Survival and disease complications in thalassemia major.

We studied survival and disease complications in 1,146 patients with thalassemia major, born from January 1, 1960 to December 31, 1987. At last follow-up, in March 1997, probability of survival to age 20 years was 89% and to age 25 years was 82% for patients born in the years 1970-1974. Patients who died had a serum ferritin level, measured the year before death, significantly higher than those who survived. Diabetes was present in 5.4% of the patients; heart failure in 6.4%; arrhythmias in 5.0%, thrombosis in 1.1%, hypothyroidism in 11.6%, HIV infection in 1.8%. Hypogonadism was diagnosed in 55% of 578 patients who had reached pubertal age: 83.5% of hypogonadic females and 78.6% of males were receiving substitutive hormonal therapy. In conclusion, the survival of patients with thalassemia major is good and improving, but the prevalence of severe complications is still high.

[Splenectomy and infection in homozygous beta-thalassemia. The uselessness of penicillin prophylaxis]. / Splenectomia ed infezioni nella beta-talassemia omozigote. Inutilità della profilassi penicillinica.

To investigate the effective usefulness of penicillin prophylaxis in splenectomized patients, we retrospectively focused on a group of sixty-two splenectomized patients affected by thalassemia major. Thirty-six out of 62 has been receiving monthly 1.200.000 Us. of benzathine-penicillin as prophylaxis. The remaining 26 did not receive prophylaxis, but was treated with antibacterial drugs as soon as symptoms of upper respiratory tract infection occurred. During a total period of eleven years of observation we did not observe any pneumococcal sepsis; the incidence of bacterial infections within the two groups is not different. We conclude for the uselessness of penicillin prophylaxis in splenectomized beta-thalassemic patients.

Restrictive diastolic abnormalities identified by Doppler echocardiography in patients with thalassemia major.

The consequences of transfusional iron overload on left ventricular diastolic filling have never been investigated systematically in patients with thalassemia major. In the present study, the pattern of left ventricular filling was assessed by Doppler echocardiography in 32 patients with thalassemia major (age, 17 +/- 5 years) who had not experienced symptoms of heart failure and had normal left ventricular systolic function. Data were compared with those obtained in 32 age-matched and sex-matched normal subjects. An abnormal Doppler pattern of left ventricular filling with increased flow velocity at mitral valve opening followed by an abrupt and premature decrease of flow velocity in early diastole was identified in the patients with thalassemia. Peak flow velocity in early diastole was increased in patients compared with controls (90 +/- 10 vs. 81 +/- 15 cm/sec; p less than 0.01), and rate of deceleration of flow velocity after the early diastolic peak and the ratio between the early and late (atrial) peaks of flow velocity were also increased (1,050 +/- 325 vs. 762 +/- 193 cm/sec2 and 2.7 +/- 0.7 vs. 2.2 +/- 0.5, respectively; p less than 0.001), whereas flow velocity deceleration time was reduced (97 +/- 22 vs. 119 +/- 19 msec; p less than 0.001). This Doppler pattern of diastolic filling is usually described as "restrictive" and reflects a decrease in left ventricular chamber compliance. A restrictive pattern of left ventricular filling was also identified in the subgroup of 16 study patients who had undergone optimal iron chelation therapy with deferoxamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Dyskeratosis congenita: unusual presenting features within a kindred.

We report on a family in which one member is affected by dyskeratosis congenita (DC), who had two cousins who died at 44 months and 36 months, respectively, with aplastic anemia and neurological abnormalities. The patient affected by DC presented with bone marrow hypoplasia at age 4; DC was diagnosed at age 6. In DC the marrow abnormalities rarely appear before the skin manifestations. The observation of this kindred poses the question whether an extremely early onset with a rapidly fatal course before the appearance of skin abnormalities is possible. We believe this report to be important for the differential diagnosis of DC and other forms of congenital aplastic anemia.

Two new human hemoglobin variants caused by unusual mutational events: Hb Zaïre contains a five residue repetition within the alpha-chain and Hb Duino has two residues substituted in the beta-chain.

