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Successful vascular adult thymus transplant has been reported in different animal models but not in rabbits. These animal models are slightly larger than the murine and substantially smaller than the porcine. We describe in rabbits a supermicrosurgical technique for vascular neonatal thymus transplant and provide histologic evidence of tissue viability.Newborn (New Zealand, n = 12, 6 female) and adult (New Zealand, n = 12, 6 female) rabbits were used as donors and recipients, respectively. Whole thymuses were extracted from donors and grafted into recipients. Immediate direct vascularization was accomplished by anastomosis to the right common carotid artery and the right external vena cava. At day 14, graft sites were surgically explored, and grafted thymuses were explanted for histologic evaluation. All recipients were followed over 2 weeks for clinical signs of graft-vs-host reaction.The vascular pedicles of the thymus grafts ranged 0.5 to 0.8 mm in vessel diameter. From the 12 transplants, 3 recipients (3/12; 25%) died during the surgical procedure because of blood loss after clamp release. On histology, from the 9 (9/12; 75%) successful at revascularization, none (0/9; 0%) had signs of acute rejection or necrosis, and all (9/9; 100%) evidenced normal cytoarchitecture. No clinical signs of graft-vs-host reaction were evidenced during follow-up.Vascular neonatal thymus transplant in rabbits is surgically feasible. This technique will enable a novel approach for studying the biology of the thymus.

Lisa Ximena Rodriguez-Rojas,1,2 Estephania Candelo,3,4 Harry Pachajoa,1,2,4 Juan Esteban Garcia-Robledo,3 Jose Antonio Nastasi-Catanese,1,2 Jorge Andres Olave-Rodriguez,2 Angela R Zambrano5 1Department of Human Genetics, Fundación Valle del Lili, Cali, Colombia; 2Faculty of Health Sciences, Universidad Icesi, Cali, Colombia; 3Fundación Valle del Lili, Centro de Investigaciones Clínicas, Cali, Colombia; 4Centro de Investigaciones en Anomalías Congénitas y Enfermedades Raras, Universidad Icesi, Cali, Colombia; 5Department of Hematology/Oncology, Fundación Valle del Lili, Cali, ColombiaCorrespondence: Lisa Ximena Rodriguez-Rojas, Department of Human Genetics, Fundación Valle del Lili, Cali, 760032, Colombia, Email lisa.rodriguez@fvl.org.coBackground: 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.Material and Methods: 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.Conclusion: 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.Keywords: MUTYH mutations, familial cancer, heterozygote MUTYH mutation, Colombia

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) (OMIM:540000) is one of the most frequent mitochondrial maternal inheritance disorders. MELAS syndrome involves multiple organs, which generates a broad spectrum of manifestations, including stroke-like episodes, dementia, seizures, lactic acidaemia, myopathy, recurrent headaches, hearing impairment, diabetes, and short stature. The most common mutation associated with this phenotype is m.3243A>G in the MT-TL1 gene, which encodes for a mitochondrial tRNALeu (UUR). This mutation affects mitochondrial protein translation process, transduce into protein synthesis impairment and cause deficits of essential proteins for ATP production such as transport chain complex subunits leading to impairment in energy production and multi-organ dysfunction. This lack of energy proficiency could stimulate mitochondrial growth in the smooth muscle and endothelial cells, causing angiopathy and impaired blood perfusion of several tissue and organs, leading to metabolic complications and stroke-like episodes. In this case report, we present a female patient with hearing impairment as the only manifestation, who underwent an anesthetic procedure for cerebral magnetic resonance imaging, developed metabolic acidosis and hyperlactatemia, and died. Finally, the biopsy revealed a post-mortem genetic variant for MELAS syndrome.

Coronavirus disease 2019 (COVID-19) has increased the risk of developing severe acute respiratory distress syndrome and subsequent moderate to severe laryngotracheal stenoses (LSTs) with an early presentation that occurs between two and three months after SARS-CoV-2 infection. We present a series of 12 cases of LST following SARS-CoV-2 infection. Dense lymphocyte infiltration with multinuclear giant cell granulomas was found on biopsy with intranuclear inclusions, suggestive of viral cytopathic effects in one case and intravascular fibrin thrombi with perivascular mononuclear infiltrate of CD3 + T lymphocytes. We present the largest and only series that describes clinical and histopathological characteristics of LTS and the management and outcomes after early laryngotracheal reconstruction in the context of the SARS-CoV-2 outbreak.

