Kingdome of Saudi Arabia King Faisal University Ahsa College of Medicine Department of pediatrics

Differential Diagnosis of Child with pallor

Manal Mubarak AlQuaimi 207000989

Objectives : - Introduction - Definition - Classifications - History - Examination - Investigation - Clinical approach summaries

1.1.Introduction : The development of pallor can be acute and associated with a life-threatening illness, or it can be chronic and subtle, occasionally first noted by someone who sees the child less often than the parents. The onset of pallor can provoke anxiety for parents who are familiar with the descriptions of the presentation of leukemia in childhood. In some instances, only reassurance may be needed, as in the case of a light complexioned or fair- skinned, non-anemic child. In other instances, pallor may occur in patients with nonhematologic conditions such as shock, anaphylaxis, respiratory failure, or hypoglycemia. Even if there is a hematologic cause for the pallor, it often is a temporary condition readily amenable to therapy. However, pallor can portend a serious disease, and when onset is acute, it can herald a true pediatric emergency for which rapid diagnosis and treatment are needed. 1.2.Definition: It is yellowish discoloration of skin and mucous membrane due to presence of hemoglobin concentration below 8 to 9 g/dL (4.96 to 5.56 mmol/L), although the complexion of the child and the rapidity of onset may influence this value. The concentration of hemoglobin in the blood can be lowered by three basic mechanisms:

Decreased erythrocyte production Increased erythrocyte destruction Blood loss

Palloor Can be Generalized or Localized. Although generalized pallor affects the entire body, its most apparent on the face, conjunctiva, oral mucosa, and nail beds. Localized pallor commonly affects a single limb , finger or toe . This review article will focus on the generalized pallor. Table I : DDx of Pallor in children :
Increased erythrocyte destruction
Hereditary spherocytosis Elliptocytosis Stomatocytosis Pyknocytosis G6PD deficiency Pyruvate kinase deficiency Sickle cell syndromes* Unstable hemoglobins Autoimmune hemolytic anemia* Isoimmune hemolytic anemia* Disseminated intravascular coagulation* Hemolytic uremic syndrome* Thrombotic thrombocytopenic Purpura* Cavernous hemangioma (Kasabach Merritt syndrome)

Decreased erythrocyte or hemoglobin production

Iron deficiency Folic acid Vitamin B12 deficiency Diamond-Blackfan anemia Fanconi's anemia Aplastic anemia Transient erythroblastopenia of childhood (TEC) Malignancy* Thalassemias Sideroblastic anemia Lead poisoning Anemia of chronic disease

Blood loss

Nonhematologic( pallor without anemia )

Respiratory failure* Shock* Hypoglycemia* Pheochromocytoma* Skin edema Fair skinned complexion

Severe trauma* Meckel's diverticulum Peptic ulcer Idiopathic pulmonary hemosiderosis

* Life threatening. Potential causes of autoimmune hemolytic anemia include idiopathic, viral infection (eg, mononucleosis, influenza, coxsackie, measles, varicella, cytomegalovirus), bacterial infection (eg, Escherichia coli, Pneumococcus, Streptococcus, typhoid fever, mycoplasma), drugs, inflammatory and collagen vascular disease (eg, systemic lupus erythematosus), and malignancy.
2.1.Classification :

pallor

Common hematological

decreased life RBC threatening production

Others

blood loss

increased RBC destruction

2.2. Hematological Causes : The common hematologic conditions that result in pallor can be divided into decreased RBC production, increased RBC destruction, and blood loss ( According to the previous table I )

2.2.1. Decreased RBC production :

2.2.1.1.Iron deficiency anemia : Most common cause of childhood anemia Its usually develop after the age of 6 months , because Neonatal iron stores usually sufficient for the first 6 months of life .Diet exclusively of whole cows milk is most common cause of nutritional iron deficiency in older infants and toddlers Symptoms vary with severity of anemiairritability, poor feed- ing, pallor, fatigue, pica, cardiac decompensation Testingmicrocytosis, hypochromia (low MCV and mean cor- puscular hemoglobin [MCH]), anisocytosis, poikilocytosis, high reticulocyte count, low serum iron, and high total iron binding capacity (TIBC)

