Acute lymphoblastic leukaemia in a child with systemic lupus erythematosus.

Haematological involvement of systemic lupus erythematosus (SLE) - which ranges from the well-described haemolytic anaemia to macrophage activation syndrome - has a large impact on both morbidity and mortality. On the other hand, association between haematological malignities and SLE - in terms of pathophysiology and molecular genetics - is an obscure entity which has not been clarified evidently to date. Herein, we present a six-year-old female with the diagnosis of SLE who developed acute lymphoblastic leukaemia following a period of myelodysplasia. It could possibly be coincidental; however, persistent cytopenia, prominent dysplasia on bone marrow smears and azathioprine treatment may be considered as possible triggers for the development of leukaemia in the present case.

Hematological features of pediatric systemic lupus erythematosus: suggesting management strategies in children.

AIM: The aim of this study was to analyze the hematological features in children with systemic lupus erythematosus (SLE) and to review our current treatment protocols. METHODS: We evaluated hematological findings of 43 children with SLE diagnosed and followed at the Pediatric Rheumatology Division of Hacettepe University, Turkey. Thirty-seven patients with hematological abnormalities were analyzed in detail. RESULTS: Median age at presentation was 13 years. Hematological involvement was seen in 86% of patients. The most common hematological finding was anemia (n = 30). Anemia was either a Coombs (+) hemolytic one, or was due to other causes. Hemolytic anemia was treated with steroids and intravenous gamma globulin (IVIG). Leucopenia and thrombocytopenia were detected in 35.1 % and 37.8 %, respectively. Bone marrow aspiration was performed in 15, mainly for cytopenia. Secondary dysplastic changes were common. Acute lymphoblastic leukemia (ALL) was diagnosed in one patient. Six patients were diagnosed as having macrophage activation syndrome (MAS). One patient died due to secondary infections and multiorgan failure despite aggressive treatment. In patients diagnosed early, treatment with steroids and cyclosporine resulted in an excellent response. Thrombotic microangiopathy was detected in two patients. Both were treated successfully with steroids and plasma exchange. Antiphospholipid and anticardiolipin antibodies were positive in 12 and 15 of the patients, respectively. Five developed deep vein thrombosis (DVT), one cerebral sinus thrombosis and one presented with purpura fulminans. They were effectively treated with anticoagulation protocol. CONCLUSION: Hematological findings should be carefully assessed and treated vigorously to prevent the morbidity and possible mortality.

Secondary hemophagocytosis in 3 patients with organic acidemia involving propionate metabolism.

Hemophagocytic lymphohistiocytosis (HLH) may develop secondary to infections, malignancies, immune deficiency syndromes, and rheumatologic and metabolic disorders. Associations between HLH and inborn errors of metabolism, including lysinuric protein intolerance, multiple sulfatase deficiency, galactosemia, Gaucher disease, Pearson syndrome, and galactosialidosis, have previously been reported in the literature. In this report the authors present 3 children with disorders of propionate metabolism--1 with methylmalonic acidemia and 2 with propionic acidemia--who developed secondary HLH during their metabolic attacks. All patients fulfilled the 5 HLH criteria of the Histiocyte Society. Familial HLH was ruled out by molecular analysis. Plasma exchange was performed for 2 of them. Unfortunately 1 died of multiorgan failure despite intensive therapy. This is the first report of such an association.

Anemia and neutropenic fever with high dose diazoxide treatment in a case with hyperinsulinism due to Munchausen by proxy.

BACKGROUND: The etiology of hyperinsulinemic hypoglycemia in adolescents is similar to that of adults. Patients resistant to medical treatment may undergo pancreatectomy. Diazoxide is the mainstay of medical treatment. Rarely bone marrow suppression is reported due to diazoxide. PATIENT: An adolescent with severe hyperinsulinemic hypoglycemia was referred for pancreatectomy after she was treated with high doses of diazoxide, octreotide and glucose. She developed anemia and febrile neutropenia in the course of diazoxide treatment that resolved with cessation of medication. The cause of the hyperinsulinemia proved to be classical Munchausen by proxy. CONCLUSION: This is the first report of bone marrow suppression involving erythroid series by diazoxide. Follow-up of blood count may be considered in patients on high dosages since anemia may be dose dependent. Munchausen by proxy poses a serious threat to children with significant morbidity and mortality. Awareness and a high index of suspicion in clinical settings with unusual causes are the mainstay for the diagnosis.

Evaluation of cardiovascular complications with 99mTc tetrofosmin gated myocardial perfusion scintigraphy in patients with thalassemia major.

OBJECTIVE: Iron overload limits the life expectancy of thalassaemic patients by causing cardiac toxicity. Iron also plays a catalytic role in the pathogenesis of atherosclerosis. The aim of this study was to evaluate the role of (99m)Tc Tetrofosmin gated myocardial perfusion scintigraphy (GMPS) in the detection of cardiac dysfunction in patients with thalassemia major. MATERIALS AND METHODS: Forty two patients with homozygous beta-thalassemia were enrolled in the study. Myocardial perfusion and wall motion were analysed in all patients (mean age 17 +/- 5.28) and 34 age-matched controls using GMPS. Clinical data, liver function tests, hemoglobin, ferritin, low density lipoprotein (LDL) and cholesterol levels, and the total number and frequency of transfusions were collected from patient records. RESULTS: 97.6 % and 78.5 % of patients had normal myocardial perfusion and wall motion respectively. Nine out of 42 thalassaemic patients had abnormal left ventricular wall motion; half of these had septal hypokinesia. No significant correlation was found between the total number of transfusions, serum ferritin levels and left ventricular ejection fraction (p = 0.442 and p = 1.00, respectively). Echocardiography revealed systolic dysfunction in 5 out of 9 patients with wall motion abnormality. LDL was normal in 38 out of 42 patients and cholesterol levels were normal in 37 out of 42 patients. CONCLUSIONS: Regional wall motion abnormalities can be seen in patients with thalassemia major. This early damage is frequently located in the septum and can be detected by GMPS. Serum ferritin levels and the number of blood transfusions are inadequate as predictors of myocardial dysfunction.

Benefit of high-dose methylprednisolone in comparison with conventional-dose prednisolone during remission induction therapy in childhood acute lymphoblastic leukemia for long-term follow-up.

Eight-year event-free survival (EFS) was evaluated in 205 patients with acute lymphoblastic leukemia (ALL), to consider the efficacy of high-dose methylprednisolone (HDMP) given during remission induction chemotherapy between 1 and 29 days. The St Jude Total XI Study protocol was used after some minor modifications in this trial. Patients were randomized into two groups. Group A (n = 108) received conventional dose (60 mg/m(2)/day orally) prednisolone and group B (n = 97) received HDMP (Prednol-L, 900-600 mg/m(2) orally) during remission induction chemotherapy. Complete remission was obtained in 95% of the 205 patients who were followed-up for 11 years; median follow-up was 72 months (range 60-129) and 8-year EFS rate was 60% overall (53% in group A, 66% in group B). The EFS rate of group B was significantly higher than of group A (P = 0.05). The 8-year EFS rate of groups A and B in the high-risk groups was 39% vs 63% (P = 0.002). When we compared 8-year EFS rate in groups A and B in the high-risk subgroup for both ages together /=10 years, it was 44% vs 74%, respectively. Among patients in the high-risk subgroup with a WBC count >/=50 x 10(9)/l, the 8-year EFS was 38% in group A vs58% in group B. During the 11-year follow-up period, a total of 64 relapses occurred in 205 patients. In group A relapses were higher (39%) than in group B (23%) (P = 0.05). These results suggest that HDMP during remission-induction chemotherapy improves the EFS rate significantly for high-risk patients in terms of the chances of cure.

Serum TNF-alpha, gamma-INF, G-CSF and GM-CSF levels in neutropenic children with acute leukemia treated with short-course, high-dose methylprednisolone.

High-dose methylprednisolone (HDMP, 20-30 mg/kg/day po) treatment has been shown to increase the number of bone marrow and peripheral blood CD34 positive progenitors and serum granulocyte-macrophage colony-stimulating factor (GM-CSF) levels in patients with ALL and AML. To investigate the effect of HDMP on some other hematopoietic regulatory cytokines, tumor necrosis factor-alpha (TNF-alpha), gamma-interferon (gamma-INF), granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6) were studied by microplate ELISA technique in 15 chemotherapy-induced neutropenic episodes of 14 children with acute leukemia (eight with ALL and six with AML) in whom HDMP was given alone (30 mg/kg/day po) for 4 days. The absolute neutrophil counts increased significantly in all neutropenic episodes on the fourth day of HDMP treatment. The TNF-alpha was 93.5 +/- 161 pg/ml in ALL and 78.3 +/- 61.4 pg/ml in AML before treatment and 76.1 +/- 160 pg/ml in ALL and 19.1 +/- 39.8 pg/ml in AML after treatment. The gamma-INF was 204.1 +/- 210.3 pg/ml in ALL and 130.8 +/- 138.3 pg/ml in AML before treatment and 28.6 +/- 50.5 pg/ml in ALL and 23.3 +/- 20.4 pg/ml in AML after treatment (P<0.05). Serum G-CSF and GM-CSF levels increased in all episodes (100%). The GM-CSF levels increased from 12.2 +/- 10.9 pg/ml to 36 +/- 24.7 pg/ml after treatment in ALL (P<0.05) and from 13.3 +/- 4 pg/ml to 45 +/- 48.1 pg/ml in AML (P<0.05). Serum G-CSF levels increased from 13.3 +/- 11.7 pg/ml to 83.3 +/- 86.8 pg/ml after treatment in ALL (P<0.05) and from 6.6 +/- 12.1 pg/ml to 28.3 +/- 11.3 pg/ml in AML (P<0.05). However, IL-6 levels were undetectable in all patients before and after therapy. These preliminary data suggest that short-course HDMP treatment could decrease serum TNF-alpha and gamma-INF and increase G-CSF and GM-CSF levels.

The effect of high-dose methylprednisolone treatment on GM-CSF level in children with acute leukemia: a pilot study.

High-dose methylprednisolone therapy (HDMP) induces acceleration of leukocyte recovery in acute lymphoblastic leukemia (ALL) and the differentiation of myeloblasts to mature granulocytes in acute myeloblastic leukemia (AML). These effects of corticosteroids have been shown to be due to the enhanced colony-stimulating activity (CSA) and responses to corticosteroids in some patients with aplastic anemia and myelodysplastic syndromes (MDS) have been related to increased CSA activity. We measured the serum (granulocyte-macrophage colony-stimulating factor (GM-CSF) levels by a sandwich linked immunoabsorbent assay (ELISA) in patients with ALL and AML at presentation and following high-dose methylprednisolone (HDMP) therapy. Serum GM-CSF levels at presentation in the ten cases studied ranged between 160 and 700 pg/ml (mean 418.5 +/- 252.5). One week following HDMP therapy GM-CSF levels increased to between 260 and 950 pg/ml (733.5 +/- 203.2). Four weeks after therapy the GM-CSF levels increased to between 470 and 1350 pg/ml (911 +/- 278.7). GM-CSF levels were markedly elevated one week after HDMP in the patients with ALL, suggesting that in addition to the lymphotoxic effects on leukemic blasts, the acceleration in neutrophil recovery may be due to release of GM-CSF induced by HDMP and its effects on myeloid progenitors.

A comparison of the effect of high-dose methylprednisolone with conventional-dose prednisolone in acute lymphoblastic leukemia patients with randomization.

In this preliminary study the efficacy of high-dose methylprednisolone (HDMP) during remission-induction chemotherapy was evaluated on 166 children with acute lymphoblastic leukemia (ALL). The St. Jude Total Therapy Study XI protocol with minor modifications was used in this trial. Patients were randomized into two groups. Group A received conventional-dose (2 mg/kg/day orally) prednisolone, and group B received high-dose methylprednisolone (HDMP, Prednol-L, 900-600 mg/m2 orally) during remission-induction chemotherapy. Complete remission was achieved in 97% of the children. For the 80 patients who were followed up for 3 years, median follow-up was 44 (range 5-60) months and the 3-year event-free survival (EFS) rate was 68.5%) overall, 58.6% in group A and 78.4% in group B. The EFS among patients in group B was significantly higher than in group A (p=0.05). When we compared the 3-year EFS of groups A and B in the high-risk groups and high-risk subgroups with white blood cell (WBC) counts > or = 50 x 10(9)/l and age > or = 10 years, the survival rates were 45% versus 77.2%, 33% versus 78% and 45% versus 89%, respectively. During the follow-up of 162 patients, relapses were significantly higher in group A. Bone marrow relapses in 162 patients, and also in a subgroup of patients > or = 10 years of age were significantly higher in group A. These results suggest that HDMP during remission-induction chemotherapy improves long-term EFS, particularly for high-risk patients.

Dramatic resolution of pleural effusion in children with chronic myelomonocytic leukemia following short-course high-dose methylprednisolone.

High-dose methylprednisolone (HDMP) which can induce--differentiation and -apoptosis of myeloid leukemic cells has been shown to be very effective in the treatment of extramedullary infiltration (EMI) of children with acute myeloblastic leukemia (AML). In the present study 2 children with chronic myelomonocytic leukemia (CMML) who had pleural effusions were given a single daily dose of oral methylprednisolone (20 mg/kg or 30 mg/kg). In addition to dramatic improvement of respiratory symptoms, pleural effusions disappeared in four days in both patients possibly due to apoptotic cell death induced by HDMP treatment. Further studies are needed to determine whether high-dose corticosteroids are also effective on the resolution of pleural effusions associated with other malignant disease.

Beta thalassaemia: a report of 20 children.

Beta-thalassaemias have a wide variety of musculoskeletal system manifestations. In this cross-sectional study, we aimed to investigate the frequency and features of musculoskeletal system problems in children with beta-thalassaemia. A total of 20 beta thalassaemic patients with an average age of 13.8 years were enrolled in the study. In all patients studied, detailed history regarding musculoskeletal involvement was taken and locomotor examinations were performed. All patients underwent radiographic examination with standing anteroposterior and lateral X-rays of the spine. Two physicians blinded for the diagnosis used Cobb technique for determining the degree of scoliosis. In 12 of 20 patients (60%) locomotor system involvement was found. Most frequent complaints were arthralgia and low back pain in 30% and 25% of patients respectively. Scoliosis was detected radiologically in 40% of patients with a lateral curve of at least 5 degrees Cobb.

Audiologic and impedancemetric findings within thalassaemic patients.

The objective of this study is to investigate hearing losses in thalassaemic patients. This study was conducted on 34 thalassemic patients of which 27 of them had thalassaemia major and the remaining 7 had thalassaemia intermedia. Six (11.11%) of the 54 ears with thalassaemia major were found to have normal hearing. Thirty-two ears (59.26%) had conductive hearing loss, 8 ears (14.81%) had mixed type of hearing loss. Moreover, in this group, there was no ear which had pure sensorineural hearing loss. Of the majority of patients having thalassaemia major and thalassaemia intermedia, an air bone gap was found even though there was no negative pressure in the middle ear. In these patients a high degree of static compliance and normal shaped, stiff amplitude, normal pressure tympanograms were observed. Moreover, in most of these patients acoustic reflexes were not obtained. These findings are rather interesting since they show the pathological changes which may cause stiffness in the middle ear sound transmission system.

Vacuolated white blood cells in thalassemia major.

We report a case of thalassemia major in which severe cytoplasmic vacuolization was seen in white blood cells as well as in their precursors. Cytochemical examination of the vacuoles revealed Sudan Black staining. Consequently, we believe that our patient had Jordans' anomaly coexisting with thalassemia major.

A warm antibody mediated acute hemolytic anemia with reticulocytopenia in a four-month-old girl requiring immunosuppressive therapy.

We present a four-month-old girl with severe hemolytic anemia and reticulocytopenia. This case is the youngest with hemolytic anemia encountered in our hospital. Findings of autoimmune hemolytic anemia were preceded by diphtheria-pertussis-tetanus (DPT) and oral polio vaccines which were given one month before. At admission, she had heart failure, her hemoglobin (Hb) was 27 gm/L, hematocrit (Hct) 8.5 percent, reticulocyte count 0.2 percent, and gamma and non-gamma Coombs tests were positive. Plasma Hb was 23 percent (N < 3%) and haptoglobin 0 mg/dl. Bone marrow aspiration smear revealed erythroid hyperplasia. No infection, immunodeficiency or malignancy could be established. She received multiple transfusions and did not respond to methyl prednisolone therapy of seven days' duration, but was successfully treated with a combination of immunosuppressive therapy (cyclophosphamide, 6-mercaptopurine, intravenous immunoglobulin and prednisolone, which was added later). This case is interesting in that the disease was preceded by DPT vaccination, was associated with reticulocytopenia and was resistant to steroids.

Serum erythropoietin in children with iron deficiency anemia.

Serum erythropoietin (EPO) levels were determined in 30 children with iron deficiency anemia. The mean age of the children, hemoglobin (Hb) levels, serum EPO levels and log EPO values were 4.7 +/- 5 years, 6.7 +/- 1.7 g/dl, 2284 +/- 3177 mU/ml and 2.81 +/- 0.82, respectively. In 83 percent of the patients poor diet was the determined cause of iron deficiency and in the remaining 17 percent, chronic blood loss. A significant negative correlation was found between the log EPO values and Hb values (r = 0.62, p < 0.01). There was no significant correlation between log EPO values and the other parameters [sex, age, mean corpuscular volume (MCV) red blood cell (RBC) red cell distribution width (RDW), serum iron, iron binding capacity]. There was a significant difference in the age of the patients with an Hb value < 5.5 g/dl and those with a value > or = 5.5 Significant differences were also observed in log EPO levels among these patients (p < 0.004). The mean Hb value of patients with log EPO values > or = 3 was lower than that in patients with log EPO values < 3 (p < 0.003). In 20 percent of the patients, serum EPO levels were much lower than the values expected from their Hb level. Serum EPO levels were high in all five patients with a history of chronic blood loss.

