Novel insights into PORCN mutations, associated phenotypes and pathophysiological aspects.

BACKGROUND: Goltz syndrome (GS) is a X-linked disorder defined by defects of mesodermal- and ectodermal-derived structures and caused by PORCN mutations. Features include striated skin-pigmentation, ocular and skeletal malformations and supernumerary or hypoplastic nipples. Generally, GS is associated with in utero lethality in males and most of the reported male patients show mosaicism (only three non-mosaic surviving males have been described so far). Also, precise descriptions of neurological deficits in GS are rare and less severe phenotypes might not only be caused by mosaicism but also by less pathogenic mutations suggesting the need of a molecular genetics and functional work-up of these rare variants. RESULTS: We report two cases: one girl suffering from typical skin and skeletal abnormalities, developmental delay, microcephaly, thin corpus callosum, periventricular gliosis and drug-resistant epilepsy caused by a PORCN nonsense-mutation (c.283C > T, p.Arg95Ter). Presence of these combined neurological features indicates that CNS-vulnerability might be a guiding symptom in the diagnosis of GS patients. The other patient is a boy with a supernumerary nipple and skeletal anomalies but also, developmental delay, microcephaly, cerebral atrophy with delayed myelination and drug-resistant epilepsy as predominant features. Skin abnormalities were not observed. Genotyping revealed a novel PORCN missense-mutation (c.847G > C, p.Asp283His) absent in the Genome Aggregation Database (gnomAD) but also identified in his asymptomatic mother. Given that non-random X-chromosome inactivation was excluded in the mother, fibroblasts of the index had been analyzed for PORCN protein-abundance and -distribution, vulnerability against additional ER-stress burden as well as for protein secretion revealing changes. CONCLUSIONS: Our combined findings may suggest incomplete penetrance for the p.Asp283His variant and provide novel insights into the molecular etiology of GS by adding impaired ER-function and altered protein secretion to the list of pathophysiological processes resulting in the clinical manifestation of GS

Novel insights into PORCN mutations, associated phenotypes and pathophysiological aspects.

BACKGROUND: Goltz syndrome (GS) is a X-linked disorder defined by defects of mesodermal- and ectodermal-derived structures and caused by PORCN mutations. Features include striated skin-pigmentation, ocular and skeletal malformations and supernumerary or hypoplastic nipples. Generally, GS is associated with in utero lethality in males and most of the reported male patients show mosaicism (only three non-mosaic surviving males have been described so far). Also, precise descriptions of neurological deficits in GS are rare and less severe phenotypes might not only be caused by mosaicism but also by less pathogenic mutations suggesting the need of a molecular genetics and functional work-up of these rare variants. RESULTS: We report two cases: one girl suffering from typical skin and skeletal abnormalities, developmental delay, microcephaly, thin corpus callosum, periventricular gliosis and drug-resistant epilepsy caused by a PORCN nonsense-mutation (c.283C > T, p.Arg95Ter). Presence of these combined neurological features indicates that CNS-vulnerability might be a guiding symptom in the diagnosis of GS patients. The other patient is a boy with a supernumerary nipple and skeletal anomalies but also, developmental delay, microcephaly, cerebral atrophy with delayed myelination and drug-resistant epilepsy as predominant features. Skin abnormalities were not observed. Genotyping revealed a novel PORCN missense-mutation (c.847G > C, p.Asp283His) absent in the Genome Aggregation Database (gnomAD) but also identified in his asymptomatic mother. Given that non-random X-chromosome inactivation was excluded in the mother, fibroblasts of the index had been analyzed for PORCN protein-abundance and -distribution, vulnerability against additional ER-stress burden as well as for protein secretion revealing changes. CONCLUSIONS: Our combined findings may suggest incomplete penetrance for the p.Asp283His variant and provide novel insights into the molecular etiology of GS by adding impaired ER-function and altered protein secretion to the list of pathophysiological processes resulting in the clinical manifestation of GS

Obesity prevalence and risk factors in 3-6 years old children living in central districts of the Metropolitan, İzmir