Jorge Andres Olave-Rodriguez,1 Francisco Javier Bonilla-Escobar,2– 4 Estephania Candelo,5,6 Lisa Ximena Rodriguez-Rojas1,7 1Universidad Icesi, Faculty of Health Sciences, Cali, Colombia; 2Somos Ciencia al Servicio de la Comunidad, Fundación SCISCO/Science to Serve the Community, SCISCO Foundation, Cali, Colombia; 3Universidad del Valle, Cali, Colombia; 4Institute for Clinical Research Education, University of Pittsburgh, Pittsburgh, PA, USA; 5Centro de Investigaciones Clínicas, Fundación Valle del Lili, Cali, Colombia; 6Centro enfermedades raras y malformaciones congenitas (CIACER), Universidad Icesi, Cali, Colombia; 7Human Genetics Department, Fundación Valle del Lili, Cali, ColombiaCorrespondence: Lisa Ximena Rodriguez-Rojas Cra. 98 ## 18-49, Cali, Valle del Cauca, ColombiaEmail lixiro@gmail.com; lisa.rodriguez@fvl.org.coBackground: Becker’s type myotonia congenita is an autosomal recessive nondystrophic skeletal muscle disorder characterized by muscle stiffness and the inability of muscle relaxation after voluntary contraction. It is caused by mutations in the CLCN1 gene, which encodes for a chloride channel mainly expressed in the striated muscle. Most cases have been reported in the European population, and only mexiletine has demonstrated a randomized placebo-controlled, double-blinded effectiveness.Case Presentation: We present two male siblings from Colombia with Latino ancestry, without parental consanguinity, with myotonia during voluntary movements, muscle hypertrophy of lower extremities, transient weakness, and severe muscle fatigue after exercise from three years of age. A genetic panel for dystrophic muscle disorders and a muscle biopsy were both negative. Genetic testing was performed in their second decade of life. Both patients’ exomic sequencing test reported the mutation c.1129C >T (p.Arg377*) affecting exon 10 of the CLCN1, generating a premature stop codon. This mutation was described as pathogenic and observed in only one other patient in the United Kingdom.Conclusion: To our knowledge, these are the first cases of Becker’s type myotonia congenita reported in Colombia. Increasing awareness of healthcare providers for this type of disease in the region could lead to the identification of undiagnosed patients. Limited availability of medical geneticists as well as genetic testing may be the cause of the lack of previous description of cases, in addition to the delay in the diagnosis of the patients. Further epidemiological studies can reveal underdiagnosed myotonias in the country and in the Latin-American region.Keywords: Becker type myotonia congenita, myotonia congenita, Colombia, muscular diseases, siblings case reports

Up to 40% of genetic and rare disorders (RD) present facial dysmorphologies. Visual assessment of facial gestalt is commonly used for clinical diagnosis, health management and treatment monitoring. Quantitative approaches to facial phenotypes are more objective and provide first diagnoses of RD with relatively high accuracy, but are mainly based on populations of European descent, disregarding the influence of population ancestry. Here we assessed the facial phenotypes associated to four genetic disorders in a Latino-American population from Colombia. We recorded the coordinates of 18 facial landmarks in 2D images from 79 controls 51 pediatric individuals diagnosed with Down (DS), Morquio (MS), Noonan (NS) and Neurofibromatosis type 1 (NF1) syndromes. We quantified facial differences using Euclidean Distance Matrix Analysis (EDMA) and assessed the diagnostic accuracy of Face2gene, an automatic deep learning algorithm with widespread use in the clinical practice.Quantitative comparisons indicated that individuals diagnosed with DS and MS were associated with the most severe phenotypes, with 58.2% and 65.4% of facial traits significantly different as compared to controls. The percentage decreased to 47.7% in NS and to 11.4% in NF1. Each syndrome presented a characteristic pattern of facial dysmorphology, supporting the potential of facial biomarkers for disorder diagnosis. However, our results detected population-specific traits in the Colombian population as compared to the facial gestalt described in literature for DS, NS and NF1. When clinical diagnosis based on genetic testing was used to verify the diagnosis based on 2D facial pictures, our results showed that Face2Gene accuracy was very high in DS, moderate in NS and NF1, and very low in MS, with low gestalt similarity scores in highly admixed individuals. Our study underscores the added value of precise quantitative comparison of facial dysmorphologies in genetic and rare disorders and the need to incorporate populations with diverse contributions of Amerindian, African and European ancestry components to further improve automatic diagnostic methods.

