Diabetes in Patients with ß-thalassemia or other Hemoglobinopathies - Analysis from the DPV Database.

Background: Diabetes mellitus is a common endocrinopathy in patients with thalassemia major, but the occurrence of hemoglobinopathies is rare in Germany and Western Europe. The longitudinal German-Austrian DPV (Diabetes Patienten Verlaufsdokumentation) registry allows a comprehensive characterization of this group of patients. Patients/methods: Patients from the DPV-registry aged<30 years with thalassemia major or other hemoglobinopathies were compared to patients with type 1 diabetes (T1D) and type 2 diabetes (T2D) using the statistical software SAS 9.4. Results: 94 patients (0.13% of patients) with hemoglobinopathies are registered in DPV. 82.4% of 17 patients with thalassemia major, 100% of 12 patients with sickle cell disease (SCD) and >90% of 65 patients with other hemoglobinopathies receive insulin treatment. In the majority of patients with thalassemia major, hemosiderosis is documented. Patients with thalassemia major developed diabetes at a median age of 14.6 [IQR 8.4-18.0] years (9.0 years [5.3-12.5] in T1D; 18.7 years [14.2-25.6] in TD2; both p<0.01). They show high HbA1c/fructosamine levels and frequent hypoglycemia, reflecting poor metabolic control. Conclusion: Diabetes in thalassemia major is probably caused by hemosiderosis due to polytransfusion, while patients with SCD/thalassemia minor are most likely affected by T1D. The high rate of hypoglycemia in patients with ß-thalassemia major may be caused by liver fibrosis and a lack of hepatic glycogen stores.

Hereditary hyperferritinemia cataract syndrome: clinical, genetic, and laboratory findings in 5 families.

BACKGROUND: The hereditary hyperferritinemia cataract syndrome (HHCS) is an autosomal dominant disorder characterized by high serum ferritin and early onset cataract. Mutations in the iron responsive element (IRE) within the 5' untranslated region of the L-ferritin (FTL) gene lead to constitutive L-ferritin synthesis resulting in hyperferritinemia. Bilateral cataract formation is caused by the intracellular accumulation of ferritin in the lens. PATIENTS: 4 children from unrelated families were referred for further exploration of hyperferritinemia which was detected during the diagnostic work-up of gastroenterological or hematological disorders. 1 patient was primarily referred for the investigation of bilateral cataract.Diagnostics included routine blood analysis, including complete blood count, iron status, liver and kidney parameters, a physical and an ophthalmological examination. Molecular genetic analysis of the FTL IRE was performed in 4 patients by PCR from genomic DNA and subsequent direct sequencing. RESULTS: All index patients presented with isolated hyperferritinemia without iron overload and had a positive family history for early onset cataract. Age at onset and disease severity varied between different families and among family members. Molecular genetic analysis revealed point mutations within the FTL IRE. CONCLUSION: In patients with hyperferritinemia but without any other sign of iron overload or inflammation HHCS should be considered to avoid complex and invasive procedures. Vice versa, in patients with familial inherited cataract the early serum ferritin measurement helps to avoid unnecessary diagnostics.

Persistent cyanosis in a 4 month old infant with severe pneumonia and haemoglobin M.

M haemoglobinaemia is a rare cause of persistant cyanosis. We report a four months old infant who suffered from severe pneumonia and respiratory distress syndrome. After return of normal respiration, cyanosis persisted. Oxygen saturation on pulse oximetry never exceeded 85%. Finally, we succeeded in isolating a haemoglobin M Saskatoon. HbM Saskatoon is normally a harmless variant. However, in conjunction with severe pneumonia, we assume that it did not only affect clinical evaluation, but also exacerbated pneumonia by reducing the oxygen binding capacity.

Haemoglobinopathies and newborn haemoglobinopathy screening in Germany.

Germany has been an immigration country since the early 1950s. In December 2007, 6.7 million non-German citizens lived in the country. However, the total number of citizens with a migration background is 15-20 million, about 9 million of whom come from countries where sickle cell disease and thalassaemias are frequent. In a country with 82 million inhabitants health authorities are not worried by the presence of probably 1000-1500 sickle cell and 450 transfusion-dependent thalassaemia patients, and therefore no screening or preventive measures have been taken so far on a national scale. There are plans for a pilot project (1 year) to screen all newborns for sickle cell disease in obstetric hospitals in 4-5 cities with more than 20% migrants. Funding and lack of an infrastructure to provide counselling are major problems.

Recent developments in iron chelation therapy.