2.2.1.2.Megaloplastic anemia (B12 , folic acid ):caused by vitamin B12 and/or folic acid deficiency , Dietary deficiency in infants seen in breast-fed infants of strict vegans or infants of B12 deficient mothers with pernicious anemia . B12 deficiency in childrenintestinal malabsorption, Crohn disease, exocrine pancreatic insufficiency, small bowel bacterial over- growth, Diphyllobothrium latum infestation, ileal resection, intestinal bypass Folate deficiency in childreninadequate intake, intestinal mal- absorption (especially celiac disease), phenytoin, phenobarbital, methotrexate, liver disease Blood smear shows macrocytic red cells and large neutrophils with hypersegmented nuclei (megaloblasts) Check red cell folate, serum vitamin level, serum methylmalonic acid (B12 deficiency), serum homocystine (folate and B12 deficiency)

2.2.1.3.Acuired aplastic anemia : - The clinical presentation of aplastic anemia is variable and includes symptoms and signs related to cytopenia : fatigue, pallor, and cardiovascular complaints caused by progressive anemia; hemorrhagic manifestations secondary to thrombocytopenia; and/or fever, mucosal ulcerations, and bacterial infections resulting from neutropenia. -A diagnosis of AA is suggested by the presence of pancytopenia with absolute reticulocytopenia, suggestive of bone marrow failure. The condition is often idiopathic but

has been associated with exposure to certain drugs and chemicals (chloramphenicol, benzene, pesticides), radiation, and viral infections (especially hepatitis). 2.2.1.4 Thalassemia The production of the globin portion of the hemoglobin molecule is reduced or absent resulting in a compensating increase of other globin chains and reduced or absent production of adult hemoglobin A. Cooley's anemia (-Thalassemia major) presents with severe pallor usually between 6 and 12 months of age, as the fetal hemoglobin level declines but the normal rise in the adult hemoglobin (HbA) production fails to occur because of reduced or absent -globin production. Although -thalassemia is often associated with Mediterranean ancestry, this disease and related disorders (eg, E- thalassemia, HgH disease) also are seen commonly in children of Southeast Asian, Indian, Pakistani, and Chinese ancestry. The presence of hepatosplenomegaly and characteristic red cell morphology, including marked variation in red cell shape, makes this diagnosis readily apparent. 2.2.1.5. Fanconi anemia Fanconi anemia is characterized by pancytopenia and associated abnormalities, including hyperpigmentation and hypopigmentation, microcephaly, strabismus, small stature, intellectual disability (mental retardation), and abnormalities of the thumbs and radii. Unlike Diamond-Blackfan, all three cell lines of the bone marrow are affected, and the hematologic abnormalities rarely develop before three to four years of age. The anemia is normochromic and macrocytic. 2.2.1.6.Sideroblastic anemia Sideroblastic anemia is a disorder of hemoglobin synthesis resulting in hypoproductive state. This disorder is characterized by a microcytic, hypochromic anemia. Sideroblastic anemia may be inherited (sex-linked) or acquired. Iron use within the developing red cell is abnormal, accounting for the presence of diagnostic ringed sideroblasts in the bone marrow. The serum iron and ferritin levels usually are markedly elevated.

2.2.2. Increased RBC destruction :

2.2.2.1. Erythrocyte enzyme defects (G6PD) Erythrocyte enzyme defects such as pyruvate kinase deficiency and certain variants of glucose-6-phosphate dehydrogenase (G6PD), may be associated with pallor from increased red blood cell destruction. In G6PD deficiency, pallor may be accentuated by acute hemolytic crises after exposure to oxidant stress (eg, naphthalene-containing moth-balls, drugs,

acidosis). Although alterations in red cell morphology sometimes are found in these enzyme disorders, assays of specific enzymes or substrates are required for definitive diagnosis. 2.2.2.2. Hereditary spherocytosis (HS) An autosomal dominant abnormality of spectrin synthesis causes abnormal RBC shape, increases splenic sequestration, and decreases RBC survival HSvariable anemia, indirect bilirubin, splenomegaly, chronic hemolysis with hemolytic and aplastic crises, microspherocytes on blood smear, RBC osmotic fragility Hereditary elliptocytosis (HE)autosomal dominant disorder of RBC membrane skeletal proteins usually with mild symptoms HEmost severe in neonates with jaundice, hemolysis, anemia, bizarre RBC morphology, low MCV .Direct (DAT) and indirect (IAT) antiglobulin tests negative

