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Objectives Hemoglobinopathies are inherited transition blood diseases associated with globin chains of the hemoglobin. However many mutations have been defined, there may be many of them not defined yet. We here report the first case of those mutations, named Hb G-Norfolk in Turkey. Case presentation A 15 years-old male patient with erythrocytosis was referred to our laboratory for the evaluation of hemoglobinopathy. In chromatographic analysis, an unidentified peak was observed. A similar identification for variant Hb could not be obtained from High-Performance Liquid Chromatography (HPLC) analyzer’s data library. No definitive diagnosis could also be made by different analyzer. Family screening and molecular genetic DNA sequence analysis were carried out. Conclusions Although there were not found any beta gene mutation of neither the patient nor his family, analyses of alpha genes A1 and A2 were performed and abnormal hemoglobines were detected for all of them. This change in the HbA2 gene was at codon85 GAC>AAC (Asp>Asn) in the heterozygous state, known as Hb G-Norfolk [HbA2:c256G>A p.Asp85Asn] based on HbVar database. Abnormal Hb bands detected by HPLC with clinical findings such as erythrocytosis or cyanosis should be investigated by sequence analysis to corroborate alpha and/or beta-globin gene mutations for avoiding misdiagnosis and misinterpretation.

Background: More than five decades ago, thalassemia major (TDT) was fatal in the first decade of life. Survival and quality of life have improved progressively thanks to the implementation of a significant advance in diagnostic and therapeutic methods, consisting mainly of a frequent transfusion program combined with intensive chelation therapy. Improvement also includes imaging methods used to measure liver and cardiac iron overload. Improved survival has led to a growing number of adults requiring specialised care and counselling for specific life events, such as sexual maturity and acquisition of a family. Aims of the study: The main aim is to present the results of a survey on the marital and paternity status in a large population of adult males with TDT and NTDT living in countries with a high prevalence of thalassemia and a review of current literature using a systematic search for published studies. Results: Ten out of 16 Thalassemia Centres (62.5%) of the ICET-A Network, treating a total of 966 male patients, aged above 18 years with β- thalassemias (738 TDT and 228 NTDT), participated in the study. Of the 966 patients, 240 (24.8%) were married or lived with partners, and 726 (75.2%) unmarried. The mean age at marriage was 29.7 ± 0.3 years. Of 240 patients, 184 (76.6%) had children within the first two years of marriage (2.1 ± 0.1 years, median 2 years, range 1.8 - 2.3 years). The average number of children was 1.32 ± 0.06 (1.27 ± 0.07 in TDT patients and 1.47 ± 0.15 in NTDT patients; p: >0.05). Whatever the modality of conception, 184 patients (76.6%) had one or two children and 1 NTDT patient had 6 children. Nine (4.8%) births were twins. Of 184 patients, 150 (81.5%) had natural conception, 23 (12.5%) required induction of spermatogenesis with gonadotropins (hCG and hMG), 8 (4.3%) needed intracytoplasmic sperm injection (ICSI) and 3 adopted a child. 39 patients with TDT and NTDT asked for medical help as they were unable to father naturally: 7 TDT patients (17.9%) were azoospermic, 17 (37.7%) [13 with TDT and 4 with NTDT] had dysspermia and 15 (33.3%) [13 with TDT and 2 with NTDT] had other “general medical and non-medical conditions”. Conclusions: Our study provides detailed information in a novel area where there are few contemporary data. Understanding the aspects of male reproductive health is important for physicians involved in the care of men with thalassemias to convey the message that prospects for fatherhood are potentially good due to progressive improvements in treatment regimens and supportive care. (www.actabiomedica.it)

Objective: Bladder cancer (BCa) is the fifth most common cancer and the second most common urinary tract cancer in worldwide. BCa accounts for 3% of all cancers and is particularly common in developed countries. Material and methods: Eighteen of the 20 patients included in the study were male, 2 were female, mean age was 65.1±12.1(range:37-75) years. The control group consisted of 19 male one female, mean age was 60.3±11.2 (range:40-70) years. A total of seven miRNAs, let-7c, miR-155, miR-125b, miR-141 miR-145, miR 181 and miR 192 were evaluated in two groups. Results: MiRNAs of bladder cancer patients and healthy individuals were compared according to endogenous miR 181 and miR 192 Delta CT values, miR125b values of bladder cancer cases were found to be significantly higher than healthy controls.(p=0.021) In our study, miR125b, which we found specific and sensitive in endogenous controls, was compatible with studies in the literature. As conclusion, we emphasize that mir125b can be used as a predictor in bladder cancer compared with the literature. The current study was funded by Republic of Turkey, Ministry of Science and Industry, KOSGEB Antalya Directorate within the scope of the project entitled “MicroRNA kits in the early diagnosis of cancer” conducted by AGTC Özel Genetik Sağlık Hizm. Tur. San. Tic. Ltd. Şti. Grand Number: 0080785533

