Non-Malignant, Hereditary

Disorders of Leukocytes
Inherited Abnormalities of Granulocyte Morphology
Nuclear Abnormalities
1. Pelger-Huet Anomaly
Hyposegmentation of the granulocytes
Increased density and coarseness of chromatin
Cytochemically and functionally normal

True Pelger-Huet Anomaly autosomal dominant, worldwide distribution

o Heterogeneous
Neutrophils either consists of two symmetric rounded lobes connected by
a fine filament
Fails to segment and thus resembles a peanut or dumbbell
pince-nez spectacles
Segmented beyond two lobes is uncommon
o Homogeneous
Rare
Nuclei remain round
Careful examination of the chromatin, which is coarse and densely
clumped, indicates that these cells are mature

2. Pseudo Pelger-Huet Anomaly

Commonly associated with malignant myeloproliferative disorders, including preleukemia or myelodysplastic syndromes
Been reported in patients with infections or tumors that have metastasized to the
bone
Acquired form
o Cells contain round nuclei such as those seen in the homozygotic form of
Pelger-Huet anomaly
o Cytoplasm of cells is frequently hypogranular

Cells should be reported as mature neutrophils

3. Hereditary Hypersegmentation

Autosomal dominant
Greater than 5 lobes
Mean of 4 lobes
Not associated with disease
o Not necessarily attributable to vitamin B12 deficiency and folate deficiency

Cytoplasmic Abnormalities
1. May Hegglin Anomaly
Rare syndrome
Leukopenia
Variable thrombocytopenia (40 80 X 109/L)
Giant platelets (hypogranular)
Gray-blue spindle-shaped inclusion in the cytoplasm of the granulocytes and
monocytes
Autosomal dominant
Resemble Dhle bodies but are larger and are present in cells other than neutrophils
Made up of dense fibrils thought to be messenger RNA
Bleeding time is prolonged and clot retraction is normal
Normal E, C, A aggregation tests
2. Alder Reilly Anomaly
Autosomal recessive trait
Presence of abnormally azurophilic granules resembling toxic granulation in the
cytoplasm of granulocytes
Granules may be seen in lymphocytes and monocytes
Do not affect function
Not seen consistently in the peripheral blood of patients exhibiting incomplete
expression of the anomaly but can be found on carseful examination of bone marrow
macrophage
May be seen in association with a group of storage disease in which
mucopolysaccharides accumulate in the cytoplasm of tissue and blood cells

Inherited Abnormalities of Granulocyte Function

1.

Job syndrome
Random movement of phagocytes is normal
Directional motility is impaired
Unknown mode of inheritance
Cells respond very slowly to chemotactic agents


2.

o Like the biblical Job, the patients suffer from persistent boils and recurrent cold
staphylococcal abscesses
Markedly increased IgE
Lazy Leukocyte Syndrome
Both random and directed movement of the cells are defective
Unknown mode of inheritance
Bone marrow reserves of granulocytes are normal
Release of cells from the marrow to the peripheral blood is poor
o Neutropenia
Cells fail to respond to inflammatory stimuli but otherwise appear to have normal
phagocytic and bacterial activity
o Low-grade fever
o Recurrent infections involving the gums, mouth, and ears

Defective Killing of Microorganisms

1. Chdiak-Higashi Syndrome
Giant cytoplasmic granules in the phagocytes and lymphocytes (basic defect may well
be in the Golgi complex)
Affects at least 6 species
o Man
o Mink
o Cattle
o Mice
o Cats
o Killer whales
Autosomal recessive trait
Albinism
Recurrent infections
Abnormally large lysosomes
Do not move well in response to chemotactic stimuli
Increased activity in the hexose monophosphate shunt
More intense respiratory burst
Abnormal granules in phagocytes are peroxidase positive, those in lymphocytes are
not
Routine coagulations studies are normal except bleeding time (prolonged)
2.

Congenital C3 Deficiency
Rare
Autosomal recessive
Heterozygous carriers - have the normal C3 activity

Homozygous carriers suffer from repeated severe infections with encapsulated

bacteria

3. Chronic Granulomatous Disease

Phagocytes ingest but cannot kill catalase-positive organisms because of the lack
of an appropriate respiratory burst
Drastic increase in oxygen uptake
Generation of a series of oxygen metabolites
o Hydrogen peroxide
o Superoxide
o Hydroxyl radical
o Singlet oxygen
Sex-linked
Autosomal recessive
4.

Glucose-6-Phosphate Dehydrogenase Deficiency

Similar to CGD
Impairs the hexose monophosphate shunt
Phagocytes are unable to produce a respiratory burst
Defective bacterial activity
Can cause anemia

5. Myeloperoxidase Deficiency
Autosomal recessive
Bacterial killing is slowed but complete

Inherited Disorders of the MonocyteMacrophage System

1. Mucopolysaccharidoses
Deficiencies in
o Hurler (Mucopolysaccharidosis I)
o Scheie (V)
o Hunter (II)
o Sanfilippo (III)
o Morquio or Morquio-Ullrich(IV) and Maroteaux-Lamy (VI)
Autosomal recessive except Hunter syndrome (sex-linked recessive)
Hunter and hurler syndrome Gargoylism
Presence of Alder-Reilly bodies

2. Lipidoses
Lipid storage diseases that are genetically determine and in which the macrophages
of one or more tissues become overloaded with lipid
Autosomal recessive except for Gaucher disease type II (inbred population)
o Highest incidence is seen in Ashkenazic Jews

a. Gaucher Disease
Most common of the lipidoses
Lack of beta-glucosidase
Macrophage accumulation of glucocerebrosidases in the spleen, liver, and bone
marrow

TYPE I
o Most common form
o adult form of the disease
o Splenomegaly
o Liver macrophages interfere with the circulation of blood through the sinusoids
o Liver function tents to deteriorate
o Bone pain most troublesome clinical problem from the patients standpoint
o CNS is not affected
o Most have normal life span
TYPE II
o Infantile or cerebral form
o More severe
o CNS is involved
o Neurologic deterioration progresses rapidly
o Death usually occurs within the first few years of life
o Gaucher disease

TYPE III
o Juvenile form
o CNS occasionally involved
o Hepatosplenomegaly and bone involvement develop rapidly
o Life expectancy is short
o Gaucher disease
o Leukopenia
o Thrombocytopenia
o Various degree of anemia (normochromic)
Gaucher cell
Large macrophage, small usually eccentrically placed nucleus

Cytoplasm is distended by glucocerebrosidases

Crumpled tissue paper
PAS positive
Serum acid phosphatase is increased

b. Niemann-Pick Disease
Abnormal accumulation of sphingomyelin and cholesterol in mononuclear phagocytic
cells and some parenchymal cells throughout the body because of a deficiency of
sphingomyelin
Five variants
o Differ on the basis of the particular isoenzyme involves and the severity of the
deficiency
Variant that develops in infancy
Most prevalent
Closely resembles the infantile form of Gaucher disease

Bone marrow contains numerous macrophages whose cytoplasm is swollen by

numerous small, uniform lipid droplets
foam cells

c. Sea-Blue Histiocytes
Syndrome marked by hepatosplenomegaly, thrombocytopenia, and accumulation in
the spleen and bone marrow of histiocytes filled with lipid-rich granules that stain
blue-green with polychrome stains such as Wright or Giemsa
Autosomal recessive
Highly familial incidence