Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors.

OBJECTIVES: To characterise the clinical features, immune manifestations and molecular mechanisms in a recently described autoinflammatory disease caused by mutations in TRNT1, a tRNA processing enzyme, and to explore the use of cytokine inhibitors in suppressing the inflammatory phenotype. METHODS: We studied nine patients with biallelic mutations in TRNT1 and the syndrome of congenital sideroblastic anaemia with immunodeficiency, fevers and developmental delay (SIFD). Genetic studies included whole exome sequencing (WES) and candidate gene screening. Patients' primary cells were used for deep RNA and tRNA sequencing, cytokine profiling, immunophenotyping, immunoblotting and electron microscopy (EM). RESULTS: We identified eight mutations in these nine patients, three of which have not been previously associated with SIFD. Three patients died in early childhood. Inflammatory cytokines, mainly interleukin (IL)-6, interferon gamma (IFN-γ) and IFN-induced cytokines were elevated in the serum, whereas tumour necrosis factor (TNF) and IL-1ß were present in tissue biopsies of patients with active inflammatory disease. Deep tRNA sequencing of patients' fibroblasts showed significant deficiency of mature cytosolic tRNAs. EM of bone marrow and skin biopsy samples revealed striking abnormalities across all cell types and a mix of necrotic and normal-appearing cells. By immunoprecipitation, we found evidence for dysregulation in protein clearance pathways. In 4/4 patients, treatment with a TNF inhibitor suppressed inflammation, reduced the need for blood transfusions and improved growth. CONCLUSIONS: Mutations of TRNT1 lead to a severe and often fatal syndrome, linking protein homeostasis and autoinflammation. Molecular diagnosis in early life will be crucial for initiating anti-TNF therapy, which might prevent some of the severe disease consequences.

Assessing the Body Composition of "Picky Eaters" Using Body Impedance Analysis: An Experience From a Tertiary Care Center.

BACKGROUND: Picky eating might be associated with a higher risk of being underweight and poor growth. This study aimed to investigate if picky eaters aged between three and 12 years showed differences in height, weight, and body composition compared to their non-picky peers using a body impedance analysis (BIA). METHODS: This cross-sectional study was conducted between March 1, 2022, and July 31, 2022, on children aged three to 12 years who presented to the outpatient pediatric clinics at Al Habib Ar Rayyan in Riyadh, Saudi Arabia. Body composition was measured using BIA after manually inserting the height, gender, and age into the machine, where body mass index (BMI), fat mass, and skeletal muscle mass were recorded. Participants were classified as under/normal/over for each body composition measurement. RESULTS: A total of 2234 children were entered into the final data analysis. Our analysis showed that 1917 (85.8%) were Saudis and 1117 (50%) were males. The mean age of participants was 6.08±2.01 years and 1151 (51.5%) were in the pre-school age. The reported prevalence of picky eaters was 1684 (75.4%), of whom, 606 (27.0%) were selective eaters, 365 (16.2%) were low appetite eaters, and 723 (32.2%) were both selective and low appetite eaters. Being underweight was significantly more common among the picky eaters 487 (28.9%) compared to those non-picky eaters 55 (10.0%) (p<0.001). Significantly, 1280 (76%) picky eaters had below-average skeletal muscle mass compared to 151 non-picky eaters (27.5%) (p<0.001). The low appetite picky eater group had more under skeletal muscle mass children 277 (75.9%) compared to the selective picky eater group 412 (68.0%) (p=0.009). Additionally, the low appetite group possessed lower muscle ratios (p=0.012) and were more underweight than the selective group (p<0.001). Furthermore, the low appetite group showed a higher percentage of children below the 3rd percentile in the height for age category (p=0.003) compared to the selective group. CONCLUSION: This study is the first of its kind in Saudi and globally to evaluate body composition using BIA among children. The study showed that picky eating is more associated with underweight children and low muscular mass. Despite the normal BMI, height, and weight of a picky eater, their skeletal muscle mass might be less than average, which could be associated with an increased risk of morbidity.

Novel homozygous pathogenic mitochondrial DNAJC19 variant in a patient with dilated cardiomyopathy and global developmental delay.

