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Assim A Alfadda,1– 3 Khalid Siddiqui,2 Mohamed Rafiullah,2 Mohammad AlKhowaiter,1 Naif Alotaibi,4 Musa Alzahrani,5 Khalifa Binkhamis,6 Amira M Youssef,2 Haifa Altalhi,7 Ibrahim Almaghlouth,8 Mohammed Alarifi,9 Saleh Albanyan,1 Mohammed F Alosaimi,10 Arthur Isnani,3 Shaik S Nawaz,2 Khalid Alayed5 1Department of Internal Medicine, College of Medicine, and King Khalid University Hospital, King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia; 2Strategic Center for Diabetes Research, College of Medicine, King Saud University, Riyadh, Saudi Arabia; 3Obesity Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia; 4Department of Medicine, College of Medicine, and King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia; 5Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia; 6Department of Pathology, College of Medicine, King Saud University, Riyadh, Saudi Arabia; 7Infection Control Department, King Khalid University Hospital, King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia; 8Rheumatology Unit, Department of Internal Medicine, King Khalid University Hospital, King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia; 9Intensive Care Department, King Khalid University Hospital, King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia; 10Pediatric Department, King Khalid University Hospital, King Saud University Medical City, King Saud University, Riyadh, Saudi ArabiaCorrespondence: Assim A Alfadda, Department of Internal Medicine and the Obesity Research Center, College of Medicine, King Saud University, P.O. Box 2925(98), Riyadh, 11461, Saudi Arabia, Tel + 966 11 467 1315, Email aalfadda@ksu.edu.saBackground: The severe manifestation of coronavirus disease 2019 (COVID-19) is known to be mediated by several cytokines and chemokines. The study aimed to compare the early cytokine profile of mild and severe COVID-19 patients to that with COVID-19-like symptoms and tested negative for Severe Acute Respiratory Syndrome Coronavirus-2 in the Reverse-Transcriptase Polymerase Chain Reaction (RT-PCR) test.Methods: This was a prospective, observational study on COVID-19 patients admitted to King Khalid University Hospital, King Saud University Medical City from June to November 2020. Clinical and biochemical data were collected from hospital charts. Blood samples were collected at the time of hospital admission to measure cytokines. A Cytokine and Growth Factor High-Sensitivity Array was used to quantitatively measure cytokines.Results: The study included 202 RT-PCR-positive individuals and 61 RT-PCR-negative individuals. C-Reactive protein (CRP) and Interleukin-10 (IL-10) levels were found significantly elevated in the RT-PCR positive group compared to the RT-PCR negative group (p=0.001). Patients with severe COVID-19 had significantly longer median hospital stays than those with mild COVID-19 cases (7 vs 6 days). They also had higher CRP and Vascular Endothelial Growth Factor (VEGF) levels and lower Interleukin-4 (IL-4) levels compared to the mild cases. CRP, interleukin-6, IL-10, VEGF, and Monocyte Chemoattractant Protein-1 (MCP-1) levels were significantly elevated in men and IL-10 was significantly higher and interleukin-8 was significantly lower in women compared to negative controls. Elevated Interferon-ɣ (IFN-γ) and IL-10 levels were seen in mild COVID-19 cases and elevated level of MCP-1 was seen in severe COVID-19 cases when categorized according to the length of stay in the hospital.Conclusion: CRP and IL-10 levels were elevated in the RT-PCR positive group. People with severe COVID-19 had higher CRP and VEGF levels and lower IL-4 levels. Elevated IFN-γ and IL-10 levels were seen in mild COVID-19 cases and elevated level of MCP-1 was seen in severe COVID-19 cases when categorized according to the length of stay in the hospital.Keywords: SARS-CoV-2, early inflammation, asymptomatic patient, proinflammatory cytokines, regulatory cytokines

Background: Familial adenomatous polyposis (FAP) syndrome has a near-100% lifetime risk of colorectal cancer. Early surveillance and prophylactic surgery have been advocated to reduce this risk. However, the surveillance practices among FAP individuals in Saudi Arabia are unknown. We aimed to explore surveillance compliance in our population, as well as the disease impact on their quality of life (QoL)., Methods: All patients with FAP who underwent surgical resection at King Saud University Medical City between 2016 and 2022 were included. Demographic data, clinical features, family history, and compliance with surveillance were collected and analyzed. QoL questionnaires: Short-form health survey (SF-36) and European Organization for Research and Treatment (EORTC) were conducted by phone interview., Results: A total of 14 patients were included with an average age of 25 years. Three patients (21.4%) were the first of their family members to develop FAP. Nine patients (64%) were untested for genetic mutation due to lack of referral to geneticists. The compliance rate toward both pre-operative colonoscopy and upper endoscopy were 78%. However, 38% and 27% compliance rates were observed toward initial and post-operative colonoscopy, respectively. The compliance rate was 14% toward thyroid ultrasound. QoL scores varied among patients, with a mean score above 60 across all SF-36 domains., Conclusion: An overall poor compliance was observed among our participants, particularly toward thyroid ultrasound. Increased health awareness and patient education are essential. In addition, the importance of surveillance and genetic counseling should be emphasized among physicians treating these patients., (© 2023. The Author(s).)

