LEUKOCYTE MORPHOLOGICAL ABNORMALITIES

GRANULOCYTES
NUCLEAR ABNORMALITIES
CYTOPLASMIC ABNORMALITIES
LYMPHOCYTES
MONOCYTES/MACROPHAGES
NUCLEAR ABNORMALITIES
HYPERSEGMENTATION/HYPERSEGMENTED NEUTROPHIL
HYPOSEGMENTED NEUTROPHILS
LE CELL
BARR BODY (SEX CHROMATIN)
HYPERSEGMENTATION/HYPERSEGMENTED NEUTROPHILS

 Normal neutrophils contain three to five lobes

that are separated by filaments
 Hypersegmented neutrophils have more than
five lobes and are usually larger than normal
neutrophils

 CLINICAL SIGNIFICANCE:
 Megaloblastic anemia
 Undritz anomaly  Hereditary neutrophil
hypersegmentation
 Myelodysplasia
HYPOSEGMENTED NEUTROPHILS
 Hyposegmentation of granulocyte nucleus
 Nuclei may appear:
 Round, ovoid (Homozygous Pelger-Huet)
 Bilobed forms the characteristic spectacle-like (“pince-nez”,
dumbbell, peanut) morphology with the nuclei attached by a
thin filament (Heterozyous Pelger-Huet)

 CLINICAL SIGNIFICANCE:
 Pelger-Huet anomaly
 Pseudo or Acquired Pelger-Huet anomaly
 Myelodysplastic syndrome
 Acute myeloid leukemia
 Myeloproliferative neoplasms
LE CELL
 Usually a neutrophil that has ingested the antibody-
coated nucleus of another neutrophil or has engulf the
homogenous, globular nuclear mass of destroyed cell
 Presence of: ANTI-NUCLEAR ANTIBODIES, cell nuclei,
phagocytes with ingested material
 Usually mistaken with a tart cell (monocyte with an
ingested lymphocyte)

 CLINICAL SIGNIFICANCE:
 Systemic Lupus Erythematosus
 Connective tissue disorders
BARR BODY

Represents the 2nd X chromosome in

females
Seen in 2-3% of neutrophils
Characteristic “DRUMSTICK” appearance
of neutrophils
CYTOPLASMIC GRANULOCYTE ABNORMALITIES
 ALDER-REILLY GRANULES
 MAY-HEGGLIN GRANULES
 CHEDIAK-HIGASHI GRANULES
 AUER RODS
 REACTIVE CHANGES/SECONDARY MORPHOLOGICAL CHANGES
 TOXIC GRANULATION
 DOHLE-AMATO BODIES/DOHLE BODIES
 CYTOPLASMIC VACOULES
 PYKNOTIC AND NECROTIC CELLS
 CYTOPLASMIC SWELLING
 ABNORMAL INCLUSIONS
 ERHLICHIA AND ANAPLASMA
 HISTOPLASMA
ALDER-REILLY GRANULES
 Darkly staining metachromatic (purple-red) cytoplasmic
granules in granulocytes (less often in monocytes and
lymphocytes
 Abnormal large primary granules
 Granules contain degraded mucopolysaccharides due to an
enzyme defect
 May resemble toxic granules (seen in infections and toxic
states)

 CLINICAL SIGNIFICANCE:
 Alder-Reilly anomaly
 Mucopolysaccharidoses (MPSs)
MAY-HEGGLIN GRANULES
 Gray-blue spindle shaped inclusions in the cytoplasm
 Large Dohle body-like inclusions in neutrophils, eosinophils,
basophils, and monocytes
 The basophilic Dohle body-like leukocyte inclusions are
composed of precipitated myosin heavy chains (mRNA)
 True Dohle bodies consist of lamellar rows of rough
endoplasmic reticulum (rRNA)

 CLINICAL SIGNIFICANCE:
 May-Hegglin anomaly
CHEDIAK-HIGASHI GRANULES
 Giant red, blue, to grayish round inclusions in the
cytoplasm
 Giant lysosomal granules in granulocytes, monocytes, and
lymphocytes
 Cells in the body are affected and exhibit abnormally large
lysosomes, which contain fused dysfunctional granules
 CLINICAL SIGNIFICANCE:
 Chediak-Higashi syndrome

