Duygu Uçkan

Successful bone marrow transplantation for DOCK8 deficient hyper IgE syndrome

Dear Editor, We report a girl with AR-DOCK8 deficiency treated successfully with allogeneic bone marrow transplantation (BMT). She was born to consanguineous parents (cousins) originating from and living in eastern Turkey. The first two children of the family were not diagnosed as immunodeficient despite hypereosinophilia and high IgE levels. They had neonatal onset pruritic eczematous dermatitis, food allergies, recurrent and severe pneumonias (LRTI) when they died at five and six yr old, respectively. Sibling 6 (the propositus) who was born after three healthy children, presented with severe neurological disease: beginning nearly 6–8 months ago with mild ataxia and gradual deterioration with restlessness, spasticity, progressive hearing, speech and vision loss, hyperactive deep tendon reflexes, Babinsky and clonus. Radiological diagnosis of progressive multifocal leukoencephalopathy (PML) with serial MRI was supported by high JCV-DNA in serum and cerebrospinal fluid (2200 copies/mL). He also was diagnosed with hyper IgE syndrome (HIES) caused by the dermatitis of neonatal onset, severe food allergies, LRTIs and high peripheral blood eosinophilia and serum IgE. There were no pneumatoceles despite recurrent pulmonary infections and cold abscesses nor joint hypermobility. We treated him with i.v. immunoglobulin (IVIG) 400 mg/kg/day for 15 days with no clinical response. As the response to rh-interferon-gamma (rhIFN-c) stimulation is shown in Tyk-2 deficient patient (1), we gave rhIFN-c to this patient with PML using 50 lg/m, ·3/wk, by sc route. He died at the age of seven yr with sepsis in our intensive care unit. The last child (DOB: 25 October 2006) of this family also presented with neonatal rash. She developed severe eczema with lichenification since the first months of life. She had multiple food, environmental and drug allergies, including lentil anaphylaxis. At the age of 18 months, she underwent further investigations after the diagnosis of her brother s JCV infection. She presented with severe disseminated ichthyosiform eczema, ectropion of the eyelids, recurrent LRTI, oral, cutaneous and ungual candidiasis. Fortunately, her brain CT was normal and the serum and CSF did not reveal JCV infection as her brother. High levels of IgE (>10 000 IU/mL) and hypereosinophilia (>5000/lL) were persistent. Serum immunoglobulin levels (G: 1580, M: 71 and A: 8.7 mg/dL) were normal except for low IgA for age while lymphocyte phenotyping revealed CD4+ T cell lymphopenia (absolute: 250/lL) with CD3+ T cell 28%, CD19+B cell 60%, CD16+56+ NK cell 5% in the peripheral blood. Her serum anti-HBs, antipolio, anti-HSV, anti-CMV, anti-EBV, anti-IgM and anti-IgG antibodies and isohemagglutinins were absent. The girl was also clinically diagnosed as autosomal recessive-HIES and treatment was initiated with IVIG, itraconazole, sulfamethoxazoletrimethoprim and rhIFN-c for prophylaxis and immune modulation. She was not responding to topical steroids, emollients and oral antihistamines. Genomic DNA of the patient, parents and her brother who died with JCV infection were evaluated for the DOCK8 gene as the possible cause for the phenotype at the Department of Immunology and Molecular Pathology of Royal Free Hospital (London, UK). Engelhardt et al. identified a homozygous large deletion up to and including exon 25 of the DOCK8 gene (c.?_3121?del), deleting the first half of the gene (JACI 2009;124:1289, patients with codes of ARH016.6, ARH016.7) (2). It could not be understood where the exact beginning of the deletion was; the first deleted exon they detected was exon 3, but as they did not analyze exon 1 and 2, it was concluded that the deletion began before or at the start of the DOCK8 gene. Because of recurrent sibling deaths, she was considered for hematopoietic stem cell Pediatr Transplantation 2012: 16: 398–399 2012 John Wiley & Sons A/S.

Acute parvovirus B19 infection mimicking juvenile myelomonocytic leukemia

Abstract: An 11‐month‐old patient with parvovirus infection mimicking juvenile myelomonocytic leukemia (JMML) is presented. The patients history, presenting physical and laboratory features, was suggestive of JMML and consisted of fever, hepatosplenomegaly, lymphadenopathy, desquamation of the skin, anemia, leukocytosis with monocytosis and trilineage dysplastic findings of the peripheral blood and bone marrow. However, positive IgM titers for parvovirus B19 followed by seroconversion, negative cytogenetics and the benign follow‐up of the patient suggested acute parvovirus infection as an etiologic factor for development of dysplastic features in the patient, and thus is recommended for consideration in the differential diagnosis of MDS. Although parvovirus B19 infection mimicking MDS has previously been shown in two patients with spherocytosis and one with subclinical immune deficiency; to our knowledge, the present report is the first describing the association of acute parvovirus B19 infection with dysplastic features mimicking myelodysplasia (MDS) in a child without a demonstrable underlying hematolymphoid disorder.

Parvovirus B19 infection associated with severe aplastic anemia in an immunocompetent patient.

Human parvovirus B19 (PVB19) infection may cause mild pancytopenia characterized by transient and spontaneous recovery in healthy subjects. Severe aplastic anemia associated with PVB19 infection in patients without an underlying disease has been described in a number of reports. Here, a previous healthy, 10-year-old girl with severe aplastic anemia associated with PVB19 infection is described. The patient underwent bone marrow transplantation from her HLA-identical sibling resulting in complete recovery. PVB19 infection should be considered as one of the causes of aplastic anemia in patients without an underlying disease.

The effect of glutamine supplementation on hematopoietic stem cell transplant outcome in children: A case-control study

Abstract:u2002 HSCT associated morbidity and mortality is usually attributed to high‐dose chemotherapy/radiotherapy regimens used for conditioning. Glutamine (Gln), a conditionally essential amino acid during severe catabolic states, has been shown to have favorable effects in patients with malignancies and in those undergoing HSCT. However, controversy exists regarding its routine use. Studies in children investigating gln supplementation are very limited. In the present study, including 21 gln‐supplemented and 20 control pediatric patients, gln supplementation was shown to reduce the duration of fever and decrease the incidence of SOS during the HSCT course. In addition, a decrease in drug‐related toxicity and a trend toward reduced incidence of severe mucositis were observed.

FLUDARABINE, CYTARABINE, GRANULOCYTE COLONY-STIMULATING FACTOR, AND IDARUBICIN (FLAG-IDA) FOR THE TREATMENT OF CHILDREN WITH POOR-PROGNOSIS ACUTE LEUKEMIA: The Hacettepe Experience

Fludarabine, cytarabine, granulocyte colony-stimulating factor (G-CSF), and idarubicin (FLAG-IDA) regimen has been proven to be a potentially useful chemotherapy regimen for relapsed or poor-prognosis childhood leukemia. The aim of the study was to evaluate complete remission (CR) rate, toxicity, and overall survival of children with poor-prognosis acute leukemia who received the FLAG-IDA regimen. Furthermore, the authors investigated the children who achieved CR following FLAG-IDA treatment regarding their eligibility for allogeneic hematopoietic stem cell transplantation (HSCT). Between January 2002 and April 2007, 25 children with poor-prognosis acute leukemia were treated with FLAG-IDA regimen in our center. Of the 25 children (16 AML, 9 ALL) with poor-prognosis acute leukemia, 7 (28.0%) received 1 cycle, 17 (68.0%) received 2 cycles, and 1 (4%) received 3 cycles of FLAG or FLAG-IDA regimen. After 44 cycles of FLAG-IDA or FLAG regimen, 10/25 (40%) children were nonresponders, 15/25 (60.0%) showed CR. Five (20%) of these patients in CR who underwent allogeneic HSCT are still in remission. The remaining 20 (80.0%) children were lost due to infection or relapse of the primary diseases. The overall survival of patients who are still alive and underwent allogeneic HSCT (mean: 40.6 ± 4.7, median: 40, range: 34–46 months) was longer than that of patients (mean: 5.5 ± 4.3, median: 4, range: 1–15 months) who did not undergo allogeneic HSCT. The CR rate was quite high in the present study using the FLAG-IDA regimen, and the authors believe this regimen is a possible option prior to allogeneic HSCT in children with poor-prognosis acute leukemia.

Venous Thromboembolism after Allogeneic Pediatric Hematopoietic Stem Cell Transplantation: A Single-Center Study.

Objective: Venous thromboembolism (VTE) in children who undergo hematopoietic stem cell transplantation (HSCT) has high morbidity. The aim of this study is to assess the incidence of VTE in allogeneic pediatric HSCT recipients and the contribution of pretransplant prothrombotic risk factors to thrombosis. Materials and Methods: We retrospectively evaluated 92 patients between April 2010 and November 2012 undergoing allogeneic HSCT who had completed 100 days post-HSCT. Before HSCT, coagulation profiles; acquired and inherited prothrombotic risk factors including FV G1691A (factor V Leiden), prothrombin G20210A, methylenetetrahydrofolate reductase (MTHFR) C677T, and MTHFR A1298C mutations; and serum homocysteine and lipoprotein (a), plasma antithrombin III, protein C, and protein S levels were obtained from all patients. Results: In the screening of thrombophilia, 8 patients (9%) were heterozygous for factor V Leiden, 5 (6%) were homozygous for MTHFR 677TT, 12 (14%) were homozygous for MTHFR 1298CC, and 2 (2%) were heterozygous for prothrombin G20210A mutation. We observed VTE in 5 patients (5.4%); a prothrombotic risk factor was found in 3 out of these 5 patients, while 4 out of 5 patients had central venous catheters. It was determined there was no significant relationship between VTE and inherited prothrombotic risk factors. Conclusion: VTE after HSCT seems to be a low-frequency event that may be due to low-dose, low-molecular-weight heparin prophylaxis, and the role of inherited prothrombotic risk factors cannot be entirely excluded without a prospective study.

CD34:CD117 co-expression in childhood acute leukemia

CD117 protein is expressed by the primitive CD34 positive haemopoietic stem cells and also demonstrated on the blasts of 30-100% of AML cases, but rarely on lymphoblasts. Therefore several investigators have used CD117 expression to exclude lymphoblastic origin of blasts. However, conflicting results exist in the literature. We investigated CD34 and CD117 status at initial presentation of 232 children with acute leukemia. CD34 was commonly expressed in all types of acute leukemias, whereas CD117 molecule seemed to be a more specific marker for leukemia of myeloid origin being demonstrated on > 5% of blasts in 60 out of 73 cases of AML patients, but rarely detected in ALL (9/140 patients). Moreover, co-expression of CD34/CD117 was extremely rare on lymphoblasts with only 3/140 ALL patients demonstrating > 5% co-expression of CD34 and CD117, and therefore we suggest that it should be used in the exclusion of ALL.

Serum zinc and alkaline phosphatase values in pediatric bone marrow transplantation patients.

Zinc (Zn) plays an important role in the maintenance of immune functions, including cellular/humoral immunity, and in the prevention of oxidative injury. Therefore, the maintenance of a normal Zn status may be important in bone marrow transplantation (BMT) patients. Serum Zn levels were determined in 35 children during the BMT period. In addition, as Zn-related factors, serum Cu levels and alkaline phosphatase (AP) activity were also measured. There was a significant decrease in Zn and AP values during the immediate post-transplant period (lowest at day +7) when compared to pre-BMT levels (p < .01). The patients who developed hypozincemia were more likely to be transplanted for a diagnosis of malignant disorder and were younger, and adverse events appeared to occur more frequently. This preliminary study suggests that maintaining a normal Zn status may be important in BMT patients and that Zn deficiency may be a risk factor for adverse events.

Neurological complications after allogeneic hematopoietic stem cell transplantation in children, a single center experience.

In this study, we retrospectively examined the data of children who underwent allo‐HSCT from HLA‐matched family donors. We analyzed the incidence, etiological factors, clinical characteristics, possible reasons, risk factors, and follow‐up of neurologic complications. BU‐based conditioning regimens were used in most of the cases (n = 62). The median duration of follow‐up for the 89 patients was 20 months (range 1–41 months). Eleven percent of transplanted children developed one or more neurological symptoms after HSCT with a median observation time of two months (range −6 days to 18 months). The median age of the four girls and six boys with neurological complication was 13 yr (range 5.3–17.6 yr). Cylosporine A neurotoxicity was diagnosed in five children, four of them were PRES. The rest of complications were BU and lorazepam toxicity, an intracranial hemorrhage, a sinovenous thrombosis, and a transient ischemic attack during extracorpereal photopheresis. No difference was found between groups of neurological complication according to age, gender, diagnosis, hospitalization time, neutrophil and platelet engraftment time, stem cell source, and conditioning regimen, acute and chronic GVHD or VOD. Neurological complication was the cause of death in one patient (1.1%).

Increased availability of family donors for hematopoietic stem cell transplantation in a population with increased incidence of consanguinity

Balcı YI, Tavil B, Tan CS, Ozgur TT, Bulum B, Cetin M, Balcı M, Yalcın S, Tezcan I, Uckan D. Increased availability of family donors for hematopoietic stem cell transplantation in a population with increased incidence of consanguinity.u2028Clin Transplant 2011: 25: 475–480.