Clinical, biochemical, and molecular insights into Cerebrotendinous Xanthomatosis: A nationwide study of 100 Turkish individuals.

OBJECTIVE: Cerebrotendinous xanthomatosis (CTX) is an inherited metabolic disorder characterized by progressive neurologic and extraneurologic findings. The aim of this retrospective, descriptive study was to explore the time of presentation and diagnosis, and to expand the phenotype and genotype of CTX, based on a nationwide and comprehensive series of patients in Turkey. METHODS: The demographic, clinical, biochemical and genotypic characteristics of the CTX patients were reviewed. Data on molecular analysis, age of onset and diagnosis, diagnostic delay, neurologic and extraneurologic symptomatology, results of plasma cholestanol levels, brain magnetic resonance imaging and electromyography at the time of diagnosis were reviewed. RESULTS: 100 confirmed CTX patients from 72 families were included. The mean age at diagnosis was 28.16 ± 14.28 years, and diagnostic delay was 18.39 ± 13.71 years. 36 patients were diagnosed in childhood. Frequency of intention tremor (p = 0.069), peripheral neuropathy (p = 0.234) and psychiatric manifestations (p = 0.396) did not differ between two groups, demonstrating the high rate in pediatric patients. Three adult patients showed a milder phenotype without neurologic involvement. Seven patients had normal plasma cholestanol levels despite neurological impairment. Sequencing of the CYP27A1 gene revealed 25 different variants, with a novel c.671_672del variant not previously described in literature. CONCLUSION: Based on the observations of this Turkish CTX cohort, it is emphasized that the true prevalence of CTX is probably underestimated and that it has a wide spectrum of clinical phenotypes even without neurological impairment. In children, abnormal cerebellar findings, peripheral neuropathy and psychiatric findings associated with intellectual disability have been suggested as warning signs to avoid diagnostic delay. In cases of clinical suspicion, molecular analysis is recommended despite normal plasma cholestanol levels, as severe neurologic involvement may occur in CTX patients without elevated cholestanol levels.

The Effect of Yoga on Early Clinical Outcomes and Pulmonary Functions in Patients Scheduled for Bariatric Surgery: a Randomized Controlled Study.

PURPOSE: The present research was undertaken to investigate the effect of yoga on pulmonary function and early clinical outcomes in patients scheduled for bariatric surgery. MATERIALS AND METHODS: This research with a randomized control group was performed on patients scheduled for bariatric surgery between October 2021 and June 2022 in the General Surgery Clinic of a University Hospital in Eastern Turkey. The sample consists of 100 randomized patients who received yoga breathing exercises and routine care. Pulmonary function test (PFT), posteroanterior chest X-rays (CXR), 6-min walk test, and oxygen saturation (SpO2) were applied as a pretest. The researcher practiced yoga for 40 min every day of the week. Post-test measurements were performed at the end of the yoga practice. Control group patients underwent the tests at the same intervals without any modifications to the standard clinical protocol. RESULTS: The difference between the control and experimental groups was significant in terms of post-test PFT measurements (p < 0.001). In the CXR of the patients, a statistically significant improvement was determined in 61.5% of the patients with yoga breathing practice (p < 0.001). Also, there was a significant increase in the 6-min walk test and SpO2 values in the experimental group (p < 0.05). CONCLUSION: Yoga practice positively affected the pulmonary function values of the patients.

Clinical and bi-genomic DNA findings of patients suspected to have mitochondrial diseases.

