Schwartz-Jampel Syndrome Type-1: Compound Heterozygosity of Two Novel Variants.

Schwartz-Jampel Syndrome (SJS) type-1 (OMIM; #255800), a rare cause of skeletal dysplasia, is characterized by myotonic myopathy, chondrodystrophy, short stature, facial and eye abnormalities. SJS Type-1 develops due to variations in the HSPG2 gene which produces the "perlecan" molecule, one of the main proteoglycans of the basement membrane. A 6-year-old girl presented with short stature, a mask face, shrunken lips, narrow palpebral opening due to blepharospasm, stiffness of facial muscles, micrognathia, overlapping teeth, a short neck, and a bell-shaped thorax due to myotonic myopathy. She was diagnosed with SJS type-1 due to compound heterozygosity of two novel variations in the HSPG2 gene. In patients with short stature and an accompanying myotonic myopathy SJS should be considered. Compound heterozygosity may cause typical clinical findings of SJS. In case of suspicion creatinine kinase levels can be measured, and the determination of myotonia may require evaluation with electromyography. Once the diagnosis is made, patients should be carefully monitored in terms of growth, neuromuscular disorders, joints problems and bone health.

Chronic inflammatory demyelinating neuropathy after etanercept therapy in the course of juvenile idiopathic arthritis.

BACKGROUND: Chronic inflammatory demyelinating neuropathy has been reported after the use of tumor necrosis factor inhibitors. The mechanisms of nerve injury caused by tumor necrosis factor inhibitors are not yet well understood. CASE: In this paper, we report a 12 year and nine month old girl who developed chronic inflammatory demyelinating neuropathy in the course of juvenile idiopathic arthritis after etanercept withdrawal. She became non-ambulant with four-limb involvement. She received intravenous immunoglobulins, steroids, and plasma exchange, but had a limited response. Finally, rituximab was given and a slow, but progressive clinical improvement was seen. She was ambulant four months after rituximab treatment. We considered chronic inflammatory demyelinating neuropathy as a probable adverse effect of etanercept. CONCLUSIONS: Tumor necrosis factor inhibitors could elicit the demyelinating process, and chronic inflammatory demyelinating neuropathy might persist despite treatment discontinuation. First-line immunotherapy may be inefficient as in our case, and aggressive treatment may be necessary.

The course of sleep habits in newly diagnosed epilepsy in children: A prospective study.

BACKGROUND: Epilepsy and sleep have a close, complex, and reciprocal relationship. Sleep may also be adversely affected by epilepsy and anti-seizure medication (ASM). This study sought to determine sleep-related problems before and after six months of treatment with ASMs follow-up in children with epilepsy, to reveal changes in sleep habits, and to determine the effect of ASMs on sleep in different types of epilepsy. METHODS: This is a prospective study that included 61 children, aged 4-18 years with newly diagnosed epilepsy, who regularly had follow-up checks and used ASM for six months, and completed the Children's Sleep Habits Questionnaire (CSHQ). Children's Sleep Habits Questionnaire was completed before and after six months of ASM, allowing for assessments based on treatment group and type of epilepsy. RESULTS: The mean ages of 61 children were 10.6 ± 3.9 years. The participants' post-treatment total scores on the CSHQ decreased by 2.9 ± 7.8 units on average compared to their pretreatment scores (p = 0.008; p < 0.01). In the levetiracetam group, post-treatment CSHQ subscale scores showed a mean decrease for bedtime resistance (p = 0.001), sleep duration (p = 0.005), sleep anxiety (p = 0.030), and total scores (p = 0.012) (p < 0.05). In the valproic acid group, post-treatment CSHQ subscale scores showed a mean decrease in sleep duration (p = 0.007) and a mean increase in daytime sleepiness (p = 0.03) (p < 0.05). CONCLUSION: Our study found that children diagnosed with epilepsy had significantly higher rates of pretreatment sleep problems, which significantly decreased in patients who regularly attended follow-up examinations and received treatment. Except for the daytime sleepiness factor, our study found that sleep-related problems improved with treatment. It was observed that the initiation of epilepsy treatment had a positive effect on the patient's sleep, regardless of the type of treatment or epilepsy.

