Transcript Fanconi Anemia

Fanconi Anemia
Assistant Professor
Dr. Akrem M. Atrushi
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It is is a syndrome characterized by defective DNA
repair that is caused by a variety of genetic mutations.
Inheritance is autosomal recessive, and the disease
occurs in all ethnic groups.
Hematologic manifestations usually begin with
thrombocytopenia or neutropenia and subsequently
progress over the course of months or years to
pancytopenia.
Typically the diagnosis is made between ages 2 and
10 years.
Clinical manifestations
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Thrombocytopenia may cause purpura, petechiae, and
bleeding
Neutropenia may cause severe or recurrent infections
Anemia may cause weakness, fatigue, and pallor.
Congenital anomalies are present in at least 50% of patients.
The most common include abnormal pigmentation of the skin
(generalized hyperpigmentation, café-au-lait or
hypopigmented spots), short stature with delicate features, and
skeletal malformations (hypoplasia, anomalies, or absence of
the thumb and radius
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Associated renal anomalies include aplasia, socalled horseshoe kidney, and duplication of the
collecting system.
Other anomalies are microcephaly,
microphthalmia, strabismus, ear anomalies,
and hypogenitalism.
Lab Findings
CBC:
*Thrombocytopenia or leukopenia typically occurs first
*Anemia follows over the course of months to years by and
progression to severe aplastic anemia.
*Macrocytosis is virtually always present
* Anisocytosis
Hb electrophoresis shows elevation in fetal hemoglobin levels
which is an important diagnostic clue.
Bone marrow reveals hypoplasia or aplasia.
Chromosomal study shows increased number of chromosome
breaks and rearrangements in peripheral blood lymphocytes
and this confirms the diagnosis
Differential Diagnosis
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Idiopathic thrombocytopenic purpura (ITP)
Acquired aplastic anemia
Leukemia
Complications
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Bleeding tendency
Recurrent infections
Endocrine dysfunction may include growth
hormone deficiency, hypothyroidism, or
impaired glucose metabolism
Increased risk of developing malignancies,
especially acute nonlymphocytic leukemia,
head and neck cancers, genital cancers, and
myelodysplastic syndromes
Treatment
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Attentive supportive care :
Patients with neutropenia who develop fever require prompt
evaluation and parenteral broad-spectrum antibiotics.
Transfusions in the management of thrombocytopenia, which
frequently becomes refractory to platelet transfusions as a
consequence of alloimmunization. Transfusions from family
members should be discouraged because of the negative effect
on the outcome of bone marrow transplantation.
Oxymetholone, is associated with hepatotoxicity, hepatic
adenomas, and masculinization, and is particularly
troublesome for female patients.
Successful bone marrow transplantation cures the aplastic
anemia
Acquired Aplastic Anemia
Acquired aplastic anemia is characterized by peripheral
pancytopenia with a hypocellular bone marrow.
 Approximately 50% of cases in childhood are idiopathic.
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Other cases are secondary to idiosyncratic reactions to
Drugs such as phenylbutazone, sulfonamides, nonsteroidal antiinflammatory drugs, and anticonvulsants.
Toxic causes include exposure to benzene, insecticides, and
heavy metals.
Infectious causes include viral hepatitis (usually non-A, non-B,
non-C), infectious mononucleosis, and human
immunodeficiency virus (HIV). In immunocompromised
children, aplastic anemia has been associated with human
parvovirus B19.
Immune mechanisms of marrow suppression are suspected in
most cases.
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Clinical &Lab Manifestations
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Weakness, fatigue, and pallor result from anemia;
petechiae, purpura, and bleeding occur because of
thrombocytopenia;
fevers due to generalized or localized infections are associated
with neutropenia. Hepatosplenomegaly and significant
lymphadenopathy are unusual
CBC shows anemia is usually normocytic, with a low
reticulocyte count. The white blood cell count is low, with a
marked neutropenia. The platelet count is typically below
50,000/ L, and is frequently below 20,000/ L.
Bone marrow aspiration and biopsy show hypocellularity,
often marked.
Treatment & Prognosis
Comprehensive supportive care :
*Febrile illnesses require prompt evaluation and
usually parenteral antibiotics.
*Red blood cell transfusions alleviate symptoms
of anemia.
*Platelet transfusions may be lifesaving, but they
should be used sparingly because many
patients eventually develop platelet
alloantibodies and become refractory to
platelet transfusions.