 Pseudo-Chediak-Higashi granules are cytoplasmic inclusions

that resemble the fused lysosomal granules in Chediak-
Higashi syndrome
 CLINICAL SIGNIFICANCE:
 Acute myeloid leukemia
 Chronic myeloid leukemia
 Myelodysplastic syndrome (MDS)
CHEDIAK-HIGASHI GRANULES
AUER RODS
 Pink or red shaped cytoplasmic granules; found in myeloid and monocytic series only
 Fused primary granules (Peroxidase stain positive)
 Faggot cells:
 Bundle of auer rods
 Seen in acute promyelocytic leukemia (APL) or M3; also associated with DIC

 CLINICAL SIGNIFICANCE:
 Acute myelogenous leukemia (AML, M1 and M2)
 Acute promyelocytic leukemia (APL, M3)
 Acute myelomonocytic leukemia (AMML, M4)
AUER RODS
 TOXIC GRANULATIONS
 Appears as dark, blue-black granules in the cytoplasm of neutrophils, usually in segmented and band forms
 Granulation may represent the precipitation of ribosomal protein (RNA) caused by metabolic toxicity within the
cells
 Are peroxidase positive and reflect an increase in acid mucosubstance within primary, azurophilic granules that
may enhance bactericidal activity
 The extent of toxic granulation is usually graded on a scale of 1+ to 4+, with 4+ being the most severe. Grading of
the granulation is dependent on the coarseness and amount of granulation within the cellular cytoplasm
 Primary granules are larger than secondary granules

 TOXIC GRANULATION CAN MIMIC GRANULATION FOUND IN ALDER-REILLY ANOMALY; one helpful defining
characteristic of toxic granulation is that in most cases, not all neutrophils are equally affected

 CLINICAL SIGNIFICANCE:
 Inflammations
 Infections
 Toxic states
 Burns
 Malignant disorders
DOHLE-BODIES/DOHLE-AMATO BODIES
 Are light/pale blue round or elongated cytoplasmic inclusions between 1-5 um consisting of remnants
of ribosomal ribonucleic acid (rRNA) arranged in parallel row; close to cellular membranes
 Are typically found in band and segmented neutrophils and can appear together with toxic granulations;
can be seen in eosinophils, basophils, monocytes, and lymphocytes
 Localized failure of cytoplasmic maturation
 PAS reaction positive
 A delay in preparing the blood film after collection may affect Dohle body appearance in that they are
more grey than blue or in some cases may not be visible
 Confused with May-Hegglin granules

 CLINICAL SIGNIFICANCE:
 Infections
 Pregnancy
 Burns
 Toxic states
CYTOPLASMIC VACUOLATIONS
 Less encountered than toxic granules and Dohle bodies
 Reflect phagocytosis, either of self (autophagocytosis) or of extracellular material

 TYPES:
 AUTOPHAGOCYTIC VACUOLES
 PHAGOCYTIC VACUOLES

 AUTOPHAGOCYTIC VACUOLES
 Tend to be small (approximately 2 um) and distributed throughout the cytoplasm
 Autophagocytosis can be induced by specimen storage in ethylene diamintetraacetic (EDTA) for more than 2
hours, autoantibodies, acute alcoholism, and exposure to high doses of Radiation

 PHAGOCYTIC VACUOLES
 Tend to be large (up to 6 um) and often accompanied by toxic granulation
 Induced by either bacteria or fungi are suggestive of sepsis
 When phagocytic vacuoles are seen, a careful examination sometimes reveals organisms within the vacuoles
PYKNOTIC AND NECROTIC CELLS
 Pyknotic nuclei in neutrophils generally indicate imminent cell death
 In a pyknotic nucleus, water has been lost and the chromatin becomes dense and dark; however, chromatin or
filaments can still be seen between nuclear lobes (depending on whether the cell is a band or segmented form)

 Necrotic nuclei are found in dead neutrophils/necrobiotic neutrophils; they are rounded nuclear fragments with no
filaments and no chromatin pattern
 Increased numbers of pyknotic or necrotic cells suggest that an extended amount of time has elapsed between blood
collection and blood film preparation

