HEREDITARY HEREDITARY ANEMIASANEMIAS

PROF. SAMIYA PROF. SAMIYA NAEEMULLAHNAEEMULLAH

Diplomate American Board of Diplomate American Board of PediatricsPediatrics

FAAP, FCPSFAAP, FCPSHead of Pediatrics DepartmentHead of Pediatrics DepartmentIslamic International Medical Islamic International Medical

College College

ANEMIAANEMIA

Defined as HB level below normal Defined as HB level below normal range range

Varies with age and sex of the Varies with age and sex of the individualindividual

Neonate Hb < 14 g/dlNeonate Hb < 14 g/dl 1-12 months: Hb <10 g/dl1-12 months: Hb <10 g/dl 1- 12 years Hb < 11 g/dl 1- 12 years Hb < 11 g/dl

IMPAIRED RED CELL IMPAIRED RED CELL PRODUCTIONPRODUCTION

Congenital Red cell aplasia Congenital Red cell aplasia Diamond Blackfan AnemiaDiamond Blackfan Anemia Fanconi AnemiaFanconi Anemia

INCREASED RED CELL INCREASED RED CELL DESTRUCTIONDESTRUCTION

Hemolytic AnemiasHemolytic Anemias

RED CELL MEMBRANE RED CELL MEMBRANE DISORDERSDISORDERS

Hereditary SpherocytosisHereditary SpherocytosisRED CELL ENZYME RED CELL ENZYME DISORDERDISORDERGlucose 6 – phosphate Glucose 6 – phosphate dehydrogenase deficiency dehydrogenase deficiency (G6PD)(G6PD)Hemoglobinopathies Hemoglobinopathies

Sickle cell diseaseSickle cell diseaseThalassemiaThalassemia

LEARNING OBJECTIVESLEARNING OBJECTIVES

Discuss the etiology of different types of Discuss the etiology of different types of hereditary anemias?hereditary anemias?

Differentiate between cell defects, Differentiate between cell defects, enzymatic defects and enzymatic defects and hemoglobinopathieshemoglobinopathies

Be able to distinguish the morphology of Be able to distinguish the morphology of different hemolytic anemiasdifferent hemolytic anemias

Discuss clinical features of sickle cell Discuss clinical features of sickle cell disease and Thalassemia Majordisease and Thalassemia Major

Correlate clinical features with Correlate clinical features with pathophysiology of the diseasepathophysiology of the disease

DIAMOND BLACKFAN DIAMOND BLACKFAN ANEMIAANEMIA

EtiologyEtiology Autosomal dominant 15%Autosomal dominant 15% Autosomal recessive 15%Autosomal recessive 15% Spradic 80%Spradic 80% FH 20%FH 20%

ANEMIAANEMIA

CONGENITAL ANOMALIES CONGENITAL ANOMALIES

Short stature

DIAGNOSISDIAGNOSIS

Low Hb% macrocyteLow Hb% macrocyte Low reticulocyte CountLow reticulocyte Count Normal bilirubinNormal bilirubin Absent red cell precussors Absent red cell precussors

on narrowon narrow

INHERITED APLASTIC INHERITED APLASTIC ANEMIASANEMIAS

Reduction or absence of all Reduction or absence of all three main line in bone marrow three main line in bone marrow leading to peripheral blood leading to peripheral blood pancytopeniapancytopenia

FANCONI’S ANEMIAFANCONI’S ANEMIA Short statureShort stature Abnormal radii & thumbsAbnormal radii & thumbs Renal manifestation Renal manifestation Pigmented skin lesionPigmented skin lesion

Increased chromosomal Increased chromosomal breakage of peripheral blood breakage of peripheral blood lymphocyteslymphocytes

Schwachman Diamond Schwachman Diamond SyndromeSyndrome

Autosomal Recessive Autosomal Recessive disorder disorder

Bone marrow failureBone marrow failure Pancreatic exocrine failurePancreatic exocrine failure Skeletal abnormalitiesSkeletal abnormalities

RED CELL MEMBRANE RED CELL MEMBRANE DISORDERSDISORDERS

Hereditary spherocytosis Hereditary spherocytosis

Hereditary elliptocytosisHereditary elliptocytosis

HEREDITARY HEREDITARY SPHEROCYTOSISSPHEROCYTOSIS

Autosomal dominant Autosomal dominant No F/H – in 25% casesNo F/H – in 25% cases Defect in genes for the skeletal Defect in genes for the skeletal

proteins of the red cells proteins of the red cells membrane spectrin, ankyrin and membrane spectrin, ankyrin and band 3 red cell losses part of its band 3 red cell losses part of its membrane passing through membrane passing through spleenspleen

in surface to volume ratio – in surface to volume ratio – causes the cells to become causes the cells to become spheroidal. spheroidal.

