Whole-exome sequencing to identify undiagnosed primary immunodeficiency disorders in children with community-acquired sepsis, admitted in the pediatric intensive care unit.

BACKGROUND: Whole-exome sequencing (WES) provides a powerful diagnostic tool for identifying primary immunodeficiency diseases (PIDs). This study explores the utility of this approach in uncovering previously undiagnosed PIDs in children with community-acquired sepsis (CAS), with a medical history of recurrent infections or a family history of PIDs. METHODS: We performed WES on DNA samples extracted from the blood of the 34 enrolled patients, followed by bioinformatic analysis for variant calling, annotation, and prioritization. We also performed a segregation analysis in available family members to confirm the inheritance patterns and assessed the potential impact of the identified variants on protein function. RESULTS: From 34 patients enrolled in the study, 29 patients (85%) with previously undiagnosed genetic diseases, including 28 patients with PIDs and one patient with interstitial lung and liver disease, were identified. We identified two patients with severe combined immunodeficiency (SCID), patients with combined immunodeficiency (CID), six patients with combined immunodeficiency with syndromic features (CID-SF), four patients with defects in intrinsic and innate immunity, four patients with congenital defects of phagocyte function (CPDF), and six patients with the disease of immune dysregulation. Autoinflammatory disorders and predominantly antibody deficiency were diagnosed in one patient each. CONCLUSION: Our findings demonstrate the potential of WES in identifying undiagnosed PIDs in children with CAS. Implementing WES in the clinical evaluation of CAS patients with a warning sign for PIDs can aid in their timely diagnosis and potentially lead to improved patient care.

A rare presentation of Carnitine palmitoyltransferase II (CPT-2) deficiency with normal acylcarnitine profile in a 10-year-old boy with muscle weakness and bilateral hearing loss; a case report.

Carnitine palmitoyltransferase II (CPT-2) deficiency is a rare and autosomal recessive disorder of long-chain fatty acids oxidation. Here, we reported a 10-year-old boy with bilateral hearing loss and a myopathic form of CPT II deficiency, which was confirmed by a molecular genetic test. He was admitted to our hospital with unexplained headaches, vomiting, and fever. Furthermore, he developed seizures, muscle weakness, neck stiffness and pain, mild respiratory distress, and an icteric appearance. The laboratory test results also showed severely elevated lactate dehydrogenase levels (LDH) and creatine phosphokinase (CPK) levels. He also had an icteric appearance with unexplained indirect hyperbilirubinemia. Further examinations revealed a normal heart and liver without any neurological disorders. Muscle pathological examination reported normal pathology without neuromuscular and mitochondrial disorders and storage diseases. Finally, molecular test analysis with next-generation sequencing (NGS) revealed CPT-II deficiency fatty acid oxidation disorder. Furthermore, we identified a homozygous pathogenic variant in the ADGRV1 gene, c.15736C>T p. (Arg5246*), which suggests the Usher syndrome type 2C and the reason for sensorineural hearing loss in this case. Our finding indicates that CPT-II can be associated with multiple symptoms and clinical features. Therefore, evaluation of CPT-II deficiency with molecular test analysis may be helpful in cases with unexplained icteric appearance, muscle weakness, and rhabdomyolysis.

COVID-19 Pandemic Experiences in Pediatric Intensive Care Unit: An Iranian Referral Hospital-Based Study.

Introduction: In late February 2020, after we had informed about the presence of some cases of COVID-19 in Iran and its rapid spread throughout the country, we decided to make the necessary arrangements for patients with critical conditions in Pediatric Intensive Care Unit (PICU) at Children's Medical Center. There are a little data on critically ill children with COVID-19 infection with ICU requirements. The aim of this study was to describe clinical characteristics, laboratory parameters, treatment, and outcomes of the pediatrics population infected by SARS-CoV-2 admitted to PICU. Materials and Methods: This study was performed between February 2020 and May 2020 in the COVID PICU of the Children's Medical Center Hospital in Tehran, Iran. Patients were evaluated in terms of demographic categories, primary symptoms and signs at presentation, underlying disease, SARS-CoV-2 RT-PCR test result, laboratory findings at PICU admission, chest X-ray (CXR) and lung CT findings, and treatment. Moreover, the need to noninvasive ventilation (NIV) or mechanical ventilation, the length of hospital stay in the PICU, and outcomes were assessed. Results: In total, 99 patients were admitted to COVID PICU, 42.4% (42 patients) were males, and 66 patients had positive SARS-CoV-2 real-time reverse transcriptase-polymerase chain reaction (RT-PCR). There was no statistically significant difference in the frequency of clinical signs and symptoms (except for fever) among patients with positive SARS-CoV-2 RT-PCR and negative ones. Among all admitted patients, the presence of underlying diseases was noticed in 81 (82%) patients. Of 99 patients, 34 patients were treated with NIV during their admission. Furthermore, 35 patients were intubated and treated with mechanical ventilation. Unfortunately, 11 out of 35 mechanically ventilated patients (31%) passed away. Conclusion: No laboratory and radiological findings in children infected with COVID-19 were diagnostic in cases with COVID-19 admitted to PICU. There are higher risks of severe COVID-19, PICU admission, and mortality in children with comorbidities.

Methenyltetrahydrofolate synthease deficiency (MTHFS deficiency): Novel mutation and brain MRI findings: A case report and glance to other cases.

This is a case report of Methenyl Tetrahydrofolate synthetase deficiency (MTHFS deficiency) characterized by global developmental delay, cerebral hypomyelination, severe spastic tonicity in extremities, and microcephaly. Mutation in the MTHFS gene was reported in the Whole Exome Sequencing (WES) and confirmed with Sanger sequencing of parents. It is of great significance to report since it would be the first case of MTHFS mutation reported from Iran and the fourth throughout the world with novel mutation and brain imaging.

Lessons from Ten Years' the Prevalence of Congenital Rubella Syndrome (CRS) in the Young Population Living in a Developing Country, Tehran; Iran.

BACKGROUND: A safe and effective rubella vaccine is available and prescribed in IRAN. OBJECTIVE: This is a survey of CRS cases collected based on WHO criteria one decade after the MR vaccination campaign (2003). METHODS: This Multi-stage prospective/cross-sectional study was carried out in three stages in 3 educational hospitals in Tehran (Rasoul Aram, Akbar Abadi, and Firoozabadi), In the first stage of the study between 2011 and 2012 total of 186 infants were evaluated, and in the second stage of the study, total 163 blood samples of infants with suspected INTRA UTERINE INFECTION were compared with a group of healthy matched infants. In the first and second stages, Rubella immunity (IgG&IgM) in cord blood was evaluated by the Eliza method. RESULTS: Despite MR vaccination in Iran, after one decade"confirmed CRS" and " compatible CRS" was diagnosed in 5 and 31 from 89 CRS suspected cases. CONCLUSION: The incidence of "confirmed CRS" in every 100 CRS suspected infants (after campaign) is 5.6 %, and 31 CRS Compatible cases are so important. Without active CRS surveillance, mild infection such as IUGR, hearing loss, heart abnormalities, impaired vision, and mental retardation even in the developed country might be missed. Fetal infection is persistent, which imposes additional costs on the country. Another mass vaccination in women and girls is needed. Also, the anti-rubella IgG testing before pregnancy in women who were not vaccinated; vaccination of women before marriage /pregnancy should be obligatory in order to prevent the CRS.

Bilateral horizontal gaze palsy in an 8-year-old girl: A rare case with NDUFS4 gene mutation.

We report a patient with complex clinical presentation including multiple neurological symptoms and eye involvement. Upon genetic investigation, the patient was found to carry a novel homozygous mutation in the NDUFS4 gene, thus adding to the heterogeneity of Leigh syndrome clinical presentation.

The first febrile seizure; predisposing factors and recurrence rate.

Objective: Febrile seizure is the most common worrisome neurologic disorder in children in terms of parental point of view. The purpose of this study was to answer distressing parents' questions about the prevalence and possibility of febrile seizure recurrence. Materials & Methods: 140 patients who were admitted due to the first febrile seizure in the six months (March up to September) of the year 2015 were enrolled to this study. Exclusion criteria include central nervous system infection, non-confirmed febrile seizure and lack of parental acceptance forlong-term inclusion in this study. All children were followed in terms of second febrile seizure during one year follow-up from the time of first febrile seizure. (3 sentences were deleted). Results: Recurrence of febrile seizure was 25.7 % during one-year follow-up. Significant risk factors for recurrence include: age less than one year old, male gender, seizure with low level of fever, family history of epilepsy, family history of febrile seizure, complex febrile seizure (focal and repeated in 24 hours), seizure duration more than 15 minutes and parental indifference to the onset of fever in their children before seizure occurrence. Although duration of fever before seizure, failureto thrive, positive history of admission in neonatal period, dystocia at birth delivery and children with day care staying were associated with greater febrile seizure recurrence; but, they did not have significant relationship with recurrence rate. Prophylaxis with benzodiazepine reduced the recurrence rate. Conclusion: Chance of febrile seizure recurrence in one-year follow-up increased in presence of risk factors expressed in finding part. Parental indifference to the onset of fever in their children that is starting before seizure was a considerable risk factor in terms of recurrence prevalence. We recommended to emphasis on parental education about this new finding as a risk factor for febrile seizure in order to prevent its future recurrence.

