RODAKS CHAPTER 26

severe combined immune deficiency (SCID)

a group of genetic immunodeficiencies affecting both cellular and humoