High prevalence of multilocus pathogenic variation in neurodevelopmental disorders in the Turkish population.

Neurodevelopmental disorders (NDDs) are clinically and genetically heterogenous; many such disorders are secondary to perturbation in brain development and/or function. The prevalence of NDDs is > 3%, resulting in significant sociocultural and economic challenges to society. With recent advances in family-based genomics, rare-variant analyses, and further exploration of the Clan Genomics hypothesis, there has been a logarithmic explosion in neurogenetic "disease-associated genes" molecular etiology and biology of NDDs; however, the majority of NDDs remain molecularly undiagnosed. We applied genome-wide screening technologies, including exome sequencing (ES) and whole-genome sequencing (WGS), to identify the molecular etiology of 234 newly enrolled subjects and 20 previously unsolved Turkish NDD families. In 176 of the 234 studied families (75.2%), a plausible and genetically parsimonious molecular etiology was identified. Out of 176 solved families, deleterious variants were identified in 218 distinct genes, further documenting the enormous genetic heterogeneity and diverse perturbations in human biology underlying NDDs. We propose 86 candidate disease-trait-associated genes for an NDD phenotype. Importantly, on the basis of objective and internally established variant prioritization criteria, we identified 51 families (51/176 = 28.9%) with multilocus pathogenic variation (MPV), mostly driven by runs of homozygosity (ROHs) - reflecting genomic segments/haplotypes that are identical-by-descent. Furthermore, with the use of additional bioinformatic tools and expansion of ES to additional family members, we established a molecular diagnosis in 5 out of 20 families (25%) who remained undiagnosed in our previously studied NDD cohort emanating from Turkey.

The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance.

Arthrogryposis is a clinical finding that is present either as a feature of a neuromuscular condition or as part of a systemic disease in over 400 Mendelian conditions. The underlying molecular etiology remains largely unknown because of genetic and phenotypic heterogeneity. We applied exome sequencing (ES) in a cohort of 89 families with the clinical sign of arthrogryposis. Additional molecular techniques including array comparative genomic hybridization (aCGH) and Droplet Digital PCR (ddPCR) were performed on individuals who were found to have pathogenic copy number variants (CNVs) and mosaicism, respectively. A molecular diagnosis was established in 65.2% (58/89) of families. Eleven out of 58 families (19.0%) showed evidence for potential involvement of pathogenic variation at more than one locus, probably driven by absence of heterozygosity (AOH) burden due to identity-by-descent (IBD). RYR3, MYOM2, ERGIC1, SPTBN4, and ABCA7 represent genes, identified in two or more families, for which mutations are probably causative for arthrogryposis. We also provide evidence for the involvement of CNVs in the etiology of arthrogryposis and for the idea that both mono-allelic and bi-allelic variants in the same gene cause either similar or distinct syndromes. We were able to identify the molecular etiology in nine out of 20 families who underwent reanalysis. In summary, our data from family-based ES further delineate the molecular etiology of arthrogryposis, yielded several candidate disease-associated genes, and provide evidence for mutational burden in a biological pathway or network. Our study also highlights the importance of reanalysis of individuals with unsolved diagnoses in conjunction with sequencing extended family members.

Successful therapeutic plasma exchange in a case with extremely severe hypertriglyceridemia secondary to diabetic ketoacidosis concomitant with type IX glycogen storage disease.

Herein, we aimed to present a child with extremely severe hypertriglyceridemia (ESHTG) secondary to diabetic ketoacidosis concomitant with type IX glycogen storage disease (GSD). Extremely severe hypertriglyceridemia (10 700 mg/dL) was detected through the apparent lipemic appearance of the sampled blood in a 17-year-old male patient with severe diabetic ketoacidosis. In spite of insulin infusion, the patient's clinical condition deteriorated to acute pancreatitis. Single sessions of therapeutic plasma exchange (TPE) along with insulin treatment have successfully intercepted the progression of the state of acute pancreatitis. The patient was also diagnosed with type IX GSD on the basis of the genetic analyses performed for the potential underlying metabolic diseases. In conclusion, underlying metabolic diseases, such as glycogen storage disease, should be investigated in patients with diabetic ketoacidosis accompanied by severe hypertriglyceridemia. If ESHTG does not relieve despite insulin infusion, and/or acute pancreatitis occurs as a complication, TPE should be kept in mind.

A Rare Presentation of Neurobrucellosis in a 6-Year-Old Pediatric Patient with Sagittal Sinus Thrombosis.

Brucellosis is one of the most common zoonosis worldwide. It is still endemic in many regions of the world. A 6-year-old female was admitted to the emergency department (ED) due to a sudden change in consciousness, urinary incontinence, vomiting, and difficulty in walking. Neurological examination demonstrated abducens nerve paralysis, mild-to-moderate motor deficit in hemiparesis in the left arm. Brain magnetic resonance imaging showed a hemorrhagic focus at the right frontal lobe and thrombosis in the superior sagittal sinus of the brain. The diagnosis of neurobrucellosis was confirmed by identifying Brucella spp. in the blood culture on the day 6 of pediatric intensive care unit admission; thus, trimethoprim-sulfamethoxazole and rifampicin, and ceftriaxone were promptly initiated. Despite neuroprotective management and acetazolamide, the patient's neurological problems and high intracranial pressure (ICP) persisted. An external ventricular drainage tube and a Codman ICP monitor were placed to be on the consent vigilance of the patient's neurological condition. The patient's ICP continued to increase despite the current treatment regimen; therefore, a decompressive bitemporal craniectomy was performed. The ICP level of the patient returned to its normal range immediately after the craniectomy. The patient did not have any notable neurologic sequelae at the first-year follow-up. Neurobrucellosis is a rare complication of systemic brucellosis and may present as meningitis, encephalitis, myelitis, radiculitis, and/or neuritis. Herein, we describe a six-year-old girl with brucellosis complicated with cerebral vein thrombosis. This case illustrates the need for close monitoring of patients with unexplained neurological signs or symptoms for brucellosis in endemic areas.

The first pediatric case of hemophagocytic lymphohistiocytosis secondary to Crimean-Congo haemorrhagic fever successfully treated with therapeutic plasma exchange accompanying ribavirin and intravenous immunoglobulin.

Although Crimean-Congo hemorrhagic fever (CCHF) is mild and self-limited in children, some patients may develop excessive bleeding, massive liver necrosis, and multiple organ failure associated with secondary hemophagocytic lymphohistiocytosis (HLH) induced by cytokine storm. Treatment of CCHF is mainly symptomatic and supportive. The efficacy of ribavirin, which is the only antiviral drug in the treatment of CCHF, remains controversial. Although therapeutic plasma exchange (TPE) has been shown to beneficial in small case series with primary and secondary HLH, there is no pediatric patient with HLH secondary to CCHF treated with TPE in the literature. In this report, we describe the first pediatric patient who was successfully recovered from HLH secondary to CCHF with ribavirin, intravenous immunoglobulin, and TPE.

Influenza Virus Associated Pediatric Acute Respiratory Distress Syndrome: Clinical Characteristics and Outcomes.

BACKGROUND AND OBJECTIVE: The aim of this multicenter retrospective study was to determine the clinical characteristics, treatment approaches and the course of pediatric acute respiratory distress syndrome (PARDS) which developed associated with the influenza virus in the 2019-20 season. METHODS: Patients included 1 month to 18 years who were diagnosed with PARDS associated with the influenza virus in the 2019-20 season. RESULTS: Sixty-seven patients were included in the study. The mean age of the patients was 64.16 ± 6.53 months, with 60% of the group <5 years. Influenza A was determined in 54 (80.5%) patients and Influenza B in 13 (19.5%). The majority of patients (73.1%) had a comorbidity. Fifty-eight (86.6%) patients were applied with invasive mechanical ventilation, Pediatric Acute Lung Injury Consensus Conference classification was mild in 5 (8.6%), moderate in 22 (37.9%) and severe in 31 (52.5%) patients. Ventilation was applied in the prone position to 40.3% of the patients, and in nonconventional modes to 24.1%. A total of 22 (33%) patients died, of which 4 had been previously healthy. Of the surviving 45 patients, 38 were discharged without support and 7 patients with a new morbidity. CONCLUSION: Both Influenza A and Influenza B cause severe PARDS with similar characteristics and at high rates. Influenza-related PARDS cause 33% mortality and 15.5% morbidity among the study group. Healthy children, especially those aged younger than 5 years, are also at risk.

Neurological Manifestations of Pediatric Acute COVID Infections: A Single Center Experience.

BACKGROUND: Coronavirus disease 2019 (COVID-19) usually leads to a mild infectious disease course in children, while serious complications may occur in conjunction with both acute infection and neurological symptoms, which have been predominantly reported in adults. The neurological complications in these patients vary based on patient age and underlying comorbidities. Data on clinical features, particularly neurological features, and prognostic factors in children and adolescents are limited. This study provides a concise overview of neurological complications in pediatric COVID-19 cases. MATERIALS AND METHODS: The retrospective study reviewed medical records of all patients who were admitted to our hospital and were diagnosed with COVID-19 by real-time reverse-transcription polymerase-chain-reaction (RT-PCR) assay between 11 March 2020 and 30 January 2021. Patients with a positive PCR result were categorized into two groups: outpatient departments patients and inpatient departments (IPD). RESULTS: Of the 2530 children who underwent RT-PCR during the study period, 382 (8.6%) were confirmed as COVID-19 positive, comprising 188 (49.2%) girls and 194 (50.8%) boys with a mean age of 7.14±5.84 (range, 0-17) years. Neurological complications that required hospitalization were present in 34 (8.9%) patients, including seizure (52.9%), headache (38.2%), dizziness (11.1%) and meningoencephalitis (5.8%). CONCLUSION: The results indicated that neurological manifestations are not rare in children suffering from COVID-19. Seizures, headaches, dizziness, anosmia, ageusia and meningoencephalitis are major neurological manifestations during acute COVID-19 disease. Although seizures were the most common cause of hospitalization in IPD patients, the frequency of meningoencephalitis was quite high. Seizures were observed as febrile seizures for children under 6 years of age and afebrile seizures for those over 6 years of age. Febrile seizure accounted for half of all seizure children.

Persistent pleural effusion in an infant with an unusual diagnosis: congenital alveolar rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is a malignant form of neoplasm that originates from skeletal muscle. RMSs can exist anywhere in the human body but are more commonly detected in the neck region and extremities. The alveolar type is one of the subtypes of RMS that has a poor prognosis. Because the clinical manifestation of a tumour can be a painless mass, symptoms might be non-contributary to the diagnosis. Herein, a four-month-old girl was admitted to the emergency department with complaints of respiratory distress without a runny nose, cough, and fever. Recurrent effusions subsided with subsequent tube thoracostomy. Video-assisted thoracoscopic surgery (VATS) was performed to determine the aetiology of the recurrent effusion. The Tru-Cut biopsy obtained during VATS resulted in the diagnosis of alveolar rhabdomyosarcoma. Pleural effusion decreased, and the tube drainage was stopped rapidly after first vincristine, actinomycin-D, and cyclophosphamide chemotherapy cycle. Persistent and recurrent pleural effusions should alert physicians to rule out unusual diagnoses like that of our case.

Occurrence of nutritional hypocalcaemic rickets-related dilated cardiomyopathy in a child with concomitant rickets and infantile-onset Pompe disease.

Infantile-onset Pompe disease is a lysosomal storage disorder characterised with hypertrophic cardiomyopathy, respiratory insufficiency, and hypotonia. Dilated cardiomyopathy is an extremely rare and curable complication of nutritional hypocalcaemic rickets. A 3-month-old female infant was referred to our paediatric ICU with a 4-day history of fatigue, tachypnoea, tachycardia, hypoxia, and respiratory failure. According to the laboratory, radiology, and echocardiography findings, she was first diagnosed with nutritional hypocalcaemic rickets-related dilated cardiomyopathy, but vitamin D and elementary calcium supplementation unmasked the underlying infantile-onset Pompe disease. Nutritional hypocalcaemic rickets and infantile-onset Pompe disease must always be kept in mind among the causes of concomitant dilated cardiomyopathy and hypertrophic cardiomyopathy.

Acute rheumatic fever presenting with severe endocarditis involving four valves, and ventricular tachycardia.

Acute rheumatic fever is the most commonly acquired heart disease in developing countries. The most common cardiac presentation is valvular disease. Although some rhythm disturbances may occur during the acute stages of the disease, ventricular tachycardia is extremely rare. Here, a case of acute rheumatic fever with severe endocarditis involving four valves and ventricular tachycardia is presented.

Use of Bedside Ultrasonography and Saline Flush Technique for Evaluation of Central Venous Catheter Placement in Children.

Our study investigated the reliability of appearance of rapid atrial swirl flow (RASF) by ultrasonography (US) in the right atrium (RA), which occurred as a result of rapid isotonic saline infusion (RISI) into the central venous catheter (CVC), in predicting catheter tip position. This prospective observational study included 95 CVC procedures performed on 77 pediatric patients (41 boys and 36 girls) with a median age of 0.6 (0.29-1.53) years. Seventy-three (76.84%) catheter tips were found to be correctly placed, and 22 (23.15%) catheter tips were misplaced. While ultrasonographic examination revealed RASF in the RA after 93 catheterization procedures, it was not observed after two catheterization procedures. One of these two catheters was an arterial catheter, and the other was a catheter that was directed toward the subclavian vein after curling around itself. There was no significant difference between the groups with incorrect and correct positioned catheter tip in terms of the appearance of RASF by US after RISI. There was no significant difference between the groups with upward (n = 8) and downward (n = 86) positioned catheter tip in terms of the time until the first appearance of RASF after RISI and the phase of RASF (P > 0.05). There was a significant difference between these two groups in terms of the disappearance time of RASF in the RA (P < 0.001). The mean disappearance time of RASF was 3 (2-3) s for downward positioned catheters and 5 (4-7) s for upward positioned catheters, respectively. When the cut-off for the disappearance time of RASF was set to 3 s, US had a sensitivity of 85.71% and a specificity of 77.91% for detecting upward positioned catheters. In conclusion, the appearance of RASF in the RA in a short time by US is not a reliable finding for correct positioning of the CVC tip in the pediatric patient group. The fact that the disappearance time of RASF in the RA is longer than 3 s indicates upward positioned CVCs. These catheters must never be used without radiological confirmation. In CVCs in which the disappearance time of RASF in the RA is shorter than 3 s, we think that the catheter can be used until radiological confirmation in emergency cases. According to the available literature, our study is the first study in children. There is a need for new studies on this subject.

A novel pathogenic frameshift variant of CD3E gene in two T-B+ NK+ SCID patients from Turkey.