Kabuki syndrome (KS) is an autosomal dominant genetic disorder in which most cases are caused by de novo mutations. KS type 1 is caused by mutations in KMT2D (OMIM: #147920) and is more common. KS type 2 is caused by mutations in KDM6A (OMIM: #300867). Both genes encode proteins that modify histones and are involved in epigenetic regulation. The enzyme histone-lysine N-methyltransferase 2D, the product of KMT2D, is expressed in most adult tissues and is essential for early embryonic development. The main clinical manifestations of KS include dysmorphic facial features, such as elongated palpebral fissures, eversion of the lateral third of the lower eyelids, and short nasal columella with a broad and depressed nasal tip. Additionally, patients also present with skeletal abnormalities, dermatoglyphic features, mild-to-moderate intellectual disability, hearing loss, and postnatal growth deficiency. We describe an 11-year-old girl from Colombia, who presented with characteristic clinical signs of KS. Genetic studies showed a KMT2D intronic variant (KMT2D NM_003482.3: c.511‐2A> T) as a cause of KS.

Colombia has a high prevalence of mucopolysaccharidosis (MPS) type IVA. Nevertheless, data regarding the mutation spectrum for MPS IVA in this population have not been completely characterized. Forty-seven families and 53 patients from seven different Colombian regions were tested for MPS IVA mutations. We compared the sequences with the N-acetylgalactosamine-6-sulfatase (GALNS) reference sequence NM_000512.4, and gene variants were reported. Bioinformatics analysis was performed using SWISS-MODEL. The mutant proteins were generated by homology from the wild-type GALNS 4FDJ template obtained from the PDB database, and visualization was performed using Swiss-PDBViewer and UCSF Chimera. The predictive analysis was run using different bioinformatic tools, and the deleterious annotation of genetic variants was performed using a neural network. We found that 79% and 21% of the cohort was homozygous and compound heterozygous, respectively. The most frequent mutation observed was p.Gly301Cys (78.3% of alleles), followed by p.Arg386Cys (10.4% of alleles). A novel mutation (p.Phe72Ile) was described and classified in silico as a pathogenic variant. This study reveals the mutation spectrum of MPS IVA in Colombia. The high prevalence of the p.Gly301Cys mutation suggests a founder effect of this variant in the Colombian population that causes diseases in the Andean region (via migration). These data can facilitate genetic counseling, prenatal diagnosis, and the design of therapeutic interventions.

BACKGROUND The epidemiology, morbidity, and burden of the disease related to airway sequelae associated with invasive mechanical ventilation (IMV) in the context of the COVID-19 pandemic remain unclear. OBJECTIVE This scoping review aims to summarize the current knowledge regarding airway sequelae after severe SARS-CoV2 infection. This knowledge will help guide research endeavors and decision-making in clinical practice. METHODS This scoping review will include participants of all genders and no particular age group who developed post-COVID airway related complication will be excluded. No exclusion criteria will be applied from country, language or document type. The information source will include analytical observational, observational studies. Unpublished data will not be completely covered as grey literature will be covered. A total of 2 independent reviewers will participate in the process of screening, selection, and data extraction, and the whole process will be performed blindly. Conflict between reviewers will be solve through discussion and additional reviewer. Results will be reported by using descriptive statistics and information will be displayed on RedCap. RESULTS The literature search was conducted in May 2022 in in the following databases; PubMed, EMBASE, SCOPUS, Cochrane Library, LILACS and Grey literature to identify observational studies; a total of 738 results were retrieved. The scoping review will be finished by March-2023. CONCLUSIONS This scoping review will describe current knowledge on the most frequently encountered laryngeal and/or tracheal sequelae in patients exposed to mechanical ventilation due to SARS-CoV-2 infection. This scoping review will find the incidence of airway sequelae post-COVID19 and the most common sequelae such as; airway granuloma, vocal fold paralysis, and airway stenoses. Future studies should evaluate the incidence of these disorders. CLINICALTRIAL