Severe hemolytic anemia after repair of primum septal defect and cleft mitral valve.

Two cases are described in which severe mechanical hemolytic anemia developed after surgical repair of primum atrial septal defect (ASD) and cleft mitral valve. In both cases there was residual mitral regurgitation after repair. Moderate mitral regurgitation and collision of the regurgitant jet with the teflon patch used for repair of the primum ASD were detected by color-Doppler echocardiography imaging. Laboratory tests showed normochromic normocytic anemia, increased indirect serum bilirubin, decreased plasma haptoglobin and hemoglobinuria. The peripheral blood smear contained numerous fragmented red cells. Following another surgical correction of the mitral valve (repair or mitral valve replacement), there was no more hemolysis. The two presented cases show that foreign materials in association with localized intracardiac turbulence may cause severe hemolysis.

Treatment of hemophilic pseudotumor with low-dose radiotherapy.

Hemophilic pseudotumor is one of the most serious complications of hemophilia and is usually treated with extensive surgery. A new treatment approach is radiotherapy. Patients with long-bone pseudotumors are usually treated with high doses of radiotherapy greater than 1500 cGy. We treated a 13-year-old hemophilic boy who had a pseudotumor of the tibia with low-dose radiotherapy (600 cGy). There was no complication during the two-and-a-half-year follow-up. Improvement of both the clinical and radiological status of the patient was noteworthy. We would like to suggest the use of low-dose radiotherapy in patients with hemophilic pseudotumors.

The effect of high-dose methylprednisolone on CD34-positive bone marrow cells in the children with acute myeloblastic leukemia.

The expression of CD34 antigen on the surface of bone marrow (BM) cells during remission induction was studied in 20 patients with CD34-negative acute myeloblastic leukemia (AML). The patients were given high-dose methylprednisolone (HDMP) alone for one week, after which time mitoxantrone and low-dose Ara-C were added. BM cells from all patients were studied one, two and four weeks after initiation of treatment to evaluate CD34 antigen expression using a three-step peroxidase antiperoxidase staining technique. The mean percentage of CD34-positive BM cells was 5.3% at presentation, increasing to 15.6% in the first week, 12.9% in the second week and 21.7% in the fourth week of therapy. During the same period the mean percentages of the initial BM blasts decreased from 64% to 22%, 7% and 2% in the first, second and fourth weeks of therapy, respectively. The increase in the CD34-positive BM cells one week after HDMP treatment alone suggests that HDMP directly or indirectly stimulates CD34-positive hematopoietic progenitor cells while decreasing BM blasts in patients with AML.

Bernard-Soulier-like functional platelet defect in myelodysplastic syndrome and in acute myeloblastic leukemia associated with trilineage myelodysplasia.

Platelet function was studied in a child with myelodysplastic syndrome (MDS: refractory anemia with an excess of blasts) and a child with acute myeloblastic leukemia (AML-M6) associated with trilineage myelodysplasia (TMDS). An acquired Bernard-Soulier-like platelet defect was considered in both patients with the findings of prolonged bleeding time and abnormally large platelets that failed to aggregate in response to ristocetin. In contrast to findings in von Willebrand's disease, the abnormal response of platelets to ristocetin could not be corrected by the addition of normal flesh plasma. The detection of abnormal platelet aggregation response to ristocetin may be a useful diagnostic finding for clonal disorders causing impaired platelet function in MDS and coexistent TMDS associated with AML. Further studies of ristocetin-induced platelet aggregation in a large number of these patients are required.

Changes of hemostatic factors in patients with hemoglobinopathies.

In this study, protein C (PC), protein S (PS), heparin cofactor II (HCFII), prothrombin fragment 1+2(PF1,2), thrombin-antithrombin III complex (TAT), von Willebrand factor (vWF) and thrombomodulin (TM) were investigated in 13 patients with beta thalassemia intermedia (TI) not requiring transfusion, six patients with sickle cell disease (SCD), and seven patients with HbS-beta thalassemia (S-BT) who were not in crisis. These hemostatic parameters were also studied in 12 healthy children assigned as a control group. Protein C and Protein S (PC-PS) were found to be decreased in TI patients and normal in S-BT patients. PC was decreased in SCD patients. In the patients with TI and SCD, the mean PF1,2 level was elevated, whereas the TAT level was not statistically different from that of the control group. These results suggested that in patients with hemoglobinopathies: a) decreased natural anticoagulants and b) enhanced procoagulant activation have been encountered. Other unexpected and interesting results of this study are the decreased vWF and elevated HCFII levels in all three patient groups.