Severe combined immunodeficiency (SCID) is the most severe form of primary immunodeficiency, which is characterized by the dysfunction and/or absence of T lymphocytes. Early diagnosis of SCID is crucial for overall survival, and if it remains untreated, SCID is often fatal. Next-generation sequencing (NGS) has become a rapid, high-throughput technology, and has already been proven to be beneficial in medical diagnostics. In this study, a targeted NGS panel was developed to identify the genetic variations of SCID by using SmartChip-TE technology, and a novel pathogenic frameshift variant was found in the CD3E gene. Sanger sequencing has confirmed the segregation of the variant among patients. We found a novel deletion in the CD3E gene (NM000733.3:p.L58Hfs*9) in two T-B+ NK+ patients. The variant was not found in the databases of dbSNP, ExAC, and 1000G. One sibling in family I was homozygous and the rest of the family members were heterozygous for this variant. T cell receptor excision circle (TREC) and kappa-deleting recombination excision circle (KREC) analyses were performed for T and B cell maturation. TRECs were not detected in both patients and the KREC copy numbers were similar to the other family members. In addition, heterozygous family members showed decreased TREC levels when compared with the wild-type sibling, indicating that carrying this variant in one allele does not cause immunodeficiency, but does effect T cell proliferation. Here, we report a novel pathogenic frameshift variant in CD3E gene by using targeted NGS panel.

Acute severe organophosphate poisoning in a child who was successfully treated with therapeutic plasma exchange, high-volume hemodiafiltration, and lipid infusion.

Acute severe organophosphate poisoning is a serious complication seen in developing and agricultural countries. Pralidoxime and high dose atropine are the standard treatments. There is no consensus about acute severe organophosphate poisonings that are unresponsive to pralidoxime, atropine, and supportive therapies. We report a case of acute severe organophosphate poisoning that was unresponsive to standard treatments and successfully treated with high-volume continuous venovenous hemodiafiltration and therapeutic plasma exchange combined with lipid infusion. J. Clin. Apheresis 31:467-469, 2016. © 2015 Wiley Periodicals, Inc.

[Very rare and life-threatening complications of bocavirus bronchiolitis: pneumomediastinum and bilateral pneumothorax]. / Bokavirus bronsiyolitinin çok nadir ve hayati tehdit eden komplikasyonlari: Pnömomediastinum ve bilateral pnömotoraks.

Human bocavirus (HBoV), that was first identified in 2005 and classified in Parvoviridae family, is a small, non-enveloped, single-stranded DNA virus, responsible for upper and lower respiratory tract infections, especially in young children. Although HBoV generally causes self-limited influenza-like illness, it may also lead to pneumonia, bronchiolitis, croup and asthma attacks. In this report, a case of acute bronchiolitis complicated with pneumomediastinum and bilateral pneumothorax caused by HBoV has been presented. A three-year-old boy was referred to our pediatric intensive care unit with a two day history of fever, tachypnea, hypoxia and respiratory failure. On auscultation, there were widespread expiratory wheezing and inspiratory crackles. The chest radiography yielded paracardiac infiltration and air trapping on the right lung and infiltration on the left lung. The patient had leukocytosis and elevated C-reactive protein level. On the second day of admission, respiratory distress worsened and chest radiography revealed right pneumothorax and subcutaneous emphysema in bilateral cervical region and left chest wall. He was intubated because of respiratory failure. In the thorax computed tomography, pneumomediastinum and bilateral pneumothorax were detected and right chest tube was inserted. Repetitive blood and tracheal aspirate cultures were negative. A nasopharyngeal swab sample was analyzed by multiplex real-time polymerase chain reaction method with the use of viral respiratory panel (FTD(®) Respiratory Pathogens 21 Kit, Fast-Track Diagnostics), and positive result was detected for only HBoV. On the ninth day of admission, pneumomediastinum and bilateral pneumothorax improved completely and he was discharged with cure. In conclusion, HBoV bronchiolitis may progress rare but severe complications, it should be kept in mind as an etiological agent of the respiratory tract infections especially children younger than five years old.

[A case of bronchiolitis obliterans secondary to human metapneumovirus bronchiolitis]. / Insan metapnömovirus bronsiyolitine ikincil gelisen bronsiyolitis obliterans olgusu.

