IFIH1 loss of function predisposes to inflammatory and SARS-CoV-2-related infectious diseases.

The IFIH1 gene, encoding melanoma differentiation-associated protein 5 (MDA5), is an indispensable innate immune regulator involved in the early detection of viral infections. Previous studies described MDA5 dysregulation in weakened immunological responses, and increased susceptibility to microbial infections and autoimmune disorders. Monoallelic gain-of-function of the IFIH1 gene has been associated with multisystem disorders, namely Aicardi-Goutieres and Singleton-Merten syndromes, while biallelic loss causes immunodeficiency. In this study, nine patients suffering from recurrent infections, inflammatory diseases, severe COVID-19 or multisystem inflammatory syndrome in children (MIS-C) were identified with putative loss-of-function IFIH1 variants by whole-exome sequencing. All patients revealed signs of lymphopaenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin and IL-6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19 or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C. There was a significant association between IFIH1 monoallelic loss of function and susceptibility to infections in males. Expression analysis showed that PBMCs of one patient with a c.2016delA variant had a significant decrease in ISG15, IFNA and IFNG transcript levels, compared to normal PBMCs, upon stimulation with Poly(I:C), suggesting that MDA5 receptor truncation disrupts the immune response. Our findings accentuate the implication of rare monogenic IFIH1 loss-of-function variants in altering the immune response, and severely predisposing patients to inflammatory and infectious diseases, including SARS-CoV-2-related disorders.

Congenital Long QT Syndrome (LQTS) in Infancy: A Challenging Case.

Long QT syndrome (LQTS), is an arrhythmia disorder, related to ventricular myocardial repolarization characterized by a prolonged QT interval on the electrocardiogram that can lead to symptomatic ventricular arrhythmias and increase the mortality rate. The prevalence of congenital LQTS is about 1 in 2000 live births. Here, we report the case of a two-month-old female, with a significant family history of early death, who was brought to our emergency with an episode of blueish discoloration. The initial workup was positive for COVID-19 in the respiratory panel, so she was admitted as a case of bronchiolitis. It was a challenge because of the overlapping presentation between a serious condition and other common pediatric illnesses. Furthermore, the paper aims to increase awareness of this condition among physicians and emphasizes the importance of obtaining a complete medical history, physical examination, and family screening in selected cases to facilitate early diagnosis and timely management.

Clinical and epidemiological features and severity markers in children admitted with multisystem inflammatory syndrome in children (MISC) in a tertiary care center in the United Arab Emirates.

BACKGROUND: Multisystem inflammatory syndrome in children (MISC) is a phenomenon that appeared in children infected with or exposed to severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The typical onset of MISC is 4-6 weeks following SARS-CoV-2 infection and is formulated to be due to an immune response. METHODS: Our study retrospectively analyzed data from a tertiary center in United Arab Emirates of MISC patients who were admitted to either general pediatric wards or pediatric intensive care (PICU) or who came exclusively for follow-up (post-PICU admission) from May 2020 to August 2021. RESULTS: The total sample size was 50 patients, and the study included a comparison of MISC-PICU admissions with MISC-non-PICU admissions. The MISC-PICU sample size was 18 patients, 50% females, with mean age of 8.3 years all were previously healthy. MISC-PICU patients had deranged blood counts with a lower hemoglobin count, a more pronounced lymphopenia and thrombocytopenia along with hypoalbuminemia. MISC-PICU patients presented with relatively higher inflammatory markers: C-reactive protein, procalcitonin, ferritin, and d-dimer. Immunological studies were significantly higher for interleukin-6 levels in PICU patients. On echocardiography, higher myocardial dysfunction was more notable in MISC-PICU patients. Likewise, MISC-PICU patients were provided with more extensive therapy. As part of our study course, we reevaluated our MISC-PICU patients twice, once at 48 h post-PICU admission and again 4-6 weeks after discharge from the hospital. No deaths have been recorded in the cohort. CONCLUSION: This study evaluated risk factors of MISC and potential severity features. Follow-up of patients on discharge showed improvement across all domains.

Rapid-Onset Obesity With Hypothalamic Dysfunction, Hypoventilation, Autonomic Dysregulation, and Neuroendocrine Tumor (ROHHADNET) Syndrome: A Case Report.