Lysosomal storage disorders (LSDs) are a group of rare and genetic diseases produced by mutations in genes coding for proteins involved in lysosome functioning. Protein defect leads to the lysosomal accumulation of undegraded macromolecules including glycoproteins, glycosaminoglycans, lipids, and glycogen. Depending on the stored substrate, several pathogenic cascades may be activated leading to multisystemic and progressive disorders affecting the brain, eye, ear, lungs, heart, liver, spleen, kidney, skin, or bone. In addition, for some of these disorders, hematological findings have been also reported. In this paper, we review the major hematological alterations in LSDs based on 56 case reports published between 2010 and 2020. Hematological alterations were reported in sphingolipidosis, mucopolysaccharidoses, mucolipidoses, neuronal ceroid lipofuscinosis, glycogenosis, glycoproteinosis, cystinosis, and cholesteryl ester storage disease. They were reported alterations in red cell linage and leukocytes, such as anemia and morphology changes in eosinophils, neutrophils, monocytes, and lymphocytes. In addition, changes in platelet counts (thrombocytopenia) and leukocyte abnormalities on non-peripheral blood samples were also reported for some LSDs. Although in most of the cases these hematological alterations are not pathognomonic of a specific disease or group of LSDs, since they can be easily identified in general clinical laboratories, their identification may contribute to the diagnosis of these disorders. In this sense, we hope that this review contributes to the awareness of the importance of hematological alterations in the diagnosis of LSDs.

The Moche were a pre-Hispanic, pre-Incan people who inhabited northwestern Peru from 50 to 850 AD and left behind a large body of ceramic artwork. We present 26 pieces from 5 museums, which seem to show individuals with malformations, minor anomalies, and possible genetic syndromes. Possible diagnoses include cleft lip and palate, ocular anomalies such as hypertelorism and orbital dystopia, oligo- and polydactyly, conjoined twinning, clubfoot, Down syndrome, Crouzon syndrome, and Seckel syndrome. These ceramic portraits suggest that these people with received a certain respect or even elevated status within their society.

Aerodigestive obstruction due to cricoid hypertrophy is a rare and potentially life-threatening condition. We present a two-year-old female patient who displayed repetitive respiratory infections, swallowing disorder, and malnutrition without any eye signs or symptoms of airway alterations. We described a patient with aerodigestive obstruction generating a marked narrowing of the trachea immediately below the larynx due to severe thickening of the cricoid cartilage. She was successfully treated with surgery, and the clinical and radiological features of this condition are presented here with a review of the literature.

Introduction: Usher syndrome has a broad phenotypic and genotypic spectrum. Developmental and epileptic encephalopathy-52 (DEE52) is a sever autosomal recessive seizure disorder that is characterized by infantile onset of refractory seizures, consequently resulting in delayed global development. This study aimed to describe the clinical features and to investigate the four variants identified in a Colombian family with Usher syndrome and KCNC2 encephalopathy syndrome.Methods and Results: We present a case of a family with two clinically relevant phenotypes: a mother with a compound heterozygous mutation causing Usher Syndrome, type IIC (USH2C) and her 15-year-old son who carried one heterozygous variant in the KCNC2 gene (p.P470S) and two cis mutations (p.V2927I and p.Q4955EfsTer10) in the ADGRV1 gene segregated from his mother, and a second non-disrupted allele. Owing to this, the boy did not present with USH2C but presented a developmental epilepsy syndrome. His younger sibling was unaffected, although he did inherit the trans mutation in a single pathogenic allele from his mother.Discussion and Conclusion: Whole-exome sequencing helps detect genes related to known and novel hearing loss and seizure syndrome. However, familiar segregation studies are an excellent method to clarify genotype-phenotype correlation in families, where multiple genes of clinically relevant have been identified. This method helps determine the genotype-phenotype relationship of a disease, which is associated with the clinical presentation and determines the pathogenicity of variants that are classified as variants of uncertain clinical significance.

This case report aims to raise awareness of the possibility of amyotrophic lateral sclerosis (ALS) diagnosis in patients presenting to the Otolaryngology Department. We describe the case of a 66-year-old woman with hoarseness who was evaluated by several physicians and was referred to an ALS specialist only a year after symptom onset. Our case highlights the importance of considering motor neuron etiologies in patients with voice complaints. Early identification and referral to a specialist are critical for accurate diagnosis and prognosis and may be the key to slowing the disease's progression.

