5q11.2 deletion syndrome revisited-Further narrowing of the smallest region of overlap for the main clinical characteristics of the syndrome.

Microdeletions at 5q11.2 are rare. Subjects show a phenotypic spectrum that overlaps CHARGE syndrome and 22q11.2 deletion syndrome. A growing number of subjects present with learning difficulty and/or intellectual disability, immune deficiency, congenital heart malformation, and dysmorphism. DHX29 and IL6ST have been proposed as candidate genes for the development of the major clinical manifestations. We present a new case and narrow down the shortest region of overlap to evaluate possible candidate genes. Our case does not present developmental delay or immune deficiency indicating a reduced penetrance for some of the main clinical manifestations. The shortest region of overlap between subjects with deletions at 5q11.2 is approximately 450 kb (position 54.3-54.7 Mb). The narrowed region comprises 10 protein coding genes, including DHX29. DHX29 is a strong candidate gene for the main features of 5q11.2-microdeletion syndrome; however, our findings suggest a joined impact of several genes as the cause of the syndrome.

Mechanisms of lenalidomide sensitivity and resistance.

The discovery that the immunomodulatory imide drugs (IMiDs) possess antitumor properties revolutionized the treatment of specific types of hematological cancers. Since then, much progress has been made in understanding why the IMiDs are so efficient in targeting the malignant clones in difficult-to-treat diseases. Despite their efficacy, IMiD resistance arises eventually. Herein we summarize the mechanisms of sensitivity and resistance to lenalidomide in del(5q) myelodysplastic syndrome and multiple myeloma, two diseases in which these drugs are at the therapeutic frontline. Understanding the molecular and cellular mechanisms underlying IMiD efficacy and resistance may allow development of specific strategies to eliminate the malignant clone in otherwise incurable diseases.

Autoimmune polyglandular syndrome presenting with jaundice and thrombocytopenia.

OBJECTIVE: To report an uncommon presentation of a rare case of autoimmune polyglandular syndrome type IIIb in an elderly woman. CLINICAL PRESENTATION AND INTERVENTION: A 62-year-old woman presented with anaemic symptoms and jaundice. Blood tests showed macrocytic anaemia due to vitamin B12 deficiency with Coombs negative haemolysis. A thyroid function test was consistent with hypothyroidism. Autoimmune antibody assays were positive for anti-parietal cell, anti-intrinsic factor and anti-thyroid peroxidase antibodies. A final diagnosis of autoimmune thyroiditis with pernicious anaemia, which constituted autoimmune polyglandular syndrome type IIIb, was made and the patient was treated with L-thyroxine, vitamin B12 injection and a blood transfusion. She was discharged uneventfully after a week of hospitalization. CONCLUSION: This case showed that the presence of one autoimmune endocrine disease should prompt clinicians to look for other coexisting autoimmune diseases which may be asymptomatic despite positive autoantibodies.

Vitamin B12 and folate deficiency: should we use a different cutoff value for hematologic disorders?

INTRODUCTION: Anemia and macrocytosis are well-defined expected hematologic findings of vitamin B12 and folate deficiency; however, some previous studies did not show a significant association of subnormal B12 with anemia and macrocytosis. METHODS: We retrospectively analyzed 17 713 laboratory patient records to evaluate vitamin B12 and folate levels in relation to anemia and macrocytosis. RESULTS: In an age- and sex-adjusted logistic regression model, low B12 status but not marginal B12 status was significantly associated with anemia [ORs respectively, 1.291 (95% CI, 1.182-1.410), 1.022 (95% CI, 0.943-1.108)] and macrocytosis [ORs, respectively, 3.853 (95% CI, 3.121-4.756), 1.031 (95% CI, 0.770-1.381)]. Also low folate status but not marginal folate status was significantly associated with anemia [adjusted ORs, respectively, 1.819 (95% CI, 1.372-2.411), 1.101 (95% CI, 0.931-1.301)] and macrocytosis [adjusted ORs, respectively, 2.945 (95% CI, 1.747-4.965), 1.228 (95% CI, 0.795-1.898)]. CONCLUSION: Our results show that increased anemia and macrocytosis are observed at values below commonly used B12 lower-reference thresholds. Determining a hematologic cutoff value may help physicians in clinical practice.