Sickle cell disease (SCD) and thalassemias are the most common monogenic diseases in the world. The number of migrants and refugees in Europe and Turkey, in the past decade, has increased dramatically due to war, violence or prosecutions in their homeland. Prevention and management of haemoglobin disorders is well established and managed in countries where these conditions were traditionally endemic or in countries that have a longstanding tradition of receiving migrants. Therefore, preventive and diagnostic programmes regarding hemoglobinopathies in immigrant populations have been implemented. The purpose of this paper it to report a summary of the experience gained in Italy, Spain and Turkey in migrants, asylum seekers and refugees. (www.actabiomedica.it)

Thalassemia (Thal) is an inherited blood disorder endemic to the Mediterranean and Middle East (e.g., KSA and UAE). This disease is caused by defects in the synthesis of one or more hemoglobin chains in red blood cells (RBCs). Alpha (α) Thal is caused by a reduced or absent alpha globin segment. Similarly, beta (β) Thal is caused by a defect in the beta globin segment. We divided the diseases into four groups: α Thal trait, α Thal disease, β Thal trait, and β Thal disease. The α or β Thal traits are milder variants of these diseases and do not require treatment; but β Thal disease (and to a lesser extent, α Thal) causes hemolytic anemia, splenomegaly, and bone deformities and requires repeated lifelong blood transfusions. This paper presents results regarding the identification of Thal variants using fluorescence spectroscopy of blood biomolecules and atomic force microscopy analysis of the morphologic features of red blood cells. The combined results provide new insights into the characteristics of these diseases. Furthermore, this study shows why β Thal disease subjects are often transfusion-dependent, and α Thal disease subjects are only occasionally transfusion dependent.

Prostate cancer (PCa) is a common type of cancer in western countries and prominent cause of mortality in men. The aim of the study was to analyze circulating miRNAs as biomarkers in the sera of healthy individuals and prostate cancer cases without biopsy.Twenty prostate cases, age (mean and range) 61,4±12.1 (45-73), and twenty healthy men, age 59,3±11.2 (44-70) were included to the study. The mean and range of prostate spesific antigen (PSA) in cancer cases and healthy individuals were 6.79±2.84 ng/ml (2.25-14.7) and 3.8±2.2 ng/ml (1.3-7.8) respectively.Seven miRNAs including two internal controls (Let7c, miR125b, miR141, miR145, miR 155, miR181 ve miR192) were evaluated in two groups. The level of miR141 was significantly lower in PCa cases than healthy individuals (p=0,004), and miR155 was significantly higher (p=0,005) in PCa cases. Both miRNAs were explored sensitive and spesific in the ROC analysis. Tumor mass were found to be associated with the level of miR-125b and miR-145. Conclusion; validation studies are required in wider patient groups in the subject of tumor effect and miRNA biomarkers in prostate cancer.

Alpha (?) thalassemia is one of the hemoglobinopaties that is inherited by autosomal recessive mode. It is caused by mutations on alpha-1 and alpha-2 globin genes. Deletional type mutations of globin genes have commonly been seen in alpha thalassemias. While small deletional mutations such as-3.7 cause ?+-thalassemia, large deletions such as-26.5-20.5 cause ?0-thalassemia. The objective of our study was to determine the profile of deletional and non-deletional ?-globin gene mutations in the Antalya population, Turkey. In present study, the presence of ?-thalassemia mutations were investigated by RDBH (reverse dot blot hybridization) among 250 patients with microcytic anemia and beta globin normal. Some positive and negative cases were confirmed by MLPA (multiplex ligation dependent probe amplification) and at the latest DNA sequencing. Eight different mutations were determined in 112 (44.8%) of patients in our study. The-??3.7 deletion was the most common mutation(73.3%). Others common mutations were the – ?20.5 (13.0%) and –MED (6.5%),--FIL (2.4%), Hb Adana (2.4%). The 97.5 % of total mutations consisted of these five mutations. Three patients with Hb H disease were found related with-? 3.7 /-(?)-20.5 genotype. One patient (2.04%) had the ??? anti-3.7 gene triplication. Two rare mutations, ?2 codon 64 (G>C) (Hb Fontainebleau) and ?2 codon 193 (G>A) (Hb G-Waimanalo), were determined by DNA sequencing firstly in Antalya Province, Turkey. Our results may be valuable to give accurate premarital genetic counseling and to apply classical prenatal and preimplantation genetic diagnosis by the complementary methods such as RDBH, MLPA and DNA sequencing for the screening of alpha thalassemia carriers. © 2021, Yuzuncu Yil Universitesi Tip Fakultesi. All rights reserved.

COVID-19 is an infectious disease caused by the SARS-CoV-2 virus. Most people with COVID-19 have a mild to moderate respiratory illness; others experience severe illness, such as COVID-19 pneumonia. The first and most accessible diagnostic information is from symptoms and signs from clinical examination. Infected patients present with a variety of manifestations. Formal diagnosis requires laboratory analysis of nose and throat samples, or imaging tests like CT scans. Emerging data suggest that coronavirus disease 2019 (COVID-19) has extrapulmonary manifestations. Sometimes these extra-respiratory manifestations may be the initial or only symptom of COVID-19, prior to fever or respiratory manifestations. In summary, our concise review shows that there is a wide range of symptoms that can be presented by COVID-19 patients. Extra-respiratory manifestations of SARS-CoV-2 infection have recently been observed in the rapidly increasing number of COVID-19 cases. Considering the broad spectrum of clinical manifestations and the increasing worldwide burden of the disease, there is an urgent need to rapidly scale up the diagnostic capacity to detect COVID-19 and its complications. (www.actabiomedica.it)

