Autoimmune Hemolytic Anemia Due to Spondyloenchondrodysplasia with Spastic Paraparesis and Intracranial Calcification due to Mutation in ACP5.

Spondyloenchondrodysplasia (SPENCD) is a rare spondylometaphyseal skeletal dysplasia with characteristic lesions mimicking enchondromatosis and resulting in short stature. A large spectrum of immunologic abnormalities may be seen in SPENCD, including immune deficiencies and autoimmune disorders. SPENCD is caused by loss of tartrate-resistant acid phosphatase activity, due to homozygous mutations in ACP5 , playing a role in nonnucleic-acid-related stimulation/regulation of the type I interferon pathway. In this article, we presented a 19-year-old boy with SPENCD, presenting with recurrent autoimmune hemolytic anemia episodes since he was 5 years old. He had short stature, platyspondyly, metaphyseal changes, intracranial calcification, spastic paraparesis, and mild intellectual disability. He also had recurrent pneumonia attacks. The clinical diagnosis of SPENCD was confirmed by sequencing of the ACP5 gene, and a homozygous c.155A > C (p.K52T) variation was found, which was reported before as pathogenic. In conclusion, in early onset chronic autoimmune cytopenias an immune dysregulation may often have a role in the etiology. Associating findings and immunologic functions should be carefully evaluated in such patients in the light of the literature. The present case shows the importance of multisystemic evaluation for the detection of SPENCD that has a monogenic etiology.

A multicenter study of radiologically isolated syndrome in children and adolescents: Can we predict the course?

OBJECTIVES: To evaluate clinical characteristics, imaging features and etiological profile of Radiologically Isolated Syndrome (RIS) along with clinical and radiological follow-up. METHODS: Demographic, clinical and radiological data of patients younger than 18 years fulfilling the criteria for RIS were retrospectively analyzed. RIS was defined by the detection of lesions meeting the revised 2010 McDonald Criteria for dissemination in space on magnetic resonance imaging (MRI) in the absence of any symptoms of demyelinating disease or an alternative cause for the MRI findings. RESULTS: There were total 69 patients (38 girls, 31 boys). The median age at index MRI was 15.7 years, and median follow-up time was 28 months. The most common reason for neuroimaging was headache (60.9%). A first clinical event occurred with median 11 months in 14/69 (20%) of cases. Those with oligoclonal bands (OCB) in cerebrospinal fluid (CSF) and follow-up longer than 3 years were more likely to experience a clinical event (p<0.05): 25% of those with OCB manifested clinical symptoms within the first year and 33.3% within the first two years compared to 6.3% and 9.4%, respectively in those without OCB. Radiological evolution was not associated with any variables: age, sex, reason for neuroimaging, serum 25-hydroxyvitamin D level, elevated IgG index, OCB positivity, total number and localization of lesions, presence of gadolinium enhancement, achievement of 2005 criteria for DIS and duration of follow-up. CONCLUSION: Children and adolescents with RIS and CSF OCB should be followed-up for at least 3 years in order to detect any clinical symptoms suggestive of a demyelinating event. Because disease-modifying treatments are not approved in RIS and no consensus report justifies their use especially in pediatric RIS, close follow-up of OCB-positive patients is needed for early recognition of any clinical event and timely initiation of specific treatment.

Clinical and Genetic Spectrum of Myotonia Congenita in Turkish Children.

BACKGROUND: Myotonia congenita is the most common form of nondystrophic myotonia and is caused by Mendelian inherited mutations in the CLCN1 gene encoding the voltage-gated chloride channel of skeletal muscle. OBJECTIVE: The study aimed to describe the clinical and genetic spectrum of Myotonia congenita in a large pediatric cohort. METHODS: Demographic, genetic, and clinical data of the patients aged under 18 years at time of first clinical attendance from 11 centers in different geographical regions of Türkiye were retrospectively investigated. RESULTS: Fifty-four patients (mean age:15.2 years (±5.5), 76% males, with 85% Becker, 15% Thomsen form) from 40 families were included. Consanguineous marriage rate was 67%. 70.5% of patients had a family member with Myotonia congenita. The mean age of disease onset was 5.7 (±4.9) years. Overall 23 different mutations (2/23 were novel) were detected in 52 patients, and large exon deletions were identified in two siblings. Thomsen and Becker forms were observed concomitantly in one family. Carbamazepine (46.3%), mexiletine (27.8%), phenytoin (9.3%) were preferred for treatment. CONCLUSIONS: The clinical and genetic heterogeneity, as well as the limited response to current treatment options, constitutes an ongoing challenge. In our cohort, recessive Myotonia congenita was more frequent and novel mutations will contribute to the literature.