 CLINICAL SIGNIFICANCE:
 Bacterial infection
 Drug intoxication
PYKNOTIC AND NECROTIC CELLS
CYTOPLASMIC SWELLING
Is a result of osmotic swelling of the
cytoplasm or by increased adhesion to
the glass slide in stimulated neutrophils
Regardless of the cause, the result is a
variation in neutrophil size or
neutrophil anisocytosis
EHRLICHIA AND ANAPLASMA
 Are small, obligate, intracellular bacteria transmitted by ticks to humans and other vertebrate hosts
 These organisms grow as a cluster (morulae) in neutrophils and monocytes
 Morulae can be mistaken for Dohle bodies in neutrophils
 Neutrophils  Anaplasma phagocytophilum and rarely in Ehrlichia ewingii
 Monocytes  Ehrlichia chaffeensis
 Human granulocytic erlichiosis (HGE) is transmitted by the black-legged tick (Ixodes scapularis) and the western
black-legged tick (I. pacificus)
HISTOPLASMA
Histoplasma capsulatum is a fungus;
this organism lives intracellularly in
cells of the mononuclear phagocyte
system, cells of the bone marrow, or
cells from sputum or effusion
specimens
The fungus appears as a tiny oval body
with a clear halo surrounding a small
nucleus
LYMPHOCYTE ABNORMALITIES
 BASKET/SMUDGE CELL
 HAIRY CELL
 SEZARY CELL
 REED-STERNBERG CELL
 RIEDER CELL
 REACTIVE LYMPHOCYTE
 HAND-MIRROR LYMPHOCYTE
 ABNORMAL PLASMA CELLS
 FLAME CELL
 GRAPE CELL

MONOCYTE/MACROPHAGE ABNORMALITIES
 GAUCHER CELLS
 FOAM CELLS
BASKET/SMUDGE CELL
 Associated with degenerated nucleus or ruptured cell
in form or basket/smudge
 THUMBPRINT APPEARANCE
 FRAGILE LYMPHOCYTES that appear during smear
preparation; ARTIFACT  appear at the end of
smears

 Clinical significance: Chronic Lymphocytic leukemia

HAIRY CELL
 Hair like cytoplasmic projections surrounding the
nucleus (fried-egg appearance)
 Isoenzyme 5 (tartrate resistant is produced in
abundance in hairy cell leukemia)

 TRAP (Tartrate-resistant acid phosphatase) stain

positive

 Clinical significance: Hairy cell leukemia

SEZARY CELL

 Lymphocyte with a convoluted nucleus/brain-like

nucleus
 Presence indicates LEUKEMIC PHASE of mycosis
fungoides (Sezary syndrome)

 Clinical significance:
 Mycosis fungoides (cutaneous T-cell lymphoma)
 Sezary syndrome (Variant of mycoses fungoides)
REED-STERNBERG/RS CELLS
Abnormal lymphocyte with an “owl’s eye appearance”
Pathognomonic sign for Hodgkin’s lymphoma
Clinical significance: Hodgkin’s Lymphoma

RIEDER CELL
Lymphocyte with a clover leaf like nucleus
Clinical significance: Chronic lymphocytic leukemia
REED-STERNBERG CELL

RIEDER CELL
REACTIVE LYMPHOCYTE
 Reactive changes in lymphocyte morphology occur as lymphocytes are stimulated when interacting with antigens
in peripheral lymphoid organs
 AKA variant, atypical, transformed, effector, plasmacytoid, Turk cells, Downey, and immunoblasts
 B and T lymphocyte activation results in the transformation of small, resting lymphocytes into proliferating larger
cells
 Reactive lymphocytes often present as a heterogeneous population of various shapes and sizes
 A plasmacytoid lymphocyte is a type of reactive lymphocyte that has some morphologic features of plasma cells

 TYPES:
 Type I: Turk’s irration plasma cytoid; lymphocyte with a large block of chromatin
 Type II: also known as IM cells; round mass of chromatin (Ballerina skirt appearance)
 Type III: Vacuolated (swiss cheese appearance)

 CLINICAL SIGNIFICANCE:
 Infectious monucleosis
 Leukemias
 Viral infections
REACTIVE LYMPHOCYTE
REACTIVE LYMPHOCYTE
FLAME CELL
Abnormal plasma cell with red to pink
cytoplasm
Associated with increased
Immunoglobulins (usually IgA)
Inclusion: Russel bodies (individual bodies
of Immunoglobulin)

CLINICAL SIGNIFICANCE:
 Multiple myeloma
 Waldenstrom’s macroglobulinemia
GRAPE CELL

 Abnormal plasma cell with small colorless

vacuoles
 AKA Berry, Mott, Morula Cell
 Inclusions: Dutcher’s bodies (intranuclear
protein inclusions)
 Large protein globules giving appearance of
grapes: “Honeycomb appearance”

 CLINICAL SIGNIFICANCE:
 Multiple myeloma
 Reactive states
GAUCHER CELL
are distinctive macrophages, single or in
clusters; “CRUMPLED TISSUE APPERANCE”
Abundant fibrillar blue-gray cytoplasm with
a striated or wrinkled appearance
(sometimes described as onion skin-like)
Positive with trichrome, aldehyde fuchsin,
periodic acid-Schiff (PAS) and acid
phosphatase

