Retrospective analysis of patients with severe combined immunodeficiency and alternative diagnostic criteria: A 20-year single centre experience.

Severe combined immunodeficiency (SCID) is an inborn errors of immunity (IEI) disorder characterized by impairment in the development and function of lymphocytes and could be fatal if not treated with hematopoietic stem cell transplant in the first 2 years of life. There are various diagnostic criteria for SCID among different primary immunodeficiency societies. We retrospectively evaluated clinical and laboratory findings of 59 patients followed up with the diagnosis of SCID at our clinic over the past 20 years in order to develop an algorithm that would help diagnosis of SCID for the countries where a high ratio of consanguineous marriage is present because these countries have not launched TREC assay in their newborn screening programs. The mean age at diagnosis was 5.80 ± 4.90 months, and the delay was 3.29 ± 3.99 months. The most common complaint and physical examination findings were cough (29.05%), eczematous rash (63%) and organomegaly (61%). ADA (17%), Artemis (14%), RAG1/2 (15%), MHC Class II (12%) and IL-2R (12%) deficiencies were the most common genetic defects. Lymphopenia (87.5%) was the most frequent abnormal laboratory finding and below 3000/mm3 in 95% of the patients. The CD3+ T cell count was 300/mm3 and below in 83% of the patients. As a result, a combination of low lymphocyte count and CD3 lymphopenia for SCID diagnosis would be more reliable for countries with high rate of consanguineous marriage. Physicians should consider diagnosis of SCID in a patient presenting with severe infections and lymphocyte counts below 3000/mm3 under 2 years of age.

Central nervous system thrombosis in pediatric acute lymphoblastic leukemia in Turkey: A multicenter study.

BACKGROUND: In patients with acute lymphoblastic leukemia (ALL), the risk of thromboembolism increases due to hemostatic changes secondary to the primary disease and due to treatment-related factors. In this multicenter study, we aimed to research the frequency of central nervous system (CNS) thrombosis occurring during treatment, hereditary and acquired risk factors, clinical and laboratory features of patients with thrombosis, treatment approaches, and thrombosis-related mortality and morbidity rates in pediatric ALL patients. PROCEDURE: Pediatric patients who developed CNS thrombosis during ALL treatment from 2010 to 2021 were analyzed retrospectively in 25 different Pediatric Hematology Oncology centers in Türkiye. The demographic characteristics of the patients, symptoms associated with thrombosis, the stage of the leukemia treatment during thrombosis, the anticoagulant therapy applied for thrombosis, and the final status of the patients recorded through electronic medical records were determined. RESULTS: Data from 70 patients with CNS thrombosis during treatment, out of 3968 pediatric patients with ALL, were reviewed. The incidence of CNS thrombosis was 1.8% (venous: 1.5 %; arterial: 0.03%). Among patients with CNS thrombosis, 47 had the event in the first 2 months. Low molecular weight heparin (LMWH) was the most commonly used treatment with a median of 6 months (min-max: 3-28 months). No treatment-related complications occurred. Chronic thrombosis findings occurred in four patients (6%). In five (7%) patients who developed cerebral vein thrombosis, neurological sequelae (epilepsy and neurological deficit) remained. One patient died related to thrombosis, and the mortality rate was 1.4%. CONCLUSION: Cerebral venous thrombosis and, less frequently, cerebral arterial thrombosis may develop in patients with ALL. The incidence of CNS thrombosis is higher during induction therapy than during other courses of treatment. Therefore, patients receiving induction therapy should be monitored carefully for clinical findings suggestive of CNS thrombosis.

The coexistence of two rare diseases thought to use the same pathologic pathway: cystic fibrosis and Niemann-Pick disease.

BACKGROUND: Cystic fibrosis (CF) is a multisystemic, autosomal recessive disease, which is caused by a mutation in the transmembrane conduction regulator protein (CFTR) gene. We present a patient who was diagnosed with CF and later diagnosed with Niemann-Pick type-A (NPA) disease, which is an autosomal recessive lysosomal lipid storage disease. CASE: A 2-month-old Syrian refugee patient was diagnosed with CF due to a high sweat test and two homozygous CFTR-related pathogenic gene mutations in our pediatric pulmonology clinic, where she was referred due to a high immunoreactive trypsinogen (IRT) value as a result of newborn screening. As the patient had neurological symptoms and hepatosplenomegaly that could not be explained by CF in the clinical follow-up, the patient was diagnosed with NPA was made with a cherry red spot on eye examination, foam cells in the bone marrow, and low sphingomyelinase activity, in addition to CF. CONCLUSIONS: Although CF and NP have common systems of involvement in both diseases, pathological symptoms have different origins. If a patient with CF has simultaneous neuromotor delay, other autosomal recessive diseases that may accompany it should be suspected. In studies, similar pathological pathways related to abnormal cholesterol accumulation in the cell were detected between NP type C and CF. But our case was NPA. As case reports on the coexistence of the two diseases increase, we believe that a better understanding of similar pathological pathways may lead to new therapeutic targets for both diseases.

