Inactivation of DRG1, encoding a translation factor GTPase, causes a recessive neurodevelopmental disorder.

PURPOSE: Developmentally regulated Guanosine-5'-triphosphate-binding protein 1 (DRG1) is a highly conserved member of a class of GTPases implicated in translation. Although the expression of mammalian DRG1 is elevated in the central nervous system during development, and its function has been implicated in fundamental cellular processes, no pathogenic germline variants have yet been identified. Here, we characterize the clinical and biochemical consequences of DRG1 variants. METHODS: We collate clinical information of 4 individuals with germline DRG1 variants and use in silico, in vitro, and cell-based studies to study the pathogenicity of these alleles. RESULTS: We identified private germline DRG1 variants, including 3 stop-gained p.Gly54∗, p.Arg140∗, p.Lys263∗, and a p.Asn248Phe missense variant. These alleles are recessively inherited in 4 affected individuals from 3 distinct families and cause a neurodevelopmental disorder with global developmental delay, primary microcephaly, short stature, and craniofacial anomalies. We show that these loss-of-function variants (1) severely disrupt DRG1 messenger RNA/protein stability in patient-derived fibroblasts, (2) impair its GTPase activity, and (3) compromise its binding to partner protein ZC3H15. Consistent with the importance of DRG1 in humans, targeted inactivation of mouse Drg1 resulted in preweaning lethality. CONCLUSION: Our work defines a new Mendelian disorder of DRG1 deficiency. This study highlights DRG1's importance for normal mammalian development and underscores the significance of translation factor GTPases in human physiology and homeostasis.

Transcatheter double stent implantation for treatment of middle aortic coarctation syndrome.

A 13-year-old boy presented with severe systemic hypertension. His upper limb blood pressure measured 190/100 mm Hg and lower limb blood pressure measured 98/64 mm Hg. The brachial pulses were bounding and femoral pulses were not palpable. Echocardiography and magnetic resonance angiography confirmed middle aortic syndrome. There was severe diffuse thoraco-abdominal coarctation with continuous Doppler run-off. Cardiac catheterization was undertaken and using a retrograde approach two Advanta V12 stents were implanted in the complex thoraco-abdominal coarctation. The gradient across the coarctation was reduced from 80 to 40 mm Hg gradient with a significant improvement in the luminal diameter of the aorta. His upper limb blood pressure reduced to 142/78 mm Hg six weeks later.

A retrospective study examining the clinical significance of testing respiratory panels in children who presented to a tertiary hospital in 2019.

Background. Respiratory tract infections are a leading cause of hospital visits in the paediatric population and carry significant associated morbidity and mortality in this population. The introduction of respiratory panel testing has been said to guide clinicians in the overall management of patients. Methods. We conducted a retrospective study examining all respiratory panels carried out in our hospital during 2019 on paediatric patients. Patients included were those who had symptoms indicative of respiratory infections who presented acutely, including those with chronic respiratory conditions. A total of 188 respiratory panel results were obtained along with collected patient data. These were analysed using SPSS V. 25.0 to get the below mentioned results. Results. The majority (76.6 %) of patients were less than 3 years with 59 % of total population being males. The majority (80.9 %) had mild clinical severity score. The most common pathogen that was detected on the respiratory panel was Enterovirus Human Rhinovirus spp, followed by the influenza viruses. Only four cases were positive for bacterial pathogens (two Mycoplasma pneumoniae , one Bordetella pertussis and one Chlamydia pneumoniae ), which accounts for 2.1 % of all panels analysed. The significance of respiratory panels in influencing treatment were analysed in the forms of change of management plans before and after results of respiratory panels. This was observed in 14.4 % of patients who were not on any empiric medication and then based on panel results were started on medications, as well as 11.7 % who were on medications already, and the medications were altered based on the result of the panel (Chi square P=0.057). This was mainly seen with cases of influenza A H1N1 patients and to a lesser extent, Mycoplasma pneumonia. Conclusion. The use of respiratory panels in our hospital had little impact on patient care and management. The main organisms that influenced clinician decision in treatment were influenza A viruses and bacterial organisms ( Mycoplasma pneumoniae , Chlamydia pneumoniae and Bordetella pertussis ). Other than that, the use of clinical judgement proved more beneficial. We recommend use of specific testing for these organisms rather than the whole panel as case to case bases, which would be more cost-effective and consistent with patient management.

MEDICAL PRACTICE IN CHILDREN PRESENTING FEVER WITH PETECHIAL RASH TO AN EMERGENCY DEPARTMENT.

INTRODUCTION: The association of fever and petechiae in children is one of the most alarming findings for a paediatrician. To quickly distinguish between benign and life-threatening conditions is challenging in many cases. We aimed to evaluate the clinical practice of children presenting with fever and petechiae as initial symptoms. METHODS: 41 patients (age 3 months-11 years) presenting with fever and petechiae were identified in an Emergency Paediatric Assessment Unit over a period of 9 months. General data, symptoms and signs were assessed for each patient. The work-up consisted in: complete blood count, inflammatory tests, coagulation tests, Monospot test, nasopharyngeal rapid tests, blood culture, and cerebrospinal fluid culture where appropriate. RESULTS: Most children were <5 years of age (70.7%). Female to male ratio was 1:2.4. The most common clinical diagnoses were: viral respiratory illness (48.8%, 20/41) and upper respiratory tract infection (17.1%, 7/41). Meningococcal disease was found in one case. CRP>6 mg/l was poorly correlated with serious illness. The following variables were strongly associated with serious illness: ill appearance, shivering, lethargy, back rigidity, ESR>50 mm/h and prolonged capillary refill time. 59% (24/41) of children were treated with antibiotics, however, at discharge 42%(10/24) of them, did not have a work-up suggestive for a bacterial illness. CONCLUSIONS: Screening for low prevalence but high morbidity conditions, as the meningococcal disease, with an extensive work-up is time and resource consuming and may lead to unmotivated antibiotic use. Larger studies are needed to change the emergency practice for management of fever and rash.