GİRİŞ VE AMAÇ: Vücutta sağlık için risk oluşturan anormal ve aşırı yağ birikimi olan aşırı kiloluluk ve obezite; 21. yüzyılın çocukluk çağında görülen en ciddi halk sağlığı sorunlarından biridir. Ergenlik öncesi aşırı kilolu olan çocukların % 40?ının ergenlik döneminde de kilo almaya devam ettiği ve bunların da % 75-85?inin obez yetişkinler haline geldikleri bilinmektedir. Bu çalışmanın amacı, İzmir İli Büyükşehir Merkez İlçelerinde üç-altı yaş çocuklardaki obezite sıklığını hesaplanmak ve obezite ile ilişkili risk faktörlerini araştırıp, ortaya koymaktır. YÖNTEM: Araştırma kesitsel tiptedir. Araştırmanın evreni İzmir Büyükşehir Belediyesi?ne bağlı merkez ilçelerden Balçova, Bornova, Buca, Çiğli, Gaziemir, Güzelbahçe, Karabağlar, Karşıyaka, Konak ve Narlıdere?de yaşayan üç-altı yaş arasındaki 130,714 çocuktur. Çalışmada toplam 413 hastaya ulaşılmıştır. Çalışmada, obezite ile ilşkili olabilcek kronik hastalık ve/veya ilaç kullanımı nedeniyle sekiz çocuk çalışma dışında bırakıldığından toplam 405 çocuğun verileri kullanıldı. Araştırmanın bağımlı değişkeni obezite varlığı, bağımsız değişkenleri ise sosyodemografik özellikler, doğum öncesi dönem ve büyümeye ait özellikler, beslenme alışkanlıkları, fiziksel aktivite alışkanlıkları, televizyon izleme, bilgisayar kullanımı, kreş ya da okula gitme durumu ve aile bireylerinin kilo durumu olarak belirlenmiştir. Çalışmaya katılan çocukların ailelerine anket uygulanıp, çocukların kilo ve boyları ölçülerek beden kitle indeksleri hesaplanmıştır. İstatistiksel çözümlemede ki-kare analizi ve lojistik regresyon kullanılmıştır. Aşırı kiloluluk ve obeziteye etkili faktörler için olasılıklar oranı hesaplanmıştır. BULGULAR: Ortalama yaşları 56,7±9,3 ay olan 405 çocukta, aşırı kiloluluk sıklığı %10,4 ve obezite sıklığı %13,1 saptanmıştır. Cinsiyet ile aşırı kiloluluk ve obezite arasında anlamlı bir ilişki bulunmamıştır (p=0,850). Aşırı kiloluluk ve obezite ile çocuğun doğum ağırlığı (p=0,045), bir yaşındaki kilosu (p=0,000), öğünlerinin düzenli olması (p=0,019), anaokulu/ilkokula gidiyor olması (p=0,016), babasının aşırı kilolu ya da obez olması (p=0,000) ve ailenin sağlık güvencesinin olmaması (p=0,031) arasında anlamlı ilişki saptanmıştır. Bu faktörler lojistik regresyon ile tekrar analiz edildiğinde anlamlı ilişkili değişkenlerin; çocuğun bir yaşındaki kilosu (OO=1,390 % 95 GA=1,139-1,698 p=001), anaokulu/ilkokula gidiyor olması (OO=3,585 % 95 GA=1,445-8,894 p=0,006), kardeşinin olmaması (OO=0,562 % 95 GA=0,350-0,903 p=0,017) ve ailenin sağlık güvencesinin olmaması (OO=4,423 % 95 GA=1,010-19,364 p=0,048) olduğu saptanmıştır. SONUÇ VE ÖNERİLER: İzmir İli Büyükşehir Merkez İlçelerinde üç-altı yaş çocuklardaki aşırı kiloluluk ve obezite sıklığının araştırıldığı bu çalışma sonuçlarına göre; aşırı kiloluluk ve obezitenin gelişmiş ülkelere benzer oranda yüksek olduğu, bir yaşındaki kilonun, anaokulu/ilkokula gidiyor olmanın, kardeş sayısının az olmasının ve ailenin sağlık güvencesinin olmamasının aşırı kiloluluk ve obeziteyi artırdığı saptanmıştır. Bu çalışmanın sonuçları, anne-babalara, çocuklara ve çocukların bakımı ile eğitimlerini sağlayan kurumlara sağlıklı ve dengeli beslenme konusunda eğitim verilmesinin gerektiğini düşündürmektedir SUMMARY INTRODUCTION: Overweight and obesity, defined as abnormal or excessive fat accumulation that presents a risk to health, create one of the most serious public health challenges of the 21st century. 40 % of children, defined as overweight, continue gaining weight during adolescence and 77-85 % of them become obese adults. The aim of this study is evaluating the obesity prevalence and risk factors in three-six years old children living in central districts of the metropolitan, İzmir. MATERIAL AND METHOD: 130,714 children living in the central districts of our city (Balçova, Bornova, Buca, Çiğli, Gaziemir, Güzelbahçe, Karabağlar, Karşıyaka, Konak and Narlıdere) were included in this cross-sectional study. A total of 413 children were reached. Eight of them were excluded because of chronic diseases and/or medication related with obesity, thus data from 405 children were assessed. The dependant variable was presence of overweight and obesity, where as independent ones were sociodemographic status, perinatal and growth factors, dietary behaviors, screen time, attendance to a daycare or school and familial overweight and obesity. A questionnaire was completed with families. Weight and lenght of the children were measured, then BMI values were calculated. Statistical analyses were performed using chi-square test and logistic regression model. OR were calculated for factors that cause risk for overweight and obesity. RESULTS: In our study group, whose mean age was 56,7±9,3 months, prevalence of overweight and obesity were % 10,4 and % 13,1, respectively. Gender was not significantly related with overweight and obesity (p=0,850). Birth weight (p=0,045), weight at one year of age (p=0,000), regular meal consumption (p=0,019), attendance to a school (p=0,016), paternal BMI values (p=0,000) and absence of familial health insurance (p=0,031) were significantly related with childhood overweight and obesity. When logistic regression model was performed, weight at one year of age (OO=1,390 % 95 GA=1,139-1,698 p=001), attendance to a school (OO=3,585 % 95 GA=1,445-8,894 p=0,006), absence of siblings (OO=0,562 % 95 GA=0,350-0,903 p=0,017) and absence of familial health insurance (OO=4,423 % 95 GA=1,010-19,364 p=0,048) were documented as risk factors. CONCLUSION AND RECOMMENDATIONS: Prevalence of overweight and obesity in our study group showed similarity with values obtained in developed countries. Weight at one year of age, attendance to a school, having no siblings and absence of familial health insurance were demonstrated as risk factors. We conclude that educational programs about healthy and balanced nutrition are necessary for parents, children and staff working at daycare centers and school

Spinal muscular atrophy with predominant lower extremity (SMA-LED) with no signs other than pure motor symptoms at the intersection of multiple overlap syndrome

Background: Mutations in the cytoplasmic dynein 1 heavy chain gene (DYNC1H1) have been associated with spinal muscular atrophy with predominant lower extremity involvement (SMA-LED), Charcot-Marie-Tooth 2O (CMT2O) disease, cortical migration anomalies, and autosomal dominant mental retardation13. SMA-LED phenotype-related mutation was found in the DYNC1H1 gene in the patient who applied with the complaint of gait disturbance. Methods: Pathogenic heterozygous c.1678G > A (p.Val560Met) mutation was detected in the DYNC1H1 gene by next-generation targeted gene analysis in the patient who had no phenotypic findings except delayed motor milestones, lumbar lordosis, and lower extremity muscle weakness. The patient's creatinine phosphokinase enzyme level and brain magnetic resonance imaging (MRI) were normal. Electromyography (EMG) had pure motor findings. Conclusion: It should be kept in mind that DYNC1H1 mutation, which we are accustomed to seeing with accompanying findings such as orthopedic and ocular dysmorphic findings, sensorineural EMG findings, and intellectual disability, can also observe with pure motor findings such as muscular dystrophy examination findings. © 2021 The Japanese Society of Child Neurolog

Clinical and Electrophysiological Prognostic Factors of Childhood Absence Epilepsy

Aim: Childhood absence epilepsy is common idiopathic epilepsy in childhood. This epilepsy, which has been shown to impair cognition, needs to be treated promptly and correctly. Therefore, determining its prognostic factors before treatment can provide prediction on the duration of treatment, drug selection, and drug dosage. Materials and Methods: The electroencephalography (EEG) and clinical findings of patients diagnosed with childhood absence epilepsy who were monitored for at least 12 months in the pediatric neurology clinics of two university hospitals between 2016 and 2020 were reviewed retrospectively. The patients were divided into two groups as responsive and unresponsive, according to seizures, EEG findings, and recurrent seizures after treatment. The epidemiological and clinical features of the two groups were compared. Results: Sixty-three patients who were diagnosed with childhood absence epilepsy according to the Panayiotopoulos criteria participated in this study. Thirty-nine (62%) of the patients were responsive to treatment (group 1), the remaining 24 patients (38%) (group 2) were unresponsive to treatment. Fifteen patients were valproate resistant, and nine patients relapsed after drug treatment withdrawal in group 2. The mean age of the patients was 7.87 +/- 1.68. The mean follow-up period was 29.1 +/- 13.6 (13-72 months) months. The mean age was lower in the responsive group of patients. The time between the onset of seizures and treatment was significantly longer in group 2. The number of patients with occipital intermittent rhythmic delta activity (OIRDA) in the responsive group was higher. A significant difference was found in the number of spike-slow wave complex and the amplitude of discharges between the two groups. Conclusion: In this study, it was seen that young age was an advantage for treatment response. Early initiation of treatment and OIRDA were good prognostic factors, while high amplitude and numerous discharges were among the poor prognostic factors