The Effect of Interleukin-1 Antagonists on Brain Volume and Cognitive Function in Two Patients With Megalencephalic Leukoencephalopathy With Subcortical Cysts.

BACKGROUND: Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare leukodystrophy characterized by early-onset macrocephaly and progressive white matter vacuolation. The MLC1 protein plays a role in astrocyte activation during neuroinflammation and regulates volume decrease following astrocyte osmotic swelling. Loss of MLC1 function activates interleukin (IL)-1ß-induced inflammatory signals. Theoretically, IL-1 antagonists (such as anakinra and canakinumab) can slow the progression of MLC. Herein, we present two boys from different families who had MLC due to biallelic MLC1 gene mutations and were treated with the anti-IL-1 drug anakinra. METHODS: Two boys from different families presented with megalencephaly and psychomotor retardation. Brain magnetic resonance imaging findings in both patients were compatible with the diagnosis of MLC. The diagnosis of MLC was confirmed via Sanger analysis of the MLC1 gene. Anakinra was administered to both patients. Volumetric brain studies and psychometric evaluations were performed before and after anakinra treatment. RESULTS: After anakinra therapy, brain volume in both patients decreased significantly and cognitive functions and social interactions improved. No adverse effects were observed during anakinra therapy. CONCLUSIONS: Anakinra or other IL-1 antagonists can be used to suppress disease activity in patients with MLC; however, the present findings need to be confirmed via additional research.

Probable association between mRNA COVID-19 vaccine and opsoclonus-myoclonus-ataxia syndrome.

Opsoclonus-myoclonus-ataxia syndrome (OMAS) in children is most often of paraneoplastic origin, but it can also result from infectious processes, toxic and metabolic disorders, and organic events that cause damage to the brainstem or cerebellum. Post-vaccination OMAS has also been reported. We report the case of a 15-year-old girl who developed OMAS 24 hours after her first dose of mRNA COVID-19 (BioNTech) vaccine.

Management and behavior-modifying recommendation effects in childhood headache.

BACKGROUND: Headaches are common in childhood. Recently, there has been an increasing trend toward pharmacological treatment. METHODS: Secondary causes were excluded first in patients who attended our clinic with headache. Those without a secondary cause were evaluated as primary headache and classified into subgroups. Behavior-modifying recommendations (adequate and regular sleep, adequate and regular nutrition, adequate fluid intake, and restriction of screen exposure) were given to all patients. Patients were re-evaluated at 1, 3, and 6 months. Pharmacologic treatment was started at the end of the first month with follow-up at the third and sixth months for those who did not benefit from the behavior-modifying recommendations. RESULTS: A total of 875 patients presented with headache complaints, of which 30.6% were evaluated as primary headache. Behavior-modifying recommendations were beneficial for 23.1% with migraine with aura; 20.3% with migraine without aura, and 36.8% with tension-type headache. CONCLUSION: Secondary causes should be excluded first in patients who present to the pediatric neurology clinic with headache. Behavioral modifications to change the lifestyle of patients diagnosed with primary headache should be tried before giving pharmacologic treatment.

Preclinical ocular microvascular changes in juvenile dermatomyositis: A pilot optical coherence tomography angiography study.

OBJECTIVES: To evaluate the macular and optic nerve head (ONH) vascular density, foveal avascular zone area, and outer retina and choriocapillaris flow in juvenile dermatomyositis (JDM) using optical coherence tomography angiography (OCTA). METHODS: Ten eyes of 10 patients with JDM and 15 age and sex-matched healthy controls were investigated in this prospective, cross-sectional study. The superficial capillary plexus (SCP) and deep capillary plexus (DCP), ONH, foveal avascular zone (FAZ) parameters, the flow area of the outer retina, and choriocapillaris were evaluated using OCTA. RESULTS: Vessel density (VD) of the parafovea (p = 0.036) and parafoveal subregions (p = 0.041 for superior hemifield, p = 0.031 for inferior hemifield, p = 0.012 for superior, p = 0.019 for nasal, p = 0.026 for inferior, and p = 0.048 for temporal) in DCP were significantly lower in the JDM group compared to healthy controls. A high inverse correlation between disease duration and these parameters was found except parafoveal superior VD in DCP. There was no significant difference between the groups in VD parameters of SCP and ONH, FAZ parameters, outer retina, and choriocapillaris flow area as well as thickness parameters. (p > 0.05 for all). Furthermore, ROC analysis revealed that all parafoveal DCP parameters showed good ability to differentiate JDM from healthy controls. CONCLUSIONS: We demonstrated a decreased vessel density in the deep parafoveal region in JDM. As a result, we hypothesized that OCTA could detect retinal microvascular changes in JDM patients who did not have clinical evidence of ocular involvement.

