The syndromic ichthyoses are generally very rare and are classified based on the mode of inheritance, and can be further subdivided according to the predominant symptoms. In our review we provide a concise overview of the most prevalent syndromic forms of ichthyosis within each subgroup. We emphasize the importance of the clinical assessment of complex syndromes even in the era of genetic testing as a first-tier diagnostic and specifically the need to actively assess potential organ involvement in patients with ichthyosis, thereby enabling efficient diagnostic and therapeutic approaches and timely access to specialized centers for rare disorders of cornifications. As part of the Freiburg Center for Rare Diseases a Center for Cornification Disorders was recently established with collaboration of the Institute of Human Genetics and the Department of Dermatology. An early diagnosis of syndromes will be of direct benefit to the patient regarding interventional and therapeutic measures e. g. in syndromes with cardiac or metabolic involvement and allows informed reproductive options and access to prenatal and preimplantation genetic diagnosis in the family.

YuPingFengSan ameliorates LPS-induced acute lung injury and gut barrier dysfunction in mice

Ethnopharmacological relevanceYupingfengsan (YPFS) is a traditional Chinese medicine decoction. YPFS comprises Astragalus mongholicus Bunge (Huangqi), Atractylodes rubra Dekker (Baizhu), and Saposhnikovia divaricata (Turcz.ex Ledeb.) Schischk (Fangfeng). YPFS is commonly used to treat chronic obstructive pulmonary disease, asthma, respiratory infections, and pneumonia, but the mechanism of action remains unclear. Aim of the studyAcute lung injury (ALI) and its severe form of acute respiratory distress syndrome (ARDS) cause morbidity and mortality in critical patients. YPFS is a commonly used herbal soup to treat respiratory and immune system diseases. Nevertheless, the effect of YPFS on ALI remains unclear. This study aimed to investigate the effect of YPFS on lipopolysaccharide (LPS)-induced ALI in mice and elucidate its potential molecular mechanisms. Materials and methodsThe major components of YPFS were detected by High-performance liquid chromatography (HPLC). C57BL/6J mice were given YPFS for seven days and then treated with LPS. IL-1β, IL-6, TNF-α, IL-8, iNOS, NLRP3, PPARγ, HO-1, ZO-1, Occludin, Claudin-1, AQP3, AQP4, AQP5, ENaCα, ENaCβ, EnaCγ mRNA in lung and ZO-1, Occludin, Claudin-1, AQP3, AQP4, AQP5, ENaCα, ENaCβ, and EnaCγ mRNA in colon tissues were measured by Real-Time Quantitative PCR (RT-qPCR). The expressions of TLR4, MyD88, NOD-like receptor thermal protein domain associated protein 3 (NLRP3), ASC, MAPK signaling pathway, Nrf2, and HO-1 in the lung were detected by Western blot. Plasma inflammatory factors Interleukin (IL)-1β, IL-6, and Tumor Necrosis Factor-α (TNF-α) were determined by Enzyme-linked Immunosorbent Assay (ELISA). Lung tissues were processed for H & E staining, and colon tissues for HE, WGA-FITC, and Alcian Blue staining. ResultsThe results showed that YPFS administration alleviated lung injury and suppressed the production of inflammatory factors, including IL-1β, IL-6, and TNF-α. Additionally, YPFS reduced pulmonary edema by promoting the expressions of aquaporin and sodium channel-related genes (AQP3, AQP4, AQP5, ENaCα, ENaCβ, and EnaCγ). Further, YPFS intervention exhibited a therapeutic effect on ALI by inhibiting the activation of the NLRP3 inflammasome and MAPK signaling pathways. Finally, YPFS improved gut barrier integrity and suppressed intestinal inflammation in LPS-challenged mice. ConclusionsYPFS protected mice against LPS-induced ALI by attenuating lung and intestinal tissue damage. This study sheds light on the potential application of YPFS to treat ALI/ARDS.