CLINICAL SIGNIFICANCE:
 Gaucher’s disease
FOAM CELL
 Macrophages with cytoplasm packed with lipid-
filled lysosomes that appear as small vacuoles
(foam) after staining

 CLINICAL SIGNIFICANCE:
 Niemann-Pick’s disease

SEA-BLUE HISTIOCYTES
 Are macrophages with lipofuscin, glycophospholipid,
and sphingomyelin contained in cytoplasmic granules,
1 to 3 um in diameter, that appear blue with Wright
stain
NON-MALIGNANT LEUKOCYTE DISORDERS
Not caused by clonal or neoplastic changes in hematopoietic precursor cells
Causes can be genetic or acquired and involve one or more lineages: neutrophil,
lymphocyte, monocyte, eosinophil, and basophil, affecting the number of circulating
cells, morphology, or both
Many of these disorders are associated with significant clinical manifestations,
although some are benign in nature
 TYPES:
 QUALITATIVE NON-MALIGNANT
 QUANTITATIVE NON-MALIGNANT/REACTIVE STATES
QUALITATIVE NON-MALIGNANT LEUKOCYTE DISORDERS
MORPHOLOGICAL ABNORMALITIES INVOLVING NEUTROPHILS
DEFECTIVE LEUKOCYTE MOTILITY/MOVEMENT
DEFECTIVE RESPIRATORY BURST
LYSOSOMAL STORAGE DISORDERS
INHERITED DISORDERS OF LYMPHOCYTES
MORPHOLOGICAL ABNORMALITIES INVOLVING NEUTROPHILS

HYPERSEGMENTATION
ALDER-REILLY ANOMALY
MAY-HEGGLIN ANOMALY
CHEDIAK-HIGASHI SYNDROME
PELGER-HUET ANOMALY
PSEUDO/ACQUIRED PELGER-HUET
PELGER-HUET ANOMALY (PHA)
 Autosomal dominant disorder characterized by decreased nuclear segmentation and distinctive
coarse chromatin clumping pattern
 Affects all leukocytes, although morphologic changes are most obvious in mature neutrophils
 Mutations in the lamin B-receptor gene
 The lamin B receptor is an inner nuclear membrane protein that combines B-type lamins and
heterochromatin and plays a major role in leukocyte nuclear shape changes that occur during normal
maturation

 TYPES:
 HETEROZYGOUS PHA  normal individuals, pince-nez appearance of the nucleus
 HOMOZYGOUS PHA  cognitive impairment, heart defects, and skeletal abnormalities may occur
; single nuclei
ALDER-REILLY ANOMALY
 Is a rare inherited disorder characterized by granulocytes (monocytes and lymphocytes less often) with
large, darkly staining metachromatic cytoplasmic granules
 AR anomaly was initially reported in patients with gargoylism; however, it can be seen in otherwise
healthy individuals
 Granulations are also seen in mucopolysaccharidoses (MPSs)

MAY-HEGGLIN ANOMALY
 A rare, autosomal dominant disorder characterized by variable thrombocytopenia, giant platelets, and
large Dohle body-like inclusions in neutrophils, eosinophils, basophils, and monocytes
 Caused by a mutation in the MYH9 gene with disordered production of myosin heavy chain type IIA,
which affects megakaryocyte maturation and platelet fragmentation
CHEDIAK-HIGASHI SYNDROME
A rare autosomal recessive disease of immune dysregulation
Mutation in the CHS1 LYST gene
Many types of cells in the body are affected and exhibit abnormally large lysosomes,
which contain fused dysfunctional granules
Clinical manifestations begin in infancy with partial albinism and severe recurrent life-
threatening bacterial infections
Patients often have bleeding issues as a result of abnormal dense granules in platelets;
death occurs before the age of 10 years
MORPHOLOGICAL ABNORMALITIES INVOLVING NEUTROPHILS
DEFECTS IN MOTILITY/MOVEMENT
 JOB’S SYNDROME
 LAZY LEUKOCYTE SYNDROME
 LEUKOCYTE ADHESION DISORDERS (LADs)
 WHIM SYNDROME
JOB’S SYNDROME
Normal random movement ; abnormal CHEMOTACTIC/DIRECTIONAL MOTILITY
Patient suffer from persistent boils and recurrent “cold” staphylococcal abcesses
Associated with increased IgE