With rare exceptions, the more than 600 human hemoglobin variants described are caused by a single point mutation. Other abnormal features, such as unequal crossing-over, frameshift mutagenesis or double mutations in the same polypeptide chain, have seldom been encountered. We report two new variants caused by such rare mutational events. Hb Zaïre [alpha 116(GH4)-His-Leu-Pro-Ala-Glu-117 (GH5)] is the second example in which a short amino acid sequence is inserted within the alpha-chain. This abnormal hemoglobin results from a tandem repetition of 5 amino-acid residues, from sequence 112 through 116, at the end of the GH corner. Hb Duino is an unstable hemoglobin. It presents within the same beta-chain, the association of two rare point mutations; these substitutions are those found in Hb Newcastle [beta 92(F8)His----Pro] and in Hb Camperdown [beta 104(G6)Arg----Ser]. Family studies demonstrated that the Hb Newcastle abnormality was a de novo mutation of a gene already carrying the Hb Camperdown substitution.

A novel beta-globin structural mutant, Hb Brescia (beta 114 Leu-Pro), causing a severe beta-thalassemia intermedia phenotype.

This study describes a patient with a thalassemia intermedia-like phenotype in whom beta-globin gene sequencing detected a novel abnormal hemoglobin (Hb) due to a T-C substitution at codon 114 of the beta-globin gene arising as a de novo mutation. The abnormal variant was designated Hb Brescia after the place of birth of the propositus. Normal sequences were detected at the in trans beta-globin locus. In addition, alpha-globin gene analysis detected a triple alpha-globin locus which was inherited from the father. The T-C change at position 114 of the beta-globin gene results in a leucine to proline substitution (Leu-Pro) in the G-helix. The resulting Hb tetramer is highly unstable and precipitates forming inclusion bodies in the peripheral red blood cells. Moreover, the Leu-Pro substitution interferes negatively with the four alpha 1 beta 1 contact points of the G-helix most likely adversely affecting the alpha beta dimer formation. The very severe phenotype presented by our patient is unusual in a heterozygote for an unstable Hb variant and may be explained by the coinheritance of the triple alpha-globin locus.

Survival and causes of death in thalassaemia major.

Survival and causes of death were studied in 1087 Italian patients with thalassaemia major who were born on or after Jan 1, 1960. At the age of 15 years, the Kaplan-Meier estimate of survival after the first decade of life was 80.6% for subjects born in 1960-64, 84.2% for those born in 1965-69, and 96.9% for those born in 1970-74. At the age of 20 years, survival from the age of 10 was 59.1% for patients born in 1960-64, and 70.2% for those born in 1965-69; at 25 years, survival from the age of 10 was 40.7% in the 1960-64 cohort. Overall survival from birth for patients born in 1970-74 was 97.4% at 10 years, and 94.4% at 15 years. The most common cause of death was heart disease, followed by infection, liver disease, and malignancy.

Growth and sexual maturation in thalassemia major.

Growth and sexual development were evaluated in 250 adolescents with beta-thalassemia major. Before transfusion hemoglobin concentration had not been less than 9.5 gm/dl in the last 5 years; desferrioxamine had been administered for 7 to 10 years, including by the subcutaneous route for 3 years. Thirty-seven percent of patients were found to be 2 SD below the mean for normal height; after age 14 years the percentage was 62% for males and 35% for females. Eighty-three percent of males and 75% of females had delayed skeletal maturation. Complete lack of pubescent changes was present in 38% of females and 67% of males aged 12 to 18 years. Only 19% of females had experienced menarche; secondary amenorrhea intervened in a third of them. A multiple regression analysis of indicators of pubertal development with age, age at first transfusion, age at splenectomy, number of transfusions, serum transaminase and ferritin, and duration and intensity of chelation therapy failed to identify the factors responsible for the variation observed in sexual maturation among patients with thalassemia.

Quantitative ultrasonic analysis of myocardium in patients with thalassemia major and iron overload.

