The gray platelet syndrome is a hereditary, usually autosomal recessive bleeding disorder caused by a deficiency of alpha granules in platelets. We detected a nonsense mutation in the gene encoding the transcription factor GFI1B (growth factor independent 1B) that causes autosomal dominant gray platelet syndrome. Both gray platelets and megakaryocytes had abnormal marker expression. In addition, the megakaryocytes had dysplastic features, and they were abnormally distributed in the bone marrow. The GFI1B mutant protein inhibited nonmutant GFI1B transcriptional activity in a dominant-negative manner. Our studies show that GFI1B, in addition to being causally related to the gray platelet syndrome, is key to megakaryocyte and platelet development.

N on-transferrin-bound iron and its labile (redox active) plasma iron component are thought to be potentially toxic forms of iron originally identified in the serum of patients with iron overload. We compared ten worldwide leading assays (6 for non-transferrinbound iron and 4 for labile plasma iron) as part of an international interlaboratory study. Serum samples from 60 patients with four different iron-overload disorders in various treatment phases were coded and sent in duplicate for analysis to five different laboratories worldwide. Some laboratories provided multiple assays. Overall, highest assay levels were observed for patients with untreated hereditary hemochromatosis and β-thalassemia intermedia, patients with transfusion-dependent myelodysplastic syndromes and patients with transfusion-dependent and chelated β-thalassemia major. Absolute levels differed considerably between assays and were lower for labile plasma iron than for non-transferrin-bound iron. Four assays also reported negative values. Assays were reproducible with high between-sample and low withinsample variation. Assays correlated and correlations were highest within the group of non-transferrin-bound iron assays and within that of labile plasma iron assays. Increased transferrin saturation, but not ferritin, was a good indicator of the presence of forms of circulating nontransferrin-bound iron. The possibility of using non-transferrin-bound iron and labile plasma iron measures as clinical indicators of overt iron overload and/or of treatment efficacy would largely depend on the rigorous validation and standardization of assays. Second international round robin for the quantification of serum non-transferrin-bound iron and labile plasma iron in patients with iron-overload disorders

Summary Baseline characteristics, disease‐management and outcome of 1000 lower‐risk myelodysplastic syndrome (MDS) patients within the European LeukaemiaNet MDS (EUMDS) Registry are described in conjunction with the validation of the revised International Prognostic Scoring System (IPSS‐R). The EUMDS registry confirmed established prognostic factors, such as age, gender and World Health Organization 2001 classification. Low quality of life (EQ‐5D visual analogue scale score) was significantly associated with reduced survival. A high co‐morbidity index predicted poor outcome in univariate analyses. The IPSS‐R identified a large group of 247 patients with Low (43%) and Very low (23%) risk score within the IPSS intermediate‐1 patients. The IPSS‐R also identified 32 High or Very high risk patients within the IPSS intermediate‐1 patients. IPSS‐R was superior to the IPSS for predicting both disease progression and survival. Seventy percent of patients received MDS‐specific treatment or supportive care, including red blood cell transfusions (51%), haematopoietic growth factors (58%) and iron chelation therapy (8%), within 2 years of diagnosis; while 30% of the patients only required active monitoring. The IPSS‐R proved its utility as a more refined risk stratification tool for the identification of patients with a very good or poor prognosis and in this lower‐risk MDS population.

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Background Diagnosis of primary immunodeficiencies (PIDs) is complex and cumbersome yet important for the clinical management of the disease. Exome sequencing may provide a genetic diagnosis in a significant number of patients in a single genetic test. Methods In May 2013, we implemented exome sequencing in routine diagnostics for patients suffering from PIDs. This study reports the clinical utility and diagnostic yield for a heterogeneous group of 254 consecutively referred PID patients from 249 families. For the majority of patients, the clinical diagnosis was based on clinical criteria including rare and/or unusual severe bacterial, viral, or fungal infections, sometimes accompanied by autoimmune manifestations. Functional immune defects were interpreted in the context of aberrant immune cell populations, aberrant antibody levels, or combinations of these factors. Results For 62 patients (24%), exome sequencing identified pathogenic variants in well-established PID genes. An exome-wide analysis diagnosed 10 additional patients (4%), providing diagnoses for 72 patients (28%) from 68 families altogether. The genetic diagnosis directly indicated novel treatment options for 25 patients that received a diagnosis (34%). Conclusion Exome sequencing as a first-tier test for PIDs granted a diagnosis for 28% of patients. Importantly, molecularly defined diagnoses indicated altered therapeutic options in 34% of cases. In addition, exome sequencing harbors advantages over gene panels as a truly generic test for all genetic diseases, including in silico extension of existing gene lists and re-analysis of existing data. Electronic supplementary material The online version of this article (10.1186/s13073-019-0649-3) contains supplementary material, which is available to authorized users.

Based on studies in laboratory animals and on measurements of the urinary metabolites (allo)tetrahydrocortisol and tetrahydrocortisone in human volunteers it has been claimed that liquorice-induced mineralocorticoid excess is caused by a unique defect in the conversion of cortisol to cortisone. To further evaluate this hypothesis we have investigated the influence of glycyrrhetinic acid (GA), the mineralocorticoid-active constituent of liquorice, on plasma cortisol and cortisone in 10 healthy young normotensive volunteers. Pure GA (500 mg/day), administered orally from days 3-10 of the study, exerted pronounced mineralocorticoid activity. Ingestion of GA resulted in an elevated urinary excretion of free cortisol and virtually unchanged plasma cortisol levels in the presence of markedly decreased levels of both plasma cortisone and urinary free cortisone. These results provide direct clinical support for the hypothesis that GA induces an inhibition of the activity of 11 beta-dehydrogenase, resulting in a blockade in the conversion of cortisol to cortisone.

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The prognosis of central nervous system (CNS) relapse of systemic non-Hodgkin lymphoma is poor with 1-year survival historically at 0% to 20%. Aiming to improve these results, we performed a multicenter phase 2 study in patients with a CNS relapse, with or without concurrent systemic relapse. Treatment consisted of 2 cycles of R-DHAP alternating with high-dose methotrexate (MTX) and was combined with intrathecal rituximab. Responding patients received a third R-DHAP-MTX cycle followed by busulfan and cyclophosphamide myeloablative therapy and autologous stem cell transplantation. In patients with persistent cerebrospinal fluid lymphoma after cycle 1, the intrathecal rituximab was replaced by intrathecal triple therapy, with MTX, cytarabine, and dexamethasone. Thirty-six patients were included. Eighteen had evidence of cerebrospinal fluid lymphoma, 24 had brain parenchymal disease, and 20 (56%) had concurrent systemic disease. The overall response rate after 2 R-DHAP-MTX was 53% (19/36), with 22% (8/36) complete remission. Fifteen patients (42%) underwent a transplant. One-year progression-free survival was 19% (95% confidence interval, 9-34): 25% in patients without and 15% in patients with systemic disease. One-year overall survival was 25% (95% confidence interval, 12-40). This treatment regimen did not result in a major improvement of outcome of secondary CNS lymphoma, especially when concurrent systemic disease was present. Registered in the Dutch trial register www.trialregister.nl, NTR1757; EudraCT number 2006-002141-37.