LAZY-LEUKOCYTE SYNDROME
Abnormal random and chemotactic movement
Cells failed to respond to inflammatory stimuli but have normal phagocytic and bactericidal
activity
LEUKOCYTE ADHESION DISORDERS (LADs)
Are rare autosomal recessive inherited conditions resulting in the inability of
neutrophils and monocytes to move from circulation to the site of inflammation
(called extravasation)
Consequences of these disorders are recurrent severe bacterial and fungal infections
Hematopoietic stem cell transplant is the only curative treatment

TYPES: LAD I, II, III, others (Shwachman-Bodian Diamond syndrome)

LEUKOCYTE ADHESION DISORDERS (LADs)
 LAD I
 Mutation in the ITGB2 gene ; gene that encodes CD18 subunit of b2 integrins, resulting in either a decreased or
truncated form of the b2integrin, which is necessary for adhesion to endothelial cells, recognition of bacteria,
and outside-in signaling
 Shortly after birth, patients suffer from recurrent infections, often affecting skin and mucosal infections
 Lymphadenopathy, splenomegaly, and neutrophilia are common findings
 LAD II
 Mutation in the SLC35C1 gene ; leukocytes have normal b2 integrins
 Defective fucose transporter and selectin synthesis
 Patients have recurring infections, neutrophilia, growth retardation, a coarse face, and other physical deformities
 LAD III
 Caused by mutations in Kindlin-3 ; Kindlin-3 protein along with talin are required for activation of b integrin and
leukocyte rolling
 Leukocytes and platelets have normal expression of integrins; however, there is failure in response to external
signals that normally results in leukocyte activation
 LAD III patients experience a mild LAD I-like immunodeficiency with recurrent infections
 Additionally, there is decreased platelet glycoprotein IIb/IIIa, resulting in bleeding similar to that seen in
Glanzmann’s Thrombasthenia
WHIM SYNDROME
 WHIM  warts, hypogammaglobulinemia, infections, and myelokathexis syndrome
 Defect in intrinsic and innate immunity
 Mutations in the CXCR4 gene
 CXCR4 protein regulates movement of white blood cells between the bone marrow and
peripheral blood
 Neutrophils accumulate in the bone marrow (myelokathexis), which results in low numbers of
circulating neutrophils
 In addition to neutropenia, lymphopenia, monocytopenia, and hypogammaglobulinemia are
present; as a result, patients experience recurrent bacterial infections and are highly susceptible
to human papillomavirus (HPV) infection, which leads to warts
DEFECTIVE RESPIRATORY BURST
CHRONIC GRANULOMATOUS DISEASE (CGD)
CONGENITAL C3 DEFICIENCY
G-6PD DEFICIENCY
MYELOPEROXIDASE (MPO) DEFICIENCY
 CHRONIC GRANULOMATOUS DISEASE (CGD)
 A rare condition caused by the decreased ability of neutrophils to undergo a respiratory burst after
phagocytosis of foreign organisms
 Can be X-linked recessive (60%) or autosomal recessive (40%)
 Caused by mutations in genes responsible for proteins that make up the reduced form of nicotinamide
adenine dinucleotide phosphate (NADPH) oxidase (NADPH oxidase deficiency)
 Patients experience life-threatening catalase-positive bacterial and fungal infections

 DETECTION OF RESPIRATORY BURST

 Chemiluminescense  uses dihydrorhodamine to measure intracellular production of reactive oxygen
species
 Nitroblue tetrazolium (NBT) test
 NBT is a yellow, water-soluble dye
 NORMAL PATIENTS: REDUCED NBT because of the generation of respiratory burst (+BLUE
FORMAZAN)
 PATIENTS WITH CGD: UNREDUCED (COLORLESS-YELLOW)
CONGENITAL C3 DEFICIENCY
 Autosomal recessive
 Heterozygous: Carriers have half the normal C3 activity (adequate for disease resistance)
 Homozygous: Repeated severe infections with encapsulated bacteria which are poorly recognized and
inefficiently phagocytized because of failure of opsonisation by C3

G-6-PD DEFICIENCY
 Absence affect the HEXOSE MONOPHOSPHATE SHUNT
 Leukocytes are unable to produce a respiratory burst, resulting in a DEFECTIVE BACTERICIDAL ACTIVITY
 G6PD is needed for the production of NADPH oxidase

