Fatma Gumruk

NBEAL2 is mutated in gray platelet syndrome and is required for biogenesis of platelet α-granules

Gray platelet syndrome (GPS) is an autosomal recessive bleeding disorder that is characterized by large platelets that lack α-granules. Here we show that mutations in NBEAL2 (neurobeachin-like 2), which encodes a BEACH/ARM/WD40 domain protein, cause GPS and that megakaryocytes and platelets from individuals with GPS express a unique combination of NBEAL2 transcripts. Proteomic analysis of sucrose-gradient subcellular fractions of platelets indicated that NBEAL2 localizes to the dense tubular system (endoplasmic reticulum) in platelets.

Gray platelet syndrome: natural history of a large patient cohort and locus assignment to chromosome 3p

Gray platelet syndrome (GPS) is an inherited bleeding disorder characterized by macrothrombocytopenia and absence of platelet α-granules resulting in typical gray platelets on peripheral smears. GPS is associated with a bleeding tendency, myelofibrosis, and splenomegaly. Reports on GPS are limited to case presentations. The causative gene and underlying pathophysiology are largely unknown. We present the results of molecular genetic analysis of 116 individuals including 25 GPS patients from 14 independent families as well as novel clinical data on the natural history of the disease. The mode of inheritance was autosomal recessive (AR) in 11 and indeterminate in 3 families. Using genome-wide linkage analysis, we mapped the AR-GPS gene to a 9.4-Mb interval on 3p21.1-3p22.1, containing 197 protein-coding genes. Sequencing of 1423 (69%) of the 2075 exons in the interval did not identify the GPS gene. Long-term follow-up data demonstrated the progressive nature of the thrombocytopenia and myelofibrosis of GPS resulting in fatal hemorrhages in some patients. We identified high serum vitamin B(12) as a consistent, novel finding in GPS. Chromosome 3p21.1-3p22.1 has not been previously linked to a platelet disorder; identification of the GPS gene will likely lead to the discovery of novel components of platelet organelle biogenesis. This study is registered at www.clinicaltrials.gov as NCT00069680 and NCT00369421.

Hyperimmunoglobulinemia D and periodic fever syndrome; treatment with etanercept and follow-up

The hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) is an autoinflammatory syndrome. It is caused by the mutations of the mevalonate kinase gene. There is no consensus for specific therapy of HIDS, but there are some case reports and studies in regards to its treatment with drugs like colchicine, steroids, nonsteroid anti-inflammatory drugs, simvastatin, anakinra, thalidomide, and etanercept. We are reporting a case evaluated for the complaints of abdominal pain and febrile episodes with massive hepatomegaly, not common finding on physical examination, its treatment with etanercept, and long-term follow-up.

Secondary hemophagocytic lymphohistiocytosis in Turkish children.

Between January 1998 and January 2005, a total of 18 children 2 weeks–72 months of age were diagnosed as having secondary hemophagocytic lymphohistiocytosis. The frequency of secondary hemophagocytic lymphohistiocytosis among total hospitalized patients during this period was 0.05% (18 of 34,250). Of the 18 patients, 8 (44.5%) had bacterial infections; cytomegalovirus and Epstein-Barr virus infections were present in 5 (28%) and 1 (5.5%), patient, respectively. Leishmaniasis was diagnosed in 2 patients (11%), and herpes simplex virus was diagnosed in 2 patients (11%). Six patients died during treatment, and 1 patient was lost to follow-up. The survival rate was 61%.

Primary hemophagocytic lymphohistiocytosis in Turkish children

Nineteen children with hemophagocytic lymphohistiocytosis (HLH) were studied in the Department of Pediatric Hematology, Hacettepe University. Patients were divided into two groups. Group 1 : Thirteen patients were classified as having a genetic etiology (7 familial, 6 presumed familial) on the basis of an affected sibling and consanguinity. There was a history of consanguineous marriage in 13 of the families. Seven of them had a history of a sibling with HLH. Group 2 : Six patients were diagnosed with sporadic HLH. The age at presentation for familial patients was 0.7-84 months (mean 21.9 - 24.9 months), and for sporadic cases it was 2.5-48 months (mean 22.7 - 19.8 months). The clinical and laboratory data of these two groups were similar at diagnosis. Thirteen cases were diagnosed premortem by bone marrow aspiration. Splenic biopsy was performed in 2 patients. Four patients were diagnosed by postmortem examination. Elevated LDH levels were found in all patients tested. No significant differences for clinical and laboratory data were found between the two groups.

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/m2/day orally) prednisolone and group B (n = 97) received HDMP (Prednol-L, 900–600 mg/m2 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 ⩽2 or ⩾10 years, it was 44% vs 74%, respectively. Among patients in the high-risk subgroup with a WBC count ⩾50 × 109/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.

