Canan Albayrak

SNX10 mutations define a subgroup of human autosomal recessive osteopetrosis with variable clinical severity.

Human Autosomal Recessive Osteopetrosis (ARO) is a genetically heterogeneous disorder caused by reduced bone resorption by osteoclasts. In 2000, we found that mutations in the TCIRG1 gene encoding for a subunit of the proton pump (V‐ATPase) are responsible for more than one‐half of ARO cases. Since then, five additional genes have been demonstrated to be involved in the pathogenesis of the disease, leaving approximately 25% of cases that could not be associated with a genotype. Very recently, a mutation in the sorting nexin 10 (SNX10) gene, whose product is suggested to interact with the proton pump, has been found in 3 consanguineous families of Palestinian origin, thus adding a new candidate gene in patients not previously classified. Here we report the identification of 9 novel mutations in this gene in 14 ARO patients from 12 unrelated families of different geographic origin. Interestingly, we define the molecular defect in three cases of “Västerbottenian osteopetrosis,” named for the Swedish Province where a higher incidence of the disease has been reported. In our cohort of more than 310 patients from all over the world, SNX10‐dependent ARO constitutes 4% of the cases, with a frequency comparable to the receptor activator of NF‐κB ligand (RANKL), receptor activator of NF‐κB (RANK) and osteopetrosis‐associated transmembrane protein 1 (OSTM1)‐dependent subsets. Although the clinical presentation is relatively variable in severity, bone seems to be the only affected tissue and the defect can be almost completely rescued by hematopoietic stem cell transplantation (HSCT). These results confirm the involvement of the SNX10 gene in human ARO and identify a new subset with a relatively favorable prognosis as compared to TCIRG1‐dependent cases. Further analyses will help to better understand the role of SNX10 in osteoclast physiology and verify whether this protein might be considered a new target for selective antiresorptive therapies.

Invasive fungal infections in children with hematologic and malignant diseases.

Background: To evaluate the clinical feature and outcome of invasive fungal infections (IFI) in children with hematologic and malign diseases. Patients and Methods: The medical records of children with hematologic and malignant diseases, who were hospitalized at our hospital between January 2010 and December 2011, were reviewed. Proven, probable, and possible IFIs were diagnosed according to the revised definitions of the European Organization for Research and Treatment of Cancer/Mycosis Study Group. The demographic, clinical, and laboratory characteristics of the patients who met the study criteria were evaluated. Results: IFI was diagnosed in 67 (7.2%) febrile episodes of 56 patients, of which 10 (1.2%) were proven, 20 (2%) probable, and 37 (4%) possible IFI. Blood culture of 10 cases with proven IFI yielded yeast and the most common isolated agent was Candida parapsilosis. Seventy percent of cases with fungemia had central venous catheter (CVC). Twenty cases with probable IFI had invasive mold infection. The cases with mold infection had higher median C-reactive protein values, lower neutrophil counts, and longer duration of neutropenia compared with the cases with yeast infection. A total of 14 patients (20.9%) died. Presence of CVC, bone marrow transplantation, total parenteral nutrition, prolonged fever, and proven/probable IFI were detected more often in patients who died, compared with patients who survived. Conclusions: IFIs are important causes of death in children with hematologic and malignant diseases. Mold infections are seen more frequently in cases with prolonged and profound neutropenia, and invasive yeast infections, especially with non-albicans Candida species, in cases with CVC. Early and effective treatment considering these findings will help to decrease the mortality.

Myelofibrosis associated with rickets in a child with down syndrome

To the Editor: Rickets is an illness which is seen in childhood due to the lack of vitamin D. Myelofibrosis is rarely associated with rickets. Say and Berkel [1] described the first case of rickets associated with myelofibrosis. All the reported cases are in infanthood [1–13]. We diagnosed and treated myelofibrosis associated with rickets in a 10-year-old male with Down syndrome. The patient presented with fever, thrombocytopenia, and anemia. He had Down syndrome which was genetically proven. His weight (14 kg), height (110 cm), and head circumference (48 cm) were below the third percentile. He had massive hepatosplenomegaly, rachitic rosaries, widened wrists, and ankles. He could sit but not walk. Hemoglobin level was 5.4 g/dl, white blood cell count was 5.6 10/L and platelet count was 26 10/L. Bone marrow aspiration demonstrated decreased erythroid, myeloid and megakaryocytic lineage, and normal myeloid/erythroid ratio. There were no signs of abnormal maturation and myelodysplasia. Leukemic infiltration was not observed. Serum calcium was 5.7 mg/dl (normal range 8.1–10.7), phosphorus 0.73 mg/dl (normal range 2.3–4.7), alkaline phosphatases 587 U/L (normal range 95–280), 25-hydroxy-vitamin D3 level 5 mg/L (normal range 30– 80). A diagnosis of rickets related to lack of D vitamin was made. Secondary hyperparathyroidism was suspected since parathyroid

Red cell glucose 6-phosphate dehydrogenase deficiency in the northern region of Turkey: is G6PD deficiency exclusively a male disease?