Here, we report the case of a rare and complex disorder, rapid-onset obesity with hypothalamic dysfunction, hypoventilation, autonomic dysregulation, and neuroendocrine tumor (ROHHADNET) syndrome, in a three-year-old girl with no significant medical history. This is the first such case reported from the UAE. ROHHADNET is a rare disorder of respiratory control and autonomic nervous system regulation with endocrine abnormalities. It typically presents in children older than 18 months with rapid weight gain. This is a challenging diagnosis as there is no clear diagnostic test, and treatment is essentially supportive. This report describes a case of ROHHADNET syndrome in a previously well child who presented with rapid weight gain followed by ophthalmoplegia, dysphagia, electrolyte disturbance, and other comorbidities. The paper outlines in detail the clinical course, investigations, and management of ROHHADNET syndrome. Cerebrospinal fluid analysis revealed oligoclonal bands, which have been reported in only two other cases of ROHHADNET syndrome. Our goal in reporting this case is to increase awareness of this condition among clinicians to facilitate early diagnosis and timely management.

Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) in a Middle Eastern patient cohort.

OBJECTIVE: This is a comprehensive characteristic study of Kawasaki disease (KD) and Multi system inflammatory syndrome in children (MIS-C) in the Middle East that creates a formula to differentiate between the two. METHODS: We conducted a descriptive comparative study of KD and MIS-C in the United Arab Emirates. Retrospective MIS-C and KD cohorts were recruited between January 2017 until August 2021.We compared clinical and laboratory characteristics between both groups. Our data were compared with 87 patients with KD or MIS-C from the literature. RESULTS: We report on123 patients. Sixty-seven (54%) met the criteria for KD (36 male, 43 Arab), and fifty-six (46%) met the criteria for MIS-C (28 male, 35 Arab). The median age was 2.2 years range (0.15-10.7) in the KD group and 7.3 years (0.7-15.2) in the MIS-C group (P < 0.001). The clinical features on admission showed an increase in gastrointestinal manifestations in MIS-C compared with KD (84% vs. 31%, P < 0.001). Laboratory tests on admission revealed a significant increase in the following tests in KD compared with MIS-C; white blood cells (mean 16.30 10(3) µcL vs. 11.56 10(3) µcL, P < 0.001), absolute neutrophils (mean 10.72 10(3) µcL vs. 8.21 10(3) µcL, P 0.008), absolute lymphocytes (mean 3.92 10(3) µcL vs. 2.59 10(3) µcL, P 0.003), erythrocyte sedimentation rate (mean 73 mm/hr vs. 51 mm/hr, P < 0.001) and platelets (median {390 10(3) µcL vs. 236 10(3) µcL, P < 0.001}). In contrast, procalcitonin and ferritin were increased in the MIS-C group (2.4 )ng/mL, 370 ng/mL; P < 0.001). Cardiac dysfunction and admission to the pediatric intensive care unit were higher in MIS-C than in KD (21% vs. 8% and 33% vs. 7.5%, respectively, P < 0.001). CONCLUSION: This study showed vast similarities between KD and MIS-C, suggesting that they lie along the same clinical spectrum. However, there are several differences between the two disease entities suggesting that MIS-C most likely represents a new severe variant of KD. Based on our findings in this study, we created a formula to differentiate between KD and MIS-C.

Kikuchi Disease in Children: A Report of Two Cases.

Kikuchi disease (KD) is a benign self-limiting rare disease with unknown etiology. Prolonged fever with tender neck lymphadenitis is the most common presentation. Blood tests are not specific, and the final diagnosis is by biopsy. We describe two patients, ages seven and twelve years, who presented with fever and neck lymphadenitis. Both cases received antibiotics for more than two weeks without improvement. Blood work showed high inflammatory markers. The manifestation of the second case overlapped with Hashimoto's disease. The later diagnosis was confirmed by lymph node (LN) biopsy.

The genomic landscape of rare disorders in the Middle East.