2.2.2.3.Sickle cell anemia (SCD): Homozygotes for the sickle gene produce mostly Hb S. Deoxygenated Hb S polymerizes causing distorted red cell anatomy, blood viscosity, red cell survival, and a predisposi- tion to vaso-occlusion In heterozygotes (sickle cell trait) there is enough Hb A in red cells to prevent polymerization of Hb S Prevalence increased in Central African, Sicilian, Italian, Greek, Turkish, Saudi Arabian, and Indian ethnicity Symptoms gall stones, splenomegaly, functional asplenia, sepsis, osteomyelitis, meningitis, pain crises due to infarcts, stroke, acute chest syndrome, fat emboli, failure to thrive, priapism, aplastic crises . 2.2.2.4. Hemolytic uremic syndrome : Clinical triad of microangiopathic hemolytic anemia, thrombotic thrombocytopenia, and renal failure due to glomerular vascular injury Usually preceded by infection with Shiga toxin (vero toxin) producing strains of Shigella or Escherichia coli 0157:H7 which causes an initial bloody diarrhea bloody diarrhea Absorbed toxin causes endothelial damage resulting in platelet deposition and microvascular occlusion Other precipitants include cyclosporine A, human immunodefi- ciency virus (HIV), pneumococcal infection, genetic C3 com- plement or factor H deficiency High index of suspicion in any child with recent history of acute bloody diarrhea. The history of oliguria is easy to miss Laboratory testingprofound anemia, blood smear with microan- giopathiced red blood cells

(RBC) fragmentation, increased blood urea nitrogen (BUN) and creatine 2.2.3.Others : Red cell injury Thermal , Mechanical, Toxins, Infection,Copper toxicity and Hypophosphatemia Blood loss Neonates : 1. Occult bleeding prior to birth2. Obstetric accidents3. Internal hemorrhage4. Excessive blood sampling Infants, children, and adolescents : 1. Trauma2. Severe epistaxis or hemoptysis3. Gastrointestinal bleeding4. Excessive menstrual bleeding

2.2.3.2.Anemia In Newborn:

Classifying the cause into :

Blood loss Twin-to-twin transfusions Chronic blood loss throughout pregnancy Infant may have pallor and microcytic, hypochromic anemia but appear otherwise well and hemodynamically stable. Infants with acute blood loss May have pallor, tachypnea, tachycardia, hypotension, and decreased tone Normocytic, normochromic anemia with a reticulocytosis will be detectable soon after birth.

Hemolysis Different maternal blood types or antigens, maternal drug use, or neonatal infections Microangiopathic hemolysis may occur in infants with thrombi, disseminated intravascular coagulation, and Kasabach-Merritt syndrome (multiple cavernous hemangiomas).

2.3.Clnical evaluation :
2.3.1.History : Important questions in the histoty :
What is the child's diet like? Ask about consumption of milk. Early introduction of 'doorstep milk' causes microscopic bleeding from the gut. Excessive milk intake (>1 pint/day) after 12 months of age can reduce solid, and therefore iron, intake. Is the diet varied? Many young children are faddy about eating iron-rich foods. Ask about pica, a symptom of lead toxicity Is there any history of bleeding? What is the child's ethnic origin and is there consanguinity? Relevant for haemoglobinopathies What are the home conditions like? Could there be exposure to fumes or old lead paint?

Initial assessment of a child with pallor should include an immediate determination of the degree of illness. If the child with pallor is not acutely ill, a deliberate search for the cause of pallor should be undertaken. A thorough yet relevant history should be obtained with particular attention to the type of onset of pallor. The slow development of pallor, which may be noticed by a family member or friend who sees the child only occasionally, suggests diminished red cell production, as is found in iron deficiency or bone marrow aplasia. However, the acute onset of pallor is consistent with the brisk hemolysis found in autoimmune hemolytic anemia and often is accompanied by jaundice, dark urine, and cardiovascular changes. After establishing the type of onset of anemia, the history can be directed toward more narrow categories of anemia or specific diseases. A detailed dietary history, with particular attention to milk intake, is important in young children with suspected iron deficiency. Vitamin B12 deficiency may accompany strict vegetarian diets from which meat and egg products are excluded for many years and may occur in breast fed infants of vegetarian mothers or mothers with pernicious anemia. Sources of internal or external blood loss should be carefully sought. Chronic gastrointestinal (GI) bleeding may escape detection until iron deficiency anemia develops. Similarly, small pulmonary hemorrhages associated with idiopathic pulmonary hemosiderosis are often mistaken for other pulmonic processes until several recurrences of iron deficiency anemia suggest a hidden site of blood loss. If increased bruising or bleeding accompanies pallor, multiple blood elements are probably affected. The circulation time for platelets is short in comparison with that of red cells. Clinical findings of thrombocytopenia often are present by the time pallor develops in patients with acquired aplastic anemia, Fanconi anemia, and acute leukemia. The family history helps in the diagnosis of hemoglobinopathies and inherited disorders of red cell membranes and enzymes. Because results of previous hemoglobin testing may have been explained inadequately or recalled inaccurately, a negative family history or newborn screening for hemoglobinopathies should not preclude evaluation of the patient's hemoglobin phenotype if a sickling disorder is suspected. A history of splenomegaly, splenectomy, or early cholecystectomy in family members may help identify a hemolytic disorder such as hereditary spherocytosis or pyruvate kinase deficiency. Finally, a well-directed review of systems is essential in looking for systemic disorders such as chronic renal disease, hypothyroidism, or juvenile idiopathic arthritis 2.3.2. Physical examination : In the examination of the severely anemic patient, pallor of