BACKGROUND Coronavirus disease 19 (COVID-19), the disease caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is already responsible for more than four and a half million deaths worldwide. With a unique pathophysiology related to respiratory failure due to interstitial pneumonia and acute respiratory distress syndrome, severe COVID-19 is qualitatively different from moderate disease. Since genetics play a crucial role in susceptibility to viral infection and propensity to develop harmful inflammatory conditions, genetic heterogeneity promotes the question of whether gene variants might influence COVID-19 outcomes. The identification of genetic variants associated with severe courses of COVID-19 is a promising option for the improvement of prognostic tools, contemplation of new therapeutic targets and the development of patient’s clinical risk stratification. OBJECTIVE We aim to perform a scoping review to assess the extent of the literature regarding the gene variants that could be associated with COVID-19 severity. METHODS The proposed scoping review will be conducted in accordance with the methodology from the Joanna Briggs Institute’s Scoping Review Network.12 The search strategy will focus on published studies without discriminating in date or language. A multiple-database search (MEDLINE, LILACS, The Cochrane Library, Science Direct, Google Scholar and OpenGrey) will be done performing the following strategy: ((("COVID-19"[Mesh] OR "SARS-CoV-2"[Mesh]) AND ("Polymorphism, Genetic"[Mesh] OR "Mutation"[Mesh] OR "Antibody Diversity"[Mesh] OR "Antigenic Variation"[Mesh]) AND ("Severity of Illness Index"[Mesh] OR "Death"[Mesh] OR "Critical Care"[Mesh] OR "Critical Illness"[Mesh] OR (severity))). This scoping review will consider observational studies and genome-wide association studies (GWAS) without discriminating in date or language. Additionally, systematic reviews that meet the inclusion criteria will also be considered. Data will be extracted from papers included in the scoping review by two independent reviewers using an already existent data extraction tool. RESULTS The conducted search was performed on February 16th in MEDLINE, LILACS, The Cochrane Library, Science Direct, Google Scholar and OpenGrey retrieved a total of 2190 results. Completion of the review is expected in late 2021. CONCLUSIONS This scoping review will be the first to map the extent of information regarding the genetic variants associated to the severity of COVID-19. The data gathered by this investigation could lead to biomarkers of severity in COVID-19 and the stratification of patients according to their genetic risk of disease severity.

Background Mild to moderate hearing loss is common in patients with mucopolysaccharidosis (MPS) IVA. The hearing loss can be conductive, sensorineural, or mixed. However, in these patients, the mixed form is frequent, attributed to the combination of conductive and neurosensory elements, with slowly progressive evolution. Conductive hearing loss may be secondary to recurrent upper respiratory tract infections, serous otitis media, and deformities of the ear ossicles due to the accumulation of glycosaminoglycans (GAGs). Meanwhile, the sensorineural form is mainly attributed to the accumulation of GAGs in the auditory system. Objective The aim of this scoping review is to understand the extent and type of evidence in relation to the physiopathology, classification, epidemiology, and clinical management of hearing loss and the effect of therapy for hearing loss in patients with MPS IVA. Methods This scoping review includes participants across all genders and of no particular age group who are diagnosed with MPS IVA and develop hearing loss as a comorbidity. No exclusion criteria (country, language, or document type) will be applicable. The information sources will include experimental and quasi-experimental, analytical observational, observational, and qualitative studies. Unpublished literature will not be covered. Grey literature will be covered. A total of 2 independent reviewers will participate in the process of screening the literature, paper selection, and data extraction, and this process will be performed blindly. When all manuscripts have been selected, disagreements that arise between the 2 reviewers at each stage of the selection process will be resolved through discussion or with an additional reviewer. Results will be reported with descriptive statistics and information will be displayed in a diagrammatic or tabular manner, as explained in the JBI guidelines. Results The literature search was performed in November 2021 in MEDLINE, LILACS (Literatura Latino-Americana e do Caribe em Ciências da Saúde), the Cochrane Library, ScienceDirect, Google Scholar, and OpenGrey; a total of 780 results were retrieved. Completion of the review is expected in mid-2022. Conclusions This scoping review will be the first to describe the extent of the information regarding the development of hearing loss in the MPS IVA population. The data gathered by this review may lead to an understanding of the grade of hearing loss in this population and allow for the assessment of possible interventions according to the disease pattern. International Registered Report Identifier (IRRID) PRR1-10.2196/32986