Since 1962, desferrioxamine (deferoxamine, DFO) has been utilized for the treatment of secondary hemosiderosis. For about 30 years, DFO therapy has been performed as nightly continuous subcutaneous infusion. About 20 years ago, the first oral iron chelator (deferiprone, DFP) was presented. Concerns about potential side effects were responsible for the late acceptance and license of this drug which is limited to the use as second-line therapy for patients with thalassemia major. During recent years, chelation therapy and its evaluation started to progress rapidly. Clinical research and drug development as well as the introduction of new methods for the assessment of iron overload contributed to these advances. By using cardiac T2 (*) MRI it was possible to examine the specific effect of a chelator on myocardial siderosis. Clinical studies using this method indicated superiority of DFP compared to DFO with respect to the treatment of myocardial siderosis. Several retrospective and first prospective clinical trials seem to confirm this observation. In parallel, treatment strategies based on the combination of DFO and DFP have been developed. Using both drugs simultaneously or sequentially, additive and synergistic effects contribute to the fast elimination of iron from different organs at risk for siderotic damage. Deferasirox (DSX) is a recently developed oral chelator which shows good efficacy and tolerability in patients with transfusional hemosiderosis due to various underlying disorders. Long-term studies will define the future importance of DSX for iron chelation treatment. For the first time, there is a choice between three commercially available chelating agents for patients with transfusional iron overload. This will allow a highly effective, individually tailored treatment hopefully leading to a fundamental improvement of patients' life expectancy and quality.

Embryonic stem cell-based reduction of central nervous system sulfatide storage in an animal model of metachromatic leukodystrophy.

Pluripotency, virtually unlimited self-renewal and amenability to genetic modification make embryonic stem (ES) cells an attractive donor source for cell-mediated gene therapy. In this proof of concept study, we explore whether glial precursors derived from murine ES cells (ESGPs) and engineered to overexpress human arylsulfatase A (hASA) can cross-correct the metabolic defect in an animal model of metachromatic leukodystrophy (MLD). Transfected ES cells showed an up to 30-fold increase in ASA activity. Following in vitro differentiation, high expression of ASA was found in all stages of neural and glial differentiation. hASA-overexpressing ESGPs maintained their ability to differentiate into astrocytes and oligodendrocytes in vitro and in vivo. After transplantation into the brain of neonatal ASA-deficient mice, hASA-overexpressing ESGPs were found to incorporate into a variety of host brain regions. Four weeks after engraftment, immunofluorescence analyses with an antibody to sulfatide revealed a 46.7+/-4.0% reduction of immunoreactive sulfatide deposits in the vicinity of the hASA-positive engrafted cells, thereby significantly extending the rate of sulfatide reduction achieved by the endogenous ASA activity of non-hASA-transfected control cells (21.1+/-5.8%). These findings provide first in vivo evidence that ES cells may serve as a potential donor source for cell-mediated enzyme delivery in storage disorders such as MLD.

Congenital erythrocytosis and polycythemia vera in childhood and adolescence.

Polycythemia vera - the most frequent form of a primary erythrocytosis in adult patients - represents an extremely rare disease in pediatric and juvenile patients as do congenital primary and secondary erythrocytoses. Frequently, in patients with these diseases clinical problems do not occur before adulthood. Systematic data on clinical and laboratory evaluations as well as on treatment regimens are sparse. In addition, in the majority of cases with congenital erythrocytosis, the etiology is unknown. For those reasons, a protocol (PV-ERY-KA 03) for the systematic collection of clinical, hematological, biochemical, biological as well as treatment data of children and adolescents with polycythemia vera or congenital erythrocytosis including the hemoglobinopathies with high affinity hemoglobin, familial 2,3-BPG deficiencies, and those of unknown origin, has been developed. These data are combined with molecular analyses which focus initially on EPO-receptor and vHL-gene examination, but will later be extended into presently unexplored pathophysiologic regulatory circuits. In addition, pathophysiologic changes due to the erythrocytosis will be studied. The co-ordinated medical care for patients with those rare diseases within a collaborative trial accompanied by scientific projects is aimed at the improvement of the treatment of these patients as well as to a better understanding of the underlying biological processes.

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.

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.

[An unusual etiology of erythrocytosis in a 23-year-old primiparous woman in the 22nd week of pregnancy]. / Ungewöhnliche Ursache einer Erythrozytose bei einer 23-jährigen Erstgebärenden in der 22. Schwangerschaftswoche.

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.

[Psychosocial aspects of beta-thalassemia: distress, coping and adherence]. / Psychosoziale Aspekte der beta-Thalassämie: Krankheitserleben, Coping und Therapiemitarbeit.