the skin and mucous membranes usually is readily apparent. When anemia is less severe or when the skin color is dark, pallor may be appreciated only in the nailbeds and palpebral conjunctivae. Vital signs Blood pressure and pulse should be measured to be sure that hypovolemic shock and high output cardiac failure are neither present nor imminent. If anemia or volume loss is mild to moderate, tachycardia may be present, but normal blood pressure is preserved.

Eyes Scleral icterus suggests shortened red cell survival with hemolysis. Conjunctival pallor, although insensitive, is often noted when the hemoglobin falls below 10 grams/dL (6.21 mmol/L). Cardiac A systolic flow murmur is often heard when the hemoglobin level falls below 8 grams/dL (4.96 mmol/L). Lymph nodes and abdomen Lymphadenopathy and splenomegaly may suggest a malignancy or an infectious disease such as mononucleosis. When splenomegaly occurs without lymphadenopathy, however, attention is drawn to hemolytic disorders such as hereditary spherocytosis and autoimmune hemolytic anemia or hemoglobinopathies. Careful auscultation of the abdomen and head may detect hemangiomas of the viscera. The finding of an unusually large and firm spleen in the absence of increasing scleral icterus suggests that red cells are being sequestered.

Skin Lack of red color in the palmar creases is associated with a hemoglobin that is less than 7 grams/dL (4.34 mmol/L). The presence of large hemangiomas suggests microangiopathic anemia. Musculoskeletal Bony abnormalities associated with red cell disorders include frontal bossing from compensatory expansion of the bone marrow in hemolytic disease and radial and thumb anomalies found in some patients with Fanconi anemia.

Physical findings as clues to the etiology of anemia

Finding Skin Hyperpigmentation Petechiae, purpura Carotenemia Jaundice Cavernous hemangioma Ulcers on lower extremities Facies Frontal bossing, prominence of the malar and maxillary bones Eyes Microcornea Tortuosity of the conjunctival and retinal vessels Microaneurysms of retinal vessels Cataracts Vitreous hemorrhages Retinal hemorrhages Edema of the eyelids Blindness Possible etiology Fanconi's aplastic anemia Autoimmune hemolytic anemia with Thrombocytopenia, hemolyticuremic syndrome, bone marrow aplasia, bone marrow infiltration Suspect iron deficiency in infants Hemolytic anemia, hepatitis, and aplastic anemia Microangiopathic hemolytic anemia S and C hemoglobinopathies, thalassemia Congenital hemolytic anemias, thalassemia major, severe iron deficiency Fanconi's aplastic anemia S and C hemoglobinopathies S and C hemoglobinopathies Glucose-6-phosphate dehydrogenase deficiency, galactosemia with hemolytic anemia in newborn period S hemoglobinopathy Chronic, severe anemia Infectious mononucleosis, exudative enteropathy with iron deficiency, renal failure Osteopetrosis

Mouth Glossitis Angular stomatitus Chest Unilateral absence of the pectoral muscles Shield chest Hands Triphalangeal thumbs Hypoplasia of the thenar eminence Spoon nails Spleen Enlargement

Vitamin B12 deficiency, iron deficiency Poland's syndrome (increased incidence of leukemia) Diamond-Blackfan syndrome Red cell aplasia Fanconi's aplastic anemia Iron deficiency Congenital hemolytic anemia, leukemia, lymphoma acute infection, portal hypertension

2.3.3.Investigations :A complete blood cell count (CBC) with differential and a reticulocyte count is the first step in determining if pallor is due to a hematologic abnormality and, in the anemic patient, the likely cause. This should be followed by : blood film, coombs test, Hgb electrophoresis, UA, blood smear of parents, vitamin B12 or serum folate levels, osmotic fragility. Imaging studies and bone marrow aspirate are done when indicated. Hemoglobin and hematocrit Anemia may be defined as a reduction in red blood cell mass or blood hemoglobin concentration below the standard for age. In practice, anemia most commonly is defined by reductions in one or both of the following:
1.