MYELOPEROXIDASE (MPO) DEFICIENCY

 Autosomal recessive ; also known as ALIUS-GRIGNASHI ANOMALY
 MPO is low or absent in neutrophils and monocytes but not in eosinophils
 Absence of MPO slows down bactericidal killing
LYSOSOMAL STORAGE DISEASES (LSDs)
 Are a group of more than 50 inherited enzyme deficiencies resulting from mutations in genes
that code for the production of lysosomal enzymes
 The result is flawed degradation of phagocytized material and buildup of undigested substrates
within lysosomes
 This causes cell dysfunction, cell death, and a range of clinical symptoms; all cells containing
lysosomes can be affected
 LSDs are classified according to the underdegraded macromolecule that accumulates in the cell
 EXAMPLES:
 LIPID STORAGE DISEASE/SPHINGOLIPIDOSES
 MUCOPOLYSACCHARIDOSES
LIPID STORAGE DISEASES/SPHINGOLIPIDOSES
Are qualitative disorders involving monocytes and macrophages
The macrophages are particularly prone to accumulate undegraded lipid products,
which subsequently leads to an expansion of the reticuloendothelial tissue
EXAMPLES:
 GAUCHER’S DISEASE
 NIEMANN-PICK’S DISEASE
GAUCHER’S DISEASE
 Most common of the lysosomal lipid storage diseases ; at least 1 in 17 Ashkenazi Jews are carriers
 It is an autosomal recessive disorder caused by a defect or deficiency in the catabolic enzyme
beta-glucocerebrosidase
 Accumulation in sphingolipid glucocerebroside in macrophages throughout the body, including
osteoclasts in bone and microglia in the brain
 Bone marrow replacement by Gaucher cells contribute to anemia and thrombocytopenia

 Pseudo-Gaucher cells can be found in bone marrow of some patients with thalassemia, chronic
myeloid leukemia, acute lymphoblastic leukemia, non-Hodgkin lymphoma, and plasma cell
neoplasms
GAUCHER’S DISEASE
NIEMANN-PICK’S DISEASE
 Characterized by accumulation of sphingomyelin in cellular lysosomes in the liver, spleen, and
lungs
 Deficiency in the enzyme acid sphingomyelinase (ASM)
 Associated with foam cells and sea-blue histiocytes in the bone marrow
 TYPES:
 TYPE A NP
 TYPE B NP
 TYPE C NP

 TYPE A
 Acute neuronopathic form ; affects mostly Eastern European Jews
 <5% normal sphingomyelinase activity ; mutation in the SMPD1 gene
 Present in infancy and is associated with failure to thrive, lymphadenopathy,
hepatosplenomegaly, vision problems, and rapid neurodegenerative decline that results in
death, usually by 4 years of age
NIEMANN-PICK’S DISEASE
 TYPE B
 Non-neuronopathic form ; more common in individuals of Northern African descent
 10-20% normal enzyme activity ; mutation in the SMPD1 gene
 Presents in the first decade to adulthood with a variable clinical course
 Although there is no neurocognitive impairment, patients experience massive
hepatosplenomegaly, heart disease, and pulmonary insufficiency