Human metapneumovirus (hMPV), formerly classified in Paramyxoviridae family is now moved into Pneumoviridae, which was described as a novel family. It causes upper and lower respiratory tract infections (LRTIs) usually in children younger than five years old. The recent epidemiological studies indicated that hMPV is the second most frequently detected virus in LRTIs of young children, following the respiratory syncytial virus (RSV). Bronchiolitis obliterans (BO) is a chronic obstructive lung disease characterized by fibrosis of the distal respiratory airways. It is usually a result of an inflammatory process triggered by a LRTI related to adenovirus, RSV, Mycoplasma pneumoniae, measles virus, Legionella pneumophila, influenza virus or Bordetella pertussis as a causative agent. In this report, a case of hMPV bronchiolitis complicated with BO has been reported to point out the complications and severity of the clinical progress belongs to this virus. A three-month-old female patient has admitted to our pediatric intensive care unit with the diagnosis of acute bronchiolitis and respiratory failure. She was born at term, weighing 2950 gram and had been hospitalized in newborn intensive care unit for 11 days with the diagnosis of transient tachypnea of the newborn and neonatal sepsis. On auscultation, there were bilateral crepitant rales, wheezing and prolonged expirium. Her oxygen saturation was 97-98% while respiratory support was given with a non-rebreathing reservoir mask. Complete blood count, procalcitonin and C-reactive protein levels were in normal ranges. The chest radiography yielded right middle lobe atalectasia, left paracardiac infiltration and bilateral air trapping. A nasopharyngeal swab sample was analyzed by a commercial multiplex real-time reverse transcriptase-polymerase chain reaction (Thermo Fisher Scientific®, USA) developed for the detection of 15 respiratory viruses. Her sample yielded positive result for only hMPV. On the 4th day of hospitalization, the patient was intubated because of respiratory failure and carbon dioxide retention. She was extubated on the 19th day but could not tolerate. In the thorax computed tomography (CT), bilateral hyperinflation, patchy infiltration, mosaic perfusion and atelectasis especially bilateral posterior areas were detected. Bronchoscopy was normal except mild bronchomalacia in right middle lobe bronchus. The patient was diagnosed as BO secondary to hMPV bronchiolitis, according to the clinical, virological, bronchoscopic and thorax CT results. On the 76th day of admission, she was discharged with respiratory support with home ventilation via a tracheostomy cannula and medical treatments of oral metilprednisolone, nebulized salbutamol and budesonide. In conclusion, hMPV should not be undervalued especially in infants with severe LRTI that can be complicated with BO.

Dermatologic manifestations of multisystem inflammatory syndrome in children during the COVID-19 pandemic.

OBJECTIVES: multi-system inflammatory syndrome in children (MIS-C) is an immune-mediated process that develops after infections like SARS-CoV-2. The authors aimed to reveal the mucocutaneous findings of patients diagnosed with MIS-C at presentation and evaluate the frequency of these mucocutaneous findings and their possible relationship with the severity of the disease. METHODS: A prospective study was conducted of 43 children admitted to a tertiary hospitals between January 2021 and January 2022 who met Centers for Disease Control and Prevention criteria for MIS-C. RESULTS: 43 children (25 [58.1%] male); median age, 7.5 years [range 0.5‒15 years]) met the criteria for MIS-C. The most common symptom was cutaneous rash 81.4%, followed by gastrointestinal symptoms 67.4%, oral mucosal changes 65.1%, and conjunctival hyperemia 58.1%. The most common mucosal finding was fissured lips at 27.9%, diffuse hyperemia of the oral mucosa at 18.6%, and strawberry tongue at 13.9%. Urticaria (48.8%) was the most common type of cutaneous rash in the present study's patients. The most common rash initiation sites were the trunk (32.6%) and the palmoplantar region (20.9%). The presence or absence of mucocutaneous findings was not significantly associated with disease severity. STUDY LIMITATIONS: The number of patients in the this study was small. CONCLUSIONS: The present study's prospective analysis detected mucocutaneous symptoms in almost 9 out of 10 patients in children diagnosed with MIS-C. Due to the prospective character of the present research, the authors think that the characteristic features of cutaneous and mucosal lesions the authors obtained will contribute to the literature on the diagnosis and prognosis of MIS-C.