case study on thalassemia

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• JNMA J Nepal Med Assoc
• v.58(226); 2020 Jun

A Child Lost to Follow Up Carrying Beta Thalassemia Major: A Case Report

Prakash banjade.

1 Department of Internal Medicine, Gan Regional Hospital, Maavah Health Center, Republic of Maldives

Jeetendra Bhandari

2 Department of Emergency Medicine, Chitwan Medical College, Chitwan, Nepal

Thalassemia is inherited autosomal recessive disorders characterized by reduced rate of hemoglobin synthesis due to a defect in alpha or beta globin chain synthesis. Maldives has a beta thalassemia prevalence rate of 16-18%. Classical symptoms of beta thalassemia are common on those patients who present late for blood transfusion which is common among the south Asian countries due to resource poor situation. This case is a rare case report of commonly occurring phenomenon which has been reported less among south Asian region. Reporting this case will help health worker to manage cases accordingly. A five and half year prior diagnosed case of beta thalassemia at age of 2 years and lost to follow up presented with cough, Dyspnoea, Irritability, fatigue with classic symptom of beta thalassemia. She was managed with blood transfusion and kept on continuous follow up for transfusion and iron overload management.

INTRODUCTION

Thalassemia is inherited autosomal recessive disorders characterized by reduced rate of hemoglobin synthesis due to a defect in alpha or beta globin chain synthesis. 1 It has high cases in Mediterranean, Middle east, Central Asia, Indian Subcontinent and Far East. 2 Maldives has a beta thalassemia prevalence rate of 1618 %. 3 Major reason for high cases in these regions is due to high pressure of Plasmodium falciparum malaria infection. 4 Beta Thalassemia majorpresents as severe anaemia, Skeletal anomaly with typical clinical and radiological manifestations. 5 More classical symptom are observed among the non or under treated patients. 2

CASE REPORT

A five and half year-old girl, from Cozy corner, L Maavah, Maldives presented to Emergency unit. She presented with cough, Dyspnea, Irritability, and fatigue. She had no fever. She was diagnosed case of Beta Thalassemia. She was diagnosed at the age of 2 years. She was diagnosed and lost to follow up. Her family history was not significant for any blood related disorder or any genetic disease.

On physical examination patient was ill looking. Her vitals were stable. She was clinically anemic with brittle hair and nail. Patient’s finger nails and skin extremities exhibited whitish tinge and sclera showed pallor. Her skin was ashen grey in color. She appeared dehydrated and had a body weight of 13.11 kg. She was underbuilt, under-nourished with a short stature, with evident icterus, and yellow tinged fingernails. Decayed upper tooth, not associated with pain or swelling. Head and Neck examination showed maxillary expansion, retracted upper lip and saddle nose; all together depicting the classical “Chipmunk facies”. Also noted yellowish tinge at the junction of hard and soft palate. Intraoral examination, localized periodontitis and broken teeth in lower anterior aspect as shown ( Figure 1 ). Her abdominal examination didn’t show and sign of enlargement of spleen. Her ophthalmologic and audiologic examination were done and were within normal limits.

Haematological examination was performed. Her haemoglobin was 4.5 gm/dl. Hematologic investigation revealed microcytic hypochromic anaemia with anisocy-tosis, poikilocytosis, nucleated Red Blood Cells (RBC). The impression drawn from the peripheral smear study was that of haemolytic anaemia favouring Thalassemia going for haemolytic crisis. Later Haemoglobin (Hb) electrophoresis was done which too was in favor of Beta Thalassemia major. Her Human immunodeficiency Virus (HIV), Hepatitis B, and Hepatitis C was negative. Liver function test and Renal function test were within normal limit.

She was planned for blood transfusion. She was given 3 pints of packed cell. She was given each packed cell at the rate of 220 ml in every 4 hours. Her vitals were monitored regularly during the transfusion to see any transfusion related complications. No complication ware obtained during transfusion. Then she was investigated for Haemoglobin (Hb) and found out to be 9.5 gm/dl. She was then discharged and advised to follow up in 15 days. In follow up visit her ferritin was investigated and was found to be 3562.69 ng/ml. Then she was started on iron chelating agent. She was kept on Deferoxamine B(DFO) 2 gm per dose at the rate of 4 times in a week and oral Deferasirox 400 mg once in a day dose. Her Hb was 7.5 mg/dl, she was transfused with a pint of packed cell and discharged hose with a follow up in 20 days for transfusion. She is hospitalized every 20 days for transfusion of packed RBC. She is investigated for Liver function test and thyroid function testis every 20 days. Her growth and development is assessed in every OPD visit for follow up.

Individual with beta thalassemia usually present in early life within first 2 years of life which was similar in this case where she was presented at the age of 2 years. 6 Patient presenting with beta thalassemia need regular blood transfusion from the early age. If patient miss to have blood transfusion then the classic clinical picture appears on patient. Classical clinical picture includes growth retardation, pallor, jaundice, brown pigmentation of skin, poor musculature, genu varum, hepatosplenomegaly, leg ulcers, development of masses from extramedullary haematopoiesis and skeletal changes that is due to bone marrow expansion. The changes in skeleton including deformity of long bones of the legs and typical craniofacial changes including bossing of the skull, prominent malar eminence, depression or bridges of nose, tendency to a mongoloid slant of the eye and hypertrophy of maxillae, which tends to expose the teeth. 2 In the child that presented has some of the feature like these which might be due to the late starting of blood transfusion due to lost to follow up. The classic symptoms like these are only seen in developing countries, in which the resources for carrying out long term transfusion program are not available or patient tend to care less for the disease. 2 If regular transfusion of blood is started early and continued then growth and development occurs for first 10-12 years. 7 In this case the development has been hampered due to lost to transfuse the blood.

Patient with Thalassemia major have a severe microcytic and hypochromic anaemia. Peripheral blood smear shows anisocytosis, poikilocytosis (speculated tear drops and elongated cells) and nucleated RBC. 6 Most of features were seen in our case too suggesting the classic case of beta thalassemia. The treatment modality is always blood transfusion in a regular basis. Transfusion was performed to this patient too. Regular transfusion corrects anaemia, suppress erythropoiesis and inhibit increased gastrointestinal absorption of iron. 6 According to Thalassemia International Federation transfusion has to be done every 2-3 weeks 8 which was performed in our case too.

The most common secondary complication that is due to transfusion is iron overload. Which can be assessed through the level of ferritin level. Complication can be overcome by the use of chelating drugs like DFO and Deferasirox. 6 Despite of chelating agent one can have growth retardation and failure of sexual maturation. Complications of iron overload adults with Human homeostatic iron regulator protein (HFE)-associated hereditary hemochromatosis: involvement of heart (dilated cardiomyopathy and pericarditis), liver(chronic hepatitis, fibrosis, and cirrhosis) and endocrine glands( diabetes mellitus, hypoparathyroidism, hypothyroidism, hypopituitarism and low adrenal secretion). 6 For the complication of iron overload serum ferritin has to be investigated along with endocrine function, cardiac function. 6 Regular blood monitoring for the above condition that may appear has been performing in our patient too. Along with the blood work the semi-annual assessment of growth and development has to be done for every paediatric patient. 6

Although a common disease among south Asian Population, case reports are very less reported on different circumstance. We have tried to report case that has failed to follow up despite the diagnosis. Complication can occur in any patient who deny to follow up so proper counselling should be done so that the patient comes in regular follow up and save the patient that can be prevented with timely intervention. Along with this the community should take active participation to help the patients for regular follow up and proper supply of blood needed for the patient.

ACKNOWLEGDEMENTS

We would like to thank the parents of patient who provided us with information as well as consent for the study. We like to thank Mr.Adam Hussain (Manager and translator) and Maavah health centre, island of Maavah, Republic of Maldives for their support during writing of this case report.

Consent: JNMA Case Report Consent Form was signedby the patient and the original article is attached withthe patient’s chart.

Conflict of Interest:

DREW C. BAIRD, MD, STUART H. BATTEN, MD, MS, AND STEVEN K. SPARKS, MD

Am Fam Physician. 2022;105(3):272-280

Author disclosure: No relevant financial relationships.

Thalassemia is a group of autosomal recessive hemoglobinopathies affecting the production of normal alpha- or beta-globin chains that comprise hemoglobin. Ineffective production of alpha- or beta-globin chains may result in ineffective erythropoiesis, premature red blood cell destruction, and anemia. Chronic, severe anemia in patients with thalassemia may result in bone marrow expansion and extramedullary hematopoiesis. Thalassemia should be suspected in patients with microcytic anemia and normal or elevated ferritin levels. Hemoglobin electrophoresis may reveal common characteristics of different thalassemia subtypes, but genetic testing is required to confirm the diagnosis. Thalassemia is generally asymptomatic in trait and carrier states. Alpha-thalassemia major results in hydrops fetalis and is often fatal at birth. Beta-thalassemia major requires lifelong transfusions starting in early childhood (often before two years of age). Alpha- and beta-thalassemia inter-media have variable presentations based on gene mutation or deletion, with mild forms requiring only monitoring but more severe forms leading to symptomatic anemia and requiring transfusion. Treatment of thalassemia includes transfusions, iron chelation therapy to correct iron overload (from hemolytic anemia, intestinal iron absorption, and repeated transfusions), hydroxyurea, hematopoietic stem cell transplantation, and luspatercept. Thalassemia complications arise from bone marrow expansion, extramedullary hematopoiesis, and iron deposition in peripheral tissues. These complications include morbidities affecting the skeletal system, endocrine organs, heart, and liver. Life expectancy of those with thalassemia has improved dramatically over the past 50 years with increased availability of blood transfusions and iron chelation therapy, and improved iron overload monitoring. Genetic counseling and screening in high-risk populations can assist in reducing the prevalence of thalassemia.