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Bone marrow transplantation is generally considered
the treatment of choice for severe aplastic anemia
when an HLA-compatible sibling donor is available
with long-term survival rate of greater than 80%.
Immunomodulation, usually with antithymocyte
globulin and cyclosporine is associated with sustained,
complete remissions in 65–80% of cases.
Both therapies are associated with an increased risk
of myelodysplastic syndromes, acute leukemia, and
other malignancies in long-term survivors.
Problem
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Rizgar is 19 months old male. He presented lastly
with 2 months history of poor feeding, ilsl health
pallor and jaundice. Abdominal examination revealed
mild distension of abdomen with splenomegaly.
What lab test is recommended the first?
What are the keys for its interpretation?
What is the type of the disease in this child?
What specific disease does he have?
What further tests will you recommend to reach that
diagnosis?
Hemolytic Anemias
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Hemolysis is defined by an increased rate of
red cell destruction with a shortening of the
normal life span of the cell from the normal
120 days to as little as a few days in severe
hemolysis
Hemolysis should be suspected as a cause of
anemia if an elevated reticulocyte count is
present
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The reticulocyte percentage can be corrected to
measure the magnitude of marrow production in
response to hemolysis as follows:
Reticulocyte index= Reticulocyt% X (observed
hematocrit / normal hematocrit) X 1 / μ
where μ is a maturation factor of 1–3 related to the
severity of the anemia as in the figure below
Hematocrit
μ
36-45
1
26-35
1.5
16-25
2
15 and below
2.5
Classification
1-Cellular Defects
Membrane Defects
*Hereditary spherocytosis
*Hereditary elliptocytosis
*Paroxysmal nocturnal hemoglobinuria
Enzyme Deficiencies
*G6PD deficiency
*Pyruvate kinase deficiency
Hemoglobin Abnormalities
*Thalassemia
*Sickle cell anemia
2- Extracellular Defects
Autoimmune hemolytic anemia
Fragmentation Hemolysis
*DIC
*TTP
*HUS
* Hypersplenism
Plasma Factors
*Liver disease
*Abetalipoproteinemia
*Vitamin E deficiency
*Wilson disease
Thalassemia
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The thalassemias are the most common genetic
disorder on a worldwide basis.
Children with thalassemia have a shorter red cell life,
fetal hemoglobin in their red cells until an older age
than normal, and red cells that are more sensitive to
oxidative stress.
The thalassaemias are classified as alpha or beta
thalassaemias,depending on which pair of globin
chains is synthesised inefficiently.
The different globin chains are coded for on either
chromosome 16 (alpha-like) or 11 (beta, delta and
gamma chains)
Alpha-Thalassemia
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Most of the -thalassemia syndromes are the
result of deletions of one or more of the alpha globin genes on chromosome 16.
Normal diploid cells have four alpha-globin
genes; thus the variable severity of the alphathalassemia syndromes is related to the number
of gene deletions
Types and manifestations
-a/aa 1 gene deleted
• Asymptomatic
• Minority show reduced mean cell volume and mean
corpuscular haemoglobin
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-a/-a or aa /- - 2 genes deleted
• Haemoglobin is normal or slightly reduced
• Reduced mean cell volume and mean corpuscular
haemoglobin
• No symptoms
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- -/ -a 3 genes deleted, Hb H disease
• Chronic haemolytic anaemia
• Reduced chain production with formation of 4 tetramers
(4 is termed Hb H)
• Hb H is unstable and precipitates in older red cells
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• Haemoglobin is 7-11 g/dl, though may be lower
• Reduced mean cell volume and mean corpuscular
haemoglobin
• Clinical features: jaundice, hepatosplenomegaly, leg ulcers,
gall stones, folate deficiency
 - -/- - 4 genes deleted, Hb Bart’s hydrops
• No chains produced
• Mainly , forms tetramers (4 Hb Bart’s)
• Intrauterine death or stillborn at 25-40 weeks or dies soon
after birth
Treatment
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Persons with a-thalassemia trait require no treatment.
Those with hemoglobin H disease should receive
supplemental folic acid and avoid the same oxidant
drugs that cause hemolysis in persons with G6PD
deficiency, because exposure to these drugs may
exacerbate their anemia.
The anemia may also be exacerbated during periods
of infection, and transfusions may be required.
Hypersplenism may develop later in childhood and
require surgical splenectomy.
Genetic counseling and prenatal diagnosis should be
offered to families at risk for hydropic fetuses.