5q- syndrome.

In recent years we have gained great insight into the molecular pathogenesis of the 5q- syndrome, the most distinct of all the myelodysplastic syndromes. It is now recognized that p53 activation, caused by haploinsufficiency for the ribosomal gene RPS14 (mapping to the commonly deleted region), is the probable cause of the erythroid defect in the 5q- syndrome. A mouse model of the human 5q- syndrome has been generated by large-scale deletion of the Cd74-Nid67 interval (containing Rps14) and the crossing of these '5q- mice' with p53-deficient mice ameliorated the erythroid progenitor defect. Recent evidence suggests that haploinsufficiency of the microRNA genes miR-145 and miR-146a may contribute to the thrombocytosis seen in the 5q- syndrome. Emerging data shows that p53 mutation may play a role in disease progression.

Mice with ribosomal protein S19 deficiency develop bone marrow failure and symptoms like patients with Diamond-Blackfan anemia.

Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia caused by a functional haploinsufficiency of genes encoding for ribosomal proteins. Among these genes, ribosomal protein S19 (RPS19) is mutated most frequently. Generation of animal models for diseases like DBA is challenging because the phenotype is highly dependent on the level of RPS19 down-regulation. We report the generation of mouse models for RPS19-deficient DBA using transgenic RNA interference that allows an inducible and graded down-regulation of Rps19. Rps19-deficient mice develop a macrocytic anemia together with leukocytopenia and variable platelet count that with time leads to the exhaustion of hematopoietic stem cells and bone marrow failure. Both RPS19 gene transfer and the loss of p53 rescue the DBA phenotype implying the potential of the models for testing novel therapies. This study demonstrates the feasibility of transgenic RNA interference to generate mouse models for human diseases caused by haploinsufficient expression of a gene.

Treatment of myelodysplastic syndromes in elderly patients.

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal neoplasms with the median age at diagnosis being in the seventh decade. If left untreated, the disease progresses to acute myeloblastic leukemia (AML). There are many options for the management of MDS, but the only potentially curative treatment is allogenic hematopoietic stem cell transplantation (allo-HSCT), which is often not an option because of advanced age or comorbidities at diagnosis or lack of a human leukocyte antigen-identical donor. MDS in the elderly should be managed similar to that in young patients, but the fact that many advanced age patients cannot undergo allo-HSCT precludes any chance of cure. Despite the main objective of prolonging overall survival and the time to progression to AML, the key is to improve quality of life for the longest possible time. To achieve these objectives, supportive care is essential. Likewise, immunomodulatory drugs, such as lenalidomide, can reduce transfusion requirements and reverse cytologic and cytogenetic abnormalities in patients with MDS with chromosome 5q deletion. Elderly patients with high-risk MDS can benefit from 5-azacitidine (5-AZA), with efficacy and safety profiles comparable with those found in patients under 75 years of age. In any patient, predictive drug response scores are required in order to ensure more rational use of these medications.

Perturbed hematopoiesis in the Tc1 mouse model of Down syndrome.

Trisomy of human chromosome 21 (Hsa21) results in Down syndrome (DS), a disorder that affects many aspects of physiology, including hematopoiesis. DS children have greatly increased rates of acute lymphoblastic leukemia and acute megakaryoblastic leukemia (AMKL); DS newborns present with transient myeloproliferative disorder (TMD), a preleukemic form of AMKL. TMD and DS-AMKL almost always carry an acquired mutation in GATA1 resulting in exclusive synthesis of a truncated protein (GATA1s), suggesting that both trisomy 21 and GATA1 mutations are required for leukemogenesis. To gain further understanding of how Hsa21 contributes to hematopoietic abnormalities, we examined the Tc1 mouse model of DS, which carries an almost complete freely segregating copy of Hsa21, and is the most complete model of DS available. We show that although Tc1 mice do not develop leukemia, they have macrocytic anemia and increased extramedullary hematopoiesis. Introduction of GATA1s into Tc1 mice resulted in a synergistic increase in megakaryopoiesis, but did not result in leukemia or a TMD-like phenotype, demonstrating that GATA1s and trisomy of approximately 80% of Hsa21 perturb megakaryopoiesis but are insufficient to induce leukemia.

