Late effects of medulloblastoma treatment: multidisciplinary approach of survivors.

PURPOSE: Medulloblastoma is one of the brain tumors with increased life expectancy due to improvements in treatment approaches. Besides the promising results, various undesirable effects can be encountered. This study's aim is to review long-term follow-up outcomes of our cases with medulloblastoma. METHODS: Age at diagnosis, histological type of medulloblastoma, resection extension, chemotherapy and radiotherapy schemes, follow-up duration, and endocrinological, neuropsychiatric, cardiological, auditory, and visual examination results were evaluated in 20 patients diagnosed between 2007 and 2018 and followed 5 years and more. RESULTS: Twenty of 53 patients were included to the study. Eleven (55%) were male. Mean age at diagnosis was 6.95 years; mean age at the time of the study was 14 years. Mean follow-up time was 8.95 years. In terms of surgery, 14 (70%) were gross total, 1 (5%) was near total, and 2 (10%) were subtotal resection. In histopathological examination, 14 (70%) were classical medulloblastoma, 4 (20%) were desmoplastic medulloblastoma, and 1 (5%) was anaplastic medulloblastoma. With regard to endocrinological evaluation, 15 (75%) patients had hypothyroidism, 5 (25%) had growth hormone deficiency, 7 (35%) had clinical growth hormone deficiency, and 5 (25%) had sex hormone disorders. In neuropsychiatric examination, 11 (55%) patients had neurological sequelae, 18 (90%) patients had psychiatric issues, and 14 (70%) patients had two or more neuropsychiatric problems simultaneously. One (5%) patient had mitral valve insufficiency. Twelve patients (60%) had hearing loss. According to visual examination, 6 (30%) patients had refraction problem, 4 (20%) had cataract, and 1 (5%) had dry eye. CONCLUSION: Careful monitoring of long-term side effects is important for improving the quality of life of medulloblastoma patients. Besides endocrinological and other somatic sequelae of the disease and treatment, increased neuropsychiatric problems showed us that only cure is not the issue while treating childhood medulloblastoma.

Assessment of biochemical bone markers of osteoporosis in children with thalassemia major.

BACKGROUND: Beta thalassemia major (ß-TM) is a common cause of skeletal morbidity and is associated with increased bone fracture risk, particularly in inadequately transfused children. The aim of this study was to investigate some potential biochemical markers as possible early predictors of BMD variations in children with ß-TM. METHODS: The study included 38 children with ß-TM and 40 sex-age matched controls. All patients were subjected to BMD assessment by dual-energy X-ray absorptiometry (DEXA). Serum beta-crosslaps (beta-CTx), osteoprotegerin (OPG), receptor activator of nuclear factor-kappa B ligand (RANKL), urinary deoxypyridinoline (DPD) and ferritin levels were compared between the groups. RESULTS: Serum OPG levels were significantly lower in thalassemic children than in controls. The mean ratio of RANKL/OPG was significantly higher in the thalassemic patients than in the control group. Osteoporosis was detected in 10 (3 female and 7 male) of 38 patients (26.3%) according to the femur Z score and in 6 of them (4 male and 2 female) (15.8%) according to the spine Z score. CONCLUSIONS: Serum OPG concentrations can be used as a biochemical marker in screening patients with beta-thalassemia major for the development of osteoporosis.

First pediatric case with primary familial brain calcification due to a novel variant on the MYORG gene and review of the literature.

Variants in the myogenesis-regulating glycosidase (MYORG) gene which is known as the first autosomal recessive gene that has been associated with primary familial brain calcification (AR-PFBC). Although adult patients have been reported, no pediatric case has been reported until now. Herein, we review the clinical and radiological features of all AR- PFBC patients with biallelic variants in the MYORG gene who were reported until now, and we report the youngest patient who has a novel homozygous variant. Since the first identification of the MYORG gene in 2018, 74cases of MYORG variants related to AR-PFBC were evaluated. The ages of symptom onset of the patients ranged between 7.5 and 87 years. The most frequent clinical courses were speech impairment, movement disorder and cerebellar signs. All patients showed basal ganglia calcification usually bilaterally with different severities. Conclusion; herein, we reported the first pediatric patient in the literature who had a novel homozygous variant in the MYORG gene with mild clinic findings.