Less deformable than normal Less deformable than normal RBS RBS

Destruction in micro Destruction in micro vasculature of the spleen vasculature of the spleen

Jaundice at birthJaundice at birth AnemiaAnemia Mild to moderate Mild to moderate

splenomegaly splenomegaly Aplastic crisesAplastic crises Gall stonesGall stones

ENZYME DEFECTSENZYME DEFECTS

Glucose 6 phosphate dehydrogenase Glucose 6 phosphate dehydrogenase (G(G66PD) deficiency PD) deficiency

Commonest red cell enzymopathy Commonest red cell enzymopathy effecting over 100 million people world effecting over 100 million people world wide wide

GG66PD in red cell essential for preventingPD in red cell essential for preventing Oxidative damage to red cells Oxidative damage to red cells So cell lacking the enzyme are suseptible So cell lacking the enzyme are suseptible

to oxidant induced hemolysisto oxidant induced hemolysis

Etiology with inherited as X Etiology with inherited as X linked effects males linked effects males

GG66PD activity in PD activity in in Red cells in Red cells Mostly in old cellsMostly in old cells

X LINKED X LINKED INHERITANCEINHERITANCE

CLINICALLY CLINICALLY

Neonatal JaundiceNeonatal Jaundice Acute hemolysis precipitected by Acute hemolysis precipitected by

Drugs Drugs Infection Infection Naphthalene in moth balls Naphthalene in moth balls Intravascular hemolysis Intravascular hemolysis Fever, malaise, dark colored Fever, malaise, dark colored

urine urine

HEMOGLOBINOPATHIESHEMOGLOBINOPATHIES

These are red blood cell disorders These are red blood cell disorders which cause hemolytic anemia which cause hemolytic anemia because of because of Reduced or absent production Reduced or absent production

of Hb A(of Hb A( & & thalassemia) thalassemia) Production of abnormal Hb e.g. Production of abnormal Hb e.g.

sickle cell disease sickle cell disease

BETA THALASSEMIA BETA THALASSEMIA AUTOSOMAL RECESSIVEAUTOSOMAL RECESSIVE

Inherited disorder Inherited disorder characterized by absence or characterized by absence or decreased synthesis of beta decreased synthesis of beta globin chain of hemoglobin globin chain of hemoglobin

Normal Fetal Hb at different Normal Fetal Hb at different agesages

At birth – 70%At birth – 70% 5 weeks – 55%5 weeks – 55% 4 months – 10%4 months – 10% 5 month – 5%5 month – 5% At one year – (< 2%)At one year – (< 2%)

HETEROZYOUS SATEHETEROZYOUS SATE

Thalassemia MinorThalassemia Minor One normal betaglobin chain One normal betaglobin chain

gene and one beta-gene and one beta-thalassemia genethalassemia gene

HOMOZYGOUSHOMOZYGOUS

Thalassemia IntermediaThalassemia Intermedia 2 2 Thalassemia genes Thalassemia genes

Thalassemia MajorThalassemia Major 2 Beta thalassemia genes2 Beta thalassemia genes

PATHOPHYSIOLOGYPATHOPHYSIOLOGY

Beta Thalassemia minor Beta Thalassemia minor Most CommonMost Common Failure of one gene coding for beta Failure of one gene coding for beta

chainchain Alpha chain – production – normal Alpha chain – production – normal Alpha chain available combine with Alpha chain available combine with

beta chainbeta chain Hb A levels Hb A levels

Excess alpha chain – stimulates Excess alpha chain – stimulates production of delta chain – Hb Aproduction of delta chain – Hb A22

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

HbFHbF Poor oxygen deliverer and high affinity for Poor oxygen deliverer and high affinity for

OO22

Only functional Hb present is AOnly functional Hb present is A22 HypoxiaHypoxia

ErythropoetinErythropoetin

Stimulated marrow to maximumStimulated marrow to maximum

Extremedullary hematopaiesis Extremedullary hematopaiesis

Splenomegaly Splenomegaly

CLINICAL CLINICAL MANIFESTATIONSMANIFESTATIONS

Thalassemia MinorThalassemia Minor The Growth & Development The Growth & Development

is normalis normal Mild anemia Hb – 10 mg./dlMild anemia Hb – 10 mg./dl

Thalassemia IntermediaThalassemia Intermedia Symptomatic by 2 – 4 yrs Symptomatic by 2 – 4 yrs

of ageof age Mod anemiaMod anemia Thalassemic faciesThalassemic facies Growth failureGrowth failure Hepatosplenomegaly Hepatosplenomegaly JaundiceJaundice