A review of the literature on COVID-19 pandemic in patients with thalassemias is presented. Globally, the prevalence of COVID-19 among β-thalassemia patients seems to be lower than in general population; associated co-morbidities aggravated the severity of COVID- 19, leading to a poorer prognosis, irrespective of age. A multicenter registry will enhance the understanding of COVID-19 in these patients and will lead to more evidence-based management recommendations. (www.actabiomedica.it)

Objectives: This study aims to investigate, retrospectively, the epidemiological and clinical characteristics, laboratory results, radiologic findings and outcomes of novel coronavirus disease-19 (COVID-19) in patients with transfusion dependent β thalassemia (β-thalassemia major-TM), non-transfusion dependent β thalassemia (β-thalassemia intermedia -TI) and sickle cell disease (SCD). Design, setting: A total of 17 Centers, from 10 countries, following 9,499 patients with hemoglobinopathies participated in the survey. Main outcome measures: Clinical, laboratory and radiologic findings and outcomes of patients with COVID-19 were collected from medical records and summarized. Results: A total of 13 patients, 7 with TM, 3 with TI and 3 with SCD, with confirmed COVID-19, were identified from 6 Centers from different countries. The overall mean age of patients was 33.7±12.3 years (range:13-66); 9/13 (69.2%) patients were females. The commonest symptoms in the 10 symptomatic patients were: fever (80%), cough (70%), headache (60%), fatigue (60%), gastrointestinal symptoms (diarrhea /vomiting/abdominal pain; 50%), tachypnea/dyspnea (40%), and sore throat (40%). Six patients had pneumonia (unilateral, bilateral or multiple opacity) and 4 needed oxygen therapy. An oxygen saturation ≤ 93% was documented in 3 patients at diagnosis. 6/10 patients had an exacerbation of anemia (2 with SCD, associated with back and chest pain in 1 patient), and 3 (

The beginning of 2020 has seen the emergence of COVID-19, an outbreak caused by a novel coronavirus, SARS-CoV-2, an important pathogen for humans. SARS-CoV-2 is an RNA virus containing 29891 nucleotides encoding 9889 amino acids. The genome is arranged as 5p-replicase (orf1/ab)-structural proteins [Spike (S) -Envelope (E) - Membrane (M) -Nucleocapsid (N)] −3. Viruses are obligate intracellular infectious agents that use the host cellular machinery to ensure their own fitness and survival. MicroRNAs (miRNA9) systems are potent post-transcriptional gene expression regulators that are important modulators of viral infections, and could play an important role in the treatment of viral infections. This review focuses to the genomic structure of coronaviruses, the functions of genomic proteins, the effects of micro RNA (miRNA) on virus replication and its pathogenesis. (www.actabiomedica.it)

Women with sickle cell disease (SCD) are of particular concern regarding the significantly increased risk of pregnancy-related morbidity, mortality, and adverse outcomes. They have limited knowledge of pregnancy and childbirth risks, as well as of the benefits and risks of contraceptives. Thus, there is an urgent need for appropriate information about reproductive family planning to reduce unintended pregnancy. Any decision regarding the use of contraceptives has to be based on the efficacy and risk/benefit ratio of the method used. Both the World Health Organization (WHO) and the Centers for Disease Control (CDC) have developed, published, and updated evidence-based guidelines for medical providers for the use of contraceptives in patients with specific medical chronic conditions. This article provides an overview of the present knowledge on the use of contraceptives in women with SCD. We believe that the collaboration between health care professionals (hematologists, obstetricians, endocrinologists, and primary care providers) can play a major role in identifying the safer contraceptive method to abolish the risks of unintended pregnancy and preserve the health status of patients with SCD.

In adult thalassemia major (TM) patients, a number of occult and emerging endocrine complications, such as: central hypothyroidism (CH), thyroid cancer, latent hypocortisolism, and growth hormone deficiency (GHD) have emerged and been reported. As the early detection of these complications is essential for appropriate treatment and follow-up, the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A) promoted a survey on these complications in adult TM patients, among physicians (pediatricians, hematologists and endocrinologists) caring for TM patients in different countries. The data reported by 15 countries are presented. The commonest endocrine complications registered in 3.114 TM adults are CH and GHD (4.6 % and 3.0 %, respectively), followed by latent hypocortisolism (1.2%). In 13 patients (0.41%) a cytological papillary or follicular thyroid carcinoma was diagnosed in 11 and 2 patients, respectively, and a lobectomy or thyroidectomy was carried out. Of 202 TM patients below the age of 18 years, the reported endocrine complications were: GHD in 4.5%, latent hypocortisolism in 4.4% and central hypothyrodisim in 0.5%. Transition phase was an area of interest for many clinicians, especially as patients with complex chronic health conditions are responding to new treatments extending their lifespan beyond imagination.. In conclusion, our survey provides a better understanding of physicians’ current clinical practices and beliefs in the detection, prevention and treatment of some endocrine complications prevailing in adult TM patients. Regular surveillance, early diagnosis, treatment and follow-up in a multi-disciplinary specialized setting are recommended. (www.actabiomedica.it)

Data on the prevalence and type of endocrine disorders in β-thalassemia intermedia (β-TI) patients are scarce. This multicenter study was designed to determine the prevalence of endocrine complications and the associated risk factors in a large group of β-TI patients. In this cross-sectional multicenter study, 726 β-TI patients, aged 2.5–80 years, registered at 12 thalassemic centers, from nine countries, were enrolled during 2017. In a subgroup of 522 patients (mean age 30.8 ± 12.1; range: 2.5–80 years) from Qatar, Iran, Oman, Cyprus, and Jordan detailed data were available. Overall, the most prevalent complications were osteopenia/osteoporosis (22.3%), hypogonadism (10.1%), and primary hypothyroidism (5.3%). In the subgroup multivariate analysis, older age was a risk factor for osteoporosis (Odds ratio: 7.870, 95% CI: 4.729–13.099, P

Background: Transfusion-dependent β-thalassemia (TDT) is associated with several complications necessitating a multidisciplinary approach for diagnosis, treatment and follow-up. Hypogonadism in female TDT patients is one of the most common endocrine complications, requiring hormone replacement therapy (HRT) throughout reproductive life. Little is known about the balance of benefits versus risks of treatment with sex steroids. Aim: The aim of this manuscript is to review the action and the associated adverse effects of HRT in hypogonadal TDT females. Design: Retrospective medical database records from a single centre, over a period of 38 years (January 1980 to June 2018), were reviewed. Study population: Forty-two cases of hypogonadism in TDT females followed in a pediatric and adolescent outpatient clinics, were in included in the study. Methods: Auxological, clinical, laboratory, hormonal and imaging investigations were reviewed, as well as all adverse events registered during HRT. Main results: In general, HRT was safe for most patients. There were few minor side effects and a couple of rare but serious adverse events. Conclusions: The study provides a representative clinical profile of long-term effects of HRT in hypogonadal adolescents and young adult TDT women. Our results highlight also the need for further research in other areas for which HRT may have a role. We hope this will contribute to a wider understanding, and potential improvement, of patient safety and quality of life. (www.actabiomedica.it)

Thalassemia and hemoglobinopathies are a major public health problem in Turkey. Hemoglobinopathy prevention programs (HPPs) were started in 33 provinces situated in Thrace, Marmara, Aegean, Mediterranean and South Eastern regions of Turkey in 2003. A premarital hemoglobinopathy test is mandatory and free of charge in this program. According to the Ministry of Health reports, 46 first level hemoglobinopathy diagnostic centers were established for premarital tests. Within the last 10 years, approximately 79.0% of married individuals per year were screened by the centers. While the percentage of premarital screening tests was 30.0% of all couples in 2003, it reached 86.0% in 2013. The number of newborn with thalassemia and hemoglobinopathies were 272 in 2002 and dropped to 25 in 2013. There has been a 90.0% reduction in affected births. Our hemoglobinopathy diagnostic center was established in 2003 and licensed by the Ministry of Health in 2004. We studied a total of 89,981 blood samples from premarital tests for 10 years and the incidence of β- and α-thalassemia (β- and α-thal) trait was found to be 6.57 and 3.56%, respectively. The distribution of the most common abnormal hemoglobins (Hbs) was: Hb S (HBB: c.20A > T) (0.31%), Hb D-Los Angeles (HBB: c.364G > C) (0.15%), Hb G-Coushatta (HBB: c.68A > C) (0.06%) and Hb E (HBB: c.79G > A) (0.02%). A total of 60 couples, both carrying β-thal trait, were directed to the prenatal diagnosis (PND) center in 10 years. The premarital hemoglobinopathy screening program is running successfully at our center and other centers in Turkey.

Women with sickle cell disease (SCD) are of particular concern due to the significantly increased risk of pregnancy-related morbidity, mortality, and adverse outcomes. They have limited knowledge of the risks of pregnancy and childbirth as well as of the benefits and risks from the use of contraceptives. Thus, there is urgent need for appropriate information about reproductive family planning to reduce unintended pregnancy. Any decision regarding the use of contraceptives has to be based on the efficacy and the risks and benefits of the method used. Both the World Health Organization (WHO) and the Center for Disease Control and Prevention (CDC) have developed, published, and updated evidence-based guidelines for medical providers for the use of contraceptives in patients with specific medical chronic conditions. This article provides an overview of the present knowledge for the use of contraceptives in women with SCD. We believe that the collaboration between health care professionals (hematologists, obstetricians, endocrinologists, and primary care providers) can play a major role in identifying the safer contraceptive method to abolish the risks of unintended pregnancy and preserve the health status of patients with SCD.