Novel Mutations in Obesity-related Genes in Turkish Children with Non-syndromic Early Onset Severe Obesity: A Multicentre Study

Objective: Non syndromic monogenic obesity is a rare cause of early onset severe obesity in the childhood period. This form may not be distinguishable from other forms of severe obesity without genetic analysis, particularly if patients do not exibit any physical abnormalities or developmental delay. The aim of this study was to screen 41 different obesity-related genes in children with non-syndromic early onset severe obesity. Methods: Children with severe (body mass index-standard deviation score >3) and early onset (<7 years) obesity were screened by next-generation sequencing based, targeted DNA custom panel for 41 known-obesity-related genes and the results were confirmed by Sanger technique. Results: Six novel variants were identified in five candidate genes in seven out of 105 children with severe obesity; two in SIM1 (p.W306C and p.Q36X), one in POMC (p.Y160H), one in PCSK1 (p.W130G fs Ter8), two in MC4R (p.D126E) and one in LEPR (p.Q4H). Additionally, two previously known variations in MC4R were identified in four patients (p.R165W in three, and p.V166I in one). Conclusion: We identified six novel and four previously described variants in six obesity-related genes in 11 out of 105 childrens with early onset severe obesity. The prevalence of monogenic obesity was 10.4% in our cohort.

The Effects of Six-Month L-Thyroxine Treatment on Cognitive Functions and Event-Related Brain Potentials in Children with Subclinical Hypothyroidism.

OBJECTIVE: The aim of this study was to investigate the cognitive status of children with subclinical hypothyroidism (SH) before and after L-thyroxine (L-T4) treatment using event-related potentials (ERPs) and neuropsychological tests. METHODS: This prospective study was conducted on a series of 20 children with mild SH (free T4 normal and thyroid-stimulating hormone level within 5-10 µIU/L) who underwent clinical and cognitive assessment before L-T4 treatment and 6 months afterwards. The recordings of ERPs were done at the time of diagnosis and after 6 months of euthyroid state. Neuropsychiatric tests for attention, perception, close and remote memory were performed on all patients and on the control group which consisted of 20 healthy children of normal intelligence. RESULTS: While pretreatment verbal memory (VM) and verbal recall (VR) scores of the SH group were significantly lower than those of the control group (p=0.004 and 0.012, respectively), no significant differences between the post-treatment and control groups were found in these scores after 6 months of L-T4 treatment. Post-treatment VM and VR scores were significantly higher than the pretreatment scores in the SH group (p=0.008 and p=0.0001). There were no significant differences between the pre-and post-treatment values of electrophysiological evaluation in N1, P2, P3 latencies or P3 amplitude (p>0.05), although there was a significant decrease in N2 latency in the post-treatment group (p=0.03). CONCLUSION: SH affects cognition in children and L-T4 replacement therapy leads to normalization of cognitive functions. Neuropsychological tests can be used as complementary measures in the evaluation of children with SH. Determining the association between ERPs and SH would contribute to the comprehensive evaluation of these children.

The Effects of Electromagnetic Field on the Endocrine System in Children and Adolescents.

Children are exposed to various kind of non-ionizan radiation in their daily life involuntarily. The potential sensitivity of developing organism to the effects of radiofrequency (RF) signals, the higher estimated specific absorption rate (SAR) values of children and greater lifetime cumulative risk raised the scientific interest for children's vulnerability to electromagnetic fields (EMFs). In modern societies, children are being exposed to EMFs in very early ages. There are many researches in scientific literature investigating the alterations of biological parameters in living organisms after EMFs. Although the international guidelines did not report definite, convincing data about the causality, there are unignorable amount of studies indicating the increased risk of cancer, hematologic effects and cognitive impairment. Although they are less in amount; growing number of studies reveal the impacts on metabolism and endocrine function. Reproductive system and growth look like the most challenging fields. However there are also some concerns on detrimental effects of EMFs on thyroid functions, adrenal hormones, glucose homeostasis and melatonin levels. It is not easy to conduct a study investigating the effects of EMFs on a fetus or child due to ethical issues. Hence, the studies are usually performed on virtual models or animals. Although the results are conflicting and cannot be totally matched with humans; there is growing evidence to distress us about the threats of EMF on children.

