[The 10-minute consultation: anemia as a chance finding].
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Adolescent↗
Biomedical subjects
E Kohne
Publications and source records attributed to E Kohne.
Treatment with hydroxyurea in thalassemia intermedia with paravertebral pseudotumors of extramedullary hematopoiesis.
Excessive ineffective erythropoiesis in thalassemia intermedia may cause paravertebral pseudotumors of extramedullary hematopoiesis. Due to the proximity to the spinal canal, these paravertebral masses carry the risk of severe neurological damage. Treatment strategies include hypertransfusion, radiotherapy, and laminectomy. Hydroxyurea, stimulating fetal hemoglobin synthesis, may represent an alternative therapeutic approach. We report on a 26-year-old patient suffering from thalassemia intermedia with progressive anemia symptoms and presenting multiple intrathoracic paravertebral pseudotumors of extramedullary hematopoiesis. Hypertransfusion therapy and splenectomy were followed by regular transfusion (baseline hemoglobin 10 g/dl) and chelation with desferrioxamine. With this treatment, clinical symptoms disappeared, paravertebral hematopoietic masses did not progress, but severe hemosiderosis developed within a few years. Hydroxyurea therapy was initiated to increase the efficacy of erythropoiesis, thereby reducing the required transfusion volume but suppressing concomitantly further expansion of extramedullary hematopoiesis, and finally leading to a reduction of transfusional iron load. Treatment was started with 4 mg/kg per day and stepwise increased to 12.5 mg/kg per day. The fetal hemoglobin concentration increased from 4.5 to 5.5 g/dl after 1 year and to 9.9 g/dl after 2 years of treatment. The yearly transfusion volume was halved during the 1st year of treatment. At present, after 26 months of treatment, the patient has been transfusion-independent for 10 months. Serum ferritin levels decreased from 2844 to 1335 ng/ml. Size and shape of paravertebral hematopoietic pseudotumors remained stable. No side effects of hydroxyurea have been observed. In thalassemia intermedia patients with extramedullary hematopoiesis, hydroxyurea may lead to independence from regular transfusion therapy without further expansion of ectopic hematopoietic tissue.
Adult↗
[An unusual etiology of erythrocytosis in a 23-year-old primiparous woman in the 22nd week of pregnancy].
CASE REPORT: A 23-year-old pregnant woman presented with erythrocytosis and a spuriously elevated HbA1c. Family history revealed that her father has been treated with phlebotomies for the last 2 years because of erythrocytosis of unknown cause. An examination of the family members demonstrated that the patient and her father were carriers of the hemoglobin (Hb) variant Hb Andrew-Minneapolis. DISCUSSION: Hb Andrew-Minneapolis belongs to a group of hemoglobin variants with a high oxygen affinity resulting in compensatory erythrocytosis. The carriers of such hemoglobin variants are usually clinically asymptomatic, exercise tolerance appears unimpaired and there is no higher incidence of cardiovascular diseases. There is no clear-cut evidence that a maternal hemoglobinopathy with high oxygen affinity is accompanied by negative consequences for the fetus or a higher abortion rate. CONCLUSION: Hemoglobinopathies with a high oxygen affinity are a rare but important differential diagnosis of polycythemia. Under these circumstances erythrocytosis has to be accepted as the primary mode of compensation and does not require treatment, as long as blood viscosity is kept within tolerable limits. An excessively elevated or lowered HbA1c without a history or symptoms of diabetes should lead to further investigations concerning the possibility of hemoglobinopathy.
Adult↗
Hemoglobinopathy York [beta146 (HC3) His==>Pro]: first report of a family history.
The rare hemoglobinopathies with abnormal oxygen binding are usually characterized by erythropoietin-mediated erythrocytosis. Bare et al. first described a hemoglobinopathy with mild erythrocytosis in a 22-year-old Caucasian woman in 1976. These authors called the abnormal hemoglobin Hb York. Hb York is characterized by a mutation at the beta146 position that changes histidine into proline. A second case of Hb York was observed by Kosugi et al. in 1983. To the best of our knowledge, no further cases have been reported. We have encountered a new case of Hb York, which was detected by agar gel electrophoresis at pH 6.0. Analysis of DNA sequences revealed a CAC-->CCC mutation in codon 146. The proportion of Hb York was approximately 50%. Analysis of oxygen transport function showed a leftward shift of the sigmoidal O2-dissociation curve. P50 was reduced to 15.5 mmHg. Investigation of family members revealed Hb York in the patient's sister, two daughters and a grandson. In retrospect, the mother of the patient may also have been affected. The mode of inheritance is autosomal dominant.