HACE1, GLRX5, and ELP2 gene variant cause spastic paraplegies.

Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of conditions that are characterized by lower limb spasticity and weakness. Considering the clinical overlap between metabolic causes, genetic diseases, and autosomal recessive HSP, differentiation between these types can be difficult based solely on their clinical characteristics. This study aimed to investigate the genetic etiology of patients with clinically suspected HSP. The study group was composed of seven Turkish families who each had two affected children and three families who each had a single affected child (17 total patients). The 17 probands (14 males, 3 females) underwent whole exome sequencing. Five typical HSP genes (FA2H, AP4M1, AP4E1, CYP7B1, and MAG) and three genes not previously related to HSP (HACE1, GLRX5, ad ELP2) were identified in 14 probands. Eight novel variants were identified in seven families: c.653 T > C (p.Leu218Pro) in the FA2H gene, c.347G > A (p.Gly116Asp) in the GLRX5 gene, c.2581G > C (p.Ala861Pro) in the HACE1 gene, c.1580G > A (p.Arg527Gln) and c.1189-1G > A in the ELP2 gene, c.10C > T (p.Gln4*) and c.1025 + 1G > A in the AP4M1 gene, c.1291delG (p.Gly431Alafs*3) and c.3250delA (p.Ile1084*) in the AP4E1 gene, and c.475 T > G (p.Cys159Gly) in the MAG gene. The growing use of next-generation sequencing improved diagnosis but also led to the continual identification of new causal genes for neurogenetic diseases associated with lower limb spasticity. The increasing number of HSP genes identified thus far highlights the extreme genetic heterogeneity of these disorders and their clinical and functional overlap with other neurological conditions. Our findings suggest that the HACE1, GLRX5, and ELP2 genes are genetic causes of HSP.

Cytotoxic lesions of the corpus callosum in children: Etiology, clinical and radiological features, and prognosis.

OBJECTIVES: Cytotoxic lesions of the corpus callosum (CLOCCs) are secondary lesions associated with entities like infection manifested by restricted diffusion on diffusion-weighted cranial magnetic resonance imaging. Our objectives are to evaluate the clinic-radiological spectrum of pediatric patients with cytotoxic lesions of the corpus callosum (CC). METHODS: Children (0-18 years) admitted between February 2017 and May 2020 with splenial lesions showing diffusion restriction on MRI, either isolated or within involvement of other parts of the brain, were included retrospectively. The primary lesions of the CC (e.g. acute disseminated encephalomyelitis, acute ischemic infarction, and glioblastoma multiforme) were excluded. CLOCCs were divided into infection-associated, metabolic disorder-associated, and trauma-associated lesions, as well as CLOCCs involving other entities. Data were collected from the medical databases. RESULTS: Forty-one patients were determined to have CLOCCs. Twenty-five (61%) were infection-associated, nine (22%) were trauma-associated, and three (7%) were metabolic disorder-associated cases, including 2 inherited disorders of metabolism. There were four (10%) patients with other entities, three with epilepsy, and one had an apparent life-threatening event. Six patients had a known etiology among the infection-associated group; one had multisystem inflammatory syndrome caused by COVID-19 and one had been infected by COVID-19 without any complications. All the infection-associated patients with isolated splenial lesions recovered totally, although six patients required intensive care hospitalization. Four trauma-associated patients had sequela lesions. CONCLUSIONS: CLOCCs are associated with a spectrum of diseases, including the new coronavirus, COVID-19 infection. Infection-associated CLOCCs has the best prognosis, although severe cases may occur. Sequelae are possible based on the etiology.

Glial fibrillary acidic protein (GFAP)-antibody in children with focal seizures of undetermined cause.

Anti-neuronal antibodies that are related with autoimmune encephalitis syndromes may also be found in children with new onset seizures or chronic epilepsy. To unravel the significance of autoimmune astrocytopathy in epilepsy, we investigated serum antibody to glial fibrillary acidic protein (GFAP), another autoantigen described in autoimmune encephalitis with seizures, in 38 children with focal seizures of undetermined cause. GFAP antibody was screened with cell based assay and indirect immunohistochemistry and was found in two boys with normal brain MRI and unrevealing medical history prior to seizures. The 2-year-old boy had chronic treatment-resistant frontal lobe epilepsy. The 2.5-year-old boy had a single episode of focal seizures and remained seizure free thereafter in a follow-up period of 4 years. Nevertheless, he showed severe cognitive and language impairment. These results suggest that autoimmune astrocytopathy may be present in some epilepsy patients. Whether this immune response is a bystander effect generated by seizure-induced astrocytosis or directly involved in epileptogenesis needs to be further studied.