The effects of long-term exposure to a 2450 MHz electromagnetic field on growth and pubertal development in female Wistar rats.

The aim of this study was to investigate the effects of a 2450 MHz electromagnetic field (EMF) (wireless internet frequency) on the growth and development of female Wistar rats. The study was conducted on three groups of rats. The prenatal and postnatal groups were exposed to EMF 1 h/day beginning from intrauterine and postnatal periods, respectively. The third group was the sham-exposed group. Growth, nutrition and vaginal opening (VO) were regularly monitored. Serum and tissue specimens were collected at puberty. Histological examinations, total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI) measurements in ovary and brain tissues and also immunohistochemical staining of the hypothalamus were performed besides the determination of serum FSH, LH, E2 and IGF-1 values. Birth masses of the groups were similar (p > 0.05). Mass gain per day was significantly lower and the puberty was significantly later in the prenatal group. Brain and ovary TOS and OSI values in the prenatal group were significantly increased (p < 0.05) compared to the control group. Serum LH levels of the prenatal and postnatal groups were increased, although serum FSH, and E2 values did not differ among the groups (p > 0.05). Histological examinations of the specimens revealed no statistically significant difference between the groups (p > 0.05). Exposure to 2450 MHz EMF, particularly in the prenatal period, resulted in postnatal growth restriction and delayed puberty in female Wistar rats. Increased TOS and OSI values in the brain and ovary tissues can be interpreted as a sign of chronic stress induced by EMF. This is the first longitudinal study which investigates the effects of EMF induced by wireless internet on pubertal development beside growth.

Iodine, copper, zinc, selenium and molybdenum levels in children aged between 6 and 12 years in the rural area with iodine deficiency and in the city center without iodine deficiency in Hatay.

AIM: Thyroid diseases related with iodine deficiency are observed commonly in our country and in the world. In this study, we aimed to investigate iodine deficiency in urine and selenium, zinc, copper or molybdenum deficiency which may accompany this in children aged between 6 and 12 years in two schools in the province of Hatay (endemic goitre region). MATERIAL AND METHODS: This study is a case-control field-study in which students aged between 6 and 12 years were included. One hundred fourteen subjects from the village of Tanisma related to the center of our province and 100 subjects from the city center of Hatay (Antakya) were included in the study. Iodine, selenium, zinc, copper and molybdenum levels were measured in the urine samples of the students included in the study. RESULTS: Iodine deficiency was found with a severe (5%), moderate (18.4%) and mild degree (43%), respectively in the village of Tanisma. Mild iodine deficiency (7%) was found in the center of Hatay. No moderate and severe iodine deficiency was found in the control group. A significant difference was found between the groups in terms of urine iodine excretion (p<0.001). A significant correlation was found between the levels of iodine, selenium, zinc and molybdenum (p<0.05). A moderately positive correlation was found between iodine and selenium (p<0.001). A moderately positive correlation was found between iodine and zinc levels (p<0.001) and a weak correlation was found between iodine and molybdenum (p<0.01). No significant correlation was found between iodine level and copper level (p>0.05). CONCLUSIONS: Selenium and zinc deficiency may accompany iodine deficiency. Selenium and zinc deficiency should be considered in individuals who are found to have iodine deficiency especially in endemic goitre regions.

Elevated leptin levels in nonobese girls with premature thelarche.