Evaluation of optic nerve diameters in individuals with neurofibromatosis and comparison of normative values in different pediatric age groups.

AIM: Our study aimed to report the normative values for optic nerve diameter in different age groups in MR imaging (MRI) in the pediatric population and to find a cut-off value for diagnosis in different age groups to be used for the diagnosis of optic glioma in patients with Neurofibromatosis 1(NF1). MATERIALS-METHODS: Orbital MRI obtained from 2011 to 2021 for children with and without NF1 were reviewed. Patients were divided into three groups: NF1 with glioma (group 1, n = 38), NF1 without glioma (group 2, n = 57), and healthy controls (group 3, n = 295). Two radiologists assessed diameter and tortuosity using validated criteria. The optic nerve measurements were obtained by two radiologists in two plans (axial and coronal sections) at five locations; retroocular, midsegment, and prechiasmatic segment on axial plane and retroocular segment and chiasmatic on coronal plane. RESULTS: Optic nerves were divided into 4 age groups: 0-2 years, 2-6 years, 6-12 years, and 12-18 years. It was observed that optic nerve diameters increased with age in healthy individuals. In subjects in groups 1 and 2, the mean diameter of the optic nerve was significantly greater at all locations compared with control individuals. Tortuosity scores were significantly associated in NF1 subjects with optic glioma than in NF1 subjects without optic glioma. CONCLUSION: We present the normative values obtained by measuring optic nerve diameters in pediatric populations (0-18 years) on MRI of our center. A rapid increase in optic nerve diameter was observed in the first 6 years of life, followed by a slower increase. Quantitative reference values for optic nerve diameter will benefit the development of objective diagnostic criteria for optic nerve gliomas (ONGs) secondary to NF1.

Angioedema-like presentation as the presenting finding of juvenile myositis and juvenile dermatomyositis in 2 patients.

BACKGROUND: Juvenile dermatomyositis (JDM) is the most common subtype of idiopathic inflammatory myopathies in childhood. Gottron's papules, shawl sign, periorbital heliotrope rash, and periungual telengiectasis are characteristic skin findings of the disease. Besides characteristic skin involvement, some other skin findings, such as angioedema, may be seen prior or in the course of the disease. The presence of angioedema in JDM is emphasized in this report. CASE PRESENTATIONS: We present 2 unrelated girls, aged 2 (case 1) and 12 years (case 2), who had developed symmetrical weakness in the proximal muscles, muscle pain, elevated muscle enzymes and angioedema. Both cases had abnormal muscle magnetic resonance imaging findings, suggestive of inflammatory myositis. Muscle biopsy was performed only in case 1, and major histocompatibility complex-1 expression on myofibers was shown consistent with JDM. Cases were diagnosed as probable and definite JDM, respectively. Angioedema was prominent, particularly in the lips and extremities of both cases, without laboratory evidence of C1 inhibitor deficiency or capillary leak syndrome, and absence of family history. Mast cell-mediated, acquired angioedema was the most likely diagnosis. In both cases, skin and muscle findings improved significantly with steroid treatment. CONCLUSION: We suggest that angioedema may be among the characteristic skin findings in JDM, and may be included in subsequent definitions.

Recurrent Blistering Skin Lesions and Reversible Monocular Abducens Paralysis in a Patient with CD59 Deficiency.

Congenital CD59 deficiency is an autosomal recessive disease characterized by mild-to-moderate chronic intravascular hemolysis, relapsing demyelinating peripheral neuropathies, and recurrent ischemic central nervous system strokes. We report a 2-year-old Turkish girl with a history of two episodes of Guillain-Barré syndrome-like acute weakness, reversible monocular abducens paralysis, and recurrent blistering skin lesions during periods of upper respiratory tract infections. Reversible monocular abducens palsy and recurrent blistering skin lesions have not been reported previously in cases of congenital CD59 deficiency.