Giant axonal neuropathy: The first Iranian case with a variation in the gigaxonin gene and a glance to the other cases.

Background: Giant axonal neuropathy (GAN) is a very rare fatal neurodegenerative disorder with clinical and allelic heterogeneity. The disease is caused by mutations in the GAN (gigaxonin) gene. Herein, we reported the clinical presentations and results of genetic analysis of the first Iranian GAN case. Methods: Phenotypic data were obtained by neurologic examination, brain magnetic resonance imaging (MRI), electromyography (EMG), electroencephalography (EEG), and sonography from the proband. Deoxyribonucleic acid (DNA) was isolated from peripheral blood leucocytes and whole exome sequencing (WES) was performed. The candidate variant was screened by Sanger sequencing in the proband and her family members. Results: The proband was a 7-year-old girl who was admitted with a chief complaint of ataxia, muscle weakness, delayed developmental milestones, and history of psychiatric disorders. She was very moody and had clumsy gait, decreased deep tendon reflexes (DTRs) of lower limbs, and kinky hair. The brain MRI revealed white matter abnormality. The EMG revealed that her disease was compatible with the chronic axonal type of sensorimotor polyneuropathy; however, her EEG was normal. Results of the WES revealed a homozygous variant; c.G778T:p.E260* in the GAN gene, indicating the GAN disorder. Conclusion: The present study affirmed GAN allelic heterogeneity and resulted in the expansion of the phenotypic spectrum of GAN pathogenic variants. Identification of more families with mutations in GAN gene helps to further understand the molecular basis of the disease and provides an opportunity for genetic counseling especially in the populations with a high degree of consanguineous marriage such as the Iranian population.

National and Sub-National Pediatric Cancer Mortality in Iran, 2000-2015.

BACKGROUND: Cancer, a common disease in adulthood, is a rare albeit slowly increasing condition among children. Currently, limited data are available on the incidence, prevalence, and mortality of these diseases in many regions, including developing countries. Herein, we are reporting national and sub-national estimates on deaths due to childhood cancers between 2000 and 2015 in Iran. METHODS: Cancer mortality rates were estimated using the national death registration system's data after addressing its incompleteness and misclassification, using demographic (complete birth history and summary birth history) and statistical analysis (spatiotemporal, Gaussian process regression, and generalized linear mixed models). We included data from cemeteries of two cities (Tehran and Isfahan) that were not included in the death registration system. We used census data and household expenditure and income surveys for data on population and other covariates used in the modeling. RESULTS: The overall age-standardized death rate (ASDR) of childhood cancers have decreased by 69.52% (80.67-49.71) in Iran (equal to an annual percent change of -3.63 [-4.53- -2.24]), declining from 12.24 (95% UI: 10.52-14.49) in 2000 to 3.73 (2.8-5.29) deaths per 100000 in 2015. This decrement was equal to an annual percent change of 4.35% over these years. Leukemia, brain, and nervous system malignancies accounted for about 66% of all cancer-related mortalities among children and adolescents in 2015, which had a 10% increase compared to 2000. Moreover, trends at the sub-national level showed that the highest and lowest ASDR of childhood cancers ranged from 2.12 to 4.99 across provinces of Iran in 2015. CONCLUSION: Although the overall mortalities have decreased, there is still inequality in the distribution of the recorded deaths. This inequality should be addressed with the improvement of the quality of care and better access to pediatric hospitals and oncologists in these areas.

Cerebellar Infarction in a 9 Year Old Child Presenting with Fever and Ataxia: A Case Report.