BACKGROUND: Rare diseases collectively impose a significant burden on healthcare systems, especially in underserved regions, like the Middle East, which lack access to genomic diagnostic services and the associated personalized management plans. METHODS: We established a clinical genomics and genetic counseling facility, within a multidisciplinary tertiary pediatric center, in the United Arab Emirates to locally diagnose and manage patients with rare diseases. Clinical genomic investigations included exome-based sequencing, chromosomal microarrays, and/or targeted testing. We assessed the diagnostic yield and implications for clinical management among this population. Variables were compared using the Fisher exact test. Tests were 2-tailed, and P < .05 was considered statistically significant. RESULTS: We present data on 1000 patients with rare diseases (46.2% females; average age, 4.6 years) representing 47 countries primarily from the Arabian Peninsula, the Levant, Africa, and Asia. The cumulative diagnostic yield was 32.5% (95% CI, 29.7-35.5%) and was higher for genomic sequencing-based testing than chromosomal microarrays (37.9% versus 17.2%, P = 0.0001) across all indications, consistent with the higher burden of single gene disorders. Of the 221 Mendelian disorders identified in this cohort, the majority (N = 184) were encountered only once, and those with recessive inheritance accounted for ~ 62% of sequencing diagnoses. Of patients with positive genetic findings (N = 325), 67.7% were less than 5 years of age, and 60% were offered modified management and/or intervention plans. Interestingly, 24% of patients with positive genetic findings received delayed diagnoses (average age, 12.4 years; range 7-37 years), most likely due to a lack of access to genomic investigations in this region. One such genetic finding ended a 15-year-long diagnostic odyssey, leading to a life-threatening diagnosis in one patient, who was then successfully treated using an experimental allogenic bone marrow transplant. Finally, we present cases with candidate genes within regions of homozygosity, likely underlying novel recessive disorders. CONCLUSIONS: Early access to genomic diagnostics for patients with suspected rare disorders in the Middle East is likely to improve clinical outcomes while driving gene discovery in this genetically underrepresented population.

A Rare Infection of Chromobacterium violaceum in an Immunocompetent Patient: A Case Report.

Chromobacterium violaceum is a motile gram-negative bacillus. It lives in water and soil and rarely causes infection in immune-competent patients. It does not respond to the classical treatment and can cause a rapid and progressive illness. Hence, it should be considered in severe infection. Physicians are not generally aware of this organism as a possible cause of infection, and this increases the risk of mortality. Here, we described a case of a 17-year-old previously healthy girl who had severe necrotic cellulitis that progressed and spread rapidly over a few days despite the treatment with antibiotics. It started after a few days of swimming in a swimming pool. She was treated successfully with a broad spectrum of antibiotics and discharged home.

Rapid whole genome sequencing of critically ill pediatric patients from genetically underrepresented populations.

We describe a case series of five infants (age range: 1-90 days; 4 females and 1 male) who presented to Al Jalila Children's intensive care units (ICU) with complex multisystem disorders. Patients were Emirati, Kenyan, Jordanian, Filipino, or Pakistani. Trio rapid whole genome sequencing (rWGS) was performed on all five patients and their parents within the hospital's genomics facility. Results were returned within ~37 h from blood sample draws and were diagnostic in 3 out of 5 patients. Positive findings were a homozygous pathogenic variant in POMT1 gene causing muscular dystrophydystroglycanopathy, a mosaic tetrasomy of the short arm of chromosome 12 (12p13.33p11.1) causing Pallister-Killian syndrome, and compound heterozygous pathogenic variants in the LIPA gene causing lysosomal acid lipase deficiency and Wolman disease. The rWGS analysis provided fast and precise diagnostic findings in those 3 patients and also aided in devising better management plans for them in the intensive care setting. For example, the 3-month-old infant with pathogenic variants in the LIPA gene is now a candidate for an FDA-approved, potentially lifesaving enzyme replacement therapy (sebelipase alfa). Our case series emphasize the feasibility and utility of rWGS in pediatric intensive care setting, in a diverse population that has long been underserved in genomic services. Significant investments in local healthcare infrastructure are needed, globally, for more equitable access of genomic medicine among vulnerable patients.

Genetic and Clinical Characteristics of Patients in the Middle East With Multisystem Inflammatory Syndrome in Children.

