Investigating the genetic profile of familial atypical cystic fibrosis patients (DeltaF508-CFTR) with neonatal biliary atresia.

Biliary atresia (BA) is a progressive inflammatory process of the biliary tree resulting in biliary obstruction. No single known genetic or environmental factor has been established to cause BA. Cystic fibrosis (CF) is a rare cause of neonatal cholestasis, and it has never been described in familial BA cases. Here, we investigate two siblings of first-degree consanguineous parents presenting with neonatal BA. Shortly after the Kasai operation, the proband developed severe respiratory symptoms attributable to a missed CF diagnosis. This was discovered after re-investigating the family history, which revealed a first-degree cousin with CF who did not manifest BA. Afterwards, we identified a pathogenic variant (DeltaF508) in CFTR in both BA-affected siblings along with their cousin. This intrigued us to study the molecular etiology behind the familial BA presentations, which exclusively contributed to BA-pathogenesis in BA-CF-affected siblings and not in their CF-only affected cousin. We applied a multistep approach to investigate the variant profile of both siblings' and their cousin's exomes. We curated the genes whose variants were shared by the BA-CF siblings but absent or heterozygous in their CF-only-affected cousin. Consequently, we identified three candidate genes (SNAPC4, UCK1, and ZHX2) besides CFTR. We propose that these genes act cumulatively or individually in inducing BA-pathogenesis-either by aggravating the biliary damage in the context of CF or increasing the susceptibility of BA as a separate CF-comorbidity. To our knowledge, this is the first report of DeltaF508 in CFTR with familial neonatal BA cases.

Potential Composite Digenic Contribution of NPC1 and NOD2 Leading to Atypical Lethal Niemann-Pick Type C with Initial Crohn's Disease-like Presentation: Genotype-Phenotype Correlation Study.

Niemann-Pick disease type C (NPC) is an autosomal recessive neurovisceral disease characterized by progressive neurodegeneration with variable involvement of multisystemic abnormalities. Crohn's disease (CD) is an inflammatory bowel disease (IBD) with a multifactorial etiology influenced by variants in NOD2. Here, we investigated a patient with plausible multisystemic overlapping manifestations of both NPC and CD. Her initial hospitalization was due to a prolonged fever and non-bloody diarrhea. A few months later, she presented with recurrent skin tags and anal fissures. Later, her neurological and pulmonary systems progressively deteriorated, leading to her death at the age of three and a half years. Differential diagnosis of her disease encompassed a battery of clinical testing and genetic investigations. The patient's clinical diagnosis was inconclusive. Specifically, the histopathological findings were directed towards an IBD disease. Nevertheless, the diagnosis of IBD was not consistent with the patient's subsequent neurological and pulmonary deterioration. Consequently, we utilized a genetic analysis approach to guide the diagnosis of this vague condition. Our phenotype-genotype association attempts led to the identification of candidate disease-causing variants in both NOD2 and NPC1. In this study, we propose a potential composite digenic impact of these two genes as the underlying molecular etiology. This work lays the foundation for future functional and mechanistic studies to unravel the digenic role of NOD2 and NPC1.

Twenty Years After Glioblastoma Multiforme Diagnosis: A Case of Long-Term Survival.

Glioblastoma multiforme (GBM) is an aggressive tumor that has a poor prognosis with a median survival of 15 months with treatment and 3-4 months without treatment. Subsets of patients are found to survive longer than two years, some survivors lived more than 10 years, and rare cases survived 20 years or more with treatment. Better prognosis has been found to be associated with many factors. Some of these factors are related to patients' characteristics, biological factors that impact tumor aggressiveness, and/or factors associated with treatment. However, the exact contribution for extended survival is still not known. Finding the factors that have a strong impact on the long survival is of high importance and can help give hope to better treat glioblastoma cases. In this report, we present a case of a glioblastoma patient who was diagnosed at the age of 47 years with more than 20-year survival. We further discuss the suggested factors that may have contributed to a better prognosis with a focus on the possible role of varicella-zoster infection in mediating long-term survival.