Background: Mitochondrial diseases are the most common group of inherited metabolic disorders, causing difficulties in definite diagnosis due to clinical and genetic heterogeneity. Clinical components are predominantly associated with pathogenic variants shown in nuclear or mitochondrial genomes that affect vital respiratory chain function. The development of high-throughput sequencing technologies has accelerated the elucidation of the genetic etiology of many genetic diseases that previously remained undiagnosed. Methods: Thirty affected patients from 24 unrelated families with clinical, radiological, biochemical, and histopathological evaluations considered for mitochondrial diseases were investigated. DNA isolated from the peripheral blood samples of probands was sequenced for nuclear exome and mitochondrial DNA (mtDNA) analyses. MtDNA sequencing was also performed from the muscle biopsy material in one patient. For segregation, Sanger sequencing is performed for pathogenic alterations in five other affected family members and healthy parents. Results: Exome sequencing revealed 14 different pathogenic variants in nine genes encoding mitochondrial function peptides (AARS2, EARS2, ECHS1, FBXL4, MICOS13, NDUFAF6, OXCT1, POLG, and TK2) in 12 patients from nine families and four variants in genes encoding important for muscle structure (CAPN3, DYSF, and TCAP) in six patients from four families. Three probands carried pathogenic mtDNA variations in two genes (MT-ATP6 and MT-TL1). Nine variants in five genes are reported for the first time with disease association: (AARS2: c.277C>T/p.(R93*), c.845C>G/p.(S282C); EARS2: c.319C>T/p.(R107C), c.1283delC/p.(P428Lfs*); ECHS1: c.161G>A/p.(R54His); c.202G>A/p.(E68Lys); NDUFAF6: c.479delA/p.(N162Ifs*27); and OXCT1: c.1370C>T/p.(T457I), c.1173-139G>T/p.(?). Conclusion: Bi-genomic DNA sequencing clarified genetic etiology in 67% (16/24) of the families. Diagnostic utility by mtDNA sequencing in 13% (3/24) and exome sequencing in 54% (13/24) of the families prioritized searching for nuclear genome pathologies for the first-tier test. Weakness and muscle wasting observed in 17% (4/24) of the families underlined that limb-girdle muscular dystrophy, similar to mitochondrial myopathy, is an essential point for differential diagnosis. The correct diagnosis is crucial for comprehensive genetic counseling of families. Also, it contributes to making treatment-helpful referrals, such as ensuring early access to medication for patients with mutations in the TK2 gene.

Primary coenzyme Q10 Deficiency-6 (COQ10D6): Two siblings with variable expressivity of the renal phenotype.

Primary coenzyme Q10 deficiency-6 (COQ10D6) is a rare autosomal recessive disorder caused by COQ6 mutations. The main clinical manifestations are infantile progressive nephrotic syndrome (NS) leading to end-stage renal disease and sensorineural deafness. A 7-year-old girl was diagnosed with steroid-resistant NS (SRNS) and an audiological work-up revealed bilateral sensorineural deafness. A renal biopsy demonstrated focal segmental glomerulosclerosis. Despite immunosuppressive therapy, her serum levels of creatinine increased and haemodialysis was indicated within 1 year after the diagnosis. Living-donor kidney transplantation was performed in the eighth month of haemodialysis. A diagnostic custom-designed panel-gene test including 30 genes for NS revealed homozygous c.1058C > A [rs397514479] in exon nine of COQ6. Her older brother, who had sensorineural hearing loss with no renal or neurological involvement, had the same mutation in homozygous form. COQ6 mutations should be considered not only in patients with SRNS with sensorineural hearing loss but also in patients with isolated sensorineural hearing loss with a family history of NS. The reported p.His174 variant of COQ8B was suggested to be a risk factor for secondary CoQ deficiency, while p.Arg174 appeared to improve the condition in a yeast model. Family segregation and the co-occurrence of biallelic p.Arg174 of COQ8B in a brother with hearing loss implied that the interaction of the altered COQ8B with the mutant COQ6 alleviated the symptoms in this family. CoQ10 replacement therapy should be initiated for these patients, as primary CoQ10 deficiency is considered the only known treatable mitochondrial disease.

Sedation for short hemato-oncologic invasive procedures in children: comparison of propofol-remifentanil and propofol-fentanyl.