Thalassemia is a group of autosomal recessive hemoglobinopathies involving ineffective production of normal alpha- or beta-globin chains, which can lead to ineffective erythropoiesis, premature red blood cell destruction, and anemia. Other common hemoglobinopathies (e.g., sickle cell disease) arise from production of abnormal globin chains. This article summarizes key evidence regarding the diagnosis and treatment of thalassemia for primary care physicians.

Epidemiology

Thalassemia prevalence is highest in Africa, India, the Mediterranean, the Middle East, and Southeast Asia. Incidence in these regions may be decreasing because of prevention programs involving premarital and preconception counseling and testing. 1 – 4

Approximately 5% and 1.5% of the world population are carriers of alpha- and beta-thalassemia, respectively. 1 , 4

Thalassemia affects 6 per 100,000 conceptions in the Americas. 5 Data specific to the United States are lacking, but California has an estimated incidence of 1 in 10,000 and 1 in 55,000 for alpha- and beta-thalassemia, respectively. 4 , 6

Pathophysiology

Hemoglobin (Hb) comprises an iron-containing heme ring and four globin chains: two alpha and two nonalpha (beta, delta, gamma). 7 – 9 See diagram at https://www.aafp.org/afp/2009/0815/p339.html#afp20090815p339-f1 . HbF is the most common type in newborns. By six months of age, HbA is predominant. Clinically significant thalassemia presents with reduced HbA production. 7 , 8

Table 1 1 , 10 , 11 and Table 2 10 – 12 detail alpha- and beta-thalassemia subtypes.

Screening and Prevention

A complete blood count should be performed in all pregnant patients to screen for thalassemia. A low mean corpuscular volume warrants Hb electrophoresis. It is also reasonable to obtain Hb electrophoresis for those in high-risk ethnic groups (African, West Indian, Mediterranean, Middle Eastern, and Southeast Asian). 13

Preconception genetic counseling and testing should be discussed with patients who have risk factors (first-degree relative with thalassemia, history of stillbirth, high-risk ethnicity, and low mean corpuscular volume). 13

Prenatal diagnosis is performed via chorionic villus sampling at 10 to 12 weeks’ gestation or amniocentesis after 15 weeks’ gestation. 13

Newborn screening for thalassemia varies by state. HbSS, beta-thalassemia/HbS, and HbS/C are the only hemoglobinopathies considered to be core conditions on the U.S. Recommended Uniform Screening Panel. Other hemoglobinopathies are listed as secondary conditions, but neither alpha- nor beta-thalassemia is included on this list. 14

SIGNS AND SYMPTOMS

Thalassemia is generally asymptomatic in trait and carrier states. 10 , 11

Moderate to severe microcytic anemia can occur in intermediate and major types of thalassemia, presenting as fatigue, lightheadedness, and syncope, as well as poor growth in children. Active hemolysis may cause hyperbilirubinemia, jaundice, and gallstones. 10

Erythropoietin stimulation from chronic anemia may induce signs of bone marrow expansion (pseudotumors, frontal bossing, maxillary hypertrophy, malar prominence, depressed nasal bridge) and extramedullary hematopoiesis (hepatosplenomegaly). 10 , 11

Nonimmune hydrops fetalis occurs in alpha-thalassemia major/Hb Bart’s disease. 11

DIAGNOSTIC TESTING

Thalassemia should be considered in patients with microcytic anemia. 10

The differential diagnosis for microcytic anemia includes iron deficiency anemia, lead poisoning, sideroblastic anemia, anemia of chronic disease, copper deficiency, zinc toxicity, and hemoglobinopathies. 15

Initial evaluation includes a complete blood count and indices, peripheral smear, serum ferritin level, and blood lead level ( Table 3 ) . 10 , 11 , 16 – 18

Peripheral smear in patients with thalassemia will typically show microcytosis, hypochromia, poikilocytosis, and target cells. 10 , 11 , 17

Normal red blood cell distribution width with microcytosis may suggest thalassemia. However, it is not sensitive or specific enough to differentiate thalassemia from iron deficiency anemia and should be used only in the context of other laboratory findings. 16

Serum ferritin measurement is the best initial test to evaluate for iron deficiency. Thalassemia should be suspected in patients with microcytic anemia and normal or elevated ferritin levels ( Figure 1 ) . 10 , 15 , 19 Other iron-related studies can be useful when the ferritin level is intermediate to low or normal but suspicion for iron deficiency anemia is still present. 10 , 19

Decreased HbA on electrophoresis is characteristic of thalassemia. Other findings include elevated HbA 2 in beta-thalassemia, and Hb Bart’s disease in alpha-thalassemia major. 10 , 17 Hb electrophoresis findings are normal in alpha-thalassemia trait and carrier states ( Table 4 ) . 10 , 20 – 22

Genetic testing should be used to confirm the diagnosis and identify mutations that correlate with severity of disease. 10 , 17

Thalassemia can present with other hemoglobinopathies ( Table 5 ) . 9

Once thalassemia is diagnosed, the degree of iron overload can be investigated further with T2*-weighted cardiac or R2*-weighted liver magnetic resonance imaging, or rarely liver biopsy. 1 , 3 , 10 , 11

Given the varied clinical manifestations of thalassemia subtypes, the Thalassaemia International Federation distinguishes between transfusion-dependent thalassemia (TDT) and non–transfusion-dependent thalassemia (NTDT). Treatment decisions are more often based on this classification than on subtype classification (i.e., carrier, trait, minor, intermedia, major). 10 , 11

Asymptomatic thalassemia subtypes do not require treatment.

Treatment goals include maintaining Hb levels at 9 to 10.5 g per dL (90 to 105 g per L), promoting normal growth, suppressing ineffective erythropoiesis and extramedullary hematopoiesis, and controlling iron overload. 3 , 10

TRANSFUSION THERAPY

Patients with TDT require regular transfusions, usually scheduled every two to five weeks. 10 Beta-thalassemia major, nondeletional HbH disease, survived Hb Bart’s disease, and severe HbE/beta-thalassemia are typically considered TDTs. 10

Those with NTDT may require occasional transfusions for symptomatic anemia, during pregnancy, before surgery, or during serious infections. They may ultimately need chronic transfusions as anemia, extramedullary hematopoiesis, and other complications worsen or to promote growth. 3 , 11

Table 6 specifies indications for transfusion. 1 , 3 , 10 , 11 , 23

Repeated transfusions increase the risk of alloimmunization, other transfusion-associated reactions, transfusion-related infections, and iron overload. 10 , 24

IRON CHELATION THERAPY

Iron chelation therapy corrects iron overload caused by hemolytic anemia, increased intestinal iron absorption, and repeated transfusions, and is recommended for TDT if ferritin levels exceed 1,000 ng per mL (1,000 mcg per L) and for NTDT when ferritin levels exceed 800 ng per mL (800 mcg per L). 3 , 10 Table 6 lists its indications. 1 , 3 , 10 , 11 , 23

Retrospective observational studies have reported decreased overall mortality and cardiac-related mortality with chelation therapy. Mortality appears to be reduced when the therapy is started earlier in life. 25 Small randomized controlled and observational studies have shown that chelation therapy effectively reduces liver and myocardial iron concentrations. 26 , 27

eTable A summarizes iron chelation therapy options.

OTHER THERAPIES

Hydroxyurea promotes HbF production, and small observational studies have shown an association between this therapy and decreased transfusion frequency in beta-thalassemia major and intermedia. 11 , 28 However, stronger evidence is lacking. 29

Hematopoietic stem cell transplantation is potentially curative for TDT. 10 , 30 Ideal candidates are younger than 12 years with a sibling donor who is a human leukocyte antigen match to the patient. 3 , 10 An unrelated matched donor could be considered. Prospective studies have shown that with transplantation, overall survival is greater than 90% and thalassemia-free survival is greater than 80%. 31

Genotyping and evaluation for transplantation (including human leukocyte antigen typing) should be ordered for all patients once, before 12 years of age if possible. In patients 12 years or older, gene therapy may be considered.

Luspatercept (Reblozyl) is an activin receptor ligand trap that promotes erythropoiesis and decreases overall transfusion burden in beta-thalassemia. In a phase 3 randomized trial, luspatercept had a number needed to treat of 6 for one adult with TDT to have a 33% reduction in transfusion burden. 32

Experimental gene therapies can induce normal beta-globin production or reactivate HbF production in patients with TDT and could dramatically reduce the need for long-term transfusions. 33 , 34

Complications of Thalassemia

Complications develop from uncontrolled chronic anemia, bone marrow expansion, extramedullary hematopoiesis, and iron overload. Iron deposition in peripheral tissues causes oxidative stress, free radical production, and organ dysfunction. 1 , 3

eTable B summarizes thalassemia-associated complications and recommended monitoring and treatment for each.