Estephania Candelo,1– 3 Maria Alejandra Estrada-Mesa,4 Adriana Jaramillo,4 Carlos Humberto Martinez-Cajas,4 Julio Cesar Osorio,4 Harry Pachajoa1,2 1Congenital Abnormalities and Rare Disease Centre (CIACER), Cali, Colombia; 2Genetics Department, Fundacion Valle del Lili, Cali, Colombia; 3Centro de Investigaciones Clínicas, Fundacion Valle del Lili, Cali, Colombia; 4Institución Universitaria Colegios de Colombia (UNICOC), Cali, ColombiaCorrespondence: Estephania Candelo Email ecandelo@icesi.edu.coBackground: DiGeorge syndrome (DG) is a genetic disorder associated with 22q11 deletion. It involves various phenotypes, including craniofacial abnormalities, congenital heart disorders, endocrine dysfunction, cognitive deficits, and psychiatric disorders. Cases commonly involve multiple anomalies. However, little is known about the condition of the oral cavity in this disorder, although palate fissure, abnormal mandible, malocclusion, and tooth hypoplasia have been identified. We aimed to determine the odontological features of patients with 22q11.2 microdeletion, in relation to gingival health and oral hygiene. We report the systemic manifestations of nine patients and results of oral evaluation of two patients. In the oral examination, oral hygiene and gingivitis were evaluated.Case Presentation: In terms of the systemic manifestations, we found high frequencies of low weight and height at birth. In terms of the oral manifestations, both examined patients presented malocclusion, enamel hypoplasia, dental crowding, anodontia, and healthy periodontium.Conclusion: Although DG has been documented to involve periodontium disease, the patients in this study exhibited more dental manifestations such as enamel defects, misalignment between the teeth and the two dental arches, anodontia, and dental crowding. As such, a multidisciplinary approach combining dentistry and healthcare is recommended in this case.Keywords: DiGeorge syndrome 22q11.2 deletion, oral manifestations, facial dysmorphism, case report

Lorena Díaz-Ordóñez,1– 3 Diana Ramírez-Montaño,1– 3 Estephania Candelo,2– 4 Carolina González-Restrepo,1 Sebastián Silva-Peña,1 Carlos Arturo Rojas,5 Mario Sepulveda Copete,5 Hector Raul Echavarria,6 Harry Pachajoa1– 3 1Basic Medical Science Department, Faculty of Health Sciences, Universidad Icesi, Cali, Colombia; 2Clinical Genetic Department, Fundación Valle del Lili, Cali, Colombia; 3Research Centre in Rare Diseases and Congenital Abnormalities (CIACER), Universidad Icesi, Cali, Colombia; 4Research Centre, Fundación Valle de Lili, Cali, Colombia; 5Gastroenterology Department, Fundacion Valle del Lili, Cali, Colombia; 6Centro Medico Imbanaco, Cali, ColombiaCorrespondence: Estephania Candelo Calle 18 122-135, Cali, 76003, ColombiaTel +57 2 5552334Fax + 57 2 555 1441Email ecandelo@icesi.edu.coBackground: CYP2C19 is a highly polymorphic gene that encodes an enzyme with the same name and whose function is associated with the metabolism of many important drugs, such as proton pump inhibitors (such as esomeprazole, which is used for the treatment of acid peptic disease). Genetic variants in CYP2C19 alter protein function and affect drug metabolism. This study aims to genotypically and phenotypically characterize the genetic variants in the CYP2C19 gene in 12 patients with acid peptic disorders and different therapeutic profiles to proton pump inhibitor (PPI) drugs. The patients were randomly selected from a controlled, randomized and blinded clinical pilot trial of 33 patients. We determined the presence and frequency of single nucleotide polymorphisms (SNPs) within exons 1– 5 and 9, the intron-exon junctions, and a fragment in the 3ʹ UTR region of the CYP2C19 gene using Sanger sequencing. Undescribed polymorphisms were analyzed by free online bioinformatics tools to evaluate the potential molecular effects of these genetic variants.Results: We identified nine polymorphisms, six of which had no reported functions. One of these genetic variants, with a functional impact, not yet reported (p.Arg132Trp) was predicted by bioinformatic tools as potentially pathogenic. This finding suggests that p.Arg132Trp could be related to poor metabolizers of drugs metabolized by CYP2C19.Conclusion: We identified the genotype spectrum of variants in CYP2C19. The genotype spectrum of variants in CYP2C19 could predict the treatment response and could support to evaluate clinical efficacy in patients treated with esomeprazole.Keywords: single nucleotide polymorphism, cytochrome P450 CYP2C19, pharmacogenetics, computational biology, treatment failure, proton pump inhibitors