Recurrent painful ophthalmoplegic neuropathy: a report of two new pediatric cases

Background. Recurrent painful ophthalmologic neuropathy (RPON), formerly known as ophthalmoplegicmigraine, is characterized by repeated attacks of one or more ocular cranial nerve palsies with an ipsilateralheadache. While steroid therapy has been reported to be beneficial for attacks, no clear consensus on prophylactictreatments exists. We present two cases emphasizing the diagnostic significance of the loss of enhancementduring the symptom-free period and valproate as a beneficial option in prophylaxis.Case 1. A 4-year-old girl presented with a one-week right frontal headache, vomiting and photophobia.Neurological examination revealed ptosis, oculomotor nerve paresis, and delay in light reflex in the right eye.Brain magnetic resonance imaging (MRI) revealed a 5.5 mm nodular enhancement in the cisternal part of the3rd cranial nerve in the right premesencephalic area. The enhancement regressed after a 6-month symptom-freeperiod. While propranolol, topiramate and flunarizine were inefficacious in prophylaxis, the patient respondedto valproate prophylaxis and benefited from the administration of steroids for one week during the attacks.Case 2. A 7-year-old girl presented with a ten-day right-sided, throbbing headache in the frontal region, oneday eye deviation and double vision. Neurological examination revealed inward gaze restriction and ptosis inthe ipsilateral eye to the headache. Brain MRI revealed a 4.5 mm, enhancing, nodular lesion in the 3rd cranialnerve lodge in the right perimesencephalic area. Her symptoms regressed in one week with dexamethasoneand she received prophylactic propranolol. Neuroimaging findings disappeared after a 3-month symptom-freeperiod. After valproate was added because of a relapse, she did not experience any further attacks.Conclusions. RPON is an uncommon disease in childhood with unknown etiology. On brain MRI with contrastduring the symptom-free period, regression of the enhancement or complete resolution of the lesion are guidingfeatures in the diagnosis. Valproate may have beneficial effects on RPON treatment.</p

A rare cause of hypercalcemia in childhood; parathyroid adenoma: Case report and review of the literature

Primer hiperparatiroidi çocuklarda çok nadir olarak görülen ve genellikle erişkin dönemde tanı konan bir hastalıktır. Paratiroid bezlerin bir veya daha fazlasında parathormon sentezinde artış sonucu ortaya çıkar. Çocuklarda görülme sıklığı 2-5/100,000 iken erişkinde bu oran 1/1000’dir. Tanı anında primer hiperparatiroidili çocukların %73-94’ünde hiperkalsemi ile ilgili semptomlar gözlenmektedir. Çocukluk çağında gerek semptomların özgül olmaması, gerekse de hastalığın erken dönemlerinde hiperkalseminin epizodik olması bu hastalarda nefrokalsinozis, nefrolitiyazis, akut pankreatit ve kemik tutulumu gibi hedef organ hasarının daha sık gözlenmesine neden olmaktadır. Tüm bu nedenlerden ötürü hastalığın erken tanınması ve etkin olarak tedavi edilmesi hedef organ hasarının engellenmesi açısından oldukça önemlidir. Bu olgu sunumunda hiperkalsemi ile ilişkili semtomları olmayan, rastlantısal olarak serum kalsiyum ve parathormon düzeyi yüksek saptanan ve hedef organ hasarı gelişmemiş paratiroid adenomlu 11 yaşında bir erkek olgu -nadir görülmesi nedeni ile- literatür bilgisi eşliğinde sunulmuştur.Hyperparathyroidism is very rare in children (incidence of 2-5 in 100 000) and occurs predominantly in adults (incidence of 1 in 1000). It is caused by increased synthesis of parathormone (PTH) by one or more pathologically effected parathyroid glands. HPT symptoms are usually non-specific and hypercalcemia may only be episodic in early period and these characteristics are the causes of late recognition and diagnosis of pediatric HPT which can culminate with endorgan damage. At the time of the diagnose 73-94% of PHPT cases in young patients are recognised as a symptomatic, and end-organ involvement, such as nephrocalcinosis, nephrolithiasis, acute pancreatitis, or bone involvement is not rare which is highly related to the prognosis. Therefore, early recognition and evaluation of symptoms would give a chance to prevent negative outcomes. In this case report we describe an incidentally diagnosed parathyroid adenoma in 11 year old asymptomatic male patient with no end-organ involvement