INTRODUCTION: Short hemato-oncologic procedures are often painful in children, and sedation should be performed outside the operating room. AIM: : The study aims to compare the effects of remifentanil with those of fentanyl administered during short hemato-oncologic interventions in children. MATERIALS AND METHODS: A prospective, randomized study was planned for 29 ASA I to III children (aged, 2 to 18 y) to undergo a total of 60 short oncologic interventions. The patients were placed into 2 groups: propofol-remifentanil (group PR) and propofol-fentanyl (group PF). Group PR was first administered propofol (2 mg/kg) and then remifentanil bolus (0.5 µg/kg). Group PF was first administered propofol (2 mg/kg) and then fentanyl bolus (0.5 µg/kg). Systolic arterial pressure, diastolic arterial pressure, mean arterial pressure, respiratory rate, peripheral oxygen saturation, and heart rate were recorded every 3 minutes during the intervention and every 5 minutes after the operation. Postanesthetic recovery scores, eye-opening time to speech, and recovery time were recorded. RESULTS: Comparison of diastolic arterial pressure in groups at minute 3 of the procedure showed significant difference (P<0.05). Eye-opening to speech (P=0.043) and recovery times (P=0.002) were shorter in group PR. CONCLUSIONS: During short hemato-oncologic interventions in children, the PR combination is a suitable one for early recovery.

Evaluation of the effect of acetyl L-carnitine on experimental cisplatin ototoxicity and neurotoxicity.

INTRODUCTION: Cisplatin (CDDP) is an effective and widely used chemotherapeutic agent for pediatric tumors, and ototoxicity is one of the dose-limiting side effects. OBJECTIVE: It was the aim of our study to investigate the effect of acetyl L-carnitine (ALCAR) on experimental CDDP ototoxicity by audiologic tests, histomorphologic, immunohistochemical and ultrastructural examinations and to investigate the apoptotic pathways. MATERIALS AND METHODS: Wistar albino rats (n = 28) were studied. Baseline audiological tests were performed in 4 groups: group 1, control; group 2, ALCAR; group 3, CDDP; group 4, CDDP + ALCAR-administered rats. Control audiological tests were performed on the 3rd day, and then the rats were sacrificed. Ear and brain specimens were examined by transmission electron microscopy, and caspase 3, 8 and 9 activities were investigated. RESULTS: The CDDP-administered rats showed significant auditory brainstem response threshold shifts using all stimuli (clicks, 6-kHz and 8-kHz tone burst) compared with the control groups. The CDDP + ALCAR-administered rats showed significant auditory brainstem response threshold shifts by only click stimuli compared with the control groups. In the brain, spiral ganglion and organ of Corti, ultrastructural damage was prominent in group 3; the number of TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling)-positive cells and caspase 3, 8 and 9 immunostaining cells was significantly high in group 3. CONCLUSION: ALCAR improves CDDP-induced auditory impairment, and also antioxidative and antiapoptotic properties of ALCAR on CDDP ototoxicity were supported by the findings.

The time to diagnosis in childhood lymphomas and other solid tumors.

BACKGROUND: There are few reports from developing countries on the factors that influence the time to diagnosis (TD) in childhood cancer. The purpose of this study was to investigate the determinants of the TD in Turkish cancer patients. PROCEDURE: A retrospective analysis was performed on 329 children diagnosed with cancer, excluding leukemia. The TD, including parent/patient time and physician time, was defined as the interval between the onset of symptoms and the final diagnosis. RESULTS: The median times for parent/patient, physician, and TD were 3, 28, and 53 days, respectively. For patient in the 1-9 years age group, physician time and TD were significantly shorter than in infants and those over 10 years. The longest median TD was recorded for children with germ cell tumors and retinoblastoma; the shortest was in children with renal tumors. When the first point of contact was a pediatrician, a private hospital or physician's office, a governmental educational hospital or a university hospital physician time was short. The longest TD was noted in patients who first contacted a non-pediatric specialist. The most significant predictors of parent/patient, physician time, and TD were metastases at diagnosis, first medical center, and first health professional contacted, respectively. CONCLUSIONS: The TD for childhood lymphomas and solid tumors was related to patient age, tumor type and location, the presence of distance metastases, first health professional, and center contacted. All physicians, especially other specialists seeing pediatric patients, need to be further sensitized to the signs and symptoms of childhood cancer.