BACKGROUND AND AIM: It has been reported that leptin receptors have been also shown in mammary epithelial cells, and it has been suggested that leptin is involved in the control of the proliferation of both normal and malignant breast cells. The aim of this study was to measure the leptin levels in girls with early breast development and to determine if leptin levels were associated with the clinic, anthropometric characteristics and other sex steroids in girls with premature thelarche (PT). METHODS: In this cross-sectional study; we examined 26 girls (mean age, 7.1 ± 0.8 years; and mean body mass index standard deviation score [BMI-SDS], 0.45 ± 0.9) referred for evaluation because of the appearance of breast buds before the age of 8 years and judged clinically to have PT, as well as 21 healthy age-matched prepubertal girls who served as controls. Breasts and pubic hair development were assessed by visual inspection and palpation using the rating scales of Tanner. RESULTS: There were significant differences between the PT and control groups regarding leptin (2.7 ± 2.4 vs 1.1 ± 1.1 ng/mL; P: 0.007) and androstenedione (0.44 ± 0.2 vs 0.29 ± 1.1 ng/mL; P = 0.019) levels despite their similar age and BMI-SDS. Leptin measurements were positively correlated with BMI-SDS (r = 0.378; P = 0.03) and androstenedione (r = 0.438; P = 0.025) levels. CONCLUSIONS: Our study demonstrated that serum leptin levels were consistently higher in children with PT than in healthy children. Our findings also support an association between increased leptin levels in PT and adrenal androgens such as androstenedione. We suggest that the increased adrenal androstenedione, observed in our patients, may serve as a precursor for the peripheral conversion to estrogens by the stimulating effect of leptin on aromatase enzyme activity in breast tissues.

Primary hypogonadism in a case with XLAG syndrome.

Patients with X-linked lissencephaly with ambiguous genitalia (XLAG) syndrome present with lissencephaly, agenesis of the corpus callosum, refractory epilepsy of neonatal onset, microcephaly, and male genotype with ambiguous genitalia. The basis of the ambiguous genitalia in XLAG syndrome is not well-known. We report a case of the fourth child of healthy consanguineous parents who was presented to the hospital because of non-febrile seizures at 2 months of life. On physical examination, microcephaly, some dysmorphic face features, and ambiguous genitalia were determined. The cranial magnetic resonance imaging of the patient showed lissencephaly, agenesis of the corpus callosum, and enlarged ventricles. His karyotype was 46, XY. He had undetectable testosterone levels and elevated gonadotropins. Neither testicular tissue nor any testosterone response to human chorionic gonadotropin stimulation test was observed. These findings suggest that the hypogonadism in this patient with XLAG syndrome is primary hypogonadism due to gonadal agenesis or dysgenesis.

Prevalence of metabolic syndrome in obese children and adolescents using three different criteria and evaluation of risk factors.

OBJECTIVE: To compare the prevalence of the metabolic syndrome (MS) in Turkish obese children and adolescents by using three different definitions and to assess the risk factors through a retrospective evaluation of anthropometric and laboratory parameters. METHODS: Sixty hundred and fourteen obese patients (307 male, 307 female; mean age: 11.3±2.5 years) were included in the study. Medical history, physical examination, anthropometric measurements, results of biochemical and hormonal assays were obtained from the hospital records. MS was diagnosed according to the modified World Health Organization (WHO), Cook and the International Diabetes Federation (IDF) consensus criteria. RESULTS: The prevalence of MS was found to be 39%, 34% and 33% according to the modified WHO, Cook and the IDF consensus criteria, respectively. MS prevalence in patients aged 12-18 years was significantly higher than that in patients between 7 and 11 years of age (p<0.05). Pubertal patients had a significantly higher MS prevalence than the non-pubertal cases (p<0.05). MS prevalence was also significantly higher in children who had a family history of heart disease, diabetes, obesity and hypertension as well as in those who had not been breast-fed (p<0.05). CONCLUSION: The use of the modified WHO criteria was found to result in a slightly higher prevalence rate for MS as compared to the other criteria. The prevalence of MS in our study population was higher than that reported in most previous studies in Turkey. A positive family history, puberty and not being breastfed in infancy were shown to be significant risk factors for MS in childhood.

Severe hypercalcemia associated with Williams syndrome successfully treated with pamidronate infusion therapy.

Infantile hypercalcemia becomes manifest in 15% of patients with Williams syndrome (WS) and generally is not clinically severe. However, some patients with WS can have severe hypercalcemia and do not respond well to traditional therapies. Recently, pamidronate has been used in the treatment of childhood hypercalcemia associated with many disorders, but there is little experience with the treatment of hypercalcemia with bisphosphonates in patients with WS. We present a 17-month-old female patient, who had been diagnosed as WS by genetic analysis, admitted to our clinic for the investigation of severe hypercalcemia (4.02 mmol/L). Because the patient did not respond very well to fluid administration, furosemide infusion, and dietary calcium restriction, pamidronate infusion was performed and calcium levels returned to normal within 2 days. This case report is presented to point out that pamidronate therapy seems to be a safe and efficient way of treating life-threatening hypercalcemia in WS.