Central Nervous System Fungal Infections in Children With Leukemia and Undergoing Hematopoietic Stem Cell Transplantation: A Retrospective Multicenter Study.

BACKGROUND: Central nervous system fungal infections (CNSFI) are seen in patients with hematologic malignancies and have high morbidity and mortality. Because of their rarity, there is limited data on CNSFI in children with no established treatment protocols or guidelines. MATERIALS AND METHODS: In this multicenter retrospective study, 51 pediatric patients with leukemia, 6 of whom had undergone bone marrow transplantation, with proven or probable CNSFI were evaluated. Fungal infections were defined as proven or probable based on European Organisation for Research and Treatment of Cancer criteria. Proven CNSFI was diagnosed by appropriate central nervous system (CNS) imaging or tissue sample findings in combination with positive microbiological results of cerebrospinal fluid. A positive culture, microscopic evidence of hyphae, a positive result of the galactomannan assays are defined as positive microbiological evidence. Probable CNSFI was defined as appropriate CNS imaging findings together with proven or probable invasive fungal infections at another focus without CNS when there is no other explanatory condition. Data was collected by using the questionnaire form (Supplemental Digital Content 1, http://links.lww.com/JPHO/A541 ). RESULTS: Seventeen patients had proven, 34 patients had probable CNSFI. Headaches and seizures were the most common clinical findings. The median time between the onset of fever and diagnosis was 5 days. The most common fungal agent identified was Aspergillus . Sixteen patients received single-agent, 35 received combination antifungal therapy. Surgery was performed in 23 patients. Twenty-two patients (43%) died, 29 of the CNSFI episodes recovered with a 20% neurological sequelae. CONCLUSION: CNSFIs should be considered in the differential diagnosis in patients with leukemia and refractory/recurrent fever, headache, neurologicalocular symptoms, and a radiologic-serological evaluation should be performed immediately. Early diagnosis and prompt management, both medical and surgical, are essential for improving clinical outcomes.

Cancer among syrian refugees living in Konya Province, Turkey.

BACKGROUND: With more than 3.6 million Syrian refugees Turkey hosts the world's largest number of Syrians. Considering the morbidity, mortality, and healthcare spending, cancer is one of the leading health and economic burden for patients and healthcare systems. However, very limited information available in the scientific literature to understand the burden and characteristics of cancer in countries hosting Syrian refugees. The aim of the present study is to evaluate the demographic and clinical characteristics, treatment outcome of Syrian cancer patients living in Konya, Turkey. METHODS: We retrospectively reviewed medical records of Syrian cancer patients at three major institutions from 2005 to 2020. The information regarding demographic and clinical characteristics of patients were identified. The number of days between the first symptom and diagnosis was considered as the "diagnostic interval". Patients who failed to attend clinics within four weeks of appointment were assumed abandoned treatment. Survival curves were estimated using the Kaplan-Meier method. RESULTS: We identified 230 adult and 38 children refugee diagnosed with cancer during the study period. With regards to adult patients, there were 114 (49.6%) male and 116 (50.4%) female. The median age at diagnosis was 52.4, 47.3 years for male, female respectively. The five most common cancer by site among all were; breast (24.8%), colorectal (10.9%), lung (7.4%), central nervous system (CNS) (7.0%), and stomach (5.2%). 93 (40.4%) had metastatic disease at diagnosis. The overall survival probability was 37.5% at five years for the adult population. Data were extracted for 20 boys and 18 girls with childhood cancer. Their median age at diagnosis was 5.8 and 6.0 years respectively. The three most common childhood cancer were; leukemias (21.1%), lymphomas (21.1%), and CNS (13.2%). Excluding leukemia, 13 (43.3%) of childhood cancer cases had the advanced disease at diagnosis. Three year survival probality was 69.5%. The median diagnostic interval for adult and childhood cancer was 96.5 (IQR = 53-165) and 23 (IQR = 13.5-59) days respectively. Twenty-one adults and four children had treatment abandonment. CONCLUSION: This study contributes to understanding the burden of cancer among Syrian refugees living in Konya, growing health issue for refugees. Larger and prospective studies will help to measure the real burden and compare the difference in cancer risk factors, care, and outcomes among the refugee and host populations.