Importance: Clinical, genetic, and laboratory characteristics of Middle Eastern patients with multisystem inflammatory syndrome in children (MIS-C) have not yet been documented. Objective: To assess the genetic and clinical characteristics of patients with MIS-C of primarily Arab and Asian origin. Design, Setting, and Participants: A prospective, multicenter cohort study was conducted from September 1, 2020, to August 31, 2021, in the United Arab Emirates and Jordan. Forty-five patients with MIS-C and a matched control group of 25 healthy children with a confirmed SARS-CoV-2 infection status were recruited. Whole exome sequencing in all 70 participants was performed to identify rare, likely deleterious variants in patients with MIS-C and to correlate genetic findings with the clinical course of illness. Exposures: SARS-CoV-2. Main Outcomes and Measures: Fever, organ system complications, laboratory biomarkers, whole exome sequencing findings, treatments, and clinical outcomes were measured. The Mann-Whitney U test was used to assess the association between genetic variants and MIS-C attributes. The Fisher exact test was used to compute the genetic burden in MIS-C relative to controls. Results: A total of 45 patients with MIS-C (23 [51.1%] male; 30 [66.7%] of Middle Eastern origin; mean [SD] age, 6.7 [3.6] years) and 25 controls (17 [68.0%] male; 24 [96.0%] of Middle Eastern origin; mean [SD] age 7.4 [4.0] years) participated in the study. Key inflammatory markers were significantly dysregulated in all patients with MIS-C. Mucocutaneous and gastrointestinal manifestations were each reported in 36 patients (80.0%; 95% CI, 66.1%-89.1%), cardiac findings were reported in 22 (48.9%; 95% CI, 35.0%-63.0%), and neurologic findings were reported in 14 (31.1%; 95% CI, 19.5%-45.6%). Rare, likely deleterious heterozygous variants in immune-related genes, including TLR3, TLR6, IL22RA2, IFNB1, and IFNA6, were identified in 19 patients (42.2%; 95% CI, 29.0%-56.7%), of whom 7 had multiple variants. There was higher enrichment of genetic variants in patients relative to controls (29 vs 3, P < .001). Patients with those variants tended to have earlier disease onset (7 patients [36.8%; 95% CI, 19.1%-58.9%] with genetic findings vs 2 [7.7%; 95% CI, 2.1%-24.1%] without genetic findings were younger than 3 years at onset) and resistance to treatment (8 patients [42.1%; 95% CI, 23.1%-63.7%] with genetic findings vs 3 patients [11.5%; 95% CI, 4.0%-29.0%] without genetic findings received 2 doses of intravenous immunoglobulin). Conclusions and Relevance: The results of this cohort study suggest that rare, likely deleterious genetic variants may contribute to MIS-C disease. This finding paves the way for additional studies with larger, diverse populations to fully characterize the genetic contribution to this new disease entity.

Signs and Symptoms of Vitamin D Deficiency in Children: A Cross-Sectional Study in a Tertiary Pediatric Hospital in the United Arab Emirates.

OBJECTIVE: This study was conducted to estimate the common signs and symptoms present in patients with vitamin D deficiency at a children's specialty hospital in Dubai, United Arab Emirates (UAE). METHODS: This descriptive cross-sectional study (n = 805) examined patients aged <18 years with a serum 25-hydroxy vitamin D concentration of <50 ng/mL and presenting to the hospital between 2017 and 2018. Variables (age, gender, nationality, vitamin D levels, signs and symptoms, and primary complaint) were described using frequencies and mean values (SD). Chi-square and Kruskal-Wallis tests were conducted. RESULTS: Among the 805 patients, 315 (39.2%) had vitamin D deficiency (<20 ng/mL). Regarding the symptoms of these 315 patients, 26% (n = 82) of them were asymptomatic, 13.3% (n = 42) of them had endocrine symptoms and other/rare symptoms, and 11.7% (n = 37) of them had gastrointestinal symptoms. The least common symptoms were found in the mixed category (mixed symptoms of different body systems), consisting of 3.5% (n = 11) of patients. Vitamin D deficiency was more common among female patients (44.8%) and Emiratis (40.5%), and the average age for patients to have vitamin D deficiency was nine years. CONCLUSION: To our knowledge, this is one of the first studies in the United Arab Emirates to focus on and examine patients with low vitamin D levels in detail. Determining the most frequent symptoms is helpful for healthcare practitioners because our results showed that most patients with the deficiency were asymptomatic. Hence, we recommend performing regular checkups for healthy and asymptomatic children to detect vitamin D deficiency before they show any symptoms.

Case Reports of Bacillus Calmette-Guérin (BCG) Osteomyelitis: A Rare Complication in Immunocompetent Infants.

Bacillus Calmette-Guérin (BCG) vaccine is a live attenuated vaccine used globally since 1921, and in the United Arab Emirates (UAE), it is administered to all newborns within the first few days of life for well-established benefits. BCG osteomyelitis is a rare complication that should be considered while assessing osteomyelitis in children. This report describes three cases of BCG osteomyelitis involving proximal metaphysis of the humerus in 11 months and three months old immunocompetent male infants and the left proximal tibia in a two-year-old immunocompetent female. To the best of our knowledge, these are the first cases to be reported in the UAE. The report outlines in detail how to make a timely diagnosis by explaining the insidious clinical presentation of BCG osteomyelitis, including its radiologic, microbiologic, and histologic aspects. As well, it outlines the treatment course carried out for these three patients. As such, this report will aid physicians in staying vigilant for such rare complication and commencing early treatment.