SKELETAL ABNORMALITIES

Stimulated expansion of bone marrow causes abnormal bone growth, including enlarged craniofacial bones and spinal deformities that can compress spinal nerves. 3 , 35 , 36

Disorders of skeletal growth, including delayed sexual maturation and endocrine disorders, are common in patients with thalassemia and result in shortened stature, increased bone turnover, and lowered bone mineral density. 3 , 35

Despite adequate transfusions and iron chelation therapy, 40% to 50% of patients with beta-thalassemia major have osteopenia or osteoporosis. 37 Physical activity, calcium and vitamin D supplementation, and hormone therapy for specific endocrine disorders are preventive strategies. 10

Bisphosphonates and zinc supplementation can improve bone mineral density in patients with thalassemia and osteoporosis, and calcium and vitamin D are also recommended. 10 , 35 , 37

ENDOCRINE DISORDERS

Diabetes mellitus arises from pancreatic iron deposition, impairing insulin production, and peripheral tissue iron deposition, impairing insulin utilization. 38

Nearly 44% of patients with beta-thalassemia major have nondiabetes endocrine disorders, most commonly hypogonadotropic hypogonadism, hypothyroidism, and hypoparathyroidism. 38

Growth hormone deficiency occurs in 8% to 14% of U.S. patients with TDT. Growth hormone treatment in children may mitigate the effects of short stature. 39

Primary or secondary amenorrhea can occur in patients with TDT. 24

Since the introduction of iron chelation therapies in 1975, the prevalence of hypogonadism, diabetes, and hypothyroidism has diminished in patients with thalassemia. 10

CARDIAC COMPLICATIONS

Worldwide, 25% of patients with beta-thalassemia major have cardiac iron overload, and 42% have cardiac complications such as electrocardiogram abnormalities, myocardial fibrosis, cardiomyopathy, pulmonary hypertension, heart failure, arrhythmias, heart valve disease, pericarditis, and myocarditis. 3 , 10 , 40

The adoption of T2*-weighted magnetic resonance imaging to detect cardiac iron overload in the early 2000s, along with effective iron chelation therapies, is estimated to have reduced cardiac mortality by 71% among patients with beta-thalassemia major in the United Kingdom. 41

Iron chelation therapy is the most widely accepted approach for preventing and treating cardiac iron overload. 10 Expert opinion, based on low-quality evidence, suggests that chelation therapy can improve asymptomatic and symptomatic heart disease and reverse early left ventricular dysfunction. 10 Additionally, lower ferritin levels are associated with prolonged survival and a lower probability of heart failure. 42

SPLENOMEGALY

An enlarged spleen results from splenic hyperfunctioning to remove defective red blood cells and erythropoietin stimulation to promote hematopoiesis. 43

Splenectomy can improve baseline Hb level by 1 to 2 g per dL (10 to 20 g per L) and reduce transfusion frequency. Splenectomy carries perioperative risks and higher long-term risk of venous thromboembolism, pulmonary hypertension, and encapsulated organism infections. 43

Splenectomy is reserved for select indications: iron overload from frequent transfusions that cannot be controlled with iron chelation therapy, hypersplenism with clinically significant cytopenias, and symptomatic splenomegaly. Splenectomy should be avoided in children younger than five years because of the high risk of sepsis postsplenectomy. 10

LIVER DISEASE

Up to 15% of U.S. patients with TDT will develop liver disease due to iron deposition, including cirrhosis (2% to 7%) and hepatocellular carcinoma (0.75% to 3.5%). 24

Liver iron concentration should be measured regularly by R2*-weighted magnetic resonance imaging starting at 10 years of age. 3 , 10

If liver iron concentration increases while on chelation therapy, patient compliance should be reviewed, and dosing, frequency, or the chelating agent may need to be changed. 10

Frequent transfusions increase the risk of hepatitis C and other bloodborne pathogens. 24

THROMBOTIC EVENTS

Observational studies have identified an increased risk of thromboembolism, particularly stroke, in patients with beta-thalassemia intermedia and major. 44

Currently, no guidelines recommend antiplatelet or anticoagulant therapy for primary prevention of thrombotic events in nonpregnant patients. The Thalassaemia International Federation does recommend thromboprophylaxis with low-molecular-weight heparin in pregnant patients with TDT or NTDT, and aspirin in pregnant patients who have had a splenectomy. 10 , 11

Patients with alpha-thalassemia intermedia (deletional HbH disease) typically have a normal lifespan and may have mild anemia and splenomegaly; a small proportion will require transfusions. Patients with nondeletional HbH disease more often require transfusions, may have TDT, and have more complications. 1

Most newborns with Hb Bart’s hydrops fetalis who did not receive intrauterine transfusion die shortly after birth. Intrauterine transfusion can increase survival. 45 One study demonstrated an increased survival rate from 40% between 1987 and 1992 to 100% between 2011 and 2016. 46 Current trials are investigating the use of intrauterine bone marrow transplantation. 47

Persons with beta-thalassemia major lived a mean of 17 years in 1970, most dying by 30 years of age. 48 Recent studies demonstrated mean survival ages of 50 and 57 for patients with beta-thalassemia major and minor, respectively. The increased survival is likely attributable to increasing availability of transfusion and iron chelation therapies, and improved iron overload monitoring. 25 , 49

This article updates a previous article on this topic by Muncie and Campbell . 9

Data Sources: This article was based on literature searches in Essential Evidence Plus, the Cochrane database, U.S. Preventive Services Task Force, PubMed, and Ovid using the term thalassemia. Search dates: October 2020 to October 2021.

The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Army Medical Department, the U.S. Army at large, or the Defense Health Agency.

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Case report article, case report: clinical and hematological characteristics of ε γδβ thalassemia in an italian patient.

• 1 Department of Pediatric Hematology/Oncology and Hematopoietic Stem Cell Transplantation (HSCT), Meyer Children's University Hospital, Florence, Italy
• 2 Department of Health Science, University of Florence, Florence, Italy
• 3 Human Genetics Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy

Introduction: ε γδβ thalassemia is a rare form of β-thalassemia mostly described in children originating from Northern Europe. Only anecdotic cases from the Mediterranean area are reported. The diagnosis is challenging, considering the rarity of the disease and its heterogeneous clinical presentation. Most patients have neonatal microcytic anemia, sometimes requiring in utero and/or neonatal transfusions, and typically improving with age.

Case Description: We report on an Italian newborn presenting with severe neonatal anemia that required red blood cell transfusion. After the first months of life, hemoglobin levels improved with residual very low mean corpuscular volume. β and α thalassemia, IRIDA syndrome, and sideroblastic anemia were excluded. Finally, a diagnosis of ε γδβ thalassemia was made after microarray analysis of single nucleotide polymorphisms revealed a 26 kb single copy loss of chromosome 11p15.4, including the HBD, HBBP1, HBG1, and HBB genes.

Conclusions: Despite its rarity, the diagnosis of ε γδβ thalassemia should be considered in newborns with severe neonatal anemia requiring in utero and/or neonatal transfusions, but also in older infants with microcytic anemia, after excluding more prevalent red blood cell disorders.

Introduction

The ε γδβ thalassemia is an extremely rare heterozygous form of β-thalassemia, with around 40 reported cases in 2019 ( 1 ). In most cases, patients originated from ethnic backgrounds where β-thalassemia was not prevalent ( Table 1 ). Despite the extreme heterogeneity of the molecular bases of β-thalassemia in Italy, the first ε γδβ thalassemia deletion has been only identified in 2016 ( 23 ).

Table 1 . Origin and presentation of previously described patients with ε γδβ thalassemia.

ε γδβ thalassemias are caused by long deletions in the β-globin cluster and exist only in heterozygous form. Except for one case ( 8 , 27 ), the reported deletions are almost exclusively unique and in most cases de novo , explaining the phenotypic heterogeneity of the disease. Indeed, multiple clinical phenotypes of ε γδβ thalassemia have been reported, ranging from normal blood cell count to severe anemia requiring in utero and/or neonatal transfusions ( Table 1 ) ( 20 ). The underlying reasons for such a spectrum of clinical characteristics are unknown, but the type and length of the deletion are not responsible, as contrasting phenotypes have been reported in heterozygotes with identical deletions within the same family ( 8 ). At the molecular level ε γδβ thalassemias fall into two distinct categories: in group I all, or a greater part of the β-globin cluster, are removed, including the β-globin gene, whereas in group II extensive upstream regions are removed, leaving the β-globin gene itself intact although its expression is silenced because of inactivation of the upstream β-locus control region ( 23 ). Furthermore, co-existent α-globin gene triplication has been suggested to exacerbate the phenotype of ε γδβ thalassemia increasing the imbalance between the α and non-α globin chain ratio during fetal life ( 16 ).

Most patients with ε γδβ -thalassemia had neonatal erythroblastosis, reticulocytosis, hypochromia, and microcytosis ( Table 1 ), that later improved with age. Anemia usually remitted spontaneously during the first months of life, and the adult phenotype is similar to that of the β-thalassemia trait, but with more severe microcytosis ( 13 ).

Herein, we describe the clinical phenotype of a novel Italian ε γδβ deletion, the second patient from Italy described in the literature and the third from the Mediterranean Area, presenting with severe microcytic anemia in the neonatal period.