[Tropical sprue]. / Sprue tropicale.

Tropical sprue associates prolonged diarrhea, a malabsorption syndrome, and nutritional deficiency in patients who live in or have visited tropical areas. Pathogenesis is still unknown but an infectious cause is suspected. Macrocytic anemia and hypoalbuminemia are present, together with progressive villus atrophy of the small intestine. Treatment with tetracycline, folic acid and proper nutritional support generally results in full recovery.

Predictive value of MCV for hazardous drinking in the community.

A recent study suggested that general practitioners (GPs) do not see the necessity of investigating MCVs which unexpectedly and only slightly exceed the reference limit, despite the association between MCV and alcohol abuse. Because a literature search could not find a study of the predictive value of the MCV for hazardous drinking in the community, such a study was undertaken among a random sample of 338 adults living in a regional Australian city. Twenty-nine of the adults admitted drinking hazardously. The MCV with the optimum sensitivity and specificity for identifying the hazardous drinkers was determined. An MCV of > 94 fl identified as many as 35% of the hazardous drinkers whilst misclassifying only 6% of the non-hazardous drinkers. The predictive value was even greater among males, 67%. We conclude that inquiring into MCVs > 94 fl will lead to GPs identifying a significant proportion of adults in the community admitting to hazardous drinking.

Lifetime treatment of mice with azidothymidine (AZT) produces myelodysplasia.

AZT has induced a macrocytic anemia in AIDS patients on long term AZT therapy. It is generally assumed that DNA elongation is stopped by the insertion of AZT into the chain in place of thymidine thus preventing the phosphate hydroxyl linkages and therefore suppresses hemopoietic progenitor cell proliferation in an early stage of differentiation. CBA/Ca male mice started on AZT 0.75 mg/ml H2O at 84 days of age and kept on it for 687 days when dosage reduced to 0.5 mg/ml H2O for a group, another group removed from AZT to see recovery, and third group remained on 0.75 mg. At 687 days mice that had been on 0.75 mg had average platelet counts of 2.5 x 10(6). Histological examination on 9 of 10 mice with such thrombocytopenia showed changes compatible with myelodysplastic syndrome (MDS). A variety of histological patterns was observed. There were two cases of hypocellular myelodysplasia, two cases of hypersegmented myelodysplastic granulocytosis, two cases of hypercellular marrow with abnormal megakaryocytes with bizarre nuclei, one case of megakaryocytic myelosis associated with a hyperplastic marrow, dysmyelopoiesis and a hypocellular marrow and two cases of myelodysplasia with dyserythropoiesis, hemosiderosis and a hypocellular marrow. Above mentioned AZT incorporation may have induced an ineffective hemopoiesis in the primitive hemopoietic progenitor cells, which is known to be seen commonly in the myelodysplastic syndrome.

Scintigraphic diagnosis of intrathoracic extramedullary hematopoiesis in alcohol-related macrocytosis.

We report the scintigraphic diagnosis of thoracic extramedullary hematopoiesis in a case of alcohol-related macrocytosis. A patient with liver cirrhosis and alcohol-related macrocytosis showed multiple rounded masses in the low thoracic paraspinal region on chest radiography and CT. Whole-body scintigraphy and SPECT imaging of the thorax, after nanocolloid administration, demonstrated expansion of the bone marrow in the humeri and femora and uptake of the tracer in the mediastinal masses, establishing the diagnosis of mediastinal extramedullary hematopoiesis. Thoracic extramedullary hematopoiesis may occur in conjunction with alcohol-related macrocytosis. Scintigraphy with 99mTc-nanocolloids is a suitable noninvasive method to establish the presence of extramedullary marrow.

Benign familial macrocytosis.

We have identified a 52-year-old woman and her 27-year-old daughter with macrocytosis, normal haemoglobin and mean corpuscular haemoglobin concentration. Macrocytosis could be demonstrated from the age of 40 and 25 respectively. All blood tests were normal including vitamin B12 and folic acid. Bone marrow investigation showed rare macroblasts without other abnormalities. Endoscopy of the upper gastrointestinal tract and ultrasonography of the abdomen were normal. Thus, persistent macrocytosis was present without evidence of diseases that might account for it. In these subjects, macrocytosis is likely to be related to the presence of a genetic defect.