Aged↗
Epidemiological situation and treatment of patients with thalassemia major in Germany: results of the German multicenter beta-thalassemia study.
At present, about 300 patients in Germany suffer from thalassemia major. In 1990, a multicenter study was introduced to identify all thalassemic patients in Germany as well as to establish a uniform therapy protocol, including follow-up diagnostic procedures. After 6 years of study, the data of 203 patients were analyzed. The majority originate from endemic regions around the Mediterranean Sea. The median age of the patients is 13.8 years (range 1-37.5 years). At present, about 20% of the patients are older than 21 years. Regarding transfusion therapy, a shortening of the average transfusion interval to 3 weeks in most cases occurred. Throughout the entire period, median baseline hemoglobin concentrations of 10.0 g/dl were observed. The evaluation of serum ferritin levels revealed considerable differences, depending on the patients' age. Thalassemic patients in the first decade of life generally presented with good therapeutic results; serum ferritin levels were below 1800 ng/ml in 76/102 patients (75%) upon entry into the study. In contrast, 51/98 patients (52%) older than 10 years had ferritin levels above 2500 ng/ml. More than half of all treated patients presented with siderotic complications such as cardiac disease in 20/157 (13%), liver disease in 32/157 (21%), impaired glucose metabolism in 22/157 (14%), hypogonadism in 39/66 (59%), and hypothyroidism in 38/157 (24%) who were under treatment at the time of first survey. Since the situation concerning siderosis and the lack of compliance proved to be particularly difficult with adolescent patients, further efforts should concentrate on this age-group.
Adolescent↗
Dominant beta-thalassaemia: a highly unstable haemoglobin is caused by a novel 6 bp deletion of the beta-globin gene.
Beta-thalassaemia is inherited as an autosomal recessive trait in most families. Particular interest has recently been focused on the molecular pathology of the rare forms with a dominant mode of inheritance. The index patient and her mother, who are described in this report, displayed typical clinical and haematological features of beta-thalassaemia intermedia with significant ineffective erythropoiesis and additional peripheral haemolysis. Molecular analysis demonstrated a heterozygous genotype for a novel 6 bp (TGGTCT) deletion of the beta-globin gene involving codons 33-35. This deletion results in the removal of two valine residues from the beta-globin chain at position 33/34 (B15/B16) and the substitution of the tyrosine residue at position 35 (C1) by an aspartic acid (beta 33-35 [B15-C1] Val-Val-Tyr-->0-0-Asp). According to the index patient's place of birth, this abnormal haemoglobin has been termed Hb Dresden. The stability of the variant and the normal beta-globin chains were similar during the incubation period of in vitro globin chain synthesis analysis. However, Hb Dresden is exquisitely unstable and cannot be detected in the peripheral blood by haemoglobin electrophoresis, high-performance liquid chromatography (HPLC) or isoelectric focusing. This instability can be explained by the vital structural role of the three affected amino acids that, in normal haemoglobin, establish a total of nine intermolecular bonds (five hydrophobic and four polar) at both the alpha1beta1 (alpha2beta2) and the alpha1beta2 (alpha2beta1) interface.
DNA↗
Anaemia, thrombocytopenia and coagulopathy due to occult diffuse infantile haemangiomatosis of spleen and pancreas.
UNLABELLED: Diffuse infantile haemangiomatosis of the spleen is a very rare lesion. Large haemangiomas may cause trapping of platelets and coagulation disorders known as Kasabach-Merrit syndrome. We here report the case of an infant with splenic and pancreatic haemangiomatosis presenting with life-threatening thrombocytopenia, anaemia and intravascular coagulation. Diagnosis was hampered by reactive erythroblastosis and non-conclusive radiological findings. While treatment with corticosteroids was ineffective, administration of antithrombin III improved coagulation parameters. After splenectomy the child recovered promptly and has remained free of disease for 3 years to date. CONCLUSION: Occult visceral haemangiomatosis without visible cutaneous haemangiomas should be included in the differential diagnosis of thrombocytopenia, anaemia and consumption coagulopathy. Antithrombin III treatment may be considered to overcome bleeding problems in patients with Kasabach-Merrit syndrome.
Anemia↗
A microdeletion syndrome due to a 3-Mb deletion on 19q13.2--Diamond-Blackfan anemia associated with macrocephaly, hypotonia, and psychomotor retardation.