The frequency of late-onset Pompe disease in pediatric patients with limb-girdle muscle weakness and nonspecific hyperCKemia: A multicenter study.

The aim of this multicenter study was to screen for late-onset Pompe disease in high-risk children with limb-girdle muscle weakness and nonspecific hyperCKemia using the dried blood spot (DBS) test. Seventy-two children from four pediatric neurology departments in Turkey were enrolled in the study: 37 with limb-girdle muscle weakness and 35 with nonspecific hyperCKemia. Acid α-glucosidase (GAA) activity was measured on DBS by tandem mass spectrometry. Six patients tested positively for Pompe disease. In three patients, one with the limb-girdle muscle weakness and two with nonspecific hyperCKemia, this was confirmed by genetic analysis. The overall frequency of late-onset Pompe disease in the study population was 4.2%. The c.1784C>T mutation found in one patient is a new mutation whereas the c.1655T>C mutation detected in the other two patients is not novel. In conclusion, Pompe disease should be suspected in patients with limb-girdle muscle weakness and nonspecific hyperCKemia. The DBS test is a safe and reliable method of diagnosis but must be confirmed by genetic analysis. In patients with a positive DBS test and negative genetic analysis, tissue assay of GAA should be considered.

Evaluation of cases with cerebral thrombosis in children.

AIM: We aimed to evaluate the patients who were followed up in our clinic with a diagnosis of cerebral sinovenous thrombosis in terms of age, sex, clinical findings, etiology, thrombophilic factors, imaging findings, treatment and prognosis. MATERIAL AND METHODS: The files of 11 patients who were followed up in our pediatric neurology clinic with a diagnosis of cerebral thrombosis between 1 December 2010 and 31 December 2014 were retrospectively analyzed. RESULTS: Seven of 11 patients were male (63.6%). The median age was 14 years (2-17 years). Six (54%) of the patients presented with a complaint of headache. Other complaints at presentation included diplopia (n:3), weakness and difficulty in speaking (n:1) and seizure (n:1). A diagnosis of pseudotumor cerebri was made in eight of the patients (72.7%). In the etiology, mastoiditis was found in three patients, mastoiditis and meningitis were found in combination in one patient, Behçet's disease was found in three patients and head trauma was found in one patient. In 3 patients, only prothrombotic genetic risk factors were present; one patient had deficiency of protein C and S, one patient had deficiency of antithrombin III and one patient had hyperhomosisteinemia in association with vitamin B12 deficiency. 1A homozygous MTFHR A1298C mutation was detected in the patient who had mastoiditis and meningitis and protein S deficiency and lupus anticoagulant were found in another patient who had mastoiditis. All patients received anticoagulant treatment and all patients recovered without neurological sequelae except one. CONCLUSIONS: Cerebral sinovenous thrombosis should be considered in patients who present with headache and focal neurological deficits. Appropriate utilization of imaging studies is necessary for the diagnosis. Detailed ear, nose and throat examination should be performed to detect mastoiditis. It is recommended that genetic risk factors should be investigated, because hereditary thrombophilis factors may have a role in children. Behçet's disease which is relatively common in our country should be considered in differential diagnosis.

Transient Splenial Lesion of the Corpus Callosum Related to Migraine with Aura in a Pediatric Patient.

