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HEREDITARY ANEMIAS PROF. SAMIYA NAEEMULLAH Diplomate American Board of Pediatrics FAAP, FCPS Head of HEREDITARY ANEMIAS PROF. SAMIYA NAEEMULLAH Diplomate American Board of Pediatrics FAAP, FCPS Head of Pediatrics Department Islamic International Medical College

ANEMIA Defined as HB level below normal range n Varies with age and sex ANEMIA Defined as HB level below normal range n Varies with age and sex of the individual n n Neonate 1 -12 months: 1 - 12 years Hb < 14 g/dl Hb <10 g/dl Hb < 11 g/dl

IMPAIRED CELL PRODUCTION n Congenital Red cell aplasia n Diamond Blackfan Anemia n Fanconi IMPAIRED CELL PRODUCTION n Congenital Red cell aplasia n Diamond Blackfan Anemia n Fanconi Anemia

INCREASED RED CELL DESTRUCTION n Hemolytic Anemias RED CELL MEMBRANE DISORDERS Hereditary Spherocytosis RED INCREASED RED CELL DESTRUCTION n Hemolytic Anemias RED CELL MEMBRANE DISORDERS Hereditary Spherocytosis RED CELL ENZYME DISORDER Glucose 6 – phosphate dehydrogenase deficiency (G 6 PD) Hemoglobinopathies Sickle cell disease Thalassemia

LEARNING OBJECTIVES n n n Discuss the etiology of different types of hereditary anemias? LEARNING OBJECTIVES n n n Discuss the etiology of different types of hereditary anemias? Differentiate between cell defects, enzymatic defects and hemoglobinopathies Be able to distinguish the morphology of different hemolytic anemias Discuss clinical features of sickle cell disease and Thalassemia Major Correlate clinical features with pathophysiology of the disease

DIAMOND BLACKFAN ANEMIA n Etiology n Autosomal dominant 15% n Autosomal recessive 15% n DIAMOND BLACKFAN ANEMIA n Etiology n Autosomal dominant 15% n Autosomal recessive 15% n Spradic 80% n FH 20%

ANEMIA ANEMIA

CONGENITAL ANOMALIES Short stature CONGENITAL ANOMALIES Short stature

DIAGNOSIS Low Hb% macrocyte n Low reticulocyte Count n Normal bilirubin n Absent red DIAGNOSIS Low Hb% macrocyte n Low reticulocyte Count n Normal bilirubin n Absent red cell precussors on narrow n

INHERITED APLASTIC ANEMIAS n Reduction or absence of all three main line in bone INHERITED APLASTIC ANEMIAS n Reduction or absence of all three main line in bone marrow leading to peripheral blood pancytopenia

FANCONI’S ANEMIA Short stature n Abnormal radii & thumbs n Renal manifestation n Pigmented FANCONI’S ANEMIA Short stature n Abnormal radii & thumbs n Renal manifestation n Pigmented skin lesion n Increased chromosomal breakage of peripheral blood lymphocytes n

Schwachman Diamond Syndrome n Autosomal Recessive disorder n Bone marrow failure n Pancreatic exocrine Schwachman Diamond Syndrome n Autosomal Recessive disorder n Bone marrow failure n Pancreatic exocrine failure n Skeletal abnormalities n

RED CELL MEMBRANE DISORDERS n Hereditary spherocytosis n Hereditary elliptocytosis RED CELL MEMBRANE DISORDERS n Hereditary spherocytosis n Hereditary elliptocytosis

HEREDITARY SPHEROCYTOSIS Autosomal dominant n No F/H – in 25% cases n Defect in HEREDITARY SPHEROCYTOSIS Autosomal dominant n No F/H – in 25% cases n Defect in genes for the skeletal proteins of the red cells membrane spectrin, ankyrin and band 3 red cell losses part of its membrane passing through spleen n

 in surface to volume ratio – causes the cells to become spheroidal. n in surface to volume ratio – causes the cells to become spheroidal. n Less deformable than normal RBS n Destruction in micro vasculature of the spleen n