 TYPE C
 Mutations in the NPC1 or NP2 gene
 Causes impaired cellular trafficking and homeostasis of cholesterol ; buildup of unesterified
cholesterol in lysosomes
 Clinical presentation in type C NP is heterogeneous with regard to age of onset and type
and severity of neurologic and psychiatric symptoms, as well as visceral involvement
 Prognosis in type C NP is poor, with most patients dying before the age of 25 years
OTHER LIPID STORAGE DISEASES
LIPID STORAGE DISEASES DEFICIENT ENZYME ACCUMULATED SUBSTANCE
TAY-SACH’S DISEASE
Hexosaminidase A GM2-gangliosides
SANDHOFF’S DISEASE
SANDHOFF’S DISEASE Hexosaminidase B Globosides
GM1-GANGLIOSIDOSIS GM1-Beta-Galactosidase GM1-gangliosides
FABRY’S DISEASE Alpha-Galactosidase Ceramide Trihexoside
METACHROMATIC
Arylsulfatase A Sulfatide
LEUKODYSTROPHY
KRABBE’S DISEASE Beta-Galactosidase Galactocerebroside
FARBER’S DISEASE Ceramidase Ceramides
MUCOPOLYSACCHARIDOSES
 Are a family of inherited disorders of mucopolysaccharide or glycoaminoglycan (GAG)
degradation
 Each MPS is caused by deficient activity of an enzyme necessary for the degradation of
dermatan sulfate, heparan sulfate, keratan sulfate, and/or chondroitin sulfate
 The partially degraded material builds up in lysosomes and results in serious physical and
cognitive problems and shortened survival
 Presence of Alder-Reilly bodies in neutrophils, monocytes, and lymphocytes ; macrophages in
the bone marrow can also demonstrate cytoplasmic metachromatic material
INHERITED DISORDERS OF LYMPHOCYTES
B-CELL DEFICIENCIES
 BRUTON-TYROSINE KINASE DEFICIENCY
 COMMON VARIABLE HYPOGAMMAGLOBULINEMIA
T-CELL DEFICIENCIES
 22q11 SYNDROMES
SEVERE COMBINED IMMUNODEFICIENCY DISEASE
 X-LINKED SCID
 ADENOSINE DEAMINASE DEFICIENCY
 WISKOTT-ALDRICH SYNDROME
 OTHERS
BRUTON-TYROSINE KINASE DEFICIENCY
 Also called as X-linked agammaglobulinemia, Bruton’s agammaglobulinemia
 Is a primary immunodeficiency disease characterized by reductions in all serum immunoglobulin isotypes
and profoundly decreased or absent B cells
 BTK deficiency is caused by a mutation in the gene encoding Bruton tyrosine kinase, resulting in decreased
production of BTK, which is important for B cell development, differentiation, and signaling
 Without BTK, lymphocytes fail to fully mature, leading to severe hypogammaglobulinemia and an
inability to produce specific antibodies
 Infants with BTK deficiency display symptoms between 4 and 6 months, once maternal antibodies have
cleared.; recurring life-threatening bacterial infections ensue
 Risk of fungal and viral (except enterovirus) infection is low because of normal T cell function

