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, it’s 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 :

Decreased erythrocyte Increased erythrocyte Blood loss Nonhematologic( p

or hemoglobin destruction allor without
production anemia )
Iron deficiency Hereditary spherocytosis Severe trauma* Respiratory failure*
Folic acid Elliptocytosis Meckel's diverticulum Shock*
Vitamin B12 deficiency Stomatocytosis Peptic ulcer Hypoglycemia*
Diamond-Blackfan anemia Pyknocytosis Idiopathic pulmonary Pheochromocytoma*
Fanconi's anemia G6PD deficiency hemosiderosis Skin edema
Aplastic anemia Pyruvate kinase deficiency Fair skinned complexion
Transient Sickle cell syndromes*
erythroblastopenia of
childhood (TEC)
Malignancy* Unstable hemoglobins
Thalassemias Autoimmune hemolytic
anemia*•
Sideroblastic anemia Isoimmune hemolytic anemia*
Lead poisoning Disseminated intravascular
coagulation*
Anemia of chronic disease Hemolytic uremic
syndrome*
Thrombotic thrombocytopenic
Purpura*
Cavernous hemangioma
(Kasabach Merritt syndrome)
 * 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 decreased
life
RBC Others
hematological threatening
production

increased RBC
blood loss
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 cow’s milk is most common cause of
nutritional iron deficiency in older infants and toddlers

Symptoms vary with severity of anemia—irritability, poor feed- ing, pallor, fatigue, pica,
cardiac decompensation

Testing—microcytosis, 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 children—intestinal malabsorption, Crohn disease, exocrine pancreatic

insufficiency, small bowel bacterial over- growth, Diphyllobothrium latum infestation, ileal
resection, intestinal bypass

Folate deficiency in children—inadequate 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 (ß-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 ß-globin production. Although ß-thalassemia is
often associated with Mediterranean ancestry, this disease and related disorders
(eg, E-ß 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

HS—variable 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 HE—most 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 testing—profound 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 Hemolysis

Twin-to-twin transfusions Different maternal blood

types or antigens, maternal
Chronic blood loss drug use, or neonatal
throughout pregnancy infections
Infant may have pallor and Microangiopathic hemolysis
microcytic, hypochromic may occur in infants with
anemia but appear otherwise thrombi, disseminated
well and hemodynamically intravascular coagulation,
stable. and Kasabach-Merritt
syndrome (multiple
Infants with acute blood loss
cavernous hemangiomas).
May have pallor, tachypnea,
tachycardia, hypotension,
and decreased tone
Normocytic, normochromic
anemia with a reticulocytosis
will be detectable soon after
birth.
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 toxicityIs 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 Possible etiology
Skin
Hyperpigmentation Fanconi's aplastic anemia
Petechiae, purpura Autoimmune hemolytic anemia with Thrombocytopenia, hemolytic-
uremic syndrome, bone marrow aplasia, bone marrow infiltration
Carotenemia Suspect iron deficiency in infants
Jaundice Hemolytic anemia, hepatitis, and aplastic anemia
Cavernous hemangioma Microangiopathic hemolytic anemia
Ulcers on lower extremities S and C hemoglobinopathies, thalassemia
Facies
Frontal bossing, prominence of the Congenital hemolytic anemias, thalassemia major, severe iron
malar and maxillary bones deficiency
Eyes
Microcornea Fanconi's aplastic anemia
Tortuosity of the conjunctival and S and C hemoglobinopathies
retinal vessels
Microaneurysms of retinal vessels S and C hemoglobinopathies
Cataracts Glucose-6-phosphate dehydrogenase deficiency, galactosemia with
hemolytic anemia in newborn period
Vitreous hemorrhages S hemoglobinopathy
Retinal hemorrhages Chronic, severe anemia
Edema of the eyelids Infectious mononucleosis, exudative enteropathy with iron deficiency,
renal failure
Blindness Osteopetrosis
Mouth
Glossitis Vitamin B12 deficiency, iron deficiency
Angular stomatitus  
Chest
Unilateral absence of the pectoral Poland's syndrome (increased incidence of leukemia)
muscles
Shield chest Diamond-Blackfan syndrome
Hands
Triphalangeal thumbs Red cell aplasia
Hypoplasia of the thenar eminence Fanconi's aplastic anemia
Spoon nails Iron deficiency
Spleen
Enlargement 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).
Age Lower limit of normal range of Hb
2. Hematocrit — The hematocrit is the (g/l)
fractional volume of a whole blood
sample occupied by red blood cells; it is 2 months 90
expressed as a percentage. As an
example, the normal HCT in a child age
2-6 95
6 to 12 years is approximately 40
months
percent (0.4 fraction).
Mean corpuscular volume — The mean 6 - 24 105
corpuscular volume (MCV) is measured directly months
by automated blood cell counters and represents 2 - 11 115
the mean value (in femtoliters, fL) of the years
volume of individual RBCs in the blood sample.
Values may be low (microcytic), normal > 12 years girls - boys - 130
(normocytic), or large (macrocytic). 120
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 MCV (95 percent confidence

limits)
As with hemoglobin and
Birth 98 to 118 hematocrit, the MCV varies with
age, necessitating the use of age-
1-3 days 95 to 121 adjusted normal values. In addition,
the measured MCV represents an
2 weeks 86 to 124 average value. If microcytic and
macrocytic red cells are present in
2 months 77 to 115
the peripheral blood as, for
3-6 months 74 to 108 example, in a patient with combined
iron deficiency and B12 deficiency,
0.5-2 years 70 to 86 the MCV may remain normal. Thus,
the peripheral smear should be
2-6 years 75 to 87 examined carefully to determine
6-12 years 77 to 95 whether the MCV reflects a single
population of red cells of uniform
12-18 years, females 78 to 102 size or two or more populations of
distinctly different size. The red cell
12-18 years, males 78 to 98 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. Treatment of compensated anemia is dictated by the cause of the anemia.
2. Patients with uncompensated anemia should be admitted to the hospital for
observation and possible transfusion.
3. Many patients with microcytic anemia or normocytic anemia have early iron-
deficiency anemia, and a course of supplemental iron is appropriate.
4. Specific treatment according to the cause.
5. 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)
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