Rudolf Benz

Human L-ferritin deficiency is characterized by idiopathic generalized seizures and atypical restless leg syndrome

Human L-ferritin deficiency causes reduced cellular iron availability and increased ROS production with enhanced oxidized proteins, which results in idiopathic generalized seizures and atypical restless leg syndrome.

Long-term follow-up of interferon-alpha induction and low-dose maintenance therapy in hairy cell leukemia.

Objective:  Interferon‐α (IFNα) was the first effective pharmacologic treatment of hairy cell leukemia (HCL). Since 1990 purine analogs replaced IFNα because of higher rates of complete remission and an invariable disease recurrence after cessation of IFNα. However, there are only limited data about long‐term maintenance treatment with IFNα and none about dose finding in this phase.

Congenital dyserythropoietic anemia type I with bone abnormalities, mutations of the CDAN I gene, and significant responsiveness to alpha-interferon therapy

Congenital dyserythropoietic anemia type I (CDA I) is a rare autosomal recessive disorder with ineffective erythropoiesis, characteristic morphological abnormalities of erythroblasts, and iron overloading. CDA I is caused by mutations in the CDAN I gene, encoding a protein named codanin-1. Complex bone abnormalities, especially syndactyly, have not been systematically described with this disease. We present two cases of morphologically and genetically confirmed CDA I with striking bone abnormalities and response to treatment with alpha-interferon. Our cases clearly document the association of skeletal anomalism with CDA I and indicate that codanin-1 may play a role in the development of the skeleton.

Interferon as an alternative to purine analogues in the treatment of hairy cell leukaemia

recommendations of the Platelet Physiology Subcommittee of Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis (Hayward et al, 2006) and with a recently published review of screening tests for platelet functions (Harrison & Mumford, 2009). The inclusion of PFA 100 test results in our diagnostic work-up also reflects the fact that this test is widely used as screening test for disturbances of primary haemostasis in the coagulation laboratories of the German-speaking countries (Streif et al, 2007). In summary, we regard our approach for diagnosing ALD and the criteria selected as being in line with present international recommendations. As long as no convincing evidence is presented on the significance of TXB2 serum determinations in patients with ALD (nota bene: not in aspirin treated patients!) we would further propose and adhere to the classification schema and criteria as published by our group.

G-CSF-induced remission in two cases of acute myeloid leukemia.

We report on two elderly patients with newly diagnosed acute myeloid leukemia (AML) who were treated in palliative intention because of comorbidities and intermediate or poor risk cytogenetics. Both received G-CSF to reduce the risk of infection related to neutropenia. Interestingly, one patient achieved a full hematological remission and the other a peripheral remission with dramatic reduction of the bone marrow blast count. Although a direct therapeutic effect of myeloid growth factors seems to be unusual in AML, the use of G-CSF or GM-CSF may be recommended in patients such as elderly patients who are not suited for intensive chemotherapy.

Unexpected cause of high fever in the blood film

![Figure][1] A 17-year-old refugee from Eritrea presented with sudden fever (to 41°C), myalgias, and headache. Three days before admission, he had arrived in Switzerland after a long journey through the Sudan and Libya and across the Mediterranean and Italy. Other than mild anemia, he had

Leriche’s syndrome and Löffler endocarditis in a 30-year-old patient presenting with hypereosinophilic syndrome

Dear Editor, Here, we report a severe complication of hypereosinophilic syndrome (HES), the onset of Leriche’s syndrome, in a 30year-old patient. A 30-year-old man was referred to our institution due to acute onset of severe pain and symmetric sensory neuropathy of both legs. Contrast enhanced computed tomography showed occlusion of aortic bifurcation (Leriche’s syndrome) (Fig. 1a). Immediate thrombectomy secured reperfusion of the lower limbs. Histopathologic workup confirmed the presence of thrombotic material. Three weeks prior to admission, the patient had been diagnosed with a hypereosinophilic syndrome and Loffler’s endocarditis. At that time, he had presented with nonspecific abdominal pain accompanied by diarrhea and progressive general weakness that he had observed for more than 2 months. Diagnostic workup showed an abnormal eosinophil count 7.5 (10/l) with a corresponding myeloproliferative bone marrow. Fluorescence in situ hybridization (FISH) analysis for rearrangements of the platelet-derived growth factor receptors alpha and beta (PDGFRα/β) were evaluated as negative (LSI 4q12 Tri-Color Rearrangement probe set; Poseidon Repeat Free, 5q33, Break probe). Echocardiography indicated the presence of Loffler endocarditis. Intracardial thrombotic formations had been detectable. Oral anticoagulation with phenprocoumone had been started, and an INR between 2 and 3 was targeted. When Leriche’s syndrome was diagnosed, the INR was 2.0. The patient had been treated with prednisolone (1 g) for 2 days with a temporary drop of eosinophilis to 1.8 (10/l). At admission, hematologic workup confirmed massive increase of eosinophils 3.6 (10/l). Screening for causes of reactive eosinophilia was negative with regard to an allergic reaction and autoimmune, parasitic, or helminthic diseases. Echocardiography confirmed Loffler’s endocarditis (Fig. 1b). Examination of the bone marrow showed a hypercellular marrow with marked increase of eosinophilic granulocytes and their progenitors (Fig. 1c). Standard cytogenetic characterization showed a normal karyotype. Using the FIP1L1Chic2-PDGFRα dual-color probe which is optimized to detect the Chic2 deletion at 4q12 FISH analysis found a deletion in chromosome 4, band q12 [del(4)(q12)] (Fig. 1d). Thomas Klag and Thomas Schnetzke have contributed equally to this work.