Pediatrik Guillain Barre Sendromu: Klinik, Elektrofizyolojik ve Prognostik Özellikler

Amaç: Bu çalışmada Guillain Barre Sendromu tanısı ile izlenen hastaların klinik, elektrofizyolojik, laboratuvar ve radyolojik bulgularının ve izlem sonuçlarının araştırılması amaçlanmıştır. Gereç ve Yöntem: 2011-2019 yılları arasında kliniğimizde Guillain Barre Sendromu tanısı almış ve en az bir yıl süre ile izlenmiş 29 hasta değerlendirildi. Hastaların demografik, klinik, laboratuvar, radyolojik ve elektrofizyolojik bulguları, tedavi ve izlem sonuçları retrospektif olarak incelendi. Hastaların fonksiyonel değerlendirmesinde Hughes skalası kullanıldı. Bulgular: Hastaların 18’i erkekti (erkek/kadın oranı: 1,64). Yaş aralığı 1,4-16,4 (ortanca 9,1) yıldı. Hastaların 21’inde (%72,4) enfeksiyon öyküsü vardı. Başvuru sırasında 26 hastanın (%89,7) derin tendon refleksleri alınamıyor veya azalmıştı. Elektrofizyolojik özelliklerine göre sekiz hasta demiyelinizan, on bir hasta akut motor aksonal, dört hasta akut sensorimotor aksonal, altı hasta Miller Fisher sendromu idi. Tüm hastalar intravenöz immünglobulin tedavisi almış, bir hastada ek olarak plazmaferez uygulanmıştı. İzlemde sekiz hastada sekelli iyileşme görülmüş, iki hastada ise hastalık tekrarlamıştı. Sonuç: Gelişmekte olan ülkelerde daha sık olarak bildirilen aksonal formlar bizim hasta grubumuzda da daha fazlaydı. Derin tendon reflekslerinin normal ya da artmış olarak bulunmasının akut flask güçsüzlük ile gelen hastalarda Guillain Barre Sendromu tanısının dışlanması için yeterli olmadığı, özellikle aksonal formların düşünülebileceği kanısına varılmıştır. Çocuklarda fonksiyonel iyileşme sık olsa da uzun dönemde kronik şikâyetlerin devam edebileceği ve rekürrensler olabileceği bilinmeli, hastalar dikkatle izlenmeye devam edilmelidir.</p

The Effect of Nusinersen Therapy on Laboratory Parameters of Patients with Spinal Muscular Atrophy

Introduction We evaluated the effect of nusinersen on clinical and laboratory parameters and presented its safety and effect on laboratory parameters. Methods Two groups were formed from among patients with spinal muscular atrophy (SMA) followed up between September 2017 and June 2021: group 1, SMA type 1; group 2, SMA type 2 and 3. The laboratory parameters were evaluated in groups 1 and 2 between doses. Motor scale tests were performed on patients before each dose of nusinersen. Results Twenty seven patients (group 1; n = 13, group 2; n = 14) were included. The mean age (+/- standard deviation) at the onset of symptoms was 3 +/- 1.21 (range, 1.5-6) months in group 1 and 12 +/- 4.27 ( range, 8-24) months in group 2. No significant laboratory treatment-related abnormalities and adverse effects were observed. The cerebrospinal fluid protein levels and the frequency of conventional LP were higher in group 1. Serum creatinine (Cr) levels were higher in group 1 before the first dose and higher in group 2 before the fifth dose (p < 0.05). With treatment, the Cr levels of group 1 decreased and group 2 remained constant or increased. We observed that the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders and Hammersmith Functional Motor Scale-Expand scores increased as our patients received treatment (p < 0.05). Conclusion Our results support the safety and efficacy of nusinersen. However, changes in Cr levels according to the clinical type and treatment suggested that serum Cr could be a candidate marker for treatment follow-up