BACKGROUND: Transient splenial lesions of the corpus callosum are rare radiological findings first described in association with epilepsy, antiepileptic drugs and viral encephalitis. However, subsequently more cases were described associated with diverse clinical conditions. CASE REPORT: We describe a 13-year-old girl suffering from migraine with aura presenting with headache, right-sided hemiparesis and encephalopathy. Brain magnetic resonance imaging revealed an ovoid lesion in the splenium of the corpus callosum. The patient's neurological symptoms resolved within 3 days without therapy and the lesion disappeared in follow up magnetic resonance images obtained 3 weeks after the onset of the symptoms. RESULTS: Migraine with aura was considered to be the cause of the lesion. To our knowledge the present case is the first report of a pediatric patient with a diagnosis of migraine with aura presenting with hemiparesis and encephalopathy. CONCLUSIONS: A diagnosis of transient lesion of the corpus callosum should be suspected in patients with migraine with aura presenting with hemiparesis and encephalopathy. A mild course and a good prognosis might be expected in the presence of a splenial lesion of the corpus callosum.

Importance of NOD2/CARD15 gene variants for susceptibility to and outcome of sepsis in Turkish children.

OBJECTIVE: Severe sepsis remains a leading cause of morbidity and mortality in children. Given the link to pathogenesis, polymorphisms in genes involved in infection and inflammation may influence the outcomes in patients with sepsis and septic shock. The role of mutations within the innate immunity receptor NOD2/CARD15 has recently been demonstrated as a risk factor for bacteremia and mortality in adult patients with sepsis. The aim of this study was to evaluate the role of mutations of the NOD2/CARD15 gene in pediatric patients with sepsis. DESIGN: Prospective cohort study. SETTING: A tertiary care, ten-bed, pediatric intensive care unit. PATIENTS: One hundred twenty-eight patients with sepsis admitted to the pediatric intensive care unit and healthy control group were included. INTERVENTIONS: Venous blood from the children with sepsis and healthy controls was collected to investigate common polymorphisms (Arg702Trp, Gly908Arg, Leu1007fsincC) within the NOD2/CARD15 gene. Standard polymerase chain reaction restriction fragment length polymorphism technique was used to determine NOD2/CARD15 gene polymorphism. MEASUREMENT AND MAIN RESULTS: R702W, G908R, and Leu1007fsinsC variants in the NOD2/CARD15 gene were determined as significant risk factors associated with susceptibility to sepsis (p = .025, p = .031, p = .014, respectively). Sepsis-related mortality was increased in children carrying the Leu1007fsinsC variant (p = .041). CONCLUSIONS: The present article is the first report of clinical implications of NOD2/CARD15 gene variants in children with sepsis. Our findings suggest that common polymorphisms in the NOD2/CARD15 gene may play a major role in susceptibility to sepsis and the outcome of sepsis in children.

Arg753Gln polymorphism of the human Toll-like receptor 2 gene from infection to disease in pediatric tuberculosis.

The aim of this study is to examine the occurrence of the Arg753Gln polymorphism of the Toll-like receptor 2 (TLR2) gene in Turkish children with pulmonary and/or extrapulmonary tuberculosis (TB) disease compared with that in healthy children with latent TB infection (LTBI) and to assess the risk of progression from LTBI to active TB disease in children. The Arg753Gln polymorphism of the TLR2 gene was studied in 198 TB patients compared with 200 ethnically and age-matched children with LTBI. The culture confirmed TB patients were more frequently Arg753Gln heterozygous [odds ratio (OR) 5.05, 95% confidence interval (95% CI) 2.61-9.76, p = 0.00], and Gln allele frequency was significantly higher in the patient group (13.86% vs 3.5%, OR 4.40, 95% CI 2.34-8.30, p = 0.00). We also showed that the frequencies of the heterozygous Arg753Gln genotype and the Gln allele were significantly higher in patients with pulmonary TB alone and in patients with definitive pulmonary plus extrapulmonary TB than in children with LTBI. Our data suggest that the Arg753Gln polymorphism of the TLR-2 gene influences the speed of progression from infection to TB disease in children. Further investigations are needed to clarify whether this polymorphism has a strong impact on susceptibility to TB in children.

Polymorphism in the p2x7 gene increases susceptibility to extrapulmonary tuberculosis in Turkish children.

The P2X7 gene polymorphisms have been linked to increased risk for pulmonary and extrapulmonary tuberculosis in some populations. In this study, the genotype and allelic frequencies 1513A-->C variant within the P2X7 gene was significantly higher than in the healthy controls (P = 0.035, P = 0.041). This is the first study demonstrating that the 1513A-->C polymorphism is associated with extrapulmonary tuberculosis in children.