Assistant Professor Dr. Akrem M. Atrushi Fanconi Anemia Assistant Professor Dr. Akrem M. Atrushi

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 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

Associated renal anomalies include aplasia, so-called 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 Idiopathic thrombocytopenic purpura (ITP) Acquired aplastic anemia Leukemia

Complications 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 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. Other cases are secondary to idiosyncratic reactions to Drugs such as phenylbutazone, sulfonamides, nonsteroidal anti-inflammatory 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.

Clinical &Lab Manifestations 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.

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 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 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

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 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 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 alpha-thalassemia 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 -a/-a or aa /- - 2 genes deleted • Haemoglobin is normal or slightly reduced • Reduced mean cell volume and mean corpuscular haemoglobin • No symptoms - -/ -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

• 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 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.