Background: The type II transmembrane protein fibrinogen-like protein 2 (FGL2) plays critical roles in hemostasis and immune regulation. The C-terminal immunoregulatory domain of FGL2 can be secreted and is a mediator of regulatory T (Treg) cell suppression. Fgl2 -/- mice develop autoantibodies and glomerulonephritis and have impaired Treg cell function., Objective: Our aim was to identify the genetic underpinning and immune function in a patient with childhood onset of leukocytoclastic vasculitis, systemic inflammation, and autoantibodies., Methods: Whole-exome sequencing was performed on patient genomic DNA. FGL2 protein expression was examined in HEK293 transfected cells by immunoblotting and in PBMCs by flow cytometry. T follicular helper cells and Treg cells were examined by flow cytometry. Treg cell suppression of T-cell proliferation was assessed in vitro., Results: The patient had a homozygous mutation in FGL2 (c.614_617del:p.V205fs), which led to the expression of a truncated FGL2 protein that preserves the N-terminal domain but lacks the C-terminal immunoregulatory domain. The patient had an increased percentage of circulating T follicular helper and Treg cells. The patient's Treg cells had impaired in vitro suppressive ability that was rescued by the addition of full-length FGL2. Unlike full-length FGL2, the truncated FGL2 V205fs mutant failed to suppress T-cell proliferation., Conclusions: We identified a homozygous mutation in FGL2 in a patient with immune dysregulation and impaired Treg cell function. Soluble FGL2 rescued the Treg cell defect, suggesting that it may provide a useful therapy for the patient., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Post-acute coronavirus disease 2019 (COVID-19) syndrome, also known as long COVID, is a prolonged illness after the acute phase of COVID-19. Hospitalized patients were known to have persisting symptoms of fatigue, headache, dyspnea, and anosmia. There is a need to describe the characteristics of individuals with post-COVID-19 symptoms in comparison to the baseline characteristics., Purpose: To investigate the clinical and biochemical characteristics of people who recovered from COVID-19 after 6 months of discharge from the hospital., Methods: This was a prospective follow-up investigation of hospitalized and discharged COVID-19 patients. Adult patients admitted to King Saud University Medical City, Riyadh, Saudi Arabia, with laboratory-confirmed COVID-19 and discharged were recruited. The baseline demographic information, comorbidities, vital signs and symptoms, laboratory parameters, COVID-19 therapy, and outcomes were collected from the medical records. Blood samples were collected for cytokines estimation. A detailed interview about signs and symptoms was undertaken during the follow-up., Results: Half of the followed-up people reported experiencing at least one of the COVID-19-related symptoms. The mean blood pressure was found higher in follow-up. People with the symptoms were characterized by low lymphocyte count, lower serum calcium levels, and hyperglycemia compared to people without any post-COVID-19 symptoms. Cytokines IL-8, VEGF, and MCP-1 were higher in people with the most frequent symptoms., Conclusion: People with post-COVID-19 symptoms were characterized by lower lymphocyte count, lower serum calcium levels, and hyperglycemia compared to people without symptoms. Individuals with the most frequent post-COVID-19 symptoms had higher baseline pro-inflammatory, chemotactic, and angiogenic cytokines., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Alfadda, Rafiullah, Alkhowaiter, Alotaibi, Alzahrani, Binkhamis, Siddiqui, Youssef, Altalhi, Almaghlouth, Alarifi, Albanyan, Alosaimi, Isnani, Nawaz and Alayed.)