Atypical teratoid/rhabdoid tumor in an infant conceived by in vitro fertilization.

BACKGROUND: Atypical teratoid/rhabdoid tumor (ATsRT) is a rare tumor and extremely aggressive embryonal neoplasm of the central nervous system. Brain tumors in infant are suggestive of some oncogenic prenatal factors. CASE PRESENTATION: We report on a case of ATRT in a 4-month-old infant conceived by in vitro fertilization (IVF). Some previous reports have raised a question about the possible relation between IVF and childhood cancer, particularly embryonal tumors. CONCLUSION: Report of such cases may provide some evidence to identify if there is a real association between congenital tumors and IVF.

Protective effects of acetyl-L-carnitine on cisplatin cytotoxicity and oxidative stress in neuroblastoma.

The most widely used platinum-derived drug is cisplatin in neuroblastoma (NB) chemotherapy, which is severely neurotoxic. Acetyl-L-Carnitine (ALC) is a natural occurring compound with a neuroprotective activity in several experimental paradigms. The aim of this study was to determine the effects of ALC on cisplatin induced cytotoxicity and oxidative stress in NB cells. SH-SY5Y (N-Myc negative) and KELLY (N-Myc positive) human NB cell lines were used. Cisplatin induced apoptosis was assessed by using a Cell Death Detection ELISA(PLUS) kit. Lipid peroxidation levels were determined by HPLC analysis. Glutathione levels were determined spectrophotometrically. ALC was used prophylactic or after cisplatin application. The level of cisplatin doses were determined in both type of NB cells at which 50% cell death occurred along with synchronized apoptosis induced. Prophylactic 10 and 50 micromol of ALC concentrations were decreased cisplatin induced lipid peroxidation compared to controls that normally exhibited apoptosis especially in SH-SY5Y cells. Cisplatin caused oxidative stress through decreasing glutathione levels in both cell types. ALC were effectively inhibited the increase in cisplatin induced oxidized glutathione and lipid peroxidation formation in NB cells. We suggested that prophylactic ALC would be a useful agent for cisplatin induced toxicity in NB cells.

Evaluation of the effect of acetyl L-carnitine on experimental cisplatin nephrotoxicity.

BACKGROUND/AIMS: To evaluate the protective effects of acetyl L-carnitine (ALCAR) on cisplatin-induced nephrotoxicity in rats, and to gain insights into the possible protective mechanisms of ALCAR against nephrotoxicity. METHODS: Twenty-eight Wistar rats were divided into four groups. Group 1 was administered saline only, group 2 was administered ALCAR, group 3 was administered cisplatin, and group 4 was administered ALCAR prior to cisplatin. Rats were sacrificed after 72 h of cisplatin/saline infusion. Serum creatinine and glomerular filtration rate values were obtained, and kidney samples were examined by light and electron microscopy. Apoptotic cell death and caspase-3, 8 and 9 activities were studied immunohistochemically. RESULTS: In group 4, ALCAR administration resulted in an improvement in kidney function tests. Histopathological findings confirmed the biochemical data. Whilst the fusion of the foot processes of podocytes was observed in group 3, they were intact in group 4 on electron-microscopic examination. Apoptotic cell death and caspase-3, 8 and 9 activities were also decreased in group 4 compared to group 3. CONCLUSIONS: Antioxidative, antiapoptotic and anti-inflammatory properties of ALCAR were supported by the findings that this agent improves kidney function tests and has the effects of tissue protection and inhibition of apoptosis in cisplatin-induced nephrotoxicity.

Aneurysmal bone cyst of rib presenting as a huge chest wall mass.