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive genetic defect that can cause hemolytic crisis. However, this disease affects both males and females. In Turkey, the frequency of this enzyme deficiency was reported to vary, from 0.25 to 18%, by the geographical area. Its prevalence in the northern Black Sea region of Turkey is unknown. The aims of this study were to assess the prevalence of G6PD deficiency in the northern region Turkey in children and adults with hyperbilirubinemia and hemolytic anemia. This report included a total of 976 G6PD enzyme results that were analyzed between May 2005 and January 2014. G6PD deficiency was detected in 5.0% of all patients. G6PD deficiency was significantly less frequent in females (1.9%, 6/323) than in males (6.6%, 43/653). G6PD deficiency was detected in 3.7% of infants with hyperbilirubinemia, 9.2% of children, and 4.5% of adults with hemolytic anemia. In both the newborn group and the group of children, G6PD deficiency was significantly more frequent in males. In the combined group of children (groups I and II), the proportion of males was 74% and 67% in all groups (P = .0008). In conclusion, in northern region of Turkey, G6PD deficiency is an important cause of neonatal hyperbilirubinemia and hemolytic crisis in children and adults. This study suggests that most pediatricians thought that G6PD deficiency is exclusively a male disease. For this reason, some female patients may have been undiagnosed.

Vitamin D levels in children with severe hemophilia A: an underappreciated deficiency.

Osteoporosis in hemophilic patients is a significant problem. The causes of osteoporosis in hemophilic patients are lack of adequate exercise, multiple hemorrhage and inflammation, and low vitamin D levels. The aim of this study was to retrospectively determine the frequency of vitamin D deficiency and insufficiency in children with severe hemophilia A. Forty-seven children with severe hemophilia were included in the study. None of the patients had previously received vitamin D supplementation. No patient had clinical or radiologic findings of rickets or seropositivity of hepatitis C virus or HIV. The mean age of the patients was 11.64 ± 5.70 (range, 2–18) years. The mean vitamin D level was 16.35 ± 7.49 ng/ml (range, 3.25–33.80). Vitamin D levels were below 10 ng/ml (severe vitamin D deficiency) in 9 cases (19%), between 10 and 19.99 ng/ml (vitamin D deficiency) in 23 cases (49%), between 20 and 29.99 ng/ml (vitamin D insufficiency) in 13 cases (28%), and above 30 ng/ml (normal vitamin D level) in 2 cases (4%). The mean serum levels of 25-hydroxy vitamin D in the children with hemophilia during winter and autumn were significantly lower than that during summer (P = 0.0028 and P = 0.0091, respectively). A majority of our hemophilic patients (96%) had low vitamin D levels. The study showed that the risk of vitamin D deficiency is the most highest during winter and autumn. Normal lifelong vitamin D levels are especially important in hemophilia because of the possible synergistic effect of vitamin D levels on periarticular and general osteoporosis, which is intrinsic to hemophilic conditions. We advise routine checking of vitamin D levels twice a year and vitamin D supplementation to maintain its level between 30 and 100 ng/ml.

Plasma Exchange in Critically Ill Children: A Single-center Experience

Öz 10 DOI: 10.4274/cayd.28199 J Pediatr Emerg Intensive Care Med 2018;5:10-14 Halil Keskin1, Muhammet Şükrü Paksu2, Nazik Yener2, Özlem Temel Köksoy2, İbrahim Kartal3, Canan Albayrak3, Davut Albayrak3 1Atatürk University Faculty of Medicine, Division of Pediatric Intensive Care Unit, Erzurum, Turkey 2Ondokuz Mayıs University Faculty of Medicine, Division of Pediatric Intensive Care, Samsun, Turkey 3Ondokuz Mayıs University Faculty of Medicine, Division of Pediatric Hematology, Samsun, Turkey Research Article / Özgün Araştırma Address for Correspondence/Yazışma Adresi: Halil Keskin MD, Atatürk University Faculty of Medicine, Division of Pediatric Intensive Care, Erzurum, Turkey Phone: +90 533 434 67 34 E-mail: keskinpediatrize@gmail.com ORCID ID: orcid.org/0000-0003-4491-1327 Received/Geliş Tarihi: 27.11.2017 Accepted/Kabul Tarihi: 29.01.2018 Copyright 2018 by Society of Pediatric Emergency and Intensive Care Medicine Journal of Pediatric Emergency and Pediatric Intensive Care published by Galenos Yayınev