Traumatic hyphema in a patient with severe hemophilia A: Clinical features and management.

PURPOSE: To describe a case of traumatic hyphema in a patient with severe hemophilia A. CASE: We present a case of a 16-year-old boy with severe hemophilia A who presented to our ophthalmology department with total hyphema and elevated intraocular pressure 3 days after a history of blunt ocular trauma on his right eye. Due to the persistent intraocular pressure elevation and total hyphema despite medical intervention, an early anterior chamber washout was performed with the replacement of factor VIII preoperatively and postoperatively. Re-bleeding or any other complications were not experienced during surgery or postoperatively. At the first postoperative week, 20/20 visual acuity and a normal intraocular pressure without antiglaucoma medication was retained and remained stable during the 6-month follow-up. CONCLUSION: In such cases with hemophilia A, traumatic hyphema, and intraocular pressure elevation despite medical intervention, an early surgical clot removal under intense factor VIII replacement could be performed. In the early postoperative period, factor replacement should be resumed in order to avoid re-bleeding.

Outcomes of Eltrombopag Treatment and Development of Iron Deficiency in Children with Immune Thrombocytopenia in Turkey

Objective: Immune thrombocytopenia (ITP) is a rare autoimmune disease and hematologic disorder characterized by reduced platelet counts that can result in significant symptoms, such as bleeding, bruising, epistaxis, or petechiae. The thrombopoietin receptor agonist eltrombopag (EPAG) is a second-line agent used to treat chronic ITP purpura in adults and children. Materials and Methods: The present retrospective study evaluated the efficacy, safety, and side effects of EPAG treatment in pediatric patients with acute refractory and chronic immune thrombocytopenia, particularly focusing on iron-deficiency anemia. Results: The diagnosis was chronic ITP in 89 patients and acute refractory ITP in 16 patients. The mean age of patients was 9.5±4.5 years (minimum-maximum: 1.2-18 years) at the beginning of EPAG treatment. The overall response rate was 74.3% (n=78). The mean time for platelet count of ≥50x109/L was 11.6±8 weeks (range: 1-34 weeks). The treatment was stopped for 27 patients (25.7%) at an average of 6.8±9 months (range: 1-38 months). The reason for discontinuation was lack of response in 18 patients, nonadherence in 4 patients, and hepatotoxicity in 2 patients. Response to treatment continued for an average of 4 months after cessation of EPAG in 3 patients. Conclusion: Results of the current study imply that EPAG is an effective therapeutic option in pediatric patients with acute refractory and chronic ITP. However, patients must be closely monitored for response and side effects during treatment, and especially for iron deficiency.

Homozygous c.130-131 ins A (pW44X) mutation in the HAX1 gene as the most common cause of congenital neutropenia in Turkey: Report from the Turkish Severe Congenital Neutropenia Registry.

BACKGROUND: Severe congenital neutropenia is a rare disease, and autosomal dominantly inherited ELANE mutation is the most frequently observed genetic defect in the registries from North America and Western Europe. However, in eastern countries where consanguineous marriages are common, autosomal recessive forms might be more frequent. METHOD: Two hundred and sixteen patients with severe congenital neutropenia from 28 different pediatric centers in Turkey were registered. RESULTS: The most frequently observed mutation was HAX1 mutation (n = 78, 36.1%). A heterozygous ELANE mutation was detected in 29 patients (13.4%) in our cohort. Biallelic mutations of G6PC3 (n = 9, 4.3%), CSF3R (n = 6, 2.9%), and JAGN1 (n = 2, 1%) were also observed. Granulocyte colony-stimulating factor treatment was given to 174 patients (80.6%). Two patients died with infectious complications, and five patients developed myelodysplastic syndrome/acute myeloblastic leukemia. The mean (± mean standard error) follow-up period was 129.7 ± 76.3 months, and overall survival was 96.8% (CI, 94.4-99.1%) at the age of 15 years. In Turkey, severe congenital neutropenia mostly resulted from the p W44X mutation in the HAX1 gene. CONCLUSION: In Turkey, mutation analysis should be started with HAX1, and if this is negative, ELANE and G6PC3 should be checked. Because of the very high percentage of consanguineous marriage, rare mutations should be tested in patients with a negative mutation screen.