Aneurysmal bone cyst is a rare benign tumor of the bone that can be difficult to distinguish from malignant tumors, especially when it presents in an unusual location. Herein, we report a six-year-old girl with a primary aneurysmal bone cyst in an uncommon location. It originated from the 4th rib and she presented with a huge chest wall mass. Despite the large size of the cyst, the only symptom was persistent cough. She was successfully treated with total excision of tumor without any complication. The patient has been followed up for 56 months without any recurrence.

Delayed renal excretion of methotrexate after a severe anaphylactic reaction to methotrexate in a child with osteosarcoma.

Although methotrexate is an agent widely used in the practice of pediatric oncology, allergic reactions to methotrexate are most unusual. Most of these reactions typically occur after repeated administration. Here, we report a severe anaphylactoid reaction to the first dose of high-dose methotrexate infusion in a child with osteosarcoma who has also experienced a delayed excretion of methotrexate. Clinicians must be aware of the possibility of a systemic, near-fatal anaphylactic reactions with methotrexate and patients who experience severe anaphylactic reactions should be followed carefully because of the possibility of delayed methotrexate excretion.

The incidence of congenital malformations in children with cancer.

We evaluated the incidence of congenital malformations in 566 children (median age: 8, M:F 1.3) with lymphomas and solid tumors using patient records. In this study, 12.7% of children either had a congenital malformation (7.8%) or a birthmark (4.9%). The incidence of patients with a childhood cancer syndrome was 3% and these cases developed typical tumors. The rate of consanguineous marriages was 12.6%, and family history of cancer was positive in 31.2%. Median age at cancer diagnosis, gender, maternal age, history of stillbirth and missed abortion, consanguinity of parents, and family history of cancer were not significantly different in cases with and without a congenital malformation. The most frequent cancers were central nervous system tumors and lymphomas. No remarkable association between a particular anomaly and a specific cancer type could be shown. The high incidence of congenital anomalies in this study may stimulate future large cohort studies in our country.

Paravertebral malignant tumors of childhood: analysis of 28 pediatric patients.

PURPOSE: To evaluate the clinical features and treatment results of the primary paravertebral malignant tumors (PMTs) in our department. METHODS: Medical records of 28 children with primary PMTs treated between 1988-2007 were analyzed retrospectively. RESULTS: Primary PMTs constituted 4.8% of the cancer cases in our department. Tumor diagnoses were mostly neuroblastoma (46.4%) and soft tissue sarcomas (35.7%). These cases presented with pain (64.3%), motor dysfunction (42.8%), sphincter dysfunction (35.7%), palpable mass (32.1%), and sensory deficits (7.1%). All tumors were extradural. Physical examination revealed motor deficits (53.6%), deep tendon reflex alterations (53.6%), sphincter dysfunction (35.7%), pathologic reflexes (25%), abnormal cutaneous reflexes (25%), and sensory deficits (17.8%). Sixteen had cord compression (CC; 13 clinical, three radiological CC). Eleven of them presented with advanced disease. Seven were managed by surgical departments by primary surgery (three unresponsive). Others were managed by pediatric oncology: five with corticosteroids+/-chemotherapy (one unresponsive), one with radiotherapy (RT), and two with surgery for the clinical CC. Surgery was tumor excision in nine, laminectomy in nine, laminotomy in one, and delayed surgery after chemotherapy in two cases. In chemotherapy and surgery groups, there were neurologic sequela associated with the advanced disease at diagnosis in 38% and 37%, respectively. At 3-year median follow-up, nine patients died, 17 are alive (four with neurologic sequela), and two are lost of follow-up. CONCLUSION: Majority of cases presented with advanced disease. Late referral is the major cause of morbidity and mortality. The CC caused by PMTs should be initially managed with corticosteroids +/- chemotherapy to avoid the adverse late effects of RT and surgery.

Stromal-predominant mesenchymal hamartoma of the liver with elevated serum alpha-fetoprotein level.