COMMON VARIABLE HYPOGAMMAGLOBULINEMIA

 One or a combination of immunoglobulins is either missing entirely or is synthesized in small quantities
 Inability of B-cells to mature to plasma cells which can be excessive production of T-suppressor cells
22q11 SYNDROMES
 All the disorders within the 22q11 deletion syndrome (mostly associated with the TBX1 gene) have variable
degrees of immunodeficiency because of the absence or decreased size of the thymus and low numbers of
T lymphocytes
 Associated with a broad range of problems such as cardiac defects, palatal abnormalities, distinctive facial
features, developmental delays, psychiatric disorders, short stature, kidney disease, and hypocalcemia
 Hematologic issues include thrombocytopenia and large platelets, autoimmune cytopenias, and increased
risk of malignancy
 Death rate is high usually before 1 year of age
 EXAMPLES:
 Nezelof’s syndrome
 DiGeorge syndrome
 Autosomal dominant Opitz GBBB
 Sedlackova syndrome
 Caylor cardiofacial syndrome
 Shprintzen syndrome
 Conotruncal anomaly face syndrome
SEVERE-COMBINED IMMUNE DEFICIENCY
 Gamma chain deficiency, or X-linked SCID, is the most common form of SCID and is caused by mutations in the IL2RG
gene
 IL2RG normally codes for the common gamma chain in leukocyte receptors that bind with interleukins 2, 4, 7, 9,
15 and 21 (provide growth, differentiation, and survival signals for B, T, and NK cells)
 Patients become symptomatic between 3 to 6 months of age as protective maternal immunoglobulins are
depleted, presenting without tonsils or lymph nodes along with severe life-threatening recurring infections
 Circulating T and natural killer (NK) lymphocytes are nearly absent; B cells are adequate in number but are
dysfunctional
 Children with gamma chain deficiency fail to thrive and death usually occurs before age 2 unless treatment with
hematopoietic stem cell transplant is successful
 Autosomal recessive adenosine deaminase deficiency represents 10% to 20% of SCID cases and is caused by one of
many mutations in the ADA gene
 ADA deficiency results in an intra- and extracellular accumulation of adenosine, which is lymphotoxic, leading to
profound decreases in T, B, and NK cells
 Patients experience a range of recurring, life-threatening bacterial, viral, and fungal infections beginning early in
life. In addition, there are skeletal abnormalities, neurologic deficits, and skin rashes
WISKOTT-ALDRICH SYNDROME
 Rare X-linked disease caused by one of more than 400 mutations in the WAS gene, which results
in decreased levels of WASp protein
 WASp is important in cytoskeletal remodeling and nuclear transcription in hematopoietic cells
 T cells are decreased; B cells, T cells and NK cells, neutrophils and monocytes are dysfunctional
which leads to bacterial, viral and fungal infections
 Risk of bleeding due to thrombocytopenia and small abnormal platelets
OTHER SCIDs:
 SEX-LINKED AGAMMAGLOBULINEMIA
 A defect in the helper cellular immune mechanism leading to agammagloulinemia
 Defect is seen only in boys
 SWISS-TYPE AGAMMAGLOBULINEMIA
 Autosomal recessive; involves loss of both T-cell and B-cell functions
 Little or no immunoglobulin is found in the blood; thymus is present but lacks lymphoid elements
 ATAXIA TELANGIECTASIA
 Autosomal recessive
 Ataxia: progressive loss of muscle coordination
 Telangiectasia: dilation of the small blood vessels
 Associated with peripheral blood lymphopenia, aplastic or hypoplastic thymus with minimal T-cell
population
 Decreased IgA and IgE, normal to increased IgG
 REACTIVE STATE ASSOCIATED CONDITIONS
NEUTROPHILIA  Acute inflammatory—collagen vascular, vasculitis
Absolute count: >7-8 x 10 9/L  Acute infectious—bacterial, some viral, fungal, parasitic
 Drugs, toxins, metabolic—corticosteroids, growth factors, uremia, Ketoacidosis
 Tissue necrosis—burns, trauma, MI, RBC hemolysis
 Physiologic—stress, exercise, smoking, pregnancy
 Neoplastic—carcinomas, sarcomas, myeloproliferative disorders
NEUTROPENIA  Drugs—cancer chemotherapy, chloramphenicol, sulfas/other antibiotics,
Absolute count: <1.75 – 1.80 x 10 9/L phenothiazines, benzodiazepine, antithyroids, anticonvulsants, quinine,
Most common type of leukopenia quinidine, indomethacin, procainamide, thiazides, Radiation
 Toxins—alcohol, benzene compounds
AGRANULOCYTOSIS  Intrinsic defects—Fanconi’s, Kostmann’s, cyclic neutropenia, Chédiak-Higashi
 Extreme neutropenia (<0.5)  Immune-mediated—collagen vascular disorders, RA, AIDS
 Infantile: Kostmann’s syndrome  Hematologic—megaloblastic anemia, myelodysplasia, marrow failure,
marrow replacement
 Infectious—any overwhelming infection
 Others—starvation, hypersplenism
EOSINOPHILIA  Allergic—urticaria, hay fever, asthma
Absolute count: >0.7 x 10 9/L  Inflammatory—eosinophilic fasciitis, Churg-Strauss syndrome
 Parasitic—trichinosis, filariasis, schistosomiasis
 Nonparasitic infections—systemic fungal, scarlet fever, chlamydial pneumonia of infancy
**eosinopenia: ACTH administration (Thorn’s  Respiratory—pulmonary eosinophilic syndromes (Löffler’s, tropical pulmonary eosinophilia), Churg-Strauss
Test) syndrome
 Neoplastic—CML, Hodgkin lymphoma, T cell lymphomas
 diopathic hypereosinophilic syndromes—affecting heart, liver, spleen, CNS, other organs
 Others—certain drugs, hematologic and visceral malignancies, GI inflammatory diseases, sarcoidosis,
Wiskott-Aldrich syndrome
BASOPHILIA
Absolute count: >0.3x109/L
MONOCYTOSIS
Absolute count: >0.9x109/L
LYMPHOCYTOSIS
Absolute lymphocyte count in:
 Adults: >4.0x109/L
 infants and young children:
>9.0x109/L
**CMV- resembles RS cells
 Myeloproliferative disease
 Allergic—food, drugs, foreign proteins
 Infectious—variola, varicella
 Chronic hemolytic anemia—especially post splenectomy
 Inflammatory—collagen vascular disease, ulcerative colitis
 Infectious—tuberculosis, subacute bacterial endocarditis, syphilis, protozoan,
rickettsial
 Recovery from neutropenia
 Hematologic—leukemias, myeloproliferative disorders, lymphomas,
multiplemyeloma
 Inflammatory—collagen vascular disease, chronic ulcerative colitis, sprue,
myositis, polyarteritis, temporal arteritis
 Others—solid tumor, immune thrombocytopenic purpura, sarcoidosis
 Infectious—many viral, pertussis, tuberculosis, toxoplasmosis, rickettsial
 Chronic inflammatory—ulcerative colitis, Crohn’s
 Immune mediated—drug sensitivity, vasculitis, graft rejection, Graves’, Sjögren’s
 Hematologic—ALL, CLL, lymphoma
 Stress—acute, transient
END