Jaundice at birth n Anemia n Mild to moderate splenomegaly n Aplastic crises n Jaundice at birth n Anemia n Mild to moderate splenomegaly n Aplastic crises n Gall stones n

ENZYME DEFECTS Glucose 6 phosphate dehydrogenase (G 6 PD) deficiency n Commonest red cell ENZYME DEFECTS Glucose 6 phosphate dehydrogenase (G 6 PD) deficiency n Commonest red cell enzymopathy effecting over 100 million people world wide n G 6 PD in red cell essential for preventing n Oxidative damage to red cells n So cell lacking the enzyme are suseptible to oxidant induced hemolysis n

Etiology with inherited as X linked effects males n G 6 PD activity in Etiology with inherited as X linked effects males n G 6 PD activity in Red cells n Mostly in old cells n

X LINKED INHERITANCE X LINKED INHERITANCE

CLINICALLY Neonatal Jaundice n Acute hemolysis precipitected by n Drugs n Infection n Naphthalene CLINICALLY Neonatal Jaundice n Acute hemolysis precipitected by n Drugs n Infection n Naphthalene in moth balls n Intravascular hemolysis n Fever, malaise, dark colored urine n

HEMOGLOBINOPATHIES n These are red blood cell disorders which cause hemolytic anemia because of HEMOGLOBINOPATHIES n These are red blood cell disorders which cause hemolytic anemia because of n Reduced or absent production of Hb A( & thalassemia) n Production of abnormal Hb e. g. sickle cell disease

BETA THALASSEMIA AUTOSOMAL RECESSIVE n Inherited disorder characterized by absence or decreased synthesis of BETA THALASSEMIA AUTOSOMAL RECESSIVE n Inherited disorder characterized by absence or decreased synthesis of beta globin chain of hemoglobin

Normal Fetal Hb at different ages n At birth – 70% n 5 weeks Normal Fetal Hb at different ages n At birth – 70% n 5 weeks – 55% n 4 months – 10% n 5 month – 5% n At one year – (< 2%)

HETEROZYOUS SATE Thalassemia Minor n One normal betaglobin chain gene and one beta-thalassemia gene HETEROZYOUS SATE Thalassemia Minor n One normal betaglobin chain gene and one beta-thalassemia gene HOMOZYGOUS Thalassemia Intermedia n 2 Thalassemia genes Thalassemia Major n 2 Beta thalassemia genes

PATHOPHYSIOLOGY Beta Thalassemia minor n Most Common n Failure of one gene coding for PATHOPHYSIOLOGY Beta Thalassemia minor n Most Common n Failure of one gene coding for beta chain n Alpha chain – production – normal n Alpha chain available combine with beta chain n Hb A levels

Excess alpha chain – stimulates production of delta chain – Hb A 2 n Excess alpha chain – stimulates production of delta chain – Hb A 2 n Still excess alpha chains – switches off gamma chain production does not function correctly. And rate of gamma chain production is greater than in normal adult so amount of Hb F. n

Hb. F n n Poor oxygen deliverer and high affinity for O 2 Only Hb. F n n Poor oxygen deliverer and high affinity for O 2 Only functional Hb present is A 2 Hypoxia Erythropoetin Stimulated marrow to maximum Extremedullary hematopaiesis Splenomegaly

CLINICAL MANIFESTATIONS Thalassemia Minor n The Growth & Development is normal n Mild anemia CLINICAL MANIFESTATIONS Thalassemia Minor n The Growth & Development is normal n Mild anemia Hb – 10 mg. /dl

Thalassemia Intermedia n Symptomatic by 2 – 4 yrs of age n Mod anemia Thalassemia Intermedia n Symptomatic by 2 – 4 yrs of age n Mod anemia n Thalassemic facies n Growth failure n Hepatosplenomegaly n Jaundice