Background: COVID-19 is diagnosed using RT-PCR assays of samples from nasal and oropharyngeal swabs. People with negative RT-PCR often presented with clinical manifestations of COVID-19. The data on such patients are lacking. The present study aims to characterize the patients who were suspected COVID-19 cases and tested negative in RT-PCR compared to patients who had been tested RT-PCR positive., Methods: This is a retrospective, observational study of adult suspected and confirmed patients of COVID-19 admitted to King Saud University Medical City, Riyadh, Saudi Arabia, from 1st March 2020 until 30th November 2020. Laboratory confirmation is done through nasal/pharyngeal swab specimens, tested positive in RT-PCR assay. Patients with initial negative RT-PCR test results were assessed again within 48-72 h to avoid false-negative results. Patient data were extracted from the electronic medical files of each included patient using a predesigned case report form., Results: The study included 488 (80.93%) patients with RT-PCR swab results positive, and 115 (19.07%) patients who were negative. Respiratory rate and diastolic blood pressure were higher among the swab-positive cases. More number of swab-negative patients had comorbidities such as coronary heart disease, chronic kidney disease, and carcinoma. Fever, cough, and shortness of breath were reported higher among the swab-positive cases. ALT and AST, and LDH levels were found higher among RT-PCR-positive patients. Serum creatinine, blood urea nitrogen and troponin were more elevated in RT-PCR-negative patients. Antibiotics, anticoagulants, and corticosteroids were used more by swab-positive patients. Significantly higher number of RT-PCR-positive patients required proning, high-flow nasal cannula, non-invasive mechanical ventilation, and invasive mechanical ventilation. Acute cardiac ischemia and death were found to be similar among the patients. However, deaths occurred significantly earlier among the swab-positive cases when compared to the swab-negative group., Conclusion: Distinctive symptoms and markers of COVID-19 are more frequent among patients who had RT-PCR-positive results., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Anal fissure (AF) in children is usually treated with laxatives and/or topical agents such as calcium channel blockers. We hypothesize that owing to the superior efficacy of Polyethylene glycol (PEG) in treating constipation in children, adding diltiazem (DTZ) might not improve healing of AF., Methods: Children ≤14 years with anal fissure presented to the pediatric surgery clinic between November 2014 and March 2016 were recruited. Randomization was performed to either PEG with DTZ or PEG with placebo. Study personnel, patients, and their families were blinded. Primary outcome was resolution of symptoms. Secondary outcomes were constipation and treatment complications at 12-week follow up., Results: 48 patients were randomized: 24 to PEG + DTZ and 24 to PEG + placebo. Both groups were similar in their baseline characteristics. At week 12, majority of patients' symptoms have improved without significant difference between groups; painful defecation at week 12: 20.8% and 8.3% (p-value 0.41), blood per rectum at week 12: 4.2% and 8.3% (p value 0.58) in the DTZ and placebo groups, respectively. Additionally, there was similar improvement in constipation in both groups., Conclusion: PEG alone was associated with similar improvement in anal fissure symptoms in children compared to PEG and topical diltiazem combined., Level of Evidence: I., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: This case-control study assessed the prevalence of psychiatric disorders in Arab (Saudi) patients with narcolepsy using a structured clinical interview., Methods: The study included 74 adult patients with narcolepsy and 265 controls matched for age and sex. Narcolepsy diagnosis was made according to the International Classification of Sleep Disorders-Third Edition. Psychiatric disorders were diagnosed via using a validated Arabic version of the Mini International Neuropsychiatric Interview DSM-IV (MINI version 6). A multivariate logistic regression model was used to assess the potential influence of narcolepsy on the comorbidity of psychiatric disorders., Results: The mean age of the patients was 29.4 ± 10.2 years, and males accounted for 81% of the study sample. Forty-four patients (60%) were diagnosed with narcolepsy type-1 (NT1) and 30 (40%) with narcolepsy type-2 (NT2). Psychiatric disorders were diagnosed in 45% of patients with narcolepsy compared with 15% of the controls (p < 0.001). The multivariate logistic regression models demonstrated that compared with the controls, patients with narcolepsy were more likely to have major depressive disorders (OR, 4.3 [CI, 2.2-8.2]), and generalized anxiety disorders (OR, 9.5 [CI, 1.8-50.2]). No difference was detected between the prevalence of various psychiatric disorders in patients with NT1 and NT2., Conclusion: Comorbid psychiatric disorders are common among Arab (Saudi) patients with narcolepsy compared with the general population. Therefore, clinicians should be aware of the comorbidity of narcolepsy and psychiatric disorders, particularly depression.