THALASSEMIA MAJORTHALASSEMIA MAJOR

DETROIT PEDIATRICIANDETROIT PEDIATRICIAN

1925 THOMAS COOLEY (Cooley 1925 THOMAS COOLEY (Cooley

Anemia)Anemia)

Profound anemiaProfound anemia

SplenomegalySplenomegaly

Bony deformities Bony deformities

Greek word Thalasa SEA BloodGreek word Thalasa SEA Blood

Universally fatal Universally fatal diseasedisease

Is now converted into Is now converted into chronic illnesschronic illness

INCIDENCEINCIDENCE

3% of world’s population carry 3% of world’s population carry Thalassemia geneThalassemia gene

PAKISTANPAKISTAN Carrier rate 4-5%Carrier rate 4-5% Pathans 5.8%Pathans 5.8% Total No of patients 50,000-60,000Total No of patients 50,000-60,000 5000 – 6000 children are born each 5000 – 6000 children are born each

yearyear

THALASSEMIA MAJORTHALASSEMIA MAJOR

Born normal at birthBorn normal at birth Starts getting Starts getting

pale,fussy,irritablepale,fussy,irritable Starts refusing feeds Starts refusing feeds

INFANTINFANT

CHILDCHILD

CLINICAL FEATURECLINICAL FEATURE Bossing of skullBossing of skull Maxillary overgrowthMaxillary overgrowth Long faceLong face HepatosplenomegalyHepatosplenomegaly Bones become thinBones become thin Fractures may occurFractures may occur Heart failureHeart failure

ADOLESCENT ADOLESCENT

COMPLICATIONSCOMPLICATIONS

Iron OverloadIron Overload Darkening of skin(Iron stimulated Darkening of skin(Iron stimulated

melanin)melanin) CardiomyopathyCardiomyopathy EndocrinopathiesEndocrinopathies Infections (Hepatitis Infections (Hepatitis

A,B,C,Malaria,HIV)A,B,C,Malaria,HIV) Failure to thriveFailure to thrive Antibody formation(10%)AlloantibodiesAntibody formation(10%)Alloantibodies

LAB DIAGNOSISLAB DIAGNOSIS

Complete Blood CountComplete Blood Count RBC MorphologyRBC Morphology Hemoglobin Hemoglobin

ElectrophoresisElectrophoresis Serum Iron& Ferritin Serum Iron& Ferritin

levelslevels Imaging StudyImaging Study

IRON OVERLOAD LEAD TO IRON OVERLOAD LEAD TO

Liver fibrosisLiver fibrosis CardiomyopathyCardiomyopathy Dysfunction of endocrine organsDysfunction of endocrine organs DiabetesDiabetes Clinical Organ dysfunctionClinical Organ dysfunction Well transfused patient dies by 10-Well transfused patient dies by 10-

25 yrs if not chelated 25 yrs if not chelated

ADULTADULT

Fertility Fertility Ability to Reproduce and bare childrenAbility to Reproduce and bare children Reduce fertility due to iron overload Reduce fertility due to iron overload

Control iron levels Control iron levels Pregnancy monitoring, reproductive Pregnancy monitoring, reproductive

assistance and perinotologist assistance and perinotologist

40 cases reported40 cases reported

KEY MESSAGESKEY MESSAGES

Screen the PopulationScreen the Population Get The Blood TestedGet The Blood Tested Detect Thalessemia TraitsDetect Thalessemia Traits Prevent them from marrying other Prevent them from marrying other

thalassemia traitsthalassemia traits CounsellingCounselling Help the children & families with Help the children & families with

ThalassemiaThalassemia

THALASSEMIA THALASSEMIA

Healthy infants have four Healthy infants have four globin globin genes.genes. The manifestation of The manifestation of thalassemic thalassemic

syndromes depend on the number syndromes depend on the number of functional of functional globlin chains globlin chains

Deletion of 4 Deletion of 4 globin chains globin chains Hb Barts Hydrops fetalis Hb Barts Hydrops fetalis Fetal anemia – edema, ascitiesFetal anemia – edema, ascities Fetus dies in utero or within hours Fetus dies in utero or within hours

of deliveryof delivery

Deletion of three Deletion of three globin globin genes genes

(HbH disease)(HbH disease) Mild – moderate anemia Mild – moderate anemia

Deletion of one or two Deletion of one or two globin globin chains chains

thalassemia traitthalassemia trait Asymptomic Asymptomic Anemia is mild or absentAnemia is mild or absent