THALASSEMIA MAJOR n DETROIT PEDIATRICIAN n 1925 THOMAS COOLEY (Cooley Anemia) n Profound anemia THALASSEMIA MAJOR n DETROIT PEDIATRICIAN n 1925 THOMAS COOLEY (Cooley Anemia) n Profound anemia n Splenomegaly n Bony deformities n Greek word Thalasa SEA Blood

Universally fatal disease Is now converted into chronic illness Universally fatal disease Is now converted into chronic illness

INCIDENCE 3% of world’s population carry Thalassemia gene n PAKISTAN n Carrier rate 4 INCIDENCE 3% of world’s population carry Thalassemia gene n PAKISTAN n Carrier rate 4 -5% n Pathans 5. 8% n Total No of patients 50, 000 -60, 000 n 5000 – 6000 children are born each year n

THALASSEMIA MAJOR Born normal at birth n Starts getting pale, fussy, irritable n Starts THALASSEMIA MAJOR Born normal at birth n Starts getting pale, fussy, irritable n Starts refusing feeds n

INFANT INFANT

CHILD CHILD

CLINICAL FEATURE Bossing of skull n Maxillary overgrowth n Long face n Hepatosplenomegaly n CLINICAL FEATURE Bossing of skull n Maxillary overgrowth n Long face n Hepatosplenomegaly n Bones become thin n Fractures may occur n Heart failure n

ADOLESCENT ADOLESCENT

COMPLICATIONS Iron Overload n Darkening of skin(Iron stimulated melanin) n Cardiomyopathy n Endocrinopathies n COMPLICATIONS Iron Overload n Darkening of skin(Iron stimulated melanin) n Cardiomyopathy n Endocrinopathies n Infections (Hepatitis A, B, C, Malaria, HIV) n Failure to thrive n Antibody formation(10%)Alloantibodies n

LAB DIAGNOSIS Complete Blood Count n RBC Morphology n Hemoglobin Electrophoresis n Serum Iron& LAB DIAGNOSIS Complete Blood Count n RBC Morphology n Hemoglobin Electrophoresis n Serum Iron& Ferritin levels n Imaging Study n

IRON OVERLOAD LEAD TO Liver fibrosis n Cardiomyopathy n Dysfunction of endocrine organs n IRON OVERLOAD LEAD TO Liver fibrosis n Cardiomyopathy n Dysfunction of endocrine organs n Diabetes n Clinical Organ dysfunction n Well transfused patient dies by 10 -25 yrs if not chelated n

ADULT Fertility n Ability to Reproduce and bare children n Reduce fertility due to ADULT Fertility n Ability to Reproduce and bare children n Reduce fertility due to iron overload Control iron levels n Pregnancy monitoring, reproductive assistance and perinotologist 40 cases reported

KEY MESSAGES Screen the Population n Get The Blood Tested n Detect Thalessemia Traits KEY MESSAGES Screen the Population n Get The Blood Tested n Detect Thalessemia Traits n Prevent them from marrying other thalassemia traits n Counselling n Help the children & families with Thalassemia n

 THALASSEMIA Healthy infants have four globin genes. n The manifestation of thalassemic syndromes THALASSEMIA Healthy infants have four globin genes. n The manifestation of thalassemic syndromes depend on the number of functional globlin chains n Deletion of 4 globin chains n Hb Barts Hydrops fetalis n Fetal anemia – edema, ascities n Fetus dies in utero or within hours of delivery n

Deletion of three globin genes n (Hb. H disease) n Mild – moderate anemia Deletion of three globin genes n (Hb. H disease) n Mild – moderate anemia n Deletion of one or two globin chains n thalassemia trait n Asymptomic n Anemia is mild or absent n