Value of Dual Energy Computed Tomography for detection of myocardial iron deposition in Thalassaemia patients: Initial experience

PURPOSE The aim of our study was to compare the value of cardiac DECT (cDECT) for detection of myocardial iron deposition to T2*w cardiac MRI (cMRI). MATERIAL AND METHODS Nineteen patients with clinical history of Thalassaemia underwent T2*-weighted cardiac MRI (cMRI) with a 1.5 T MR scanner (MAGNETOM Symphony, Siemens Medical Solutions, Erlangen, Germany) and cardiac dual energy CT (cDECT) with a DSCT scanner (SOMATOM Definition, Siemens Medical Solutions, Erlangen, Germany) on the same day. HU values obtained from cDECT scans and T2*-values from cMRI were statistically correlated to calculate significance levels. Table times were measured for both cDECT and cMRI and compared. Patients were asked to grade their subjective comfort during the examination. RESULTS In all patients cDECT scans were successfully acquired. HU values of septal muscle correlated strongly with T2*-values, whereas no correlation was found for paraspinal muscle. Table time was significantly shorter for cDECT compared to cMRI (mean: 3.7 min vs. 11.2 min) and subjective patient comfort was rated comfortable for cDECT and average to poor for cMRI. Mean radiation dose was 0.71 mSv. CONCLUSION cDECT scans seem to be possible for evaluation of myocardial iron load in pediatric Thalassaemia patients.

Efficacy of daily and weekly iron supplementation on iron status in exclusively breast-fed infants.

Iron deficiency anemia (IDA) remains the most prevalent nutritional deficiency in infants worldwide. The purpose of this study was to determine the efficacy of daily and weekly iron supplementation for 3 months to improve the iron status in 4-month-old, exclusively breast-fed healthy infants. Infants 4 months of age were eligible for the open, randomized controlled trial if their mothers intended to continue exclusive breast-feeding until the infants were 6 months of age. Infants or mothers with iron deficiency (ID) or IDA on admission were excluded. The infants (n = 79) were randomly assigned to three groups, the first group receiving daily (1 mg/kg daily), the second group weekly (7 mg/kg weekly), and the third group no iron supplementation. Anthropometric measurements were taken on admission and at 6 and 7 months of age. Iron status was analyzed on admission and monthly for 3 months. Both hematologic parameters and anthropometric measurements were found to be similar among the three groups during the study period. Seven infants (31.8%) in the control group, six (26.0%) in the daily group, and three (13.6%) in the weekly group developed ID or IDA (P > 0.05). Infants whose mothers had ID or IDA during the study period were more likely to develop ID or IDA independently from iron supplementation. Serum ferritin levels decreased between 4 and 6 months of age in the control and daily groups; the weekly group showed no such decrease. In all groups, the mean levels of serum ferritin were significantly increased from 6 months to 7 months of age during the weaning period. In this study, which had a limited number of cases, weekly or daily iron supplementation was not found to decrease the likelihood of IDA. In conclusion, exclusively breast-fed infants with maternal IDA appeared to be at increased risk of developing IDA.

Familial Selective Vitamin B12 Malabsorption (Imerslund-Grasbeck Syndrome) in a Pool of Turkish Patients

Thirty-six patients with Imerslund-Gräsbeck syndrome are presented. The mean ages at presentation and diagnosis were 4.7 +/- 3.7 years and 7.2 +/- 4.2 years, respectively. The mean hemoglobin level was 5.8 +/- 2.2 g/dL, the mean cell volume was 104.9 +/- 11.6 fL, the white blood cell count was 4479 +/- 2022/mm3, and the serum vitamin B12 level was 96.9 +/- 73 pg/mL. At diagnosis, 5 of the 36 patients, aged 5 to 16 years, had neurologic symptoms. All the patients had severe megaloblastic changes in bone marrow precursor cells. Proteinuria was detected in 78% of them. Patients with proteinuria had a younger age of onset (P < 0.0001) and diagnosis (P < 0.001) compared with those without proteinuria. In all patients, vitamin B12 excretion unbound to intrinsic factor after a flushing dose of vitamin B12 was lower than normal, and there was no appreciable correction in urinary vitamin B12 excretion after binding of intrinsic factor. The impairment of vitamin B12 absorption studies in Schilling tests; however, showed great variation among patients. Serum haptoglobin values were close to zero in all patients, indicating the presence of that intravascular hemolysis in Imerslund-Gräsbeck syndrome. Variations among patients in the age of presentation, degree of impairment of vitamin B12 absorption, and presence or absence of proteinuria suggest a heterogeneity in etiology of Imerslund-Gräsbeck syndrome at the molecular level.

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.