SICKLE CELL DISEASE SICKLE CELL DISEASE HbSSHbSS

Commonest genetic disorders in UK Commonest genetic disorders in UK in 2000 birthsin 2000 births

Blacks from tropical AfricaBlacks from tropical Africa

Etiology Etiology Point mutation in codon 6 of Point mutation in codon 6 of globin globin

chain which causes change in chain which causes change in aminoacid encoded from aminoacid encoded from Glutamine to ValineGlutamine to Valine

FORMSFORMS

Sickle cell anemiaSickle cell anemia SC diseaseSC disease Sickle Sickle thalassemia thalassemia

SICKLE CELL ANEMIA SICKLE CELL ANEMIA HbSSHbSS

Patients are hemozygons for Patients are hemozygons for Hbs i.e. virtually all their Hb Hbs i.e. virtually all their Hb is Hbsis Hbs

No HbA – no normal No HbA – no normal genes genes

SC DISEASESC DISEASE

Affected children Affected children inherit inherit

Hbs – one parent Hbs – one parent HbC- other parentHbC- other parent

SICKLE SICKLE THALASSEMIA THALASSEMIA

Affected children inheritAffected children inherit Hbs from – one parentHbs from – one parent thalassemia – trait – 2thalassemia – trait – 2ndnd parent parent No normal No normal -globin genes and most -globin genes and most

patients can make no Hb A so can patients can make no Hb A so can transmit Hb S to their offspringtransmit Hb S to their offspring

Symptoms are similar to those with Symptoms are similar to those with sickle cell anemia.sickle cell anemia.

SICKLE TRAITSICKLE TRAIT

Inheritance of HbS from one Inheritance of HbS from one parentparent

Normal Normal - globin gene – other - globin gene – other parentparent

40% of the Hb is HbS40% of the Hb is HbS Carriers of HbSCarriers of HbS AsymptomaticAsymptomatic

CLINICAL CLINICAL MANIFESTATIONSMANIFESTATIONS

Anemia 6 – 8 gm/dAnemia 6 – 8 gm/d JaundiceJaundiceVASO - OCCLUSIVE VASO - OCCLUSIVE

CRISESCRISESLate infancy Late infancy Hand – foot syndromeHand – foot syndrome Bones of limbs & spineBones of limbs & spine Cerebral & pulmonary Cerebral & pulmonary

infarction infarction Acute strokeAcute stroke

PRECIPITATING FACTORSPRECIPITATING FACTORS

Exposure to coldExposure to cold Dehydration Dehydration Excessive exerciseExcessive exercise StressStress HypoxiaHypoxia Infection Infection

ACUTE ANEMIAACUTE ANEMIA Hemolytic crisisHemolytic crisis Associated with infectionAssociated with infection Aplastic crisisAplastic crisis

By parvo virus infection By parvo virus infection complete or temporary caestion of complete or temporary caestion of

red blood cell productionred blood cell production Sequestration crisisSequestration crisis

Sudden splenic enlargementSudden splenic enlargement Abdominal painAbdominal pain Circulatory collapseCirculatory collapse

INFECTIONSINFECTIONS

Susceptibily to infections as Susceptibily to infections as pneumococcus & hemophitus pneumococcus & hemophitus influenzaeinfluenzae

Increased incidence of Bone Increased incidence of Bone infection by salmonellainfection by salmonella

Chronic sickling microinfarction in Chronic sickling microinfarction in spleenspleen

Neonatal Diagnosis – at birth Neonatal Diagnosis – at birth guthrie testguthrie test

Prenatal diagnosis by Prenatal diagnosis by chorionic villus sampling at chorionic villus sampling at the end of 1the end of 1ststtrimestertrimester

MANAGEMENT STEPSMANAGEMENT STEPS Regular red cell transfusionsRegular red cell transfusions

Chelation therapyChelation therapy

Growth monitoring and follow upGrowth monitoring and follow up

Management of complications Management of complications

Psychosocial support Psychosocial support

Splenectomy Splenectomy Bone marrow transplantationBone marrow transplantation Cord blood transplantationCord blood transplantation Drugs stimulating gamma chainsDrugs stimulating gamma chains Gene therapyGene therapy Prevention and antenatal Prevention and antenatal

diagnosisdiagnosis

MANAGEMENT STEPSMANAGEMENT STEPS

MULTI DISCIPLINARY MULTI DISCIPLINARY APPROACHAPPROACH

PediatricianPediatrician HematologistHematologist GynecologistGynecologist Physician Physician SurgeonSurgeon OphthalmologistOphthalmologist E NT SpecialistE NT Specialist Lab technicianLab technician PsychologistPsychologist psychiatristpsychiatrist

Social workerSocial worker Parents Parents PatientPatient