A homozygous recurring mutation in WISP3 causing progressive pseudorheumatoid arthropathy.

WISP3 is a member of the CCN (for CTGF, CYR61, and NOV) gene family, which encodes cysteine-rich secreted proteins with roles in cell growth and differentiation. Mutations in the WISP3 gene are associated with the autosomal recessive skeletal disorder, also known as progressive pseudorheumatoid arthropathy of childhood (PPAC). We diagnosed three siblings from a non-consanguineous family with PPAC. The patients were asymptomatic in early childhood. Signs and symptoms of disease that include progressive joint stiffness, swelling of the finger joints, and osteopenia, and slow linear growth developed between 2 and 8 years of age. PCR amplification and direct sequencing of the WISP3 gene revealed a homozygous mutation at nucleotide 156 of the WISP3 gene, resulting in a Cys52-to-ter substitution. This mutation has previously been reported in French, Italian, and Arab families. Interestingly, the C52X mutation was found to be associated with a c.248G-->A (G83E) variation, suggesting the existence of a founder effect. By contrast, the presence of the same aberration in three different ethnic groups could imply that this particular site is prone to mutation. Basal fasting concentrations of growth hormone, insulin-like growth factor-1, and insulin-like growth factor binding protein-3, as well as glucose and insulin levels revealed no aberrations. In conclusion, consideration of this rare disease that causes significant morbidity with short stature, osteopenia and arthritic complaints would prevent unnecessary examinations and treatment attempts. Testing for this specific mutation in suspected cases could provide a rapid and definitive diagnosis.

The prevalence and significance of incidental middle ear and mastoid cavity abnormalities on MRI in a pediatric population.

OBJECTIVE: The purposes of this study were to determine the prevalence of abnormalities in the middle ear and mastoid cavity on the magnetic resonance imaging (MRI) in children and correlate the results with clinical data, tympanometric findings and paranasal sinus changes. MATERIALS AND METHODS: A total of 85 consecutive pediatric patients for suspected non-inflammatory intracranial pathologies were prospectively examined. MRI was conducted for the suspected intracranial pathology. All patients were also examined by an otolaryngologist for otologic pathologies. A tympanometry examination was performed in patients prior to MRI scan. RESULTS: In 23 (27.1%) of 85 (39 males, 46 females) children, MRI demonstrated middle ear and/or mastoid cavity abnormalities. MRI abnormalities of the middle ear and/or mastoid cavity were correlated with clinical data and tympanometric findings. CONCLUSIONS: Incidental abnormal signal intensities in the middle ear and/or mastoid cavity are frequent in children, especially in first years of life. MRI will demonstrate incidental middle ear and mastoid cavity abnormalities seems to have clinical significance.

Prevalence of abdominal ultrasonographic abnormalities in patients with sickle cell disease.

PURPOSE: The aim of this study was to evaluate the type and prevalence of abdominal ultrasonographic abnormalities in patients with sickle cell disease. MATERIALS AND METHODS: A total of 102 patients with sickle cell disease at the Center of Hemoglobinopathy of the Antakya State Hospital were screened for intra-abdominal abnormalities by abdominal ultrasonography (US). Eightyfour patients were homozygous for sickle-cell disease (S/S), and 18 patients were compound heterozygotes for sickle cell-Beta thalassemia (S/Beta(thal)). At the time of examination, 15.7% (16/102) of patients had undergone splenectomy, and 18.6% (19/102) of patients had undergone cholecystectomy. RESULTS: The most frequent US findings (expressed as percentages of all patients) were hepatomegaly (71.6%), renal enlargement (30.4%), autosplenectomy (33.3%), cholelithiasis (30.4%) and splenomegaly (17.4%). A bright liver was identified in 6 patients (5.9%), an echogenic pancreas in 4 patients (3.9%), and pancreatic punctate echogenic foci were identified in 5 patients (4.9%). Medullary or diffusely increased renal echogenicity was observed in 16 patients (15.7%). Sonographic findings typical of renal papillary necrosis were observed in one patient with S/S. Periportal lymphadenopathy was detected in 10 (11.9%) of 84 patients of the S/S group, and 2 (11.1%) of 18 patients of S/Beta(thal) group. CONCLUSION: Abdominal ultrasonographic imaging of patients with sickle cell disease revealed a high prevalence of abdominal abnormalities, especially in solid organs.