IN-HOSPITAL OUTCOMES OF PATIENTS PRESENTING WITH ANTERIOR WALL MYOCARDIAL INFARCTION WITH RIGHT BUNDLE BRANCH BLOCK

BACKGROUND: Acute myocardial infarction is a common heart disease associated with signicant morbidity and mortality. Data on the Clinical, Electrocardiographic and Angiographic prole of acute anterior wall ST-elevation myocardial infarction with Right Bundle Branch Block with q waves in leads v1, v2 are scarce. The aim of this study is to compare the mortality and in hospital outcomes of patients with anterior wall myocardial infarction with RBBB and without RBBB. The study design is a METHODS: retrospective study among the patients admitted with acute anterior wall STEMI with qRBBB and non qRBBB pattern on ECG during the time period March to August 2022. All relevant clinical and treatment data were collected from the medical records department, Government Royapettah Hospital. ECGs taken during the hospitalization of the patient were subjected to detailed analysis and their outcomes were recorded. RESULTS: Among the 50 patients with anterior wall myocardial infarction 11 patients presented with qRBBB pattern. Out of these 11patients, 7 patients had higher Killip score at presentation and 4 of them succumbed to death (57%).The in-hospital mortality rate was higher among those who had anterior wall myocardial infarction with qRBBB pattern when compared to non qRBBB pattern. There was a higher incidence of cardiogenic shock (54%) among patients with qRBBB pattern. Acute anterior wall MI wit CONCLUSION: h qRBBB myocardial infarction is a severe form of acute coronary syndrome with higher in-hospital mortality and morbidity necessitating early recognition and prompt institution of reperfusion therapy. Cardiogenic shock, ventricular tachycardia, higher Killip and TIMI scores at presentation are signicant predictors of inhospital mortality

The Unique Spectrum of MUTYH Germline Mutations in Colombian Patients with Extracolonic Carcinomas.

Protein MUTYH, encoded by the gene MUTYH, is an important mismatch repair enzyme in the base-excision repair pathway of DNA repair. When genetically altered, different neoplastic conditions can arise. One of the widely known syndromes associated with MUTYH mutations is MUTYH-associated polyposis, a form of familial colorectal cancer syndrome. MUTYH may also be a driver in other familial cancer syndromes, as well as breast cancer and spontaneous cancer cases. However, some controversies about the role of these alterations in oncogenesis remain, especially when affected in a heterozygous way. Most available data on MUTYH mutations are on Caucasian patients. We analyzed a small cohort of non-Caucasian, Colombian cancer patients with MUTYH germline heterozygous mutations, clinical features suggestive of familial cancer, and extensive genetic studies with no other mutations and without MUTYH-associated polyposis. With this case series, we intended to provide important data for the understanding of MUTYH as a possible driver of familial cancer, even when only heterozygous mutations are found.

Clinical expression of parasitic arthritis – joint inflammatory process

Introduction. Parasitic arthritis is associated with infestation of the patient’s body of parasitic species of worms and protozoan microorganisms. Now it has been established that parasitic arthritis can be caused by almost any species of these creatures. The objective of the study was to research the clinical-evolutionary features of cases of parasitic infections associated with damage of the osteo-articular system in helminthic pathologies. Materials and methods. 161 patients were included in the study, which were divided into 3 groups of differentiated observation by the pathogen of infestation and the clinical variant of parasitic arthritis. The first group (97 patients) consisted of patients with parasitic arthritis associated with echinococcosis infestation, the 2nd (31 patients) – patients with parasitic arthritis associated with Toxocara canis and the 3rd (33 patients) included subjects with parasitic arthritis associated with of Giardia lamblia infestation. Results and discussion. Echinococcosis was manifested more often by the axial (65.67%) and peripheral (31.34%) clinical forms, while the mixed form was being extremely rare (2.98%) (p &lt; 0.001). The power of connection with the type of arthritis has reached the degree of statistical significance (p &lt; 0.001). Parasitic arthritis due to Toxocara canis showed an overwhelming predominance of peripheral forms of joint syndrome (70.96%), with an insignificant share of axial (12.9%) and mixed form (16.13%) (p &lt; 0.01), with a connection to the peripheral form of parasitic arthritis (p &lt; 0.01). The clinically developed form of parasitosis caused by Giardia lamblia manifested a predominantly mixed joint syndrome (57.89%), confirming a predominantly peripheral impairment (36.84%) of the axial (5%) with a statistically significant difference (p &lt; 0.05), as well as a connection for the mixed-peripheral form of parasitic arthritis (p &lt; 0.05). Conclusions. Parasitic arthritis is characterized by the diversity of clinical joint manifestations, which fall into 3 clinical variants: induced by infestation with Echinococcus, Toxocara canis and Giardia lamblia, among which giardiasis correlates with a more severe clinical course, followed by echinococcosis and toxocariasis. Despite a large number of painful and inflamed joints that are also associated with an advanced radiological stage of joint damage, parasitic arthritis is characterized by a comparatively diminished articular painful syndrome.