Due to the recent alarming increase in the incidence of hepatocellular carcinoma (HCC) in thalassemias, the aim of the present report is to review briefly the frequency, the major risk factors and the surveillance of HCC in β-thalassemias. Over the past 33 years, 153 cases of HCC were reported in patients with thalassemia, mainly in Italy, and Greece. Among HCV-infected patients additional factors promoting development of HCC, included: advanced age, male sex, chronic hepatitis B (CHB) coinfection, and iron overload. For early diagnosis of HCC sequential ultrasound screening is recommended especially for thalassemia patients with chronic hepatitis C (CHC), that coincide with (one or more) additional risk factors for HCC. Here we report also the preliminary data of thalassemic patients, above the age of 30 years, followed in 13 different centers. The total number of enrolled patients was 1,313 (males: 612 and 701 females). The prevalence of HCC in thalassemia major patients [characterized by transfusion-dependency (TDT)] and thalassemia intermedia [characterized by nontransfusion dependency (NTDT)] was 1.68 % and 1.98 % ,respectively The lowest age at diagnosis was 36 years in TDT and 47 years in NTDT patients.We hope that our review can be used to develop more refined and prospective analyses of HCC magnitude and risk in patients with thalassemia, and to define specific international guidelines to support clinicians for an early diagnosis and treatment of HCC in thalassemic patients.

Background: Oxidative damage and increasing of lipid peroxidation are caused by chronic iron overload in patients with beta thalassemia major. Fatty acids are important structural elements for palmitoylation of membrane proteins which constitute a great part of natural membranes. Oxidative damages caused by reactive oxygen derives in thalassemic erythrocytes can be determined with lipid peroxidation, protein oxidation, and antioxidant system elements. The aim of study was to evaluate the relationship between amino acid and fatty acid levels with iron overload and antioxidant enzymes in beta thalassemia major. Methods: A total 40 patients with beta thalassemia major with regular blood transfusion and chelating agents were included in the study. The levels of serum amino acid, fatty acid, ferritin, antioxidant enzymes and malondialdehyde were measured. Results: Only C16-palmitoyl level was found significantly low in patients, other fatty acids and amino acids were in normal range. There were lower malondialdehyde and ferritin levels in patients with low C-16 palmitoyl level (p

Sickle cell anemia (SCA) is an inherited blood disorder with worldwide incidence of 15%; out of this, it is found in up to 20% in countries like Kingdom of Saudi Arabia and Bahrain. The standard conventional method of detection is complete blood count (CBC) followed by hemoglobin electrophoresis or high-performance liquid chromatography (HPLC) or both. In this context, spectral detection of variants of sickle cell anemia (SCA) is an innovative technique, which when made accurate and reliable could be an effective alternative, since the instrumentation is compact (5 kg) and hence portable. This makes mass screening even in remote villages possible. In this paper, we give the essential aspects of fluorescent spectral features of sickle cell trait (SCT), sickle cell disease (SCD), beta (β) thalassemia trait (BTT) + SCD, and beta (β) thalassemia disease (BTD) + SCD. All the above four major variants could be discriminated among themselves and also from the normal control blood sample. All these analyses could be carried out with 5 ml of blood, in a time period of 10 minutes. The results of this paper give strong support for an alternative method, a spectral technique, for molecular-level diagnosis of sickle cell anemia and other closely related blood disorders.

Sickle Cell Disease (SCD) is an increasing global health problem and presents significant challenges to European health care systems. Newborn screening (NBS) for SCD enables early initiation of preventive measures and has contributed to a reduction in childhood mortality from SCD. Policies and methodologies for NBS vary in different countries, and this might have consequences for the quality of care and clinical outcomes for SCD across Europe. A two-day Pan-European consensus conference was held in Berlin in April 2017 in order to appraise the current status of NBS for SCD and to develop consensus-based statements on indications and methodology for NBS for SCD in Europe. More than 50 SCD experts from 13 European countries participated in the conference. This paper aims to summarise the discussions and present consensus recommendations which can be used to support the development of NBS programmes in European countries where they do not yet exist, and to review existing programmes., SCOPUS: ar.j, info:eu-repo/semantics/published

Novel β-globin gene mutations are still occasionally being reported, especially when evaluating milder phenotypes. We report here a novel putative mutation in the promoter region of the β-globin gene and assess its clinical implications. A family, parents and four siblings, with hematological and clinical features suspected of being β-globin gene mutation(s), were involved in this study. In addition to hematological and clinical evaluations of the whole family, molecular analyses of the β-globin gene were performed by direct sequencing. Sequencing of the β-globin gene revealed a novel genomic alteration in the regulatory region of the gene. This novel genomic alteration was defined as HBB: c.-127G C according to the Human Genome Variation Society (HGVS) nomenclature. Two siblings were found to be carriers of the HBB: c.-127G C mutation, while the other two siblings were carriers of the codon 8 (-AA) (HBB: c.25_26delAA) deletion of the β-globin gene. The mother was a compound heterozygote for the codon 8 and HBB: c.-127G C mutations. Based on hematological and clinical evaluations, we conclude that this novel β-globin gene promoter region change would be associated with a mild phenotype of β-thalassemia (β-thal).