Macrocephaly and bitemporal arachnoid cysts not associated with glutaric aciduria type I in a child.

A 45-month-old child who had bitemporal arachnoid cysts and macrocephaly unrelated to glutaric aciduria type 1 (GA 1) was reported. The patient was admitted to the emergency unit after head trauma at 11 months of age. CT and MRI showed bitemporal arachnoid cysts (BACs). Acylcarnitine profile was normal in serum using tandem mass spectrometry. Urine and blood screening tests were within normal range for metabolic disorders. There were no unusual organic acids in urine and blood samples. No additional clinical findings of metabolic disorders such as GA 1 developed during follow-up. The majority of children affected with GA 1 have macrocephaly and BACs on CT or MRI. These signs should alert neurosurgeons to the possibility of GA 1. Neurosurgeons evaluating patients with head trauma or suspected non-accidental head injury should include GA 1 in the differential diagnosis of BACs associated with macrocephaly, and an evaluation should be performed.

Dimensions of internal jugular veins in Turkish children aged between 0 and 6 years in resting state and during Valsalva maneuver.

OBJECTIVE: We aimed to establish the values of the internal jugular vein (IJV) sizes in Turkish children aged between 0 and 6 years. METHODS: Ninety-four normal children included in this study. All of the children were imaged by ultrasonography (USG) at the level of the cricoid cartilage. The maximal antero-posterior (AP) and transverse (T) diameters of the IJV were measured during regular breathing and Valsalva maneuver. RESULTS: The mean transverse diameter of the right and left IJV were 8.11+/-3.01 and 7.64+/-2.68 mm in resting state. These values changed to 12.57+/-4.34 and 10.82+/-3.80 mm in Valsalva state, respectively. The AP diameters were found to be 5.43+/-2.07 for the right and 5.86+/-4.53 mm for the left IJV at rest. During VM, these values changed to 8.70+/-2.40 and 8.30+/-2.90 mm for the right and left IJV, respectively. There was no significant difference on the evaluation of the relationship between the right and left diameters of the IJV. While there were significant differences in sizes between the resting and Valsalva states. Also, the T diameter of the right IJV during Valsalva state was greater than those of the left. There were significant correlations between the diameters of the IJV and the age, weight and height of the children. CONCLUSION: The results we obtained in this study may be important in an attempt of intravascular intervention to IJV. These values may also be important for the comparison with the IJV sizes of the patients who have phlebectasia.

Effects of valproic acid on hearing in epileptic patients.

OBJECTIVE: Since some case reports about the ototoxicity of valproic acid have been published, probable adverse effects of valproic acid on hearing in the epileptic patients became a subject of interest. We wanted to investigate if ototoxicity occurs in pediatric epileptic patients using VPA for long terms. METHODS: Twenty-one epileptic patients who have been using valproic acid at least for 6 months as monotherapy and 21 age-sex matched controls were included in the study. Audiometric tests were performed to all patients between the frequencies of 125 and 16,000 Hz. The effects of dosage, duration of therapy and serum levels of the VPA, on the audiometric results were investigated and the audiometric results were compared between the groups. RESULTS: There was no difference in hearing thresholds of the groups between 125 and 16,000 Hz frequencies. Relation could not be established between the duration of VPA therapy, dosage of the drug, blood level of drug, age and sex of the patients and the auditory signs. CONCLUSIONS: Although we could not find any deleterious effect of VPA on hearing thresholds in our patient series, we think it is useful to perform audiometric tests at intervals while VPA is being used for long periods, considering the presented case reports about sensorineural hearing loss.