Case Description

A male, full-term infant of Tuscanian origin was born by induced vaginal delivery due to meconium-stained amniotic fluid. He presented with clinical and laboratory signs of sepsis (increased white blood cell count, C-reactive protein, and indirect bilirubin) and received wide spectrum antibiotics. Laboratory evaluations revealed microcytic anemia (hemoglobin, Hb, 10.8 g/dL, mean corpuscular volume, MCV, 65.4 fL). The clinical condition rapidly improved and hemoglobin rose to 12 g/dL, with persistent microcytemia. At the first follow-up visit at 1 month of age, hemoglobin had dropped to 6.4 g/dL, with a MCV of 53.8 fL, a mean cell hemoglobin concentration of 18.3 g/dL, a hematocrit of 19.9%, and an increased reticulocyte count (0.2 × 10 6 /L) ( Figure 1 ). No other signs of hemolysis were detected (normal bilirubin and lactate dehydrogenase levels). The peripheral blood smear revealed microcytic hypochromic erythrocytes with anisopoikilocytosis ( Figure 2 ). Hemoglobin electrophoresis showed a normal pattern with an unusually high proportion of HbA (HbF 47%, HbA2 0.8%, HbA 52.2%), no abnormal hemoglobin variants, nor evidence of β-thalassemia; abdominal ultrasound showed splenomegaly. The patient received a red blood cell transfusion and supplementation of iron and folic acid, which proved ineffective. Therefore, bone marrow aspiration was performed to exclude the presence of ring sideroblasts with Prussian blue staining ( Figure 2 ); normal plasmatic hepcidin values ruled out an Iron-Refractory Iron Deficiency Anemia (IRIDA) syndrome.

Figure 1 . Timeline graph showing the chronological evolution of the values of hemoglobin and mean corpuscular volume from birth to last follow-up. Hemoglobin electrophorese studies and transfusions are also reported. Hb, hemoglobin; EPh, electrophoresis; MCV, mean corpuscular volume.

Figure 2 . Peripheral blood smear (A) performed in the neonatal period, showing hypochromic erythrocytes with anisopoikilocytosis; isolated target cells, ovalocytes, ellissocytes, and dacrocytes are also visible (600x magnification, MGG). Bone marrow aspirate (B) performed at 2 months of age showing mild dyserythropoiesis (1000x magnification, MGG); no ring sideroblasts were found in the smear [ (C) 1000x magnification, Pearls coloration].

At 6 months of age, the blood cell count of the patient was consistent with a thalassemia trait (hemoglobin 9 g/dL, red blood cell 6.19 × 10 12 /L, MCV 52 fL, mean cell hemoglobin, MCH, 6.3 pg). The hemoglobin electrophoresis showed HbA2 value of 3.3%, and α gene deletions were excluded using Multiplex Ligation Probe Amplification (MLPA). Conversely, MLPA showed a heterozygous deletion in the short arm of chromosome 11 ( Figure 3 ). This was confirmed by microarray analysis of single nucleotide polymorphisms that revealed a 26 kb single-copy loss of a genomic region localized at 11p15.4. The lost genetic material included the HBD, HBBP1, HBG1 - and partially HBB - genes, a finding consistent with ε γδβ thalassemia. The family history was negative for similarly affected individuals and targeted parental testing via quantitative polymerase chain reaction confirmed the presence of a de novo deletion.

Figure 3 . Multiplex Ligation Probe Amplification (MLPA) showing a deletion of the OR51V1-1, HBB, HBD, HBBP1, HBG1 and HBG2 genes (red dots) on the short arm of chromosome 11. All deletion were detected in the heterozygous form. The first deleted probe was the 486 on the OR51V1-1 gene (hg18 loc.11–005,177842), while the last was the 373, after the end of the HBG2 gene (hg18 loc.11–005,233895).

At last follow-up (5 years of age), the patient had a hemoglobin of 11.2 g/dL, a MCV of 52.9 fL, and a MCH of 17 pg; hemoglobin electrophoresis revealed 0.1% of HbF and 3.3% of HbA2 ( Figure 1 ). The patient was in good clinical condition, with normal growth (72 nd centile of height and 80 th centile of weight, WHO curves) and cognitive development. No splenomegaly was found at the abdominal ultrasound, nor signs of iron overload/deficiency. Therefore, no specific follow-up plan nor specific interventions in case of minor ailments were deemed necessary, as for β-trait carriers.

Anemia during the neonatal period represents a challenge for the pediatrician, mainly for the multiplicity of conditions that are responsible for the condition during the first weeks of life. The etiology of neonatal anemia usually falls into three major categories: blood loss, decreased production, and increased destruction of erythrocytes ( 28 ). The differential diagnosis for hemolytic anemia in the newborn period includes alloimmunity, erythrocyte membrane defects, enzyme deficiencies, and hemoglobinopathies. The most frequent hemoglobinopathy associated with critically ill infants and hemolytic anemia is α thalassemia with deletion of three α globin genes ( 28 , 29 ).

ε γδβ thalassemia usually presents as severe neonatal hemolytic anemia that requires in utero and/or neonatal transfusions but this condition is rarely considered among the causes of neonatal anemia and therefore misdiagnosed, as in our case. A reduced MCV without abnormalities on hemoglobin electrophoresis in a newborn is not always detected in ε γδβ thalassemia ( Table 1 ), but when it is found, it can orient toward the diagnosis. Despite the high incidence of thalassemias in Italy, the significant microcytosis in our patient was initially deemed secondary to iron deficiency, as the intercurrent sepsis misdirected high indirect bilirubin values as a sign of hemolysis.

Although uncommon during the neonatal period, microcytosis can occur secondary to iron deficiency following feto-maternal hemorrhage. However, in most cases, it is associated with thalassemia, also depending on the α thalassemia allele frequency, which varies in different populations ( 30 ). After the neonatal period, the hematologic phenotype of microcytosis associated with normal hemoglobin electrophoresis, which is typical of ε γδβ thalassemia, can be associated to or confused with α thalassemia, but also, in presence of normal ferritin levels, with IRIDA. Unlike previously suggested, the severe phenotype of our patient was not justified by the presence of α triplication, which was excluded by MLPA analysis.

There is no established explanation for the phenotypic heterogeneity of the disease, but it is not dependent on the type and length of deletion ( 8 ). Although at the molecular level ε γδβ thalassemias fall into two distinct categories, the associated phenotypes of the two groups are similar. Therefore, the variable severity is likely to be influenced by other genetic and environmental factors.

The remission of anemia after the first months of life is a consequence of the increasing production of β-globin that reduces the imbalance between α/non-α globin chain synthesis. The residual adult phenotype is similar to that of the β-thalassemia trait but with normal, rather than increased, levels of hemoglobin A2 due to the loss of one δ locus, while the fetal hemoglobin is normal or minimally increased ( 13 ). The normal HbA2 levels make the hematologic phenotype also similar to that of carriers of α-thalassemia ( 23 ). However, data collected by Rooks et al. suggest that adult heterozygotes for ε γδβ -thalassemias tend to have more severe microcytosis and hypochromia even than β 0 -thalassemia carriers ( 13 ).

In conclusion, this case remarks the importance of considering the ε γδβ thalassemia in the differential diagnosis of hypochromic microcytic hemolytic anemias in the newborn period. In the post-natal period, microcytosis with normal ferritin values and without abnormalities on hemoglobin electrophoresis should also raise the suspicion for ε γδβ thalassemia.

Data Availability Statement

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

Ethics Statement

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. Written informed consent was obtained from the minor(s)' legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.

Author Contributions

IF and FP wrote the manuscript and MV and CF critically reviewed it. IF, EC, and TC followed the patient. MM performed the genetic analysis. All authors contributed to the article and approved the submitted version.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords: thalassemia, ε γδβ , children, newborn, anemia

Citation: Fotzi I, Pegoraro F, Chiocca E, Casini T, Mogni M, Veltroni M and Favre C (2022) Case Report: Clinical and Hematological Characteristics of ε γδβ Thalassemia in an Italian Patient. Front. Pediatr. 10:839775. doi: 10.3389/fped.2022.839775

Received: 20 December 2021; Accepted: 07 February 2022; Published: 17 March 2022.

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Copyright © 2022 Fotzi, Pegoraro, Chiocca, Casini, Mogni, Veltroni and Favre. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Claudio Favre, claudio.favre@meyer.it

† These authors share first authorship

Heterogeneity of TDT

The role of regular transfusions in hbe β thalassemia, red cell alloimmunization in patients starting transfusions as adults, postnatal management of bart hydrops fetalis: atm, correspondence, challenges in chronic transfusion for patients with thalassemia.

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Ashutosh Lal; Challenges in chronic transfusion for patients with thalassemia. Hematology Am Soc Hematol Educ Program 2020; 2020 (1): 160–166. doi: https://doi.org/10.1182/hematology.2020000102

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Visual Abstract

The introduction of regular red cell transfusions 60 years ago transformed β-thalassemia major from a fatal childhood illness into a chronic disorder. Further advances in the prevention of transfusion-transmitted infections and management of iron overload have allowed survival and quality of life to approach normal. However, transfusion therapy for some other thalassemia syndromes continues to challenge clinical decision-making. Nearly one-half of the patients with E ß thalassemia are transfusion-dependent, yet the criteria for initiating transfusions or hemoglobin targets are not well defined. Patients with thalassemia intermedia who begin transfusions as adults are at very high risk for developing red cell alloimmunization and serious hemolytic transfusion reactions. In the growing number of survivors of Bart hydrops fetalis, the approach to transfusion therapy and iron chelation is rapidly evolving. A collaboration between hematology and transfusion medicine specialists will be essential to improving patient care and developing evidence-based guidelines.

Recognize the heterogeneity of transfusion-dependent thalassemia and its impact on management

Understand barriers to the effective use of red cell transfusions in thalassemia intermedia, hemoglobin E beta thalassemia, and alpha thalassemia major.

In the past decade, the classification of patients into transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT) was widely adopted. These terms were beneficial in planning the management of iron overload or choosing stem cell transplant or other curative therapy based upon a patient’s transfusion status. However, this approach can conceal the tremendous heterogeneity of TDT, a phenotypic group that encompasses β-thalassemia major, severe β-thalassemia intermedia, hemoglobin (Hb) E (HbE) β thalassemia, and certain α-thalassemia syndromes. Among these, β-thalassemia major is the largest category and is usually associated with the presence of 2 severe β-globin mutations. 1   These infants become symptomatic from anemia within the first year and regular transfusions are instituted before 2 years of age. 2   The natural history of β-thalassemia major has been the best characterized among various entities constituting TDT, and, consequently, the transfusion guidelines recommended by various groups for β-thalassemia major are largely similar. 1,3-8  

The guidelines developed for β-thalassemia major may not be appropriate in managing the other thalassemia syndromes that require regular transfusions. The severity of β thalassemia is determined by the imbalance between the α and non-α globin chains. A reduced or complete absence of β-globin synthesis leads to accumulation of excess α-globin chains that are toxic to the erythroid precursors. 9,10   The surplus of α-globin chains can be mitigated when 1 or both β-thalassemia alleles are mild (β + or β ++ ), there is concurrent deletion of α-globin genes, or elevated synthesis of γ-globin persists. 9   Elevated γ-globin synthesis sometimes arises from hereditary persistence of fetal Hb, but milder increases are more often from quantitative trait loci in Xmn1-HBG2 , HMIP , and BCL11A . 11   Various forms of β thalassemia may also differ in the total endogenous Hb (F, A, or E) or the oxygen-affinity characteristics (A and E compared with F) 12   that modify the adaptation to anemia. 13   Individuals with severe forms of α thalassemia, in contrast, produce nonfunctional Hb (Hb Bart or HbH), which causes underestimation of the true severity of anemia. 14   In β-thalassemia intermedia and HbE β thalassemia, the decision to commence regular transfusions is influenced not only by the severity of symptoms, but also on medical judgement. The latter is a subjective assessment of whether long-term prognosis would be better by accepting symptomatic anemia without transfusions instead of transfusion dependence and the associated potential complications. The recognition that patients with NTDT have worse quality of life than those with TDT and are at risk for severe complications has led to the extension of chronic transfusions to a larger proportion of patients than in the past. 15-18  

HbE β thalassemia is caused by compound heterozygosity for the E mutation (HBB:c.79G>A) and a β-thalassemia mutation. 19   The prevalence of HbE β thalassemia follows the distribution of the E mutation, which reaches very high frequencies in southeast Asia, southern China, and south Asia. Immigration from Asia to the west has increased the awareness of this syndrome and its distinctive natural history compared with β-thalassemia syndromes (caused by 2 β-thalassemia mutations). 20   The severity of HbE β thalassemia ranges from a mild, asymptomatic anemia to the development of transfusion dependence from early life. 19   The E mutation activates a cryptic splice site that reduces synthesis of β E messenger RNA. 21   The variable decrease in β E output is 1 of the factors underlying the variable disease phenotype, even though HbE is a functional Hb. The severity of β mutation (β + instead of β 0 ), coinheritance of α-thalassemia trait, and genetic traits that increase γ-globin synthesis reduce the severity of HbE β thalassemia. 19   Why patients may have dissimilar physiological response to nearly identical Hb levels, and why erythropoietin response to anemia declines with age, is incompletely understood. 22   One characteristic that differentiates HbE β thalassemia from β thalassemia (intermedia or major) is the different functional properties of HbE and HbF. Patients with HbE β thalassemia compensate by rightward shift in the oxygen affinity, which is not seen in β thalassemia where the HbF is the predominant Hb. 12   Although clinical symptoms increase progressively with severity of anemia, it may not be possible to predict the likelihood of transfusion dependence based on Hb concentration alone.

The patient was diagnosed with HbE β 0 thalassemia based on results of newborn screening. She was asymptomatic in early childhood with no limitation of physical activity, mild facial skeletal changes, and normal growth. Her Hb concentration was maintained between 6.7 and 7.1 g/dL without any blood transfusion. At 7 years of age, the spleen started to enlarge from 3 to 6.5 cm along with a decline in height velocity. She started regular blood transfusion at 10 years of age that led to resumption of normal growth and a decrease in spleen size to 2 cm ( Figure 1 ).

Case 1 depiction. In a patient with HbE β thalassemia (case 1), progressive increase in spleen size and reduced growth velocity led to start of regular transfusions (arrow). Transfusions led to reduction in splenomegaly over the following 2 years.

The patient was diagnosed with E β 0 thalassemia at 3 years and started regular transfusions with iron chelation. He was splenectomized at 12 years due to higher blood requirements and splenomegaly, following which Hb was spontaneously maintained between 6.9 to 7.2 g/dL. He was transfused intermittently 1 to 2 times per year when Hb dropped below 7 g/dL. In his early 20s, he developed dyspnea and continuous oxygen requirement from severe pulmonary arterial hypertension and heart failure. He had severe iron overload with liver iron concentration of 38 mg/g and cardiac magnetic resonance imaging T2* of 4.9 ms. Heart failure and pulmonary hypertension improved with supportive management, regular transfusions, and iron chelation ( Figure 2 ).

Case 2 depiction. In a transfusion-dependent patient with HbE β thalassemia (case 2), splenectomy was followed by discontinuation of regular transfusions. Fifteen years later, severe pulmonary arterial hypertension and congestive heart failure developed. These pathological changes were reversed by resumption of transfusions (arrow) and supportive care. LVEF%, left ventricular ejection fraction (percent); PASP, pulmonary artery systolic pressure.

As expected for β-globin disorders, newborns with HbE β thalassemia do not develop anemia until the synthesis of HbF declines significantly over the first 6 months of life. Some infants display the classic symptoms observed in β-thalassemia major, including failure to thrive, hepatosplenomegaly, pallor, and fatigue. 23   More often, the symptoms are mild and escape attention until an incidental viral infection or a routine blood test reveals anemia. In California, where universal newborn screening is practiced for thalassemia, observations suggest that normal growth and development persist up to 1 year and beyond in many, but not all, infants with HbE β thalassemia. When the diagnosis is made later during life due to pallor, anemia, facial skeletal changes, growth failure, hepatosplenomegaly, or jaundice, the age at presentation is an important marker of the severity of disease. 24  

Decisions on appropriate timing to either initiate or discontinue chronic transfusion therapy, although difficult, are of principal importance to the management of HbE β thalassemia. 22   Patients with baseline Hb <6 g/dL should be placed on transfusions even when asymptomatic. Conversely, it is unlikely that patients with baseline Hb >8 g/dL would benefit from transfusions. Finally, those with Hb between 6 and 8 g/dL should be evaluated according to the proposed guidelines ( Table 1 ). Our practice is to evaluate children with HbE β thalassemia in the clinic every 3 months for careful assessment of growth, splenomegaly, facial skeletal changes, and Hb level. Electronic medical records are useful to review trends over time and to store photographs for assessment of bony changes.

Indications to begin chronic transfusion therapy in HbE β thalassemia

In our practice, splenectomy is discouraged as a strategy to avoid the need for transfusions because the effect on Hb may be short-term and it does not address the underlying severe pathophysiology. 22,25   On the contrary, splenectomy increases the risk of infections and a number of serious long-term complications such as thromboembolism, pulmonary hypertension, and iron-induced endocrinopathies. 25   Other avenues to improve anemia include hydroxyurea, which produces an ∼1 g/dL rise in total Hb in 50% of patients, 26-28   however, the response in HbE β thalassemia is variable and insufficient to eliminate the need for transfusions. 18   Luspatercept is an approved therapy to reduce the transfusion requirements in patients with TDT including HbE β thalassemia. 29   Results of a phase 2, open-label study of luspatercept in NTDT showed ≥1.5 g/dL improvement in Hb in 14 of 31 subjects, 30   but the pivotal trial has not yet been done. Mitapivat, a pyruvate kinase activator in the red cells, is also being evaluated in NTDT. 31  

Case 2 highlights the underrecognition of iron overload in patients with NTDT. 18,32   Patients who receive only intermittent transfusions can develop marked iron overload over time. Gastrointestinal absorption of iron is increased in nontransfused patients due to hepcidin insufficiency induced by ineffective erythropoiesis and elevated erythroferrone. 33-35   Screening for iron overload is recommended in all patients with NTDT irrespective of transfusion history. Although magnetic resonance imaging for assessment of liver iron concentration is more accurate, 36   we consider serum ferritin to be useful as a screening test for iron overload. Serum ferritin values underestimate the liver iron overload in NTDT compared with TDT, therefore, LIC should be measured when ferritin exceeds 300 ng/mL. Iron chelation is indicated if LIC is >5 mg/g liver weight 36   with deferasirox at a starting dose of 3.5 to 7 mg/kg per day (5-10 mg/kg if the dispersible tablet is used). 37   We evaluate liver iron concentration every 6 months during therapy and stop chelation therapy when LIC <3 mg/g is achieved.

The development of antibodies to red cell antigens is a significant threat to the long-term success of transfusion therapy. 38-43   In the United States, the proportion of patients with thalassemia with red cell alloimmunization is 17% to 22%, only slightly lower than sickle cell disease (19% to 31%). 38,44,45   Older age at initiation of transfusions and splenectomy are identified as major risk factors for developing alloimmunization in thalassemia. 38,41,46   The specificity of antibody and the risk of alloimmunization is influenced by the disparity in red cell antigens among different ethnic groups. 47   In countries where thalassemia predominantly affects immigrant communities, the greater degree of donor-recipient red cell antigen mismatch can elevate the risk of alloimmunization, as shown in Table 2 . 39,44,46,48-50   In particular, the low frequency of Kell and c antigens in patients of Asian background facilitates development of alloimmunization. 39,46   One-half of the patients with 1 alloantibody will develop further antibodies against 1 or more additional antigens. 44   Transfusions can become progressively more difficult and it may become nearly impossible to find matched units for certain patients. The most frequent antibodies are against Rh and Kell groups, 41,44   which implies that universal phenotypic matching for these antigens can be a cost-effective method to prevent development of most red cell antibodies in thalassemia. 41,46  

RBC antigen frequencies and prevalence of alloantibodies

RBC antigen frequencies among ethnic groups 48-50   and prevalence of significant alloantibodies among patients with TDT in the western region of the United States, 39,46   and North America and United Kingdom. 38  

pts, patients.

Fy a or Fy b .

†Jk a or Jk b .

A 50-year-old woman with β-thalassemia intermedia who had undergone splenectomy recently changed hospitals. She was diagnosed at the age of 30 years but was only transfused during pregnancy. Due to worsening fatigue, regular transfusions were recommended by her new hematology team. A red cell phenotype was checked, and an antibody screen was found to be negative. She was given 2 red cell units matched to c, E, and Kell antigens. Later that night, she developed chills and fever. Her Hb levels were 7.1 and 9.0 g/dL, respectively, before and after the transfusion. Laboratory testing showed that her lactate dehydrogenase was normal, bilirubin rose from 1.2 to 1.7 mg/dL, haptoglobin was low, and urine contained trace Hb. Two weeks later, the antibody screen was positive and anti-Fyb was identified. Historical antibody data obtained from the previous blood bank showed anti-c, anti-E, anti-Kell, and anti-Fyb antibodies had been previously identified 15 years ago. The patient was successfully maintained on regular transfusions with extended phenotypically matched red blood cells. Anti-Fyb could no longer be identified after 4 years, although her antibody screen was intermittently positive due to development of anti-Cw antibody ( Figure 3 ).

Case 3 depiction. In a patient with β-thalassemia intermedia with prior exposure to blood and negative antibody screen (case 3), the transfusion of red cell units matched only to Rh and Kell antigens led to the reemergence of anti-Fyb antibody and delayed hemolytic transfusion reaction. Regular transfusions were possible with extended phenotypic matching of red cell units. Anti-Fyb was no longer detectable after 4 years, though antibody screen remained positive intermittently due to other alloantibodies. IAT, indirect antiglobulin test.

Although considered a much greater risk in sickle cell disease, 51   delayed hemolytic transfusion reactions (DHTRs) are also observed in thalassemia. 52   Hemolytic transfusion reactions have been reported due to anti-E, anti-Jk b , anti-Jk a , anti-c, anti-S, anti-Kell, and anti-f. 39   More than 25% of older children and adults with thalassemia will develop an alloantibody following 1 or more transfusions when red cell matching is limited to ABO/D only. 41,44,46   In the absence of further antigenic exposure, one-third of alloantibodies become undetectable within the first year of follow up. Anti-Jka antibodies are very evanescent, falling below the limit of detection within the first month of initial detection, whereas the anti-Kell and anti-E antibodies are undetectable in >50% at 6 months. 53,54   Between 20% and 25% of individuals of Chinese and Asian Indian ethnicity are Jka − , 60% to 80% are E − , and virtually all are Kell − . 48,55   An additional concern is c antigen which is negative in 40% to 50% of Asian patients, but the evanescence rate for anti-c antibody is lower (25%) compared with the other alloantibodies. 39  

Sensitized patients who receive a later transfusion, based on a negative antibody screen, rapidly increase antibody titer with reexposure that develops into a DHTR of variable severity. 51   DHTRs are less likely in regularly transfused patients where antibody screening is performed every few weeks and newly developed antibodies are unlikely to become undetectable before the next transfusion. 56   However, low-titer antibodies may be missed, or antibodies may develop while donor red cells are still circulating in significant amounts, leading to hemolysis. Intermittently transfused patients, on the other hand, are at high risk for antibody evanescence between transfusion episodes. The number of such patients with thalassemia, transfused 1 to 6 times per year, is small in the United States but significant in regions where blood availability is limited. Infrequent transfusions may be recommended during an infection, surgery, or pregnancy. 25   Transfusions during pregnancy are associated with a very high risk of alloimmunization, but these antibodies decrease in titer when transfusions are discontinued after childbirth. 57   Patient transfer between hospitals poses a persistent challenge to transfusion safety. 58   The lack of comprehensive antibody history can easily lead to the transfusion of red cells to which the patient is previously sensitized but now has a negative antibody screen. Although attempts have been made to provide patients with transfusion cards that list their phenotype and red cell antibodies, their use remains erratic. The absence of a centralized database for multiply transfused patients remains a serious shortcoming of the current practice of chronic transfusion therapy. 59  

The deletion of all 4 α-globin genes (--/--, homozygous α 0 thalassemia, or α-thalassemia major [ATM]) causes severe fetal anemia. 14,60   As fetal viability depends upon the preservation of embryonic ζ genes (ζ-/ζ-, or --/ζ-), the most frequent α 0 deletion associated with ATM is the southeast Asian deletion (-- SEA ). 14   The major Hb species in ATM is Hb Bart (γ 4 ), formed by self-association of γ chains into tetramers in the absence of α chains. Because Hb Bart is ineffective in transporting oxygen, most pregnancies end in fetal demise following a variable period of hydrops (Bart hydrops fetalis). 60   Intrauterine transfusions (IUTs) are essential for the fetus to reach viability with acceptable neonatal outcome. 61,62   All infants with ATM are transfusion-dependent from birth and require recognition of the nonfunctional Hb fractions for correct management. 62,63  

A child was born to parents who were carriers of the -- SEA deletion and had previously experienced a hydrops-associated stillbirth. During this pregnancy, fetal hydrops was detected at 20 weeks of gestation, and managed by IUT performed on 6 occasions. The baby, born at 37 weeks weighing 3.0 kg, was stable and underwent a red blood cell exchange transfusion at 48 hours. Following discharge, he started regular red cell transfusions every 4 weeks. The average pretransfusion Hb was 9.7 g/dL with Hb Bart and HbH accounting for 20% to 36% of the total value. Starting at 8 months, the transfusion regimen was changed to maintain HbH <20%, which corresponded to HbA >9.0 g/dL and total Hb of ∼11 g/dL in the pretransfusion blood sample. Growth proceeded at the normal pace, and developmental assessment at 3 years showed age-appropriate attainment of milestones ( Figure 4 ).

Case 4 depiction. A newborn with α-thalassemia major (− SEA /− SEA ) was initially transfused with a goal of maintaining total Hb of 9 to 10 g/dL in the pretransfusion period (case 4). This was associated with effective functional Hb (total Hb − sum of HbH and Hb Bart) between 6 and 7 g/dL. Transfusion regimen was modified (arrow) to maintain HbA 9 to 10 g/dL, which was achieved with total Hb of ∼11 g/dL in the pretransfusion blood sample.

The management of ATM is evolving with experience gained from data in international registries 61   and publication of case series. 62-65   In the absence of existing consensus guidelines, our institutional practices are provided in this discussion to fill gaps in published literature. Questions about the optimal management of pregnancies affected by ATM are being evaluated in an ongoing clinical trial (NCT02986698, fetus.ucsf.edu ).

The hematological management of ATM commences as soon as the diagnosis is suspected during pregnancy. In that small proportion of cases in which both parents are known carriers of the α 0 -thalassemia trait, the diagnosis should be established expeditiously with DNA testing from chorionic villus biopsy instead of ultrasound surveillance for fetal changes suggestive of hydrops. In most cases, however, the first indication is the detection of hydrops on ultrasound during the second trimester. In such cases, a presumptive diagnosis of ATM is appropriate when severe fetal anemia is observed by Doppler ultrasonography, 66   and the pregnant woman is not alloimmunized to RhD or other red cell antigens but has microcytosis and hypochromia. Hematologists have a critical role to play in confirmation of the diagnosis, nondirective counseling of the family, and prenatal management of the fetus.

When the decision is made to continue the pregnancy, the first IUT should be initiated as soon as possible. The strategy for conducting IUT in ATM is derived from consensus guidelines from the Society for Maternal-Fetal Medicine. 67   The decision to proceed with fetal blood sampling and IUT should be based on the detection of severe fetal anemia (defined as elevated peak systolic velocity in the fetal middle cerebral artery on Doppler ultrasonography 68   ) irrespective of the presence of hydrops. 67   Because Hb Bart, which constitutes nearly all the Hb in ATM, does not participate in oxygen transport, fetal hypoxia is disproportionate to any given Hb level. 69   The goals of complete correction of anemia or suppression of fetal erythropoiesis must be balanced against the risk of acute cardiovascular alterations and hyperviscosity with IUT. 67   Fetal anemia develops early in ATM with a mean Hb of 6.8 g/dL at 18 weeks, 69   which implies that there could be a role for intraperitoneal IUT prior to 18 weeks of gestation when intravascular IUT using the umbilical vein becomes feasible.

Resolution of hydrops is expected with an adequate IUT regimen. Specific to the diagnosis of ATM is the recommendation to measure Hb Bart in addition to total Hb in the pretransfusion sample. Following the initial gradual correction of anemia, the target hematocrit following transfusion after 24 weeks of gestation should be chosen at the higher end of the recommended range (40% to 50%). 67   An HbA level >10 g/dL and Hb Bart <20% in the pretransfusion fetal blood sample is expected with these goals. The delivery is planned at 37 to 38 weeks with the last IUT no later than 35 weeks of gestation. 67  

Perinatal events in ATM following suboptimal fetal management are characterized by a high incidence of preterm birth, intrauterine growth retardation, cesarean delivery, birth trauma, and difficult resuscitation. Newborns exhibit respiratory distress, pulmonary hypertension, organomegaly, effusions, and hyperbilirubinemia. 61,62   Some may have congenital anomalies affecting the genitourinary system. Anemia is profound and further distinguished by a high proportion of nonfunctional Hb Bart if >2 to 3 weeks have elapsed from the last intrauterine transfusion. An urgent simple transfusion with 5 to 10 mL/kg of high hematocrit red cell unit is usually given. When the proportion of Hb Bart is very high, an exchange transfusion will rapidly improve tissue oxygenation. The goal during the first few weeks is to maintain total Hb >12 g/dL and Hb Bart <20% while the need for critical care continues.

Following stabilization, infants are in a transition period up to 6 months with intensive transfusion support under close monitoring. This period is marked by the switch from Hb Bart to HbH, resolution of hepatosplenomegaly and cardiomegaly, improvement in thrombocytopenia and transaminitis, and the establishment of consistent weight gain. Transfusions aim to maintain nadir total Hb >12 g/dL with the total nonfunctional Hb (Hb Bart plus HbH) <20%. The interval between transfusions is initially 2 weeks, but gradually lengthened to 3 weeks. Red cell antigens should be determined by genetic testing to provide antigen-matched blood. At the end of 6 months, infants transition to a chronic transfusion protocol in which pretransfusion HbA is >9.0 g/dL and transfusion frequency is 3 to 4 weeks. Following the absolute HbA level instead of total Hb is important, otherwise children with ATM are at risk for undertransfusion. 63   Infusion centers lacking access to rapid Hb electrophoresis or high-performance liquid chromatography can aim to maintain the pretransfusion total Hb at 10.5 to 11 g/dL and reticulocyte count <500 000/μL. 63   Splenectomy is not recommended in the management of ATM. Transfusional iron overload is observed early within a few months after birth, but the assessment and management of iron in ATM is not well defined. Because of the concerns over hepatic inflammation and renal immaturity, chelation is postponed until 12 months of age.

The management of TDT should be adapted to the heterogeneity conferred by various genotypes. Although a universal transfusion protocol for TDT is unfeasible, common principles underlie the long-term goals of transfusion therapy for individuals with thalassemia. With improvement in life expectancy, decisions about initiation and intensity of transfusion support in TDT should be guided by long-term natural history studies that span the various life stages.

Ashutosh Lal, UCSF Benioff Children’s Hospital, 747 52nd St, Oakland, CA 94609; e-mail: [email protected] .

Competing Interests

Conflict-of interest disclosure: A.L. provided consultancy services to Chiesi USA and received research funding from Bluebird bio, Insight Magnetics, La Jolla Pharmaceutical Company, Novartis, Protagonist Therapeutics, and Terumo Corporation.

Author notes

Off-label drug use: None disclosed.

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Case Report: β-thalassemia major on the East African coast

Alexander W. Macharia Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing George Mochamah Roles: Conceptualization, Formal Analysis, Investigation, Writing – Review & Editing Johnstone Makale Roles: Data Curation, Formal Analysis, Methodology, Project Administration Thad Howard Roles: Data Curation, Formal Analysis, Investigation, Methodology Neema Mturi Roles: Investigation, Methodology, Resources Peter Olupot-Olupot Roles: Validation, Writing – Review & Editing Anna Färnert Roles: Validation, Writing – Review & Editing Russell E. Ware Roles: Methodology, Visualization, Writing – Review & Editing Thomas N. Williams Roles: Funding Acquisition, Methodology, Supervision, Visualization, Writing – Review & Editing

β-thalassemia major, rs33941849, East Africa, HbA2, sequencing

Introduction

β-thalassemia is rare in most of Africa, with the exception of North Africa where the prevalence, causal pathogenic variants and disease outcomes have all been well described previously ( Hamamy & Al-Allawi, 2013 ). We recently reported elevated levels of HbA 2, suggestive of β-thalassemia, in a small proportion of children participating in a cohort study conducted in Kilifi county on the coast of Kenya ( Macharia et al ., 2019 ). We subsequently sequenced samples from the same children and found that 0.6% were carriers of one of four different β-thalassemia pathogenic variants: the β 0 -thalassemia variants CD22 (GAA➝TAA) (rs33959855), initiation codon (ATG➝ACG) (rs33941849) and IVS1-3ʹ end del 25bp (rs193922563) and the β + -thalassemia variant IVS-I-110 (G➝A) (rs35004220). Whereas the mutations observed in North Africa resemble those found in Middle Eastern countries, those identified in Kilifi were a mixture of mutations reported from Asia and the Middle East. To the best of our knowledge, no cases of β-thalassemia major – a condition in which both HBB genes are affected by a β 0 -thalassemia mutation to result in the complete loss of normal β 0 -globin production - have yet been reported from the East Africa region. Here, we describe what is, to the best of our knowledge, the first case of β 0 -thalassemia major to be recognised from within this region.

Written informed consent was provided by the parents of the study participant. Ethical approval for the study was granted by the Kenya Medical Research Institute Ethical Review Committee in Nairobi, Kenya (Number: SCC3891).

Patient report

The child, a two-and-a-half-year-old female, presented to Kilifi County Hospital in Kenya, with a one-week history of left sided abdominal swelling. No previous hospital admissions were reported. Clinical history suggested delayed developmental milestones; specifically, she was unable to walk without support. The child was the fourth born of five siblings, all of whom were alive and well as were both of her parents. Both her parents were of Mijikenda ethnolinguistic ancestry and no recent genetic admixture was apparent from the clinical history. On physical examination, the child was pale but had no signs of clinical jaundice. Her vital signs were essentially normal with the exception of a fever measured at 38.8 ° C per axilla. Fronto-maxillary skull bossing was apparent. Her abdomen was distended, soft and non-tender, massive splenomegaly being detected at 8cm below the costal margin. She was severely malnourished with a weight of 8.8 kg, a height of 78.5 cm, a height for age z-score (HAZ) of -3.79, a weight for age z-score (WAZ) of -3.20 and a weight for height z-score (WHZ) of -1.23. Further examination was essentially normal. The timeline of events is given in Table 1 .

Table 1. Timeline of events.

A full hemogram revealed marked anemia (Hb 6.6 g/dL), a low mean corpuscular volume (MCV) of 64 fL, a low mean corpuscular hemoglobin (MCH) of 19.4 pg, and a raised total white blood cell (WBC) count of 49.6 × 10 9 /µl which were predominantly lymphocytes. Her platelet count was normal at 321 × 10 6 /L and her creatinine mildly elevated at 32 μmol/l. Blood cultures and tests for malaria were negative. A peripheral blood film revealed nucleated red blood cells (RBCs), microcytes, dacrocytes, acanthocytes, giant platelets and a marked lymphocytosis ( Table 2 ).

Table 2. Complete blood count and peripheral blood film from the child with β-thalassemia.

Abbreviations: WBC, white blood cells; RBC, red blood cells; Hb, hemoglobin; HCT, hematocrit; MCV, mean cell volume; MCH, mean cell hemoglobin; PBF, peripheral blood film. ¢Age=2.5 years, ‡Age=3.5 years.

The child was admitted to the general pediatric ward with a working diagnosis of iron deficiency anemia, potentially complicated by bacterial sepsis, and with a differential diagnosis of sickle cell anemia. She was treated empirically with iron and folic acid supplementation for her anemia and with intravenous penicillin and gentamicin to cover sepsis. She was also prescribed malaria prophylaxis with proguanil pending analysis for sickle cell anemia by high-performance liquid chromatography (HPLC). Her fever subsided within two days of admission, at which point she was discharged home on oral amoxicillin, with follow-up planned for the following week.

The results of her HPLC analysis, received after discharge from hospital, revealed the absence of normal adult hemoglobin (HbA), normal levels of HbA 2 at 2.5% and elevated levels of fetal hemoglobin (HbF) (>80% of total Hb) that eluted in adjacent peaks A1b (16%) and LA1C/cHb1 (76.5%) ( Figure 1 ). The complete absence of HbA suggested a diagnosis of β 0 -thalassemia major. We therefore sequenced her HBB gene region as described in detail previously ( Clark & Thein, 2004 ), which revealed that the child was homozygous for the initiation codon (ATG➝ACG) mutation (rs33941849).

Figure 1. HPLC chromatograms from study participants with normal hemoglobin A individual (HbAA), homozygous hemoglobin S (HbSS) and homozygous β-thalassemia patient at first admission (age 2.5 years) and at second admission (age 3.5 years).

Initially lost to follow-up, the child re-presented at the age of three years 11 months with a one-week history of a cough and fever. On examination at that time, her spleen remained grossly enlarged at 10 cm, and she remained malnourished with a HAZ of -4.98, a WAZ of -4.01 and a WHZ of -0.99. Although hemodynamically stable, she was profoundly anemic (Hb 2.2 g/dL) and was therefore transfused and treated with folic acid supplementation and nutritional support. Repeat HPLC analysis revealed the continued absence of HbA together with elevated levels of HbF (>80%) and HbA 2 (at 5%) ( Figure 1 ). PCR for the α -3.7 deletional form of α-thalassemia was negative.

To the best of our knowledge, this is the first case of homozygous β-thalassemia to be reported from the East Africa region. The mutation responsible disrupts the transfer RNA binding site to result in a β 0 form of the disease. It appears to be rare in other populations: only 45 carriers have been reported in the literature to date, 20 of which were from our recently reported study ( Macharia et al ., 2020 ). Other reports of carriers have come from a wide range of countries including Switzerland ( Beris et al ., 1993 ), Belgium ( Wildmann et al ., 1993 ), Russia ( Molchanova et al ., 1998 ), India ( Gorakshakar et al ., 2018 ; Gupta et al ., 2002 ) and the former Yugoslavia ( Jankovic et al ., 1990 ). The only homozygous case described to date was a male child of Pakistani origin who presented at 10 months of age with a palpable liver and spleen at 7 cm and 3 cm below costal margin, respectively. His Hb was 9.2 g/dl, MCV of 73 fl and MCH of 33 pg. He was also found to be homozygous for the α -3.7 -thalassemia deletion and to have a Bantu β-globin gene cluster haplotype. He was managed with regular blood transfusions ( Khan et al ., 2000 ).

On comparing the current and previously described cases, all had anemia, a low MCV and massive splenomegaly. In our current patient, we also observed elevated levels of HbF and varying levels of HbA 2 at the two points of testing, an observation which is common in β-thalassemia major ( Steinberg & Rodgers, 2015 ). Options for the treatment of this condition in our context are limited. Throughout much of the world, first line management includes the provision of regular, leuco-depleted blood transfusions together with extended antigen typing of transfused blood to reduce the risk of alloimmunization. Iron-chelation is also used to mitigate the risk of iron overload ( Steinberg et al ., 2009 ) while more recently, allogeneic hematopoietic cell transplantation (HCT) is also being used as a potentially curative therapy. However, all these strategies are beyond the capacity of our local health-care system. Nevertheless, there is growing evidence to support the use of hydroxyurea, an HbF inducer, in the treatment of transfusion and non-transfusion dependent β-thalassemia ( Algiraigri et al ., 2017a ; Algiraigri et al ., 2017b ). We will investigate this strategy together with surgical splenectomy if the child returns for further follow-up in the hope that these will reduce the frequency at which transfusions will be required.

Conclusions

We have previously estimated the birth prevalence of β-thalassemia major in our local community at approximately 1 in 100,000 ( Macharia et al ., 2020 ). Nevertheless, low awareness of this condition among clinicians and the low availability of diagnostic facilities within the region mean that historically, individuals with β-thalassemia major have probably been misdiagnosed with other conditions such as sickle cell anemia or iron deficiency anemia as was the case with this child. As such, we hope that our case study will raise awareness about the existence and clinical importance of β-thalassemia major as a public health problem within the East Africa region and lead to the development of locally appropriate diagnostic and treatment guidelines.

Data availability

Underlying data.

All data underlying the results are available as part of the article and no additional source data are required.

Written informed consent for publication of their clinical details was obtained from the parents of the patient.

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Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Hemoglobinopathies and thalassemia

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• Martin H. Steinberg , Boston Medical Center, Boston, USA
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• OSCE Slideshow
• Observed OSCE
• Experts speak
• Preparation
• Last minute
• In the exam hall
• Things to remember
• B. OSCE Slideshow
• C. Case Presentation
• D. OSCE By Topics
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• Case Presentation

Case presentation : Thalassemia

9 September 2011, 20:38

Dr. Tushar Maniar

By Dr. ADITI   SHAH

This is a common case that is asked in the exam. We have put the relevent points to be covered while taking the case . Also, some of the Q &A are mentioned. Your feedback is welcome.

Case : THALASSEMIA

• Consanguinity
• Was admitted for receiving blood transfusion
• Onset of noticing pallor —- months of age
• Investigated and found to have an abnormal blood disorder
• Time of 1 st transfusion
• Frequency of transfusion
• Any increase in frequency now
• How many bags of blood at present… so calculate his trans requirement in ml/kg/year
• Where receives trans?… charitable blood bank? Hospital? General ward bed ( to highlight financial constraints
• h/o rash or fever during trans
• when was chelation started
• what drug… how is it taken, how much dose, how many times a week
• any other treatment (ca, folic acid, antifailure drugs, hormonal supplements etc)
• registered with thal society?
• Advised for inv every 3 months
• any special vaccines( if taken mention here or mention in immunization history)
• any special inv done like MRI, bone scan
• if advised surgery ( splenectomy), mention here

NEGATIVE HISTORY

• H/O not gaining adequate ht, Secondary sexual characters, Recent increase in frequency of transfusion , with easy fatigability, easy bruisability, repeated infections and fever, Abdominal distension, Bone pain/ joint pain ( osteopenia, osteoporosis, AVN head of femur), Change in facial profile with prominent bones ( compli of disease itself)
• h/o fatigue, swelling legs, palpitation ( cardiac iron overload)
• h/o jaundice, right hypochondriac pain ( liver iron overload)
• nausea , vomiting, pain at injection site, bone pain, joint pain,rash, jaundice, repeated inf ( compli of chelation)

FAMILY HISTORY:

Inv in parents, sibling… mention who are thal traits

NUTRITIONAL HISTORY

IMMUNIZATION – complete till date

• mention cost of chelation and trans per month
• concessional rate from thal society
• earning members
• mention about financial constraints if any

GENERAL EXAMINATION:

• thal facies- elaborate
• pallor present, no “ICCLE”, no platynychia. No koilonychia
• Any hyperpigmentation

Abdomen: liver — cm below costal margin in mcline, nontender, firm, smooth surface, rounded borders, liver span—-, upper border felt in — intercostal space

Spleen: — cm, splenic notch, smooth surface, moves with respi

ALL SYSTEMS in detail

COMMON QUESTIONS:

• 5 most common mutations in Indian population with β thalassemia are 619 bp deletion
• IVS 1-5 (G-C)
• IVS 1-1 (G-T)
• FS 8/9 (+G)
• FS 41/42(-CTTT) 9
• Hb electrophoresis pattern in normal and in thal  variants
• Which communities

Kutchis, Sindhis, Punjabis, Bhanushalis, Lohanas, Mahars, Neobuddhists, Gowdas

• Which chromosome   -11
• In 1 sentence describe blood trans in a thal pt

10- 15 ml/kg of pure red cell transfusion which are fresh, saline washed, leucodepleted , ABO and rh compatible at not more than 3-4 ml/kg/hour under supervision to maintain Hb above 10gm%

• Reason for thal facies – bone marrow hyperplasia
• Hypertransfusion regimen – maintain pretransfusion HB >10 gm%
• Supertransfusion regimen – maintain pretransfusion HB >12 gm%
• Moderate trans regimen – maintain pretransfusion HB between 9 and 10.5 gm%
• No of normoblasts in adequately trans child – <5/100 WBCs
• Causes of growth failure in thal – endocrine dysfunction + anemia+hypersplenism+ DFX+liver disease
• Endocrine work up- when to do?

GTT, thyroid function test , ca, phosphorus every year from 5 yrs age.

• MRI T2* values for cardiac iron load

>20ms- normal, 10-20 borderline iron overload, <10- severe iron overload

• MRI T2* values for liver iron load Liver T2 * values of >6.3ms are considered normal, 6.3-2.7ms are mild, 2.7-1.4ms are moderate and <1.4ms are severe iron overload.
• Aims of chelation : ferritin <2500 ng/ml
• DFO- dose, duration, compli
• DFP- details
• DFX- details
• Shuttle hypothesis   : use of 2 chelators together for better iron removal : eg DFP+DFO
• Ind of splenectomy – >210 ml/kg/year of transfusion requirement
• Why is this not a thal variant? 

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