BACKGROUND: Longtime outcome in case of thalassemia depends on the patients' adherence in home treatment to reduce hemosiderosis. This study describes the patients' perspective, their typical coping strategies, health related locus-of-control-beliefs and psychosocial influences on adherence. PATIENTS AND METHODS: A battery of questionnaires was employed to 43 patients with thalassemia major (3 to 26 years old) treated in Germany according to the german multicenter study respectively their parents: the Ulm Thalassemia Inventory, the KIDCOPE, the Multidimensional Health Locus of Control Scales and the Giessen Complaint List. Clinical symptoms of hemosiderosis were correlated with psychosocial variables. RESULTS: The patients feel more distressed from their treatment than from their illness itself. They react to disease-related distress with a variety of coping strategies. Some of the most frequent coping strategies are maladaptive, indicating feelings of helplessness. Internal locus-of-control-beliefs were low and fatalistic locus-of-control-beliefs were high compared with other clinical groups. The self-reported adherence to the iron chelation treatment is correlated with age, gender, age at the start-point of the treatment and emotional distress. Complaints, coping strategies and locus of control are independent from adherence as well as from hemosiderosis. CONCLUSION: Patients with thalassemia major need more information about their disease and about the benefits of iron chelation therapy. Additional psychosocial support should reduce emotional distress, strengthen coping competence and lead to a better integration of therapy in daily life.

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.

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.

Anaemia in pregnant Ghanaian women: importance of malaria, iron deficiency, and haemoglobinopathies.

In sub-Saharan Africa, anaemia in pregnancy results from multiple causes including malaria, iron deficiency and haemoglobinopathies. In a cross-sectional study among 530 pregnant women in Ghana in November-December 1998, red blood cell indices were analysed with respect to malaria, serum concentrations of ferritin and C-reactive protein (CRP), and the haemoglobin and alpha-globin genotypes. Anaemia (haemoglobin [Hb] < 11 g/dL) was found in 54% of the women; 63% harboured malaria parasites at predominantly low numbers. Ferritin levels were considerably influenced by malaria and inflammatory processes (CRP > 0.6 mg/dL). Depending on the definition applied, the prevalence of iron deficiency ranged between 5% and 46%. The HbAS trait was observed in 14%, HbAC and elevated HbF in 7% each, and sickle cell disease in 1%. Heterozygous beta-thalassaemia was present in 1% of the women and alpha(+)-thalassaemia in 33% (29% heterozygous, 4% homozygous). Women with HbAS had higher malaria parasite densities than those with HbAA. In individuals with highly elevated HbF (> 10%), parasitaemia occurred in 27% only. Low gravidity, second trimester of pregnancy, malaria, raised CRP levels, and homozygous alpha(+)-thalassaemia were independent risk factors for anaemia in multivariate analysis. alpha(+)-Thalassaemia, however, was associated with a lesser degree of malarial anaemia when compared to non-thalassaemic women. Iron deficiency appears not to be a major health problem in this population. Haemoglobinopathies are common but, except for homozygous alpha(+)-thalassaemia, do not substantially contribute to anaemia in pregnancy. alpha(+)-Thalassaemia ameliorates malarial anaemia in pregnant women.

[Beta-thalassemia in Germany. Results of cooperative beta-thalassemia study]. / beta-Thalassämie in Deutschland. Ergebnisse der kooperativen beta-Thalassämie-Studie.

At present, about 300 patients with thalassemia major are living in Germany. Starting in 1991, a multicenter study in Germany has concentrated on identifying all patients suffering from thalassemia as well as on establishing a uniform therapy protocol including follow-up diagnostic procedures. After six years of study, the data of 198 patients suffering from thalassaemia major were analysed. The majority of these patients originate from endemic regions around the Mediterranean Sea. The patient's median age is 13.8 years (range 1-37.5 yrs.). At present, about 20% of 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 haemoglobin concentrations of 10.0 g/dl could be observed. The evaluation of serum ferritin levels revealed considerable differences depending on patients age. 60% of patients in the first decade of life showed good therapeutic results with serum ferritin levels below 1800 ng/ml. In contrast, 52% of patients older than ten years presented with ferritin levels above 2500 ng/ml. During the observation, a decreasing number of patients with ferritin levels above 2500 ng/ml was observed in patients aged 15 to 21 years of age. The situation of patients aged 9 to 15 years proved to be more problematic. More than half of all treated patients presented with siderotic complications as cardiac disease in 13%, liver disease in 21%, impaired glucose metabolism in 14%, hypothyroidism in 24% and hypogonadism in 59% of all patients. These values did not change considerably during the observation apart from an increase of cardiac disorders to 20%. Since the situation concerning siderosis and the lack of compliance proved to be particularly difficult in adolescent patients, further efforts has to concentrate on this age group.

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.

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.

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.