Paroxysmal non-kinesigenic dyskinesia due to spinal cord infiltration of low-grade B cell non-Hodgkin's lymphoma

Dear Editor, A 65-year-old female patient was referred to our clinic due to singultus, nausea and vomiting. Splenomegaly without lymphadenopathy was found. The remaining clinical examination and an MRI scan of the brain were normal. Bone marrow examination was morphologically unremarkable, but the light-chain scattergram in flow cytometry showed a significant B cell population which was double negative although a clear light-chain restriction indicating a clonal population was not present. We therefore planned a splenectomy for further diagnosis. However, the patient developed rapidly progressing symmetrical tetraparesis. A spinal MRI scan revealed an extensive intramedullary area of intense contrast enhancement on T1-weighted images, comprising the spinal cord from C1 downwards (Fig. 1a). A biopsy was not possible without a significant potential risk for irreversible neural damage. The cerebrospinal fluid (CSF) contained CD20positive lymphocytes of lymphoplasmocytoid aspect compatible with non-Hodgkins lymphoma. We began a treatment with high-dose steroids and intrathecal liposomal cytarabine and performed a splenectomy to classify the suspected B cell lymphoma. The spleen showed an infiltration of the red pulp with neoplastic CD5-negative B lymphocytes with some lymphoplasmocytoid differentiation. However, due to the artefacts caused by the preceding treatment with high-dose glucocorticosteroids, a further subclassification of the lymphoma was not possible. Two weeks after the initial lumbar punction, no lymphoma cells could be detected in the CSF. The patient received a treatment with rituximab (375 mg/m) on day 1 followed by methotrexate (3,500 mg/m) on day 2 (3 cycles every 14 days). The MRI of the neuroaxis normalised completely (Fig. 1b). Unfortunately, 3 weeks after the onset of the initial symptoms, the patient started to have episodes of involuntary hand movements. During these episodes, she noted forceful adduction and flexion in the metacarpo-phalangeal joints of both thumbs, as well as flexion in the metacarpo-phalangeal joints of the fingers. Either hand alone or both hands simultaneously could be affected (video Segment 1). The individual episodes lasted 30 to 40 s and occurred every 60 s to 30 min, both during wakefulness and sleep. They started and ceased spontaneously. In particular, they could not be triggered by active hand or finger movements or by sensory stimuli applied to the arms or the neck (video Segment 2). We diagnosed symptomatic short-lasting paroxysmal non-kinesigenic dyskinesia (PNKD). While carbamazepine had only a minor and short-lived effect, benzodiazepines, pregabalin, levetiracetam and morphine had none. The missing response to pharmaceutical treatment was reminiscent of idiopathic PNKD. During rehabilitation, both the tetraparesis and dyskinesia gradually resolved, and 4 months Electronic supplementary material The online version of this article (doi:10.1007/s00277-011-1258-4) contains supplementary material, which is available to authorized users.

Neisseria elongata infection associated with complement inhibition during treatment of paroxysmal nocturnal haemoglobinuria

We report a 54-year-old man who had been diagnosed with paroxysmal nocturnal haemoglobinuria (PNH) 5 years previously (Images). After meningococcal vaccination, eculizumab treatment had been commenced, leading to improved blood values and no further thrombotic events. An indwelling venous line was inserted because of poor venous access. One episode of Citrobacter koseri infection had occurred 4 years previously and was treated with ciprofloxacin. No significant infection occurred thereafter until this current presentation with a short history of fever up to 39 1°C. On clinical examination his blood pressure was 100/63 mmHg and his pulse was 106/min; however, no clear site of infection could be detected. Blood cultures were taken and amoxicillin/clavulanic acid was immediately started. Fever resolved within 1 day and the patient improved rapidly. Neisseria elongata was grown from all blood cultures (two peripheral blood and two from the indwelling line). Intravenous antibiotics were continued for 14 days with blood cultures remaining negative after cessation of the treatment. Neisseria elongata is a nonmotile, strictly aerobic, Gramnegative bacillus. In contrast to other Neisseria spp., which are either cocci or diplococci, it has a unique rod-like shape. The bacterium is mainly found in the oral cavity and pharynx and was previously considered to be non-pathogenic to humans. However, there are an increasing number of reports of endocarditis and osteomyelitis caused by this organism. Endocarditis often requires early surgical intervention. One of the most important predisposing factors for infections due to the “typical” pathogenic Neisseria species, N. meningitidis and N. gonorrhea, is a deficiency in complement activity resulting from pharmacological inhibition. Eculizumab used in PNH is a strong inhibitor of the final complement pathway. A recent study showed an increased risk of infections due to N. meningitides despite the mandatory vaccinations. Infections with N. gonorrhea have also been described. It appears likely that, in addition, complement inhibition favours N. elongata infection. Such infections should be treated without delay. Treatment duration is influenced by individual factors, such as the presence of an indwelling venous line, which increases the risk of disease recurrence if not removed.

