HEREDITARY ANEMIAS

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HEREDITARY ANEMIAS

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

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ANEMIA

• Defined as HB level below normal range
• Varies with age and sex of the individual
• Neonate Hb lt 14 g/dl
• 1-12 months Hb lt10 g/dl
• 1- 12 years Hb lt 11 g/dl

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• IMPAIRED RED CELL PRODUCTION
• Congenital Red cell aplasia
• Diamond Blackfan Anemia
• Fanconi Anemia

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INCREASED RED CELL DESTRUCTION

• Hemolytic Anemias

RED CELL MEMBRANE DISORDERS Hereditary
Spherocytosis RED CELL ENZYME
DISORDER Glucose 6 phosphate dehydrogenase
deficiency (G6PD) Hemoglobinopathies Sickle cell
disease Thalassemia
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LEARNING OBJECTIVES

• 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

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DIAMOND BLACKFAN ANEMIA

• Etiology
• Autosomal dominant 15
• Autosomal recessive 15
• Spradic 80
• FH 20

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ANEMIA
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CONGENITAL ANOMALIES
Short stature
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DIAGNOSIS

• Low Hb macrocyte
• Low reticulocyte Count
• Normal bilirubin
• Absent red cell precussors on narrow

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INHERITED APLASTIC ANEMIAS

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

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FANCONIS ANEMIA

• Short stature
• Abnormal radii thumbs
• Renal manifestation
• Pigmented skin lesion
• Increased chromosomal breakage of peripheral
  blood lymphocytes

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

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RED CELL MEMBRANE DISORDERS

• Hereditary spherocytosis
• Hereditary elliptocytosis

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HEREDITARY SPHEROCYTOSIS

• Autosomal dominant
• No F/H in 25 cases
• 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

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

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

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ENZYME DEFECTS

• Glucose 6 phosphate dehydrogenase (G6PD)
  deficiency
• Commonest red cell enzymopathy effecting over 100
  million people world wide
• G6PD in red cell essential for preventing
• Oxidative damage to red cells
• So cell lacking the enzyme are suseptible to
  oxidant induced hemolysis

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• Etiology with inherited as X linked effects males
  
• G6PD activity in ? in Red cells
• Mostly in old cells

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X LINKED INHERITANCE
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CLINICALLY

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

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HEMOGLOBINOPATHIES

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

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BETA THALASSEMIA AUTOSOMAL RECESSIVE

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

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• Normal Fetal Hb at different ages
• At birth 70
• 5 weeks 55
• 4 months 10
• 5 month 5
• At one year (lt 2)

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

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PATHOPHYSIOLOGY

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

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• Excess alpha chain stimulates production of
  delta chain Hb A2 ?
• 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.

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• HbF
• Poor oxygen deliverer and high affinity for O2
• Only functional Hb present is A2
• Hypoxia
• Erythropoetin
• Stimulated marrow to maximum
• Extremedullary hematopaiesis
• Splenomegaly

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CLINICAL MANIFESTATIONS

• Thalassemia Minor
• The Growth Development is normal
• Mild anemia Hb 10 mg./dl

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

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THALASSEMIA MAJOR

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

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• Universally fatal disease
• Is now converted into chronic illness

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INCIDENCE

• 3 of worlds population carry Thalassemia gene
• PAKISTAN
• Carrier rate 4-5
• Pathans 5.8
• Total No of patients 50,000-60,000
• 5000 6000 children are born each year

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THALASSEMIA MAJOR

• Born normal at birth
• Starts getting pale,fussy,irritable
• Starts refusing feeds

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INFANT
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CHILD
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CLINICAL FEATURE

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

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ADOLESCENT
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COMPLICATIONS

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

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LAB DIAGNOSIS

• Complete Blood Count
• RBC Morphology
• Hemoglobin Electrophoresis
• Serum Iron Ferritin levels
• Imaging Study

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IRON OVERLOAD LEAD TO

• Liver fibrosis
• Cardiomyopathy
• Dysfunction of endocrine organs
• Diabetes
• Clinical Organ dysfunction
• Well transfused patient dies by 10-25 yrs if not
  chelated

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ADULT

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

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KEY MESSAGES

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

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? THALASSEMIA

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

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• Deletion of three ? globin genes
• (HbH disease)
• Mild moderate anemia
• Deletion of one or two ? globin chains
• ? thalassemia trait
• Asymptomic
• Anemia is mild or absent

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SICKLE CELL DISEASE HbSS

• Commonest genetic disorders in UK in 2000 births
• Blacks from tropical Africa
• Etiology
• Point mutation in codon 6 of ? globin chain which
  causes change in aminoacid encoded from
• Glutamine to Valine

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FORMS

• Sickle cell anemia
• SC disease
• Sickle ? thalassemia

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SICKLE CELL ANEMIA HbSS

• Patients are hemozygons for Hbs i.e. virtually
  all their Hb is Hbs
• No HbA no normal ? genes

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SC DISEASE

• Affected children inherit
• Hbs one parent
• HbC- other parent

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SICKLE ? THALASSEMIA

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

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SICKLE TRAIT

• Inheritance of HbS from one parent
• Normal ? - globin gene other parent
• 40 of the Hb is HbS
• Carriers of HbS
• Asymptomatic

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CLINICAL MANIFESTATIONS

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

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PRECIPITATING FACTORS

• Exposure to cold
• Dehydration
• Excessive exercise
• Stress
• Hypoxia
• Infection

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ACUTE ANEMIA

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

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INFECTIONS

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

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

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MANAGEMENT STEPS

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

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MANAGEMENT STEPS

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

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MULTI DISCIPLINARY APPROACH

• Social worker
• Parents
• Patient

• Pediatrician
• Hematologist
• Gynecologist
• Physician
• Surgeon
• Ophthalmologist
• E NT Specialist
• Lab technician
• Psychologist
• psychiatrist