Juvenile Myelomonocytic Leukemia in Turkey: A Retrospective Analysis of 65 Patients

Objective: This study aimed to define the status of juvenile myelomonocytic leukemia (JMML) patients in Turkey in terms of time of diagnosis, clinical characteristics, mutational studies, clinical course, and treatment strategies. Materials and Methods: Data including clinical and laboratory characteristics and treatment strategies of JMML patients were collected retrospectively from pediatric hematology-oncology centers in Turkey. Results: Sixty-five children with JMML diagnosed between 2002 and 2016 in 18 institutions throughout Turkey were enrolled in the study. The median age at diagnosis was 17 months (min-max: 2-117 months). Splenomegaly was present in 92% of patients at the time of diagnosis. The median white blood cell, monocyte, and platelet counts were 32.9x109/L, 5.4x109/L, and 58.3x109/L, respectively. Monosomy 7 was present in 18% of patients. JMML mutational analysis was performed in 32 of 65 patients (49%) and PTPN11 was the most common mutation. Hematopoietic stem cell transplantation (HSCT) could only be performed in 28 patients (44%), the majority being after the year 2012. The most frequent reason for not performing HSCT was the inability to find a suitable donor. The median time from diagnosis to HSCT was 9 months (min-max: 2-63 months). The 5-year cumulative survival rate was 33% and median estimated survival time was 30±17.4 months (95% CI: 0-64.1) for all patients. Survival time was significantly better in the HSCT group (log-rank p=0.019). Older age at diagnosis (>2 years), platelet count of less than 40x109/L, and PTPN11 mutation were the factors significantly associated with shorter survival time. Conclusion: Although there has recently been improvement in terms of definitive diagnosis and HSCT in JMML patients, the overall results are not satisfactory and it is necessary to put more effort into this issue in Turkey.

Autosomal recessive osteopetrosis with a unique imaging finding: multiple encephaloceles

Osteopetrosis is a hereditary form of sclerosing bone dysplasia with various radiological and clinical presentations. The autosomal recessive type, also known as malignant osteopetrosis, is the most severe type, with the early onset of manifestations. A 5-month-old infant was admitted to our hospital with recurrent respiratory tract infections. Chest X-ray and skeletal survey revealed the classic findings of osteopetrosis, including diffuse osteosclerosis and bone within a bone appearance. At follow-up, the patient presented with, thickened calvarium, multiple prominent encephaloceles, and dural calcifications leading to the intracranial clinical manifestations with bilateral hearing and sight loss. Autosomal recessive osteopetrosis is one of the causes of encephaloceles and this finding may become dramatic if untreated.

Pancytopenia As the Initial Manifestation of Brucellosis in Children.

Presenting with severe thrombocytopenia and pancytopenia is rare in children with brucellosis, and at the beginning it can be misdiagnosed as a hematological or a viral hemorrhagic disease. The follow-ups of 52 patients diagnosed with brucellosis from January, 2008, to December, 2013, in our clinic have shown the following results. Eleven out of these 52 patients revealed the fact that they had pancytopenia at the admission phase. Anemia and leukopenia were defined as hemoglobin levels and leukocyte counts below the standard values in terms of ages, thrombocytopenia as thrombocyte counts below 150,000/mm(3), and severe thrombocytopenia as thrombocyte counts below 20,000/mm(3). The most frequent admission symptoms and findings of the patients with pancytopenia were fever (75%), fatigue (50%), splenomegaly (75%), and hepatomegaly (41%). Laboratory results were hemoglobin 9.3±0.96 gram/dL, white blood cell count 2226±735.9/mm(3), and thrombocyte count 70,090±47,961/mm(3). The standard tube agglutination test was positive for all patients, and Brucellosis spp. were isolated in the blood cultures of six (54%) patients. Three of the 11 patients had severe thrombocytopenia, and they were admitted with complaints of epistaxis, gingival bleeding, petechiae, and purpura. At the beginning, two of three cases were misdiagnosed as Crimean-Congo hemorrhagic fever (CCHF), another zoonotic endemic disease in Turkey. Pancytopenia improved with treatment of brucellosis on all patients. In conclusion, brucellosis can show great similarity with hematologic and zoonotic diseases like CCHF. Brucellosis should be considered in the differential diagnosis of pancytopenia, treatment-resistant immune thrombocytopenia, and viral hemorrhagic disease, especially in countries where brucellosis is endemic.