Cerebellar acute ischemic stroke (AIS) can be a complication of minor head trauma, vertebral artery dissection, vasospasm or systemic hypoperfusion. CT scan usually is negative few hours after acute infarction. Magnetic resonance imaging (MRI) is superior to CT scan for posterior fossa lesions and also in acute phase of cerebellar stroke especially in children. Here we report a 9 yr old girl referred to the Pediatric Emergency Room, Moosavi Hospital, Zanjan, Iran in January 2017 presenting with sudden onset of headache and recurrent vomiting, ataxia, and history of 3 consecutive days of fever and malaise. In the report of MRI, there were abnormal low T1 and high T2 signal intensity in left cerebellar hemisphere involving superior and middle cerebellar peduncles. After 4 days of admission, the patient became drowsy, symptoms progressed and transferred to the pediatric intensive care unit (PICU). The patient underwent hemispherectomy surgery of the left cerebellar hemisphere because of acute obstructive hydrocephaly. After 5 months of occupational therapy, the force of her extremities was normal and the ataxia completely disappeared. Childhood acute ischemic stroke although rare can happen with cerebellar involvement. Because in our patient the first brain CT scan was nearly normal and a false negative rate for initial computed tomography (CT) scanning of 60%-80% also contributes to missed and delayed diagnosis of childhood AIS, for every child presenting with acute ataxia without identified cause in addition to CT scan, MRI also being ordered and from the beginning besides other causes, stroke be contemplated as a cause of ataxia.

The Neuroimaging Studies in Children with Ventriculoperitoneal Shunt Complications: A 10 Years Descriptive Sudy in Tehran.

BACKGROUND: Any mismatch between the production and absorption of CSF results in hydrocephalus. In most cases, the selected choice of treatment is the ventriculoperitoneal shunt insertion. Although, the surgery could have complications such as infection, shunt malfunction, subdural hematoma, seizure and Shunt immigration; so, the early and proper detection of these complications could result in better prognosis. The aim of this study was to evaluate and compare the efficacy of CT scan, CSF analysis and X-ray radiography in detection of shunt complications and problems in shunt placement and further follow-up in hospitalized children. METHODS: The medical records of children in Rasul Akram hospital in Tehran were reviewed retrospectively in the last 10 years, from 2006 to 2016. All data were recorded in the prepared form including the age, sex, shunt complication, CT scan and CSF characteristics. RESULTS: The total number of 95 patients were interfered in this study including 56 males (58.9%) and 39 females (41.1%). The mean age at the onset of complications were 2.8±2.2 years-old. The shunt obstruction (60%) and infection (25.3%) were the most common complications. The CT scan was able to detect 36.5% of shunt complications. The CT scan had the sensitivity and specificity of 50 and 87%, respectively in detection of shunt obstruction. The all cases of brain hematoma and hemorrhage were revealed by CT scan. On the other hand, the CT scan had 20% of sensitivity and 60% of specificity in the detection of shunt infection. The CSF evaluation in shunt infection revealed 92% hypoglycemia, 87.5% pleocytosis, and 62.5% positive CSF culture. CSF had the sensitivity, specificity, positive predictive value and negative predictive value of 92, 82, 63 and 97%, respectively. The patient's symptoms and signs were helpful in obtaining higher test accuracy. CONCLUSION: The CT scan was not a good sensitive and specific study in the detection of shunt obstruction and infection, but it was very accurate in detection of hemorrhage and hematoma. On the other hand, CSF evaluation was a reliable test in shunt infection disclosure.

Frequency and Type of Hepatic and Gastrointestinal Involvement in Juvenile Systemic Lupus Erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is a frequent rheumatology disorder among children. Since hepatic involvement is a common systemic manifestation in lupus, the frequency and type of hepatic involvement were determined in pediatric cases of SLE admitted to Children's Medical Hospital from 2005 to 2014. METHODS AND PATIENTS: In this observational case-series study, 138 pediatric cases of SLE were admitted in Children's Medical Center (a pediatric rheumatology referral center in Tehran, Iran) enrolled from 2005 to 2014 and the outcomes, frequency, and type of hepatic involvement were assessed among them. RESULTS: Hepatic involvement was reported in 48.55% of total SLE patients. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and both enzymes higher than normal upper limits were detected in 8.7%, 5%, and 34.7% of lupus patients, respectively. Increased level of liver enzymes was categorized as less than 100, between 100 and 1000, and more than 1000 levels in 23.1%, 23.1%, and 2.1% of cases. The only gastrointestinal involvement in lupus patients contributing to hepatic involvement was gastrointestinal bleeding. Rising in liver enzymes was detected mostly in lupus patients without gastrointestinal bleeding (52.2% without versus 25.8% with gastrointestinal bleeding, P = 0.007). CONCLUSION: Approximately half of the pediatric patients suffering from SLE have hepatic involvement. No significant correlation was observed between various organs involvement and abnormal level of liver enzymes.