Von Hippel-Lindau disease (VHL) is a heritable condition caused by pathogenic variants in VHL and is characterized by benign and malignant lesions in the central nervous system (CNS) and abdominal viscera. Due to its variable expressivity, existing efforts to collate VHL patient data do not adequately capture all VHL manifestations. We developed a comprehensive and standardized VHL database in the web-based application, REDCap, that thoroughly captures all VHL manifestation data. As an initial trial, information from 86 VHL patients from the University Health Network/Hospital for Sick Children was populated into the database. Analysis of this cohort showed missense variants occurring with the greatest frequency, with all variants localizing to the α- or β-domains of VHL. The most prevalent manifestations were central nervous system (CNS), renal, and retinal neoplasms, which were associated with frameshift variants and large deletions. We observed greater age-related penetrance for CNS hemangioblastomas with truncating variants compared to missense, while the reverse was true for pheochromocytomas. We demonstrate the utility of a comprehensive VHL database, which supports the standardized collection of clinical and genetic data specific to this patient population. Importantly, we expect that its web-based design will facilitate broader international collaboration and lead to a better understanding of VHL., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Enamel renal syndrome (ERS) is a rare autosomal recessive disorder not fully characterized. Here we investigated ERS characteristics in 11 patients from 5 Brazilian families through clinical examination, imaging, renal ultrasonography, laboratory tests and DNA sequencing. The patients' age ranged from 6 to 25 years-old, and the presence of hypoplastic amelogenesis imperfecta, microdontia, intra-pulpal calcification, impacted posterior teeth with hyperplastic pericoronal follicles, gingival fibromatosis, ectopic calcifications on gingival and pericoronal tissues, and nephrocalcinosis were common findings to all patients. Only 4 patients showed abnormal laboratory tests (vitamin D, parathyroid hormone, phosphate, calcium). Intellectual disability and renal cysts were present in 2 patients each. Biallelic loss of function mutation in FAM20A gene, characterized by one base pair deletion in exon 11, resulting in a frameshift replacing a glutamine at codon 483 for a lysine and terminating at position 24 [NG&#95;029809.1: c.1447delG; p.(Glu483Lysfs*24)], was detected in all patients, strongly suggesting a founder effect. Our results reinforce the distinct orofacial features of ERS, which are the clue for kidney examination and genetic testing. Early diagnosis is essential to minimize the deleterious effects related to ERS. Here we report the largest series of patients with ERS in a same population, and describe, for the first time, a founder mutation for FAM20A., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Von Hippel-Lindau (VHL) disease is a hereditary tumor syndrome in which carriers are at an increased risk of developing a variety of tumors in multiple organ systems. A clinical diagnosis of VHL is determined by the presence of specific clinical manifestations while a molecular genetic diagnosis results from a pathogenic variant in the VHL gene. The majority of mutations occur in VHL coding exons and DNA analysis of these regions has a reported sensitivity of nearly 100%. However, rare variants in the VHL gene promoter may be detected in some cases of suspected VHL disease. We report two cases where VHL promoter variants were detected and describe the role of multi-step mRNA and protein analysis in the diagnostic evaluation of these cases., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

BCAP31, encoded by BCAP31, is involved in the export of transmembrane proteins from the endoplasmic reticulum. Pathogenic variants in BCAP31 results in global developmental delay, dystonia, deafness and dysmorphic features in males, called deafness, dystonia, and cerebral hypomyelination (DDCH) syndrome. We report a new patient with BCAP3-associated encephalopathy, DDCH syndrome, sensorineural hearing loss, generalized dystonia, and choreoathetosis. This 3.5-year-old boy had microcephaly and failure to thrive within the first 3 months of life. His brain MRI showed bilateral increased signal intensity in globus pallidus at age 3 months raising the suspicion of mitochondrial encephalopathy. His muscle biopsy revealed pleomorphic subsarcolemmal mitochondria collection in electron microscopy. Respiratory chain enzyme activities were normal in muscle. He was enrolled to a whole exome sequencing research study, which identified a hemizygous likely pathogenic truncating variant (c.533&#95;536dup; p.Ser180AlafsX6) in BCAP31, inherited from his mother, who had sensorineural hearing loss and normal cognitive functions. We report a new patient with BCAP31-associated encephalopathy, DDCH syndrome, mimicking mitochondrial encephalopathy. We also report a heterozygous mother who has bilateral sensorineural hearing loss. This patient's clinical features, muscle histopathology, brain MRI features, and family history were suggestive of mitochondrial encephalopathy. Whole exome sequencing research study confirmed the diagnosis of BCAP31-associated encephalopathy, DDCH syndrome., (© 2017 Wiley Periodicals, Inc.)

Enamel-renal syndrome (OMIM #204690) is an uncommon disorder characterized by amelogenesis imperfecta and nephrocalcinosis and is caused by mutations in FAM20 A. We report 2 patients with enamel-renal syndrome who exhibited the typical features of this syndrome and a homozygous nonsense mutation in the FAM20 A gene (c.406 C>T), genetically confirming the diagnosis. They also exhibited 2 undescribed clinical features, hypertrichosis and hearing loss. Alterations in genes frequently associated with nonsyndromic hearing loss in the Brazilian population, including connexin 26 (GJB2), connexin 30 (GJB6) and mitochondrial 12 S rRNA (m.A1555 G mutation), were not found. These results suggest a putative function of FAM20 A in the development of the inner ear and in the formation of hair. The presence of nephrocalcinosis is a risk factor for renal impairment, and it is important to perform regular renal monitoring in order to avoid renal failure., (Copyright © 2016 Elsevier Inc. All rights reserved.)