Hypoparathyroidism (HPT) is a rare disease with leading symptoms of hypocalcemia, associated with high serum phosphorus levels and absent or inappropriately low levels of parathyroid hormone (PTH). In patients with thalassemias it is mainly attributed to transfusional iron overload, and suboptimal iron chelation therapy. The main objectives of this survey were to provide data on the prevalence, demographic and clinical features of HPT in thalassemia major (TM) and intermedia (TI) patients living in different countries, and to assess its impact in clinical medical practice. A questionnaire was sent to all Thalassemia Centres participating to the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescence Medicine (ICET-A) Network. Seventeen centers, treating a total of 3023 TM and 739 TI patients, participated to the study. HPT was reported in 206 (6.8%) TM patients and 33 (4.4%) TI patients. In general, ages ranged from 10.5 to 57 years for the TM group and from 20 to 54 years for the TI group. Of the 206 TM patients and 33 TI patients with HPT, 117 (48.9%) had a serum ferritin level >2.500 ng/ml (54.3% TM and 15.1% TI patients) at the last observation. Hypocalcemia varied in its clinical presentation from an asymptomatic biochemical abnormality to a life-threatening condition, requiring hospitalization. Calcium and vitamin D metabolites are currently the cornerstone of therapy in HPT. In TM patients, HPT was preceded or followed by other endocrine and non-endocrine complications. Growth retardation and hypogonadism were the most common complications (53.3% and 67.4%, respectively). Although endocrine complications were more common in patients with TM, non-transfused or infrequently transfused patients with TI suffered a similar spectrum of complications but at a lower rate than their regularly transfused counterparts. In conclusion, although a large international registry would help to better define the prevalence, comorbidities and best treatment of HPT, through the result of this survey we hope to give a clearer understanding of the burden of this disease and its unmet needs. HPT requires lifelong therapy with vitamin D or metabolites and is often associated with complications and comorbidities. Therefore, it is important for endocrinologists and other physicians, who care for these patients, to be aware of recent advances of this disorder.(www.actabiomedica.it)

Changes in thyroid function and thyroid function tests occur in patients with β-thalassemia major (TM). The frequency of hypothyroidism in TM patients ranges from 4% to 29 % in different reports. The wide variation has been attributed to several factors such as patients' genotype, age, ethnic variations, treatment protocols of transfusions and chelation, and varying compliance to treatment. Hypothyroidism is the result of primary gland failure or insufficient thy­roid gland stimulation by the hypothalamus or pituitary gland. The main laboratory parameters of thyroid function are the assessments of serum thyroid-stimulating hor­mone (TSH) and serum free thyroxine (FT4). It is of primary importance to interpret these measure­ments within the context of the laboratory-specific normative range for each test. An ele­vated serum TSH level with a normal range of serum FT4 level is consistent with subclinical hypothyroidism. A low serum FT4 level with a low, or inappropriately normal, serum TSH level is consistent with secondary hypothyroidism. Doctors caring for TM patients most commonly encounter subjects with subclinical primary hypothy­roidism in the second decade of life. Several aspects remain to be elucidated as the frequency of thyroid cancer and the possible existence of a relationship between thyroid dysfunction on one hand, cardiovascular diseases, components of metabolic syndrome (insulin resistance) and hypercoagulable state on the other hand. Further studies are needed to explain these emerging issues. Following a brief description of thyroid hormone regulation, production and actions, this article is conceptually divided into two parts; the first reports the spectrum of thyroid disease occurring in patients with TM, and the second part focuses on the emerging issues and the open problems in TM patients with thyroid disorders.

The Thalassemia center of Antalya State Hospital was established in 1994 in Antalya, Turkey. The number of newborns with thalassemia decreased statistically because of actions taken as a result of prevention studies. A total of 388 patients, including 246 with thalassemia major (63.4%), 86 with thalassemia intermediate (22.1%), 23 with sickle cell+β-thalassemia (5.9%), 20 with sickle cell disease (5.1%), and 13 with other hemoglobin abnormalities (3.3%), were studied. Complications were found to be as follows: cardiomyopathy in 45 of them (11.5%), diabetes mellitus in 10 (2.5%), hypothyroidism in 17 (4.3%), hypoparathyroidism in 2 (0.5%), osteoporosis in 53 (13.6%), growth retardation in 110 (28.3%), and hypogonadism in 75 patients (19.3%). The incidence of autoantibody and alloantibody in patients with thalassemia major was 5.6% and 10.5%, respectively. Transfusion-transmission diseases evaluated in patients found the incidence of hepatit A virus IgG to be 97.5%, that of HBs Ab to be 99.5%, HBs Ag to be 0.5%, HCV Ab to be 18%, CMV IgG to be 72.3%, CMV IgM to be 2%, and HIV-Ab to be 0%. Therefore, for the first time in our country the thalassemia center was established as a model and included subunits and a team. It served all patients for 15 years until the team was dispersed; thereafter, most of the patients were not followed up on a regular basis.

Background Haemoglobinopathies constitute the commonest recessive monogenic disorders worldwide, and the treatment of affected individuals presents a substantial global disease burden. β-thalassaemia is characterised by the reduced synthesis (β+) or absence (βo) of the β-globin chains in the HbA molecule, resulting in accumulation of excess unbound α-globin chains that precipitate in erythroid precursors in the bone marrow and in the mature erythrocytes, leading to ineffective erythropoiesis and peripheral haemolysis. Approximately 1.5% of the global population are heterozygotes (carriers) of the β-thalassemias; there is a high incidence in populations from the Mediterranean basin, throughout the Middle East, the Indian subcontinent, Southeast Asia, and Melanesia to the Pacific Islands. Aim The principal aim of this paper is to review, from a historical standpoint, our knowledge about an ancient disease, the β-thalassemias, and in particular, when, how and in what way β-thalassemia spread worldwide to reach such high incidences in certain populations. Results Mutations involving the β-globin gene are the most common cause of genetic disorders in humans. To date, more than 350 β-thalassaemia mutations have been reported. Considering the current distribution of β- thalassemia, the wide diversity of mutations and the small number of specific mutations in individual populations, it seems unlikely that β-thalassemia originated in a single place and time. Conclusions Various processes are known to determine the frequency of genetic disease in human populations. However, it is almost impossible to decide to what extent each process is responsible for the presence of a particular genetic disease. The wide spectrum of β-thalassemia mutations could well be explained by looking at their geographical distribution, the history of malaria, wars, invasions, mass migrations, consanguinity, and settlements. An analysis of the distribution of the molecular spectrum of haemoglobinopathies allows for the development and improvement of diagnostic tests and management of these disorders.

Regular desferrioxamine (DFO) usage in patients with thalassemia major (TM) ameliorates hepatic, cardiac and endocrine dysfunction, improves growth and sexual maturation and prolongs survival. The difficulties of administering DFO with classic pumps are well known. The aim of this study was to compare the iron accumulation and cost effects between the continuous 48 hours infusion of DFO with infusor pump and the intermittent 40 hours infusion with classic pump in patients with TM. A total of 54 patients with TM were divided to two groups, first group includes 27 patients (18 female, 9 male) aged between 5.5 and 20.5 years, and were infused a total of 100 mg/kg DFO with infusor in 48 hours. Second group includes 27 patients (18 female, 9 male) aged between 6 and 22 years, were infused a total of 200 mg/kg DFO in 4 days with an intermittent infusions for about in 40 hours. After one year of treatment, the patients were compared from a clinical view point and cost of medical treatment. No statistical difference was found between infusor pump and classic pump in terms of cost-effectiveness.Talassemi majörlü hastalarda düzenli desferrioksamin (DFO) kullanımı hepatik, kardiyak ve endokrin bozuklukları düzeltir, büyüme ve seksüel olgunlaşmayı arttırır ve sağkalımı uzatır. DFO’yu klasik pompa ile vermenin zorlukları bilinmektedir. Bu çalışmanın amacı sürekli 48 saat infüzyon pompası ile DFO verilmesi ile aralıklı 40 saat klasik pompa infüzyonu arasında demir birikimi ve maliyet-etkinlik karşılaştırması yapmaktır. Talassemi majörlü 54 hasta iki gruba ayrılmıştır. Birinci grupta yaşları 5.5 ile 20.5 arasında değişen 27 hasta (18 kadın, 9 erkek) 48 saatte infüzyon pompası ile toplam 100 mg/kg DFO, yaşları 6 ile 22 yıl arasında değişen 27 hastalı k (18 kadın, 9 erkek) ikinci gruba ise aralıklı infüzyon ile 4 günden toplam 200 mg/kg DFO verilmiştir. Tedaviden bir yıl sonra gruplar klinik ve maliyet-etkinlik açısından değerlendirilmiştir. Bir yılın sonunda iki grup arası nda klinik ve maliyet-etkinlik açısından anlamlı bir fark bulunmamıştır.

Compound heterozygosity for Hb Tyne and HbS, that is very rare, was identified by direct DNA sequencing of the beta-globin gene in a Turkish patient. Hematological investigation of a girl at the age of 9 due to the presence of HbS (40.7%) led to the identification of a compound heterozygosity at codons 5-6. This was found to be the result of substitution of cytosine (C) for thymidine (T) at the fifth position and a substitution of adenine (A) for thymidine (T) at the sixth position of the beta globin gene. As a result of these mutations, the order of amino acids at codons 5-6 was changed from Pro-Glu to Ser-Val, respectively. Since the co-inheritance of Hb Tyne and HbS had not been reported in literature before, our case set an example for identification of coinheritance of Hb Tyne and HbS for the first time. Therefore, such cases may be considered as an important example for understanding the structural variants of hemoglobin and may provide important clues for critical amino acids responsible for stabilization of hemoglobin tetrameric structure and genetic counseling.Nadir görülen Hb Tyne ve HbS birlikteliği, hematolojik tetkik sonucu %40.7 HbS bulunan dokuz yaşındaki bir kız çocukta, beta-globin geninin direkt DNA dizi analizi sonucu ile kodon 5 ve kodon 6’da tanımlanmıştır. Bu mutasyonlar beta-globin geninde 5. kodonda sitozin yerine timinin, 6. kodonda adenin yerine timinin yer alması ile Hb Tyne ve HbS varyantları olarak ortaya çıktıkları görüldü. Bu mutasyonların sonucu olarak 5. ve 6. kodonlardaki aminoasitler ise sırasıyla Pro ve Glu yerine Ser ve Val şeklinde değişmişlerdir. Hb Tyne ve HbS’nin birlikte kalıtımı ilk defa bizim olgumuzda gözlenmiş olup, bu bulgu hemoglobinin yapısal varyantlarının, tetrame rik yapısının stabilizasyonu için sorumlu kritik aminoasitlerin öneminin anlaşılmasında ve doğru genetik danışma verilmesinde önemli rol oynayabilir.

Our aim in this study was to investigate the effects of transfusion on pulmonary function tests (PFT) in patients with thalassemia. A total of 43 patients (34 major, 6 intermedia and 3 S/B thalassemics), 21 females and 22 males aged 6 to 29 (mean ± SD: 13.82 ± 4.96) years participated. PFT was performed using a spirometry (ST-250) programmed with European Community for Coal and a Steal (ECCS) equations. Transfusion did not effect the PFT parameters at the pre- and posttransfusion period and but the type of pulmonary function disorders partially changed after transfusion in our patients.Bu çalişmada amacimiz talasemili hastalarda transfüzyonun solunum fonksiyon testlerine (SFT) etkisini saptamakti. Kir küç olgu (34 majör, 6 intermedia ve 2 S/B talasemili hasta, çalişmaya alindi. Yirmi bir kadin ve 22 erkek hasta 6-29 yaşlarinda idi (ortalama ± SD: 13.82 ± 4.96 yil). SFT, ECCS ile programli ST-250 spirometre ile yapildi. Transfüzyon genelde pre- ve posttransfüzyon SFT`yi etkilemese de bozuk olan pulmoner fonksiyonun tipinde transfüzyondan sonra kismi değişiklikler gözlendi.

Hemoglobin beta (HBB): c.*+96TC substitution is very rare among β-globin gene mutations and its clinical significance remains to be clarified. The present study aimed to investigate the role of HBB: c.*+96TC in the β-thalassemia intermedia phenotype in a Turkish family. The proband and parents were screened for β-globin gene mutations via direct sequencing. Hematological and physical examination results were recorded, and correlated according to genotype. The proband was compound heterozygous for Cod 8 (-AA) and HBB: c.*+96TC, whereas his mother and father were heterozygous for Cod 8 (-AA) and HBB: c.*+96TC, respectively. The father had almost normal hematological findings, whereas the mother had the typical β-thalassemia trait phenotype. The proband was diagnosed as mild β-thalassemia intermedia based on hepatosplenomegaly and hematological findings. To the best of our knowledge this is the first report of HBB: c.*+96TC mutation in a Turkish family. HBB: c.* 96TC substitution is a very rare, but clinically relevant β-globin gene mutation. Additionally, we think that if 1 spouse is a carrier for β-globin gene mutation the other should be screened for silent mutations, such as HBB: c.*+96TC mutation of the β-globin gene, even if she/he does not have any clinical or hematological signs of the β-thalassemia trait phenotype.Hemoglobin beta (HBB): c.*+96TC, β-globin geninde çok nadir görülen ve klinik önemi henüz tam olarak aydınlatılamamış bir değişimdir. Bu çalışmada; bir Türk ailede HBB: c.*+96TC değişiminin beta-talasemi intermedia fenotipi üzerine etkisini araştırmayı amaçladık. Beta-talasemi intermedia ön tanılı çocuk ile anne ve babasının β-globin gen mutasyonları DNA dizi analizi yöntemiyle tarandı. Aile bireylerinin hematolojik ve klinik bulguları elde edilerek, genotipleri ile birlikte değerlendirildi. Direkt DNA dizi analizi yöntemiyle mutasyon taranması sonucunda, olgunun Cod 8 (-AA) ve HBB: c.*+96TC mutasyonları açısından birleşik heterozigot olduğu belirlendi. Annenin Cod 8 (-AA) mutasyonu, babanın ise HBB: c.*+96TC mutasyonu yönünden taşıyıcı oldukları görüldü. Anne klasik beta-talasemi taşıyıcı bulgularına sahip iken, babanın klinik ve hematolojik açıdan normale yakın olduğu belirlendi. Diğer yandan olgu, hematoloji bulgularına ek olarak, hepato-splenomegalinin varlığı ile ılımlı tip beta-talasemi intermedia tanısı aldı. Bu çalışmada, HBB: c.*+96TC değişimi ilk kez bir Türk ailesinde bildirilmektedir. Cod 8 (-AA) ve HBB: c.*+96TC değişimleri açısından birlikte heterozigot olan olguda, sadece Cod 8 (-AA) mutasyonu ile açıklanamayacak klinik bulguların gözlenmesi nedeniyle, HBB: c.*+96TC’ nın taşıyıcılarda sessiz, ancak başka bir mutasyonla birlikte olduğunda hastalık şiddetini artıran, klinik açıdan önemli bir β-globin geni mutasyonu olduğu sonucuna varıldı. Ayrıca, çiftlerden birinin taşıyıcılığının genetik testlerle kesinleştiği durumlarda, diğerinin klinik ve hematolojik olarak taşıyıcı bulgularına sahip olmasa bile, HBB: c.*+96TC gibi hematolojik açıdan sessiz mutasyonlar için taranması gerektiğini önermekteyiz.