Summary Purpose We present a prospective case series that aimed to report the functional (voice and swallowing) outcomes of delayed laryngeal reinnervation following vagal interruption by resection of vagal paraganglioma and schwannoma. Materials and Methods A dedicated, anonymized database was established in 2012 with a minimum eighteen-month follow up set for this report. Internationally validated self- and observer-reported measures were recorded preoperatively and at six, 12 and, 18 months together with demographics, diagnoses, and operative details. Results A total of eight patients with a median age of 46 (37-54) underwent excision of vagal paraganglioma (five) and schwannoma (three) with few mild complications. Three underwent selective and five non selective reinnervation. Seven out of eight patients underwent synchronous injection medialization. The voice handicap index (VHI-30) improved from a baseline median 83 (range 52-102) to 7.5 (5-58) at 18 months; maximum phonation time improved from median 8 (range 5-15) to 10.5 (8.5-11); voice grade (“G” in grade, roughness, breathiness, asthenia, and strain [GRBAS] scoring) improved from median three (severe impairment, range 0-3) to one (mild impairment, 0-2); Eating Assessment Tool (EAT-10) score improved from median 12 (range 3.5-27) preoperatively to one (0-16); and reflux symptom index (RSI) improved from median 25 (range 17-36) to 7 (0-36). One patient exhibited no discernible reinnervation, while the remainder exhibited good cord bulk and tone, though without purposive abduction. Conclusion Delayed laryngeal reinnervation for high vagal paralysis is a safe technique associated with good voice and swallowing outcomes by 12-18 months. Potential confounders in this small series and the absence of a control arm both limit conclusions, but this study suggests that further prospective, controlled studies, and/or case registration are merited.

Congenital disorders of glycosylation (CDGs) are a group of inborn errors of glycan metabolism with multi-systemic manifestations. More than 100 different types of CDGs have been reported. The form involving the asparagine-linked glycosylation 13 (ALG13) gene is an uncommon X-linked form of these pathologies.To describe the clinical features in one patient with ALG13-CDG and to compare them with previously reported cases.A 11-years-old boy, child of consangui neous parents, with hypotonia, severe developmental delay, intellectual disability, feeding difficulties, congenital heart disease (patent ductus arteriosus and mitral regurgitation), without epilepsy or coa gulation disorders. The metabolic screening showed unclear results, including N-glycosylation stu dies in plasma that were normal. Therefore, whole-exome sequencing (WES) was performed which identified a previously unreported variant in the ALG13 gene: c.428CT (p.P143L) in hemizygous state; confirmed by Sanger sequencing. His mother was a carrier of the same variant.This is the first report of a Colombian patient with ALG13-CDG without epilepsy. The findings in this patient broaden the phenotypic spectrum of ALG13-CDG known to date and support that N- glycosylation disorders may be present in normal biochemical analysis. WES has become a cost- effective technique that allows the identification of disease-causing mutations in diseases with a broad phenotypic and genotypic spectrum.

Hemophagocytic lymphohistiocytosis (HLH) is an exaggerated activation of the immune system which can be either primary (familial) or secondary. Familial hemophagocytic lymphohistiocytosis type 3 (FHL-3) is a severe immune disorder, caused by mutations in the UNC13D gene, which codes for a protein crucial to the cytotoxic function of lymphocytes.To describe the diagnostic relevance of next-generation sequencing in the approach of a patient with suspected FHL and to demonstrate the effectiveness of bone marrow transplantation as the only curative measure.4-year-old preschool male, previously healthy, who presented with mononucleosis syndrome and positive IgM for Epstein Barr virus, developing hepatosplenomegaly and progressive clinical de terioration. A lymphoproliferative syndrome was suspected, which was ruled out by bone marrow aspiration, finding evidence of active hemophagocytosis. The patient met the criteria for hemophago cytic syndrome (bone marrow aspiration, pancytopenia, elevated ferritin, and hypertriglyceridemia) and, given the lack of response to first-line management, including antiviral treatment, a possible primary etiology was considered. A molecular study was completed with NGS that was positive for FHL-3. Due to the progressive clinical deterioration, a bone marrow transplantation was performed, presenting successful results after the first year had elapsed.NGS is an indispensable tool in the diagnosis of FHL, mainly when the response to standard treatment is not adequate and facilitates the timely implementation of the necessary therapeutic measures.