We report on a boy with congenital pure red blood cell aplasia [Diamond Blackfan anemia (DBA)] and severe congenital hypotonia, macrocephaly, hypertelorism, a broad and tall forehead, medial epicanthus, and facial hypotonia with mouth-breathing and drooling, an affable and out-going personality, and a general psychomotor retardation. These features show similarity to the phenotype of the X-linked FG syndrome. DBA was diagnosed at the age of 4 months, and the boy underwent treatment with transfusion and with prednisolone. He had a normal 46, XY karyotype, but fluorescence in situ hybridization (FISH) analysis to metaphase chromosomes revealed a 3-Mb deletion on 19q13.2. This chromosomal region has previously been linked to the DBA phenotype and one 19q13 microdeletion has been identified in a patient with DBA. This deletion coincides with the deletion reported here. We suggest that the complex phenotype of our patient, including both DBA and the associated features, represent a microdeletion syndrome.
Chromosome Deletion↗
Identification of new prognosis factors from the clinical and epidemiologic analysis of a registry of 229 Diamond-Blackfan anemia patients. DBA group of Société d'Hématologie et d'Immunologie Pédiatrique (SHIP), Gesellshaft für Pädiatrische Onkologie und Hämatologie (GPOH), and the European Society for Pediatric Hematology and Immunology (ESPHI).
Diamond-Blackfan anemia (DBA) is a constitutional disease characterized by a specific maturation defect in cells of erythroid lineage. We have assembled a registry of 229 DBA patients, which includes 151 patients from France, 70 from Germany, and eight from other countries. Presence of malformations was significantly and independently associated with familial history of DBA, short stature at presentation (before any steroid therapy), and absence of hypotrophy at birth. Two hundred twenty-two patients were available for long-term follow-up analysis (median, 111.5 mo). Of these individuals, 62.6% initially responded to steroid therapy. Initial steroid responsiveness was found significantly and independently associated with older age at presentation, familial history of DBA, and a normal platelet count at the time of diagnosis. Severe evolution of the disease (transfusion dependence or death) was significantly and independently associated with a younger age at presentation and with a history of premature birth. In contrast, patients with a familial history of the disease experienced a better outcome. Outcome analysis revealed the benefit of reassessing steroid responsiveness during the course of the disease for initially nonresponsive patients. Bone marrow transplantation was successful in 11/13 cases; HLA typing of probands and siblings should be performed early if patients are transfusion dependent, and cord blood should be preserved. Incidence of DBA (assessed for France over a 13-y period) is 7.3 cases per million live births without effect of seasonality on incidence of the disease or on malformative status. Similarly, no parental imprinting effect or anticipation phenomenon could be documented in families with dominant inheritance.
Abnormalities, Multiple↗
Diagnosis of diabetes in cystic fibrosis and thalassemia major.
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Adolescent↗
Glucose intolerance in patients with thalassemia major: insulin resistance and hyperproinsulinemia.
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Adolescent↗
CD95 (APO-1/FAS)-mediated apoptosis in cytokine-activated hematopoietic cells.
Elimination of peripheral T cells is crucially regulated via apoptosis through CD95 (APO-1/Fas) receptor ligand interaction. Because homeostasis in hematopoietic cells may also involve the CD95 system, we analyzed CD95 expression and sensitivity to CD95-induced apoptosis in human bone marrow cells. During hematopoiesis CD95 is differentially expressed on distinct cell types and at different maturational stages with an increase in receptor density from early CD34+ stem cells to maturing progenitor cells. Incubation of bone marrow cells with anti-APO-1 (anti-CD95) induces apoptosis in maturing erythroblasts and neutrophil progenitors (10-19%) and to a lesser extent in stem cells and myeloblast/proerythroblasts (4-9%). On in vitro culture, CD95 expression is particularly upregulated on activated CD71+ myeloid progenitors. Hematopoietic cytokines (stem cell factor, interleukin-3, granulocyte macrophage colony-stimulating factor [GM-CSF], and granulocyte-colony-stimulating factor [G-CSF] contribute to upregulation of CD95 on bone marrow cells. CD95-induced apoptosis in activated progenitors was markedly enhanced by activating cytokines. Thus cytokines known to mediate proliferation, survival, and maturation, in hematopoiesis do not prevent, but rather facilitate negative growth regulation via the CD95 pathway in activated cells. Deregulation of the CD95 system may provide a molecular basis for the development of bone marrow failure or immune-mediated cytopenia. Defects in the CD95 pathway may contribute to the development of hematopoietic malignancy by abrogating CD95-mediated growth control of activated cells.
Apoptosis↗
Silastic catheters for home antibiotic therapy in patients with cystic fibrosis.