Mesenchymal hamartoma of the liver (MHL) is an uncommon, benign, tumor-like lesion and is usually diagnosed in the first 2 years of life. Its pathogenesis remains unclear. Treatment of choice is radical excision. The authors report a case of solid stromal predominant MHL in a 12-month-old male infant who also had an elevated serum alpha-fetoprotein level. He also had hypospadias, which might represent a spectrum of developmental anomalies. It usually presents as an asymptomatic mass, however, as in the reported case, it may cause several complications due to the compression of surrounding structures. He was successfully treated with total excision of the pedunculated large tumor without any complication.

Unilateral juvenile (virginal) hypertrophy of the breast.

Juvenile hypertrophy of the breast (JHB) is an uncommon, benign disorder and typically occurs in peri-pubertal females. The etiology ofJHB is uncertain. It may represent an end-organ hypersensitivity of the breast to normal levels of sex steroids. Clinically, it is characterized by rapid enlargement of breasts, either unilateral or bilateral. The definitive diagnosis is made by histopathologic examination. Treatment recommendations include surgery and hormonal therapy, although hormonal manipulation is still controversial in pediatric patients. Here we report a 13-year-old girl with unilateral JHB who did not require surgery or medical treatment.

Pilomatricoma in children: a frequently misdiagnosed superficial tumor.

Pilomatricomas are the most common superficial tumors in children, but they are frequently misdiagnosed preoperatively. There are some characteristic features of pilomatricomas that can help clinicians differentiate it from other tumors. The authors report 3 children with head and neck pilomatricomas, one with multiple tumors. They emphasize some clinical features that may help in differential diagnosis to avoid unnecessary investigations before surgical removal.

Conjunctival involvement in chronic recurrent multifocal osteomyelitis.

PURPOSE: To report a case of chronic recurrent multifocal osteomyelitis (CRMO) with conjunctival involvement. METHODS: Retrospective chart review. RESULTS: A 10-year-old girl who complained of fatigue and debilitating pain in both hips and legs for >1 year had recurrent episodes of redness and discharge in both eyes with little response to different topical medications. The diagnosis of CRMO was confirmed with the help of magnetic resonance imaging, bone scan, and bone biopsy results. She had moderate hyperemia and multiple discrete salmon-colored lesions in both palpebral and fornical conjunctivae. Biopsy revealed chronic inflammatory infiltration composed predominantly of lymphocytes forming a follicular pattern. Conjunctival lesions worsened during relapses of skeletal symptoms, improved during remission, and resolved shortly after the initiation of oral prednisolone therapy. No recurrence was observed during 16 months of follow-up. CONCLUSIONS: Salmon-colored conjunctival lesions may accompany CRMO and respond favorably to systemic steroid therapy.

Late presentation of cystic adenomatoid malformation type 4 of lung in an asymptomatic child.

Congenital cystic adenomatoid malformation of lung is an uncommon embryonic developmental anomaly usually diagnosed perinatally. Rarely the presentation is delayed until childhood and adulthood. Herein we present a 10-years-old girl with a late presentation of congenital cystic adenomatoid malformation type 4 of lung who was diagnosed coincidentally.

Veno-occlusive disease in a child with rhabdomyosarcoma after conventional chemotherapy: report of a case and review of the literature.

Although veno-occlusive disease of the liver is a well-known complication of high-dose chemotherapy and bone marrow transplantation, it has rarely been observed in children who receive conventional chemotherapy. Most cases in the literature consists of children with Wilms tumor. It has been very uncommon in rhabdomyosarcoma patients until recently, although they commonly receive similar anticancer agents. Here the authors report a 2-year-old boy with rhabdomyosarcoma who developed veno-occlusive disease while receiving VAC (vincristine, actinomycin D, cyclophosphamide) chemotherapy regimen according to the IRS-IV protocol. The patient gradually recovered during 2 weeks with supportive treatment only.