Microarray-based comparative genomic hybridisation reveals additional recurrent aberrations in adult patients evaluated for myelodysplastic syndrome with normal karyotype

The myelodysplastic syndromes (MDS) are a heterogeneous group of haematopoietic stem cell disorders characterized by ineffective haematopoiesis, dysplasia, cytopenia and a propensity to evolve towards acute myeloid leukaemia (AML). MDS affect predominantly the elderly with median age at diagnosis above 70 years. According to the European LeukemiaNet, for diagnosis of adult MDS, examinations of peripheral blood, bone marrow aspirate and biopsy and chromosome banding analysis (CBA) are mandatory and fluorescence in-situ hybridisation (FISH) and flow cytometry immunophenotyping are recommended, whereas microarraybased comparative genomic hybridisation (aCGH) and molecular genetics are suggested for special circumstances (Malcovati et al, 2013). CBA detects aberrations in approximately 50% of de novo MDS (Platzbecker et al, 2012). Recent studies have shown that high resolution techniques increase the abnormality rate. To the best of our knowledge, the majority of aCGH studies in MDS involve series of patients with known diagnoses. Therefore, we sought to evaluate the additional information obtained by aCGH compared to CBA in a large cohort of patients undergoing primary diagnostic evaluation for suspected MDS. Bone marrow samples (n = 237) referred for diagnostic evaluation of MDS were analysed. Informed consent was obtained from all patients. Subsequently, MDS was clinically confirmed in 135 (57%) cases (median age, 71 years; range: 14–94 years) but could not be established in 69 (29%) patients with cytopenia (median age, 67 years; range: 5–87 years), (non-confirmed MDS patients). Other haematological malignancies were diagnosed in 33 (14%) patients, who were excluded (Table SI). Chromosome banding analysis was performed according to the guidelines of the Association for Clinical Cytogenetics, and was successful in 97% confirmed MDS and 94 2% nonconfirmed MDS. 33 1% confirmed MDS patients had an abnormal karyotype. This percentage of abnormal cases is lower than the expected rate of approximately 50%. However, the reported rates vary from 30-60% depending on the MDS risk types included. In our cohort 21 5% MDS patients had refractory anaemia with excess blasts type1/2. Thus, our finding is concordant to with similar recently published cohorts (Ciabatti et al, 2017). Nine (13%) non-confirmed MDS patients had an abnormal karyotype. Microarray-based comparative genomic hybridisation was performed using the AFFYMETRIX CYTOSCAN HD ARRAY KIT (Affymetrix, Santa Clara, CA, USA). Single samples were analysed with the CHROMOSOME ANALYSIS SUITE software (Affymetrix) using cut-offs of 500 Kb for copy number alterations (CNA), excluding the known copy number variants (CNVs) listed in the Database of Genomic Variants (http://dgv.tca g.ca/dgv/app/home), and 10 Mb for copy neutral loss of heterozygosity (cnLOH) unless genes or regions known to be relevant for haematological malignancies were involved or mosaicism was observed (O’Keefe et al, 2010; Schoumans et al, 2016). The cut-off for CNA (5 Mb) proposed by Schoumans et al (2016) was not applied, because it is just a proposition to facilitate and standardize the interpretation of somatic results. aCGH was successful in all cases, and was abnormal in 52 6% confirmed MDS cases and 29% patients with non-confirmed MDS (Tables SII and SIII). Microarray-based comparative genomic hybridisation increased the detection rates of cytogenetic aberrations by 19 5% for confirmed MDS, which is within the expected range, and 16% for non-confirmed MDS. However, CBA analysis detected low-level mosaicism or balanced aberrations in 6 confirmed MDS and 2 non-confirmed MDS cases (Table SIV), which highlights the utility of CBA and indicates that it cannot be replaced by aCGH. Microarray-based comparative genomic hybridisation identified abnormalities that were not detected by CBA in 40 (29 6%) MDS cases and 12 (17 4%) non-confirmed MDS cases (Tables I and II). MDS patients with normal karyotype based on CBA seem to have reduced survival if cryptic abnormalities are present. However, in contrast to gains, only the presence of submicroscopic deletions seems to adversely affect outcome in MDS (Volkert et al, 2016). In our study, cnLOH were observed in 18 5% of MDS, involving almost all chromosomes (Fig S1). Some of the deletions and cnLOH identified in our study are known to contain genes that are possibly relevant in myeloid neoplasms or known tumour suppressor genes. It has been suggested that MDS patients with cnLOH in 7q, 17p, or 11q could be classified into higher cytogenetic risk groups (Makishima et al, 2010). cnLOH 7q was detected in 3 MDS cases and one non-confirmed MDS. cnLOH 11q and 17p were seen in 2 and 3 MDS cases, respectively and in no non-confirmed MDS Correspondence