UNLABELLED: Repeated 14-day courses of intravenous antibiotic therapy for patients with cystic fibrosis (CF), who have been colonized with Pseudomonas aeruginosa (PA), is one currently accepted treatment. Conventional intravenous cannulas for antibiotic delivery often have a short line life leading to frequent venipunctures. Therefore we used silastic catheters as a peripheral venous access. Silastic catheters (15 cm, 0.6 mm diameter) were inserted 10 cm into a cubital vein in 15 patients with CF (age 5-32 years) for 20 antibiotic courses. After the antibiotic infusion the catheter was flushed with 200 U heparin (2 ml Vetren). In all patients the antibiotic therapy was delivered as a home therapy. In 15 antibiotic courses the silastic catheter could be continuously used for 14 days. One patient with methicillin resistant Staphylococcus aureus received antibiotic therapy for 54 consecutive days using the same silastic catheter. The catheter had to be removed in four courses: once because of thrombophlebitis with local inflammation, once because of burning pain during infusion and occlusion twice. In one case the patient removed his catheter because of technical problems. No other serious side effects occurred. Ten patients had previously received intravenous antibiotics at least once. The median line life of the last used conventional peripheral cannula of all patients was 4 days versus 14 days with the use of the silastic catheter (P < 0.005). All patients preferred the silastic catheter to other venous access. CONCLUSION: Because of the long line life and easy handling, silastic catheters may be an alternative venous access to perform home antibiotic therapy in patients with CF.
Adolescent↗
Cardiac and extracardiac complications in infants of diabetic mothers and their relation to parameters of carbohydrate metabolism.
UNLABELLED: Despite the current improvement of diabetes care in pregnancy, neonatal complications are still more frequent than in the general population. Even in fetuses of well controlled diabetic mothers, myocardial hypertrophy can be demonstrated although it is not related to maternal metabolic control. The objective of this study was to determine perinatal complications and the course of myocardial hypertrophy in newborns who had been prenatally monitored and to relate the findings to neonatal parameters of carbohydrate metabolism. Perinatal complications and echocardiographic evidence of myocardial hypertrophy were determined in 104 neonates of closely followed diabetic mothers. Cord blood was obtained for determination of insulin, C-peptide and glycosylated fetal haemoglobin (HbF1c). In cases of myocardial hypertrophy, the echocardiographic examinations were repeated until normalisation of the myocardial wall thickness. The most striking finding was myocardial hypertrophy in 25% of the 104 neonates, which predominantly involved the interventricular septum. This is in contrast to the prenatal symmetrical hypertrophy of the ventricular walls and may be explained by perinatal changings of ventricular geometry. There was no sign of outflow tract obstruction, and myocardial hypertrophy resolved within 6 months. Insulin and C-peptide were elevated in the majority of the newborns, whereas HbF1c was significantly decreased. Neither the maternal type of diabetes nor neonatal metabolic data were related to the somatic findings. CONCLUSION: Myocardial hypertrophy still occurs in infants of diabetic mothers despite their good metabolic control reflected by the decreased fraction of glycosylated fetal hemoglobin which points to low fetal blood sugar levels during the last intra-uterine weeks.
Carbohydrates↗
Beta-thalassaemia in the immigrant and non-immigrant German populations.
In Germany homozygous beta-thalassaemia mainly occurs in the immigrant population from endemic regions. In non-immigrants beta-thalassaemia is rare. Heterozygous beta-thalassaemia minor, however, is more common and must be considered in the differential diagnosis of hypochromic anaemia. The clinical and molecular data of 221 homozygous patients and 256 non-immigrant German heterozygous individuals are presented. Clinically, 87% (n = 192) of the homozygotes are classified as thalassaemia major (TM) and the other 13% as thalassaemia intermedia (TI). There is a wide spectrum of 39 thalassaemia mutations which occur with relatively low frequencies in individual cases. In 17/29 TI patients 'mild' mutations have been found and in 16/29 there are mutations that are associated with increased gamma-globin gene activity. alpha-Thalassaemia is rare and found only in 3/29. In the 256 Germans with heterozygous beta-thalassaemia there are 27 different thalassaemia mutations. The three most common are Mediterranean, together accounting for 61%. Also relatively common (5%) is an otherwise rare frameshift mutation of codon 83 (FS83 deltaG). The other mutations occur in < 10 individuals. Two mutations described here are novel. One of them affects position -2 of the intron 1 splice acceptor site (IVSI-129 A-G) and the other is a deletion of a single G in codon 15/16 (FS 15/16 deltaG). These data suggest that beta-thalassaemia in Germans was introduced from the Mediterranean in about two-thirds of cases and that the remaining third has probably originated locally.