SICKLE CELL DISEASE Hb. SS Commonest genetic disorders in UK in 2000 births n SICKLE CELL DISEASE Hb. SS Commonest genetic disorders in UK in 2000 births n Blacks from tropical Africa Etiology n Point mutation in codon 6 of globin chain which causes change in aminoacid encoded from n Glutamine to Valine n

FORMS Sickle cell anemia n SC disease n Sickle thalassemia n FORMS Sickle cell anemia n SC disease n Sickle thalassemia n

SICKLE CELL ANEMIA Hb. SS Patients are hemozygons for Hbs i. e. virtually all SICKLE CELL ANEMIA Hb. SS Patients are hemozygons for Hbs i. e. virtually all their Hb is Hbs n No Hb. A – no normal genes n

SC DISEASE Affected children inherit n Hbs – one parent n Hb. C- other SC DISEASE Affected children inherit n Hbs – one parent n Hb. C- other parent n

SICKLE THALASSEMIA Affected children inherit n Hbs from – one parent n thalassemia – SICKLE THALASSEMIA Affected children inherit n Hbs from – one parent n thalassemia – trait – 2 nd parent n No normal -globin genes and most patients can make no Hb A so can transmit Hb S to their offspring n Symptoms are similar to those with sickle cell anemia. n

SICKLE TRAIT Inheritance of Hb. S from one parent n Normal - globin gene SICKLE TRAIT Inheritance of Hb. S from one parent n Normal - globin gene – other parent n 40% of the Hb is Hb. S n Carriers of Hb. S n Asymptomatic n

CLINICAL MANIFESTATIONS Anemia 6 – 8 gm/d n Jaundice VASO - OCCLUSIVE CRISES Late CLINICAL MANIFESTATIONS Anemia 6 – 8 gm/d n Jaundice VASO - OCCLUSIVE CRISES Late infancy n Hand – foot syndrome n Bones of limbs & spine n Cerebral & pulmonary infarction n Acute stroke n

PRECIPITATING FACTORS Exposure to cold n Dehydration n Excessive exercise n Stress n Hypoxia PRECIPITATING FACTORS Exposure to cold n Dehydration n Excessive exercise n Stress n Hypoxia n Infection n

ACUTE ANEMIA Hemolytic crisis n Associated with infection n Aplastic crisis n By parvo ACUTE ANEMIA Hemolytic crisis n Associated with infection n Aplastic crisis n By parvo virus infection n complete or temporary caestion of red blood cell production n Sequestration crisis n Sudden splenic enlargement n Abdominal pain n Circulatory collapse n

INFECTIONS Susceptibily to infections as pneumococcus & hemophitus influenzae n Increased incidence of Bone INFECTIONS Susceptibily to infections as pneumococcus & hemophitus influenzae n Increased incidence of Bone infection by salmonella n Chronic sickling microinfarction in spleen n

Neonatal Diagnosis – at birth guthrie test n Prenatal diagnosis by chorionic villus sampling Neonatal Diagnosis – at birth guthrie test n Prenatal diagnosis by chorionic villus sampling at the end of 1 sttrimester n

MANAGEMENT STEPS n Regular red cell transfusions n Chelation therapy n Growth monitoring and MANAGEMENT STEPS n Regular red cell transfusions n Chelation therapy n Growth monitoring and follow up n Management of complications n Psychosocial support

MANAGEMENT STEPS n Splenectomy n Bone marrow transplantation n Cord blood transplantation n Drugs MANAGEMENT STEPS n Splenectomy n Bone marrow transplantation n Cord blood transplantation n Drugs stimulating gamma chains n Gene therapy n Prevention and antenatal diagnosis

MULTI DISCIPLINARY APPROACH n n n n n Pediatrician Hematologist Gynecologist Physician Surgeon Ophthalmologist MULTI DISCIPLINARY APPROACH n n n n n Pediatrician Hematologist Gynecologist Physician Surgeon Ophthalmologist E NT Specialist Lab technician Psychologist psychiatrist Social worker n Parents n Patient n