Pharmacological Approaches in Neurofibromatosis Type 1-Associated Nervous System Tumors.

Neurofibromatosis type 1 is an autosomal dominant genetic disease and a common tumor predisposition syndrome that affects 1 in 3000 to 4000 patients in the USA. Although studies have been conducted to better understand and manage this disease, the underlying pathogenesis of neurofibromatosis type 1 has not been completely elucidated, and this disease is still associated with significant morbidity and mortality. Treatment options are limited to surgery with chemotherapy for tumors in cases of malignant transformation. In this review, we summarize the advances in the development of targeted pharmacological interventions for neurofibromatosis type 1 and related conditions.

Acute and Post-Acute Neurological Complications of COVID-19.

Coronavirus disease 2019 (COVID-19) is an emerging global health emergency caused by the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The global outbreak of SARS-CoV-2 infection has been declared a global pandemic by the World Health Organization (WHO). The clinical presentation of SARS-CoV-2 infection depends on the severity of the disease and may range from an asymptomatic infection to a severe and lethal illness. Fever, cough, and shortness of breath are among the most common symptoms associated with SARS-CoV-2 infection. Accumulating evidence indicates that COVID-19 patients commonly develop neurological symptoms, such as headache, altered mental status, anosmia, and myalgia. In this comprehensive literature review, we have summarized the most common neurological complications and reported neurological case studies associated with COVID-19, and neurological side effects associated with COVID-19 treatments. Additionally, the post-acute COVID-19 syndrome and long-term neurological complications were discussed. We also explained the proposed mechanisms that are involved in the pathogenesis of these neurological complications.

Effect of Genetic Testing on Diagnosing Gastrointestinal Pediatric Patients with Previously Undiagnosed Diseases.

PURPOSE: Four consanguineous Jordanian families with affected members of unknown gastrointestinal related diseases were recruited to assess the utility and efficiency of whole exome sequencing (WES) in reaching the definitive diagnosis. PATIENTS AND METHODS: Members from four consanguineous Jordanian families were recruited in this study. Laboratory and imaging tests were used for initial diagnosis, followed by performing WES to test all affected members for the detection of causative variants. Sanger sequencing was used for validation. RESULTS: We had a 100% success rate identifying each case presented in this study. CONCLUSION: This is the first study applying a WES testing approach in the diagnosis of pediatric diseases in Jordan. Our results strongly suggest the need to implement WES as an evident diagnostic tool in the clinical setting, as it will subsequently allow for proper disease management and genetic counseling.

Enteric anendocrinosis attributable to a novel Neurogenin-3 variant.

Congenital diarrhea and enteropathies (CODEs) are a group of monogenic disorders that often present with severe diarrhea in the first weeks of life. Enteric anendocrinosis (EA), an extremely rare cause of CODE, is characterized by a marked reduction of intestinal enteroendocrine cells (EC). EA is associated with recessively inherited variants in Neurogenin-3 (NEUROG3) gene. Here we investigate a case of a male infant who presented with mysterious severe malabsorptive diarrhea since birth. Thorough clinical assessments and laboratory tests were successful to exclude the majority of differential diagnosis categories. However, the patient's diagnosis was not established until the genetic test using whole-exome sequencing (WES) was performed. We identified a novel homozygous missense disease-causing variant (DCV) in NEUROG3 (c.413C>G, p.Thr138Arg). Moreover, molecular dynamic simulation analysis showed that (p.Thr138Arg) led to a global change of the NEUROG3 orientation affecting its DNA binding capacity. To the best of our knowledge, this is the first time to apply WES to reach a differential diagnosis of patients with CODEs. Our study not only expands our knowledge about NEUROG3 variants and their clinical consequences but also proves that WES is a very effective tool for the diagnosis of CODEs. This might be of value in early diagnosis of diseases and prenatal CODEs detection.