BACKGROUND: Dilated cardiomyopathy with ataxia syndrome (DCMA) or 3-methylglutaconic aciduria type V is a rare global autosomal recessive mitochondrial syndrome that is clinically and genetically heterogeneous. It is characterized by early-onset dilated cardiomyopathy and increased urinary excretion of 3-methylglutaconic acid. As a result, some patients die due to cardiac failure, while others manifest with growth retardation, microcytic anemia, mild ataxia, and mild muscle weakness. DCMA is caused by variants in the DnaJ heat shock protein family (Hsp40) member C19 gene (DNAJC19), which plays an important role in mitochondrial protein import machinery in the inner mitochondrial membrane. METHODS: We describe a single affected family member who presented with cardiomyopathy, global developmental delay, chest infection, seizures, elevated excretion of 3-methylglutaconic acid, and 3-methylglutaric acid in the urine. RESULTS: Whole-exome sequencing followed by Sanger sequencing revealed a homozygous frameshift variant in the reading frame starting at codon 54 in exon 4 in the DNAJC19 gene (c.159del [Phe54Leufs*5]), which results in a stop codon four positions downstream. Quantitative gene expression analysis revealed that DNAJC19 mRNA expression in this patient was substantially reduced compared to the control. CONCLUSIONS: We present a novel variant in the DNAJC19 gene that causes rare autosomal recessive mitochondrial 3-methylglutaconic aciduria type V. By comparing the current case with previously reported ones, we conclude that the disease is extremely heterogeneous for reasons that are still unknown.

Unusual Presentation of Kawasaki Disease in a 13-year-old Saudi Boy.

Kawasaki disease (KD), formerly known as mucocutaneous lymph node syndrome, is one of the most quintessential self-limiting forms of vasculitides among children. Nevertheless, sparse cases of adulthood KD have been also identified. Despite the self-limited (indolent) nature of this disease, patients tend to present with fever and signs of acute inflammation which may averagely last for up to 12 days without treatment, yet high index of clinical suspension is needed in atypical cases early during the course of the disease in order to minimize associated morbidity and mortality. Herein, we report an unorthodox case of KD of a 13-year-old male patient who started with cervical lymph node enlargement, followed by fever.

Interpretation of the tuberculin skin test in bacille Calmette-Guérin vaccinated and nonvaccinated school children.

BACKGROUND: Our objective was to conduct a prevalence survey of purified protein derivative (PPD) reactions among Lebanese healthy school children to identify those with tuberculosis or latent tuberculosis and to investigate the effect of bacille Calmette-Guérin (BCG) vaccine on the interpretation of PPD reactivity. METHODS: A self-administered questionnaire, including demographic characteristics, time of prior BCG vaccine and number of doses, known household contact with tuberculosis as well as parents' characteristics and living conditions was administered. PPD testing was performed on all children in diverse Lebanese regions aged 3 to 19 years. Reactivity that measured <5 mm were considered negative induration, doubtful if between 5 and 9 mm and positive if 10 mm or above. Chest radiographs were obtained as part of the evaluation for children with positive induration. RESULTS: Of 4895 children, 4271 entered into the final data analysis. A total of 3259 children (76.3%) did not develop a reaction to PPD (0 mm), 170 (4%) had 1 to <5 mm reading, 509 (11.9%) had 5 to 9 mm and 333 (7.8%) had > or =10 mm. Approximately 62% of the vaccinated children had received BCG vaccine in first year of life. Two hundred ninety (61.8%) of 469 children < or =5 were vaccinated and 179 (38.2%) were not. Only 22 of the youngest vaccinated had positive PPD. Twelve children were diagnosed with tuberculosis, a prevalence of 280 per 100,000. However, the prevalence of latent tuberculosis was 7.51%. CONCLUSION: Our prevalence of tuberculosis and latent tuberculosis is a sentinel indicator of continued transmission in the community. The data support the current recommendations that children who receive BCG can and should be tested with PPD for latent tuberculosis and tuberculosis.

How to Improve Eating Behaviour during Early Childhood.

Eating behaviour disorder during early childhood is a common pediatric problem. Many terminologies have been used interchangeably to describe this condition, hindering implementation of therapy and confusing a common problem. The definition suggests an eating behaviour which has consequences for family harmony and growth. The recent Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition does not cover the entire spectrum seen by pediatricians. Publications are substantive but level of evidence is most of the time low. This purpose of this review is to clarify terminology of eating behaviour problems during early childhood; including benign picky eating, limited diets, sensory food aversion, selective eating, food avoidance emotional disorder, pervasive refusal syndrome, tactile defensiveness, functional dysphagia, neophobia and toddler anorexia. This tool is proposed only to ease the clinical management for child care providers. Diagnostic criteria are set and management tools are suggested. The role of dietary counselling and, where necessary, behavioural therapy is clarified. It is hoped that the condition will make its way into mainstream pediatrics to allow these children, and their families, to receive the help they deserve.