Hemoglobin This is a measure of the concentration of the red blood cell (RBC) pigment hemoglobin in whole blood, expressed as grams per 100 mL (dL) of whole blood (or mmol/L). The normal value for HGB in a child age 6 to 12 years is approximately 13.5 g/dL (8.38 mmol/L). Hematocrit The hematocrit is the fractional volume of a whole blood sample occupied by red blood cells; it is expressed as a percentage. As an example, the normal HCT in a child age 6 to 12 years is approximately 40 percent (0.4 fraction). Age 2 months 2-6 months 6 - 24 months 2 - 11 years > 12 years Lower limit of normal range of Hb (g/l) 90 95 105 115 girls 120 boys - 130

2.

Mean corpuscular volume The mean corpuscular volume (MCV) is measured directly by automated blood cell counters and represents the mean value (in femtoliters, fL) of the volume of individual RBCs in the blood sample. Values may be low (microcytic), normal (normocytic), or large (macrocytic).

The MCV provides a quick, accurate, and readily available method of distinguishing the microcytic anemias (iron deficiency, thalassemia syndromes) from the normocytic (membrane disorders, enzyme deficiencies, autoimmune hemolytic anemia, most hemoglobinopathies) or macrocytic (bone marrow/stem cell failure, disorders of B12 and folic acid absorption or metabolism) anemias.

Mean corpuscular volume as a function of age in children Age Birth 1-3 days 2 weeks 2 months 3-6 months 0.5-2 years 2-6 years 6-12 years 12-18 years, females 12-18 years, males MCV (95 percent confidence limits) 98 to 118 95 to 121 86 to 124 77 to 115 74 to 108 70 to 86 75 to 87 77 to 95 78 to 102 78 to 98

As with hemoglobin and hematocrit, the MCV varies with age, necessitating the use of ageadjusted normal values. In addition, the measured MCV represents an average value. If microcytic and macrocytic red cells are present in the peripheral blood as, for example, in a patient with combined iron deficiency and B12 deficiency, the MCV may remain normal. Thus, the peripheral smear should be examined carefully to determine whether the MCV reflects a single population of red cells of uniform size or two or more populations of distinctly different size. The red cell distribution width (RDW) is elevated in the presence

of increased variation in red cell size. Other parameters used in Morphological classification: Mean corpuscular hemoglobin concentration The MCHC is a calculated index (MCHC =HGB/HCT), yielding a value of grams of HGB per 100 mL of RBC. Values in the normal range (33 to 34 g/dL), indicate that cells are normochromic, whereas values lower than normal indicate the presence of hypochromia. MCHC values vary depending upon the age of the child , with infants having a higher value than older children. MCHC also increases with decreasing gestational age. Red cell distribution width The red cell distribution width (RDW) is a quantitative measure of the variability of RBC sizes in the sample (anisocytosis). The RDW is a function of MCV and, therefore, normal values vary slightly with age. However, normal values generally are between 12 and 14 %. The RDW is especially helpful in differentiating iron deficiency from thalassemia in the pediatric patient with microcytic anemia. Patients with a RDW greater than 20 are more likely to have iron deficiency, whereas patients with normal RDW values are more likely to have thalassemia or the anemia of chronic disease .

2.3.4. APPROACH The initial approach to a patient with pallor includes determining if the patient is seriously ill and requires immediate supportive measures. Afterward, the history should be taken to determine if the pallor was acute or insidious in onset. A complete blood count with differential, mean corpuscular volume (MCV), and reticulocyte count will help further delineate the cause: Treatment Approach :
1. 2.

Treatment of compensated anemia is dictated by the cause of the anemia. Patients with uncompensated anemia should be admitted to the hospital for observation and possible transfusion. Many patients with microcytic anemia or normocytic anemia have early irondeficiency anemia, and a course of supplemental iron is appropriate. Specific treatment according to the cause. Consider admission if: Possible malignancy or infiltrative disorder Hb < 6 (including iron deficiency) Haemolysis Needs transfusion (Where possible defer transfusion until a definitive diagnosis is made)

3.

4. 5.

References : Websites: www.Uptodate.com, Evaluation of Pallor in Children, Authors: Char Witmer, MD, Catherine Books : textbook of pediatric emergency medicine 6th edition Pediatrics at glance (2002) Current essential pediatrics