Juvenile Myelomonocytic Leukemia in Turkey: A Retrospective Analysis of Sixty-five 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.

A National Registry of Thalassemia in Turkey: Demographic and Disease Characteristics of Patients, Achievements, and Challenges in Prevention.

OBJECTIVE: The Turkish Society of Pediatric Hematology set up a National Hemoglobinopathy Registry to demonstrate the demographic and disease characteristics of patients and assess the efficacy of a hemoglobinopathy control program (HCP) over 10 years in Turkey. MATERIALS AND METHODS: A total of 2046 patients from 27 thalassemia centers were registered, of which 1988 were eligible for analysis. This cohort mainly comprised patients with ß-thalassemia major (n=1658, 83.4%) and intermedia (n=215, 10.8%). RESULTS: The majority of patients were from the coastal areas of Turkey. The high number of patients in Southeastern Anatolia was due to that area having the highest rates of consanguineous marriage and fertility. The most common 11 mutations represented 90% of all ß-thalassemia alleles and 47% of those were IVS1-110(G->A) mutations. The probability of undergoing splenectomy within the first 10 years of life was 20%, a rate unchanged since the 1980s. Iron chelators were administered as monotherapy regimens in 95% of patients and deferasirox was prescribed in 81.3% of those cases. Deferasirox administration was the highest (93.6%) in patients aged <10 years. Of the thalassemia major patients, 5.8% had match-related hemopoietic stem cell transplantation with a success rate of 77%. Cardiac disease was detected as a major cause of death and did not show a decreasing trend in 5-year cohorts since 1999. CONCLUSION: While the HCP has been implemented since 2003, the affected births have shown a consistent decrease only after 2009, being at lowest 34 cases per year. This program failure resulted from a lack of premarital screening in the majority of cases. Additional problems were unawareness of the risk and misinformation of the at-risk couples. In addition, prenatal diagnosis was either not offered to or was not accepted by the at-risk families. This study indicated that a continuous effort is needed for optimizing the management of thalassemia and the development of strategies is essential for further achievements in the HCP in Turkey.

Posterior reversible encephalopathy syndrome in children: a case series.

Posterior reversible encephalopathy syndrome is characterized by hypertension, seizure, headache, clouding of consciousness, and visual disturbance, and is diagnosed in the presence of typical lesions on magnetic resonance imaging. We retrospectively evaluated five patients who were diagnosed as having posterior reversible encephalopathy syndrome and followed up in Meram Medical Faculty, Pediatric Intensive Care and Hematology wards, between January 2010 and January 2014. We reviewed the demographic and clinical data, and neuroimaging findings. The primary diseases of the subjects included acute lymphocytic leukemia (n=2), Henoch-Schönlein purpura (n=1), systemic lupus erythematous (n=1), and acute poststreptococcal glomerulonephritis (n=1). The mean age was 10±4.58 years (range, 5-14 years). Acute elevation of blood pressure was found in all patients (n=5). Initial neurologic manifestations included seizure, clouding of consciousness, headache, and visual disturbance. After the diagnosis was made through clinical evaluations and magnetic resonance imaging, complete clinical recovery was obtained in all patients with the appropriate therapeutic approach. In conclusion, posterior reversible encephalopathy syndrome should be considered in the differential diagnosis of patients who present with encephalopathy and underlying diseases such as nephritis, vasculitis, malignancy accompanied by hypertension, and a history of use of medication.

Ophthalmic manifestations in recently diagnosed childhood leukemia.

PURPOSE: To determine the prevalence and the pattern of ocular involvement in children with leukemia at the time of diagnosis. METHODS: The data of patients with leukemia who underwent complete ophthalmic examination at the time of diagnosis between January 2005 and December 2014 were retrospectively reviewed. Demographic data, type of leukemia, ocular findings, blood parameters, and duration of follow-up were analyzed. RESULTS: A total of 185 patients (111 male and 74 female) were included in the study, with a median age of 6.0 years (range 0.5-18.0 years) and a median follow-up time of 36.0 months (range 0.5-108.0 months). Ocular signs were present in 24.3% of the patients at the time of diagnosis and 37.8% of them were symptomatic. The prevalence of ocular involvement was 20.4% in patients with acute lymphocytic leukemia (ALL) and 36.4% in patients with acute myelocytic leukemia (AML) (p = 0.051). Fatality rate was significantly higher in subjects with AML compared with ALL (p = 0.019), but was not significantly different between patients with and without ocular involvement (p = 0.166). There were no significant differences in hemoglobin levels, white blood cell counts, or platelet counts between patients with ALL and AML. Platelet counts were significantly lower in patients with ocular signs compared with subjects without ocular involvement (p = 0.012), while hemoglobin levels and white blood cell counts did not differ significantly. CONCLUSIONS: Various ocular signs may be present at the time of diagnosis in childhood leukemia, even in patients without any symptoms. Routine ophthalmic examination should be performed in recently diagnosed children with leukemia.

Essential thrombocythemia with Mpl W515 K mutation in a child presenting with Budd-Chiari syndrome.

Essential thrombocythemia (ET) is an extremely rare childhood disorder characterised by clonal expansion of megakaryocytic lineage in bone marrow, leading to a persistent increase in the number of circulating thrombocytes and thus increased risk for thrombotic and haemorrhagic events. The molecular mechanisms of ET are not fully understood. Most children with ET have the JAK2 V617F somatic mutation; however, another mutation, involving a W to L or K substitution at Mpl codon 515, was reported in a small proportion of adult ET patients that is extremely rare in children. Herein, we describe a Mpl W515K somatic mutation in a paediatric case of ET who presented with Budd-Chiari syndrome. No paediatric patient harbouring a Mpl W515K mutation has been previously reported.

Novel mutations of integrin αIIb and ß3 genes in Turkish children with Glanzmann's thrombasthenia.

Glanzmann's thrombasthenia (GT) is an inherited disorder of platelet aggregation, characterized by qualitative and quantitative defect on platelet αIIbß3 integrin (GpIIb/IIIa), resulting in lifelong bleeding tendency due to defective platelet plug formation. The αIIb gene (ITGA2B) and ß3 gene (ITGB3) are closely located at chromosome 17q21.31-32. ITGA2B consist of 30 exons and encoding α chain, whereas ITGB3 has 15 exons and encoding ß chain. Until now, according to the Human Gene Mutation Database (HGMD), 138 mutations at ITGA2B gene and 101 mutations at ITGB3 gene have been identified. We aimed to determine whether there was any mutation in the ITGA2B and ITGB3 genes, and a correlation between clinical phenotype and genotype in Turkish GT patients. We examined 20 patients with GT followed at the Department of Pediatric Hematology, Meram Faculty of Medicine, for Clinical and Laboratory Findings and Molecular Genetic Analysis. Peripheral blood was collected from patients, and a written informed consent for genetic analysis was obtained from parents. DNA was isolated from by proteinase K and phenol/chloroform extraction. ITGA2B and ITGB3 genes were screened by polymerase chain reaction. There were 12 females and 8 males with a median age of 15.25 years. Major clinical presentations of these patients were mucocutaneous bleedings. The most common bleeding type was epistaxis (85%). Life-threatening bleedings were seen in five patients. Seven (35%) patients showed various mutations in the ITGA2B or ITGB3 genes. We detected four novel mutations in three different regions and two mutations defined previously within the ITGA2B gene. These changes are at exon 4; c.570 T > G alteration, at exon 13 c.1277 T > A, c.1291 T > G alterations, at exon 19 c.1921A > G alterations. And from the start point of exon 14, behind 107 bases, we detected a heterozygous alteration at Thymine to Guanine. According to PolyPhen Database Program and NCBI Multiple Alignment Tool Database, four transitions are conserved at evolutionary process, so we can say that these transitions are novel mutations. c. 468T > G alteration at exon 4 and c. 1378 T > A alteration at exon 13 were reported to HGMD previously. Screening the exons of the ITGB3 gene from the same patient groups, we reported a novel missense mutation at exon 5, at nucleotide 680. No correlation was found between clinical phenotype and genotype. These mutations were described for the first time in Turkish population, and all novel mutations are not defined previously. Furthermore, collaborative studies are needed for the population point of view.

Spontaneous rupture of the spleen in a patient with systemic lupus erythematosus initially presented as Evans syndrome.

BACKGROUND: Although splenic abnormalities are common in patients with lupus, spontaneous rupture of spleen is extremely rare. OBSERVATIONS: A 15-year-old boy with new-onset Evans syndrome subsequently diagnosed as systemic lupus erythematosus developed spontaneous rupture of spleen during the course of his illness. Despite the severe thrombocytopenia, he was managed conservatively with gradual regression of hematoma without further complication. CONCLUSIONS: Splenic rupture may occur spontaneously in the course of systemic lupus erythematosus. We conclude that conservative treatment of splenic rupture may be preferred especially in immunocompromised patients to avoid surgical complications.