Clinical and electrophysiological predictors of behavioral disorders in patients with benign childhood epilepsy with centrotemporal spikes.

PURPOSE: Long-term seizure and developmental outcomes of benign childhood epilepsy with centrotemporal spikes (BECTS) are thought to be good. Studies have shown that behavioral disorders may accompany BECTS. We aimed to investigate the frequency of behavioral disorders in patients with BECTS and evaluate their relationship to epilepsy features. METHODS: Data for 41 patients with BECTS followed up at our clinic between December 2019 and June 2020 were analyzed. Behavioral disorders and intelligence were evaluated by the Turgay Diagnostic and Statistical Manual of Mental Disorders 4th Edition - Disruptive Behaviour Disorders Rating Scale and Wechsler Intelligence Scale for Children Revised, respectively. Patients with a diagnosis of BECTS were divided into 2 groups: children with a behavioral disorder and children without a behavioral disorder. Demographic characteristics, clinical and electroencephalography (EEG) findings, and intelligence level were compared between the two groups. RESULTS: Twelve of the patients (29%) were classified as having attention-deficit/hyperactivity disorder (ADHD) and 2 (5%) were classified as having oppositional defiant disorder (ODD). The age at seizure onset was earlier in patients with behavioral disorders (p = 0.023). Bilateral interictal epileptic discharges (IEDs) were more common in children with behavioral disorders than children without behavioral disorders (p = 0.039). The most preferred antiseizure medication was carbamazepine, followed by levetiracetam and valproic acid. The intelligence score of the patients with BECTS was in the normal range in both groups. The total, verbal, and performance scores were lower in patients with a behavioral disorder than in patients without a behavioral disorder, but there was no statistically significant difference between the two groups. CONCLUSION: Behavioral disorders may be present in approximately one-third of patients with BECTS. Early onset of seizures and the presence of bilateral IEDs may be risk factors for behavioral disorders in children with BECTS.

Acute flaccid myelitis outbreak through 2016-2018: A multicenter experience from Turkey.

AIM: We aim to describe the demographic characteristics, etiology, neurophysiology, imaging findings, treatment, prognosis, and prognostic factors of acute flaccid myelitis. METHODS: The clinical data, laboratory test and, magnetic resonance imaging (MRI) results of pediatric patients diagnosed with acute flaccid myelitis according to the Centers for Disease Control criteria between August 1, 2016, and December 31, 2018, from 13 centers in Turkey were reviewed. RESULTS: Of the 34 cases identified, 31 were confirmed (91.2%). Eighteen patients (55.9%) were boys. The median patient age was 4 years (interquartile range 2.5-6.9 years). Most of the patients were admitted in 2018 (n = 27). A preceding history of a febrile illness was reported in all patients, with a median of 4 days (interquartile range 3-7 days) before symptom onset. Thirty-one patients had T2 hyperintensity on spinal MRI, and 18 patients had cerebrospinal fluid pleocytosis. The most common infectious agents were entero/rhinoviruses (n = 5) in respiratory specimens. All patients except one received immunotherapy either alone or in combination. Among 27 patients with follow-up data 24 had persistent weakness. Involvement of four limbs together with an abnormal brain MRI at onset were associated with a poor prognosis. CONCLUSION: The number of patients with acute flaccid myelitis increased since 2012, spiking with every 2-year interval, largely in the pediatric population. The median age decreases with every outbreak. Clinicians should be aware of the clinical picture for early collection of specimens and early start of rehabilitation programs. Further studies are needed to better characterize the etiology, pathogenesis, risk factors, and treatment of this rare condition.

Monogenic lupus due to spondyloenchondrodysplasia with spastic paraparesis and intracranial calcification: case-based review.