Recurrent Mutations of the Active Adenylation Domain of UBA1 in Atypical Form of VEXAS Syndrome.

Recurrent Mutations of the Active Adenylation Domain of UBA1 in Atypical Form of VEXAS Syndrome.

Syndromic forms of congenital hyperinsulinism.

Congenital hyperinsulinism (CHI), also called hyperinsulinemic hypoglycemia (HH), is a very heterogeneous condition and represents the most common cause of severe and persistent hypoglycemia in infancy and childhood. The majority of cases in which a genetic cause can be identified have monogenic defects affecting pancreatic β-cells and their glucose-sensing system that regulates insulin secretion. However, CHI/HH has also been observed in a variety of syndromic disorders. The major categories of syndromes that have been found to be associated with CHI include overgrowth syndromes (e.g. Beckwith-Wiedemann and Sotos syndromes), chromosomal and monogenic developmental syndromes with postnatal growth failure (e.g. Turner, Kabuki, and Costello syndromes), congenital disorders of glycosylation, and syndromic channelopathies (e.g. Timothy syndrome). This article reviews syndromic conditions that have been asserted by the literature to be associated with CHI. We assess the evidence of the association, as well as the prevalence of CHI, its possible pathophysiology and its natural course in the respective conditions. In many of the CHI-associated syndromic conditions, the mechanism of dysregulation of glucose-sensing and insulin secretion is not completely understood and not directly related to known CHI genes. Moreover, in most of those syndromes the association seems to be inconsistent and the metabolic disturbance is transient. However, since neonatal hypoglycemia is an early sign of possible compromise in the newborn, which requires immediate diagnostic efforts and intervention, this symptom may be the first to bring a patient to medical attention. As a consequence, HH in a newborn or infant with associated congenital anomalies or additional medical issues remains a differential diagnostic challenge and may require a broad genetic workup.

Analysis of exome data in a UK cohort of 603 patients with syndromic orofacial clefting identifies causal molecular pathways.

Orofacial cleft (OC) is a common congenital anomaly in humans, which has lifelong implications for affected individuals. This disorder can be classified as syndromic or non-syndromic depending on the presence or absence of additional physical or neurodevelopmental abnormalities, respectively. Non-syndromic cleft is often non-familial in nature and has a complex aetiology, whereas syndromic forms tend to be monogenic. Although individual OC-related syndromes have been frequently described in the medical literature, there has not been a comprehensive review across syndromes, thereby leaving a gap in our knowledge, which this paper aims to address. Six hundred and three patients with cleft-related human phenotype ontology terms were identified within the Deciphering Developmental Disorders study. Genes carrying pathogenic/likely pathogenic variants were identified and reviewed enabling a diagnostic yield of 36.5%. In total, 124 candidate genes for syndromic OC were identified, including 34 new genes that should be considered for inclusion in clinical clefting panels. Functional enrichment and gene expression analyses identified three key processes that were significantly overrepresented in syndromic OC gene lists: embryonic morphogenesis, protein stability and chromatin organization. Comparison with non-syndromic OC gene networks led us to propose that chromatin remodelling specifically contributes to the aetiology of syndromic OC. Disease-driven gene discovery is a valid approach to gene identification and curation of gene panels. Through this approach, we have started to unravel common molecular pathways contributing to syndromic orofacial clefting.