BACKGROUND: Patients with beta-thalassemia major present with severe anemia and need continuous transfusion therapy. The consequent iron overload leads to hemochromatosis. Initial cardiac dysfunction has been documented even in thalassemics without clinical manifestations of heart failure as well as by conventional echocardiographic-Doppler techniques. The purpose of this study was to assess the acoustic quantitative properties of myocardium in patients with iron overload. METHODS AND RESULTS: Thirty-eight patients with beta-thalassemia major, without clinical signs of cardiac failure, and 20 age- and sex-matched young controls were studied by echocardiography. An on-line analysis of the ultrasonic radiofrequency signal was performed to obtain quantitative operator-independent measurements of the integrated backscatter (IB) signal of the ventricular septum and the posterior wall. The integrated values of the radiofrequency signal were normalized for the pericardial interface and expressed in percent (IB%). Thalassemic patients had been receiving transfusion therapy for 16 +/- 5 years and had received 313 +/- 138 transfusion units; they all had received chelation treatment (desferroxiamine) for 9 +/- 2 years. Patients and controls showed comparable values of echocardiographically assessed percent fractional shortening (32 +/- 3% versus 36 +/- 4%, p = NS), whereas thalassemics showed higher values of left ventricular mass index (118 +/- 30 versus 98 +/- 15 g/m2, p < 0.05). The IB% values were higher in patients with thalassemia major than in controls for both septum (35 +/- 14% versus 21 +/- 6%, p < 0.001) and posterior wall (16 +/- 6% versus 11 +/- 3%, p < 0.001). In thalassemic patients, no significant correlation was found between the septum IB% value and hematological parameters, such as the total number of transfusions (r = 0.2, p = NS) or the mean ferritin value (r = 0.1, p = NS). No significant correlation was also found between the septum IB% value and the echocardiographically assessed left ventricular mass index (r = 0.2, p = NS). CONCLUSIONS: These data demonstrate that myocardial reflectivity is abnormally increased in patients with thalassemia major under transfusion treatment, probably due to myocardial iron deposits and/or secondary structural changes. These quantitatively assessed abnormalities in regional reflectivity can be detected when conventional echocardiographic parameters of systolic left ventricular function are undistinguishable from normal controls.

The incidence and natural course of transfusion-associated GB virus C/hepatitis G virus infection in a cohort of thalassemic patients. The Cooleycare Cooperative Group.

To evaluate the risk of transmitting blood-borne GB virus C/hepatitis G virus (GBV-C/HGV) and to define the natural course of infection, we performed a prospective study in a cohort of multitransfused beta-thalassemics during a 6-year follow-up period. We analyzed serum samples of 150 patients collected at 3-year intervals from 1990 to 1996. GBV-C/HGV RNA was determined by reverse transcriptase-polymerase chain reaction and antibodies to E2-protein by an enzyme immunoassay. At baseline, 14.5% of patients had viremia and 18.5% anti-E2. None of the patients with anti-E2 in 1990 subsequently became viremic. Of the 100 GBV-C/HGV RNA-, anti-E2- patients, 10 acquired infection during follow-up, as indicated by positivity of GBV-C/HGV RNA (n = 2), anti-E2 (n = 7), or both markers (n = 1) in 1996. The incidence was 1.7 per 100 person-years (95% confidence interval [CI], 0.8 to 3). Since approximately 19,000 blood units were transfused to these patients during follow-up, the risk of infection was 5.3 in 10,000 units (95% CI, 2 to 8.5). Six of 22 viremic patients cleared the virus during follow-up; 4 of them became anti-E2+. Twelve of 28 patients lost anti-E2 reactivity during follow-up. In conclusion, more than 25% of infections resolve within 6 years; the presence of anti-E2 seems to be protective against infection. Anti-E2 reactivity may decrease with time.

Thromboembolic events in beta thalassemia major: an Italian multicenter study.

Thromboembolic (TE) events have been frequently reported in beta-thalassemic patients in association with known risk factors such as diabetes, complex cardiopulmonary abnormalities, hypothyroidism, liver function anomalies, and postsplenectomy thrombocytosis. In a recent survey involving 9 Italian thalassemic centers, we identified 32 patients with TE episodes in a total of 735 subjects, of whom 683 had thalassemia major and 52 thalassemia intermedia, corresponding to 3.95 and 9.61%, respectively. There was a great variation in localization: the main one (16/32) was CNS, with a clinical picture of headache, seizures and hemiparesis. Other localizations were the pulmonary (3 patients), mesenteric (1 patient) and portal (2 patients) sites. There were 6 cases of deep venous thrombosis (2 in the upper limbs, 4 in the lower ones). Intracardiac thrombosis was found in 2 subjects and clinical and laboratory signs of DIC were observed in 2 others during pregnancy. Since our patients with TE events present a statistically significantly higher incidence of associated dysfunction (cardiomyopathy, diabetes, liver function anomalies, hypothyroidism) than those without TE events (50 vs. 13.8%), we suggest close monitoring of those patients who are at higher risk of developing TE events because of the presence of one or more of these predisposing factors.