Spondyloenchondrodysplasia (SPENCD) is a rare skeletal dysplasia characterized with platyspondyly and metaphyseal lesions of the long bones mimicking enchondromatosis, resulting in short stature. SPENCD often coexists with neurologic disorders and immune dysregulation. Spasticity, developmental delay and intracranial calcification are main neurologic abnormalities. Large spectrum of immunologic abnormalities may be seen in SPENCD, including immune deficiencies and autoimmune disorders with autoimmune thrombocytopenia and systemic lupus erythematosus as the most common phenotypes. SPENCD is caused by loss of tartrate-resistant acid phosphatase (TRAP) activity, due to homozygous mutations in ACP5, playing a role in non-nucleic acid-related stimulation/regulation of the type I interferon pathway. We present two siblings, 13-year-old girl and 25-year-old boy with SPENCD, from consanguineous parents. Both patients had short stature, platyspondyly, metaphyseal changes, spastic paraparesis, mild intellectual disability, and juvenile-onset SLE. The age at disease-onset was 2 years for girl and 19 years for boy. Both had skin and mucosa involvement. The age at diagnosis of SLE was 4 years for girl, and 19 years for boy. The clinical diagnosis of SPENCD was confirmed by sequencing of ACP5 gene, which revealed a homozygous c.155A > C (p.K52T), a variant reported before as pathogenic. Juvenile-onset SLE accounts for about 15-20% of all SLE cases. But, the onset of SLE before 5-years of age and also monogenic SLE are rare. Our case report and the literature review show the importance of multisystemic evaluation in the diagnosis of SPENCD and to remind the necessity of investigating the monogenic etiology in early-onset and familial SLE cases.

SUDEP: The First Case Series in Turkey.

INTRODUCTION: Sudden unexpected death in epilepsy (SUDEP) is defined as the sudden, unexpected, witnessed or unwitnessed, non-traumatic, and non-drowning death of patients with epilepsy with or without evidence of a seizure, excluding documented status epilepticus, and in whom postmortem examinations do not reveal a toxicological or anatomic cause for death. In this study, data on patients who passed away under observation in the epilepsy clinic due to sudden, unexpected death have been compiled, and we also aim to emphasize the importance of SUDEP in Turkey. METHODS: This study was performed with a total of nine cases. Data were obtained from hospital records, information given by the families of patients, the database of the General Directorate for Civil Services of the Ministry of Internal Affairs of Turkey, and from the Ankara Metropolitan Municipality Cemetery Information System. As the basis of classification and definition, the proposals suggested by Nashef et al., which were made to the International League Against Epilepsy (ILAE) in 2011, were taken into consideration. RESULTS: Eight of the patients were classified as probable SUDEP and one of them as possible SUDEP; the mean age at SUDEP was 33 years, and the average follow-up period was 19.7 years. In these cases, except for known risk factors (generalized tonic-clonic seizures, nocturnal seizures, severe epilepsy, more frequent seizures, younger age at the onset of epilepsy, unwitnessed seizures, polytherapy, and mental handicap), a different risk factor was not identified. CONCLUSION: This study is the first case series on SUDEP in Turkey. Postmortem studies are the most important shortcoming of the study. However, the importance of the topic is highlighted by presenting the available data. SUDEP deserves more attention during the daily practice of neurologists, pediatric neurologists, forensic physicians, and family physicians. If death is sudden and unexpected in a patient with epilepsy, SUDEP should be considered, regardless of the clear causes of death.

Nitric oxide synthase gene polymorphisms in children with primary nocturnal enuresis: a preliminary study.

AIMS: Recent studies demonstrated some differences in urinary electrolytes of enuretic children. Intrarenal nitric oxide (NO) serves as a major regulator of renal sodium and water excretion like an endogenous diuretic. This study aimed to investigate endothelial (eNOS), and neuronal (nNOS) NO synthase gene polymorphisms in children with primary nocturnal enuresis (PNE). MATERIALS AND METHODS: The eNOS gene polymorphism was investigated in 171 Turkish children (57 PNE cases and 114 healthy, non-enuretic controls), and nNOS gene polymorphism was determined in 158 Turkish children (83 PNE cases and 75 healthy, non-enuretic controls). The glu298asp (G/T) polymorphism of the eNOS and C276T (C/T) polymorphism of nNOS genes were genotyped using PCR. RESULTS: The distribution of GG, TG, and TT genotypes for eNOS gene was 48%, 33%, and 19% in PNE, compared with 61%, 26%, and 13% in the controls (p > 0.05). The distribution of CC, TC, TT and genotypes for nNOS gene was 31%, 29%, and 40% in PNE compared with 10%, 43%, and 47% in the controls. CC genotype was found higher in enuretic children (p = 0.002). The eNOS and nNOS gene polymorphisms were not associated with positive family history, frequency of enuresis, and clinical response to desmopressin. CONCLUSIONS: This study is the first to search the NOS gene polymorphisms in children with PNE. It was determined that eNOS gene polymorphism may not be associated with PNE, while nNOS gene polymorphism, a predominantly CC genotype, may be associated with PNE in Turkish children. Further studies with larger samples together with the detection of enuresis gene may help determine the exact role of nNOS gene polymorphism in enuresis.