Asia, Southeastern↗
Thalassemia intermedia: compound heterozygous beta zero/beta(+)-thalassemia and co-inherited heterozygous alpha(+)-thalassemia.
The relative excess of alpha- over beta-globin chains in the erythroid precursors is the chief pathophysiological factor of homozygous beta-thalassemia. The clinical picture is usually characterized by a transfusion-dependent dyserythropoietic anemia (thalassemia major). However, some patients present with moderate anemia that does not require regular blood transfusions (thalassemia intermedia). The molecular heterogeneity of beta-thalassemia mutations and changes of alpha- and gamma-globin gene expression play an important role in modifying the clinical phenotype. We report here on a female Greek patient with homozygous beta-thalassemia but normal growth and development, excellent exercise tolerance, and no need of blood transfusions. She is thus mildly affected clinically, although there is marked pallor, jaundice, and hepatosplenomegaly. These signs correspond to her marked hypochromic, microcytic anemia with erythroid hyperplasia of the bone marrow. beta-Globin genotyping shows here to be compound heterozygous for the codon 39 C-->T beta zero-nonsense mutation and for the T-->C beta(+)-mutation at position 6 of the splice consensus at the exon 1/intron 1 junction (CD39 C-->T/IVS1-6 T-->C). alpha-Globin gene mapping demonstrates the presence of a 3.7-kb alpha (+)-thalassemia deletion on one allele (-alpha 3.7/alpha alpha). Taken together, this study identifies a complex interaction of genetic factors that do not significantly alter the clinical phenotype when present alone but ameliorate the course of homozygous beta-thalassemia when inherited in combination.
Base Sequence↗
[Monitoring pregnant patients from risk countries with sickle cell disease and thalassemia. Clinical aspects, screening and prenatal diagnosis].
At the present time, about 3.5 million people from Turkey, Greece, Italy, the Middle East, Africa and Asia are living in Germany. They are potential carriers of beta-thalassaemia and haemoglobinopathies such as sickle cell disease. These diseases are new for most of us and represent a challenge to physicians, taking care of these patients. Not only do we have to learn about the clinical problems of homozygous patients and how to handle them, we also have to become acquainted with the problems related to the heterozygous carrier stage. The large number of asymptomatic pregnant carriers of beta-globin anomalies is a particular challenge for obstetricians. They need to identify carriers through haemoglobin electrophoresis screening, inform the carrier about the meaning of being a carrier, screen the woman's partner, refer for genetic counselling and suggest and explain prenatal diagnosis in case the partner is also a carrier. There is as yet no cure for thalassaemia and sickle cell disease, except for bone marrow transplantation in a few selected cases. Therefore, prenatal diagnosis presents a valuable method of preventing severe chronic diseases. Screening does not only allow genetic counselling, the information gained has also clinical implications for carriers of beta-thalassaemia. In this paper a summary is given of the pathophysiological and clinical features of thalassaemia and sickle cell disease and molecular biology methods to diagnose thalassaemias and sickle cell disease are discussed. In addition, a screening programme for pregnant women from countries at risk is suggested to enable physicians to give optimal care and initiate prenatal diagnosis.
Anemia, Sickle Cell↗
A deletion/inversion rearrangement of the beta-globin gene cluster in a Turkish family with delta beta zero-thalassemia intermedia.
The most common forms of hereditary persistence of fetal hemoglobin synthesis (HPFH) and delta beta zero-thalassemia result from simple deletions of the beta-globin gene cluster or from point mutations in the gamma-globin gene promoters. These naturally occurring mutants extend our understanding of globin gene regulation and hemoglobin switching. Furthermore, they provide the opportunity to test in vivo hypothetical switching models that are based on the experimental approach. We report here a family with delta beta zero-thalassemia from Turkey with a complex rearrangement of the beta-globin gene cluster that involves two deletions of 11.5 kb and 1.6 kb, and an inversion of 7.6 kb. The larger deletion removes both the delta-and the beta-globin genes with 3' flanking sequences, whereas the smaller deletion affects DNA of unknown function. The inversion contains the entire L1 repeat 3' of the beta-globin gene. There are structural motifs near the breakpoints (introduction of an "orphan" nucleotide, multiple direct and inverted repeats) suggesting a nonhomologous type of recombination event. The hematologic phenotype and the molecular structure of the rearranged beta-globin gene cluster are consistent with a competitive relationship between the fetal and the adult globin genes and/or with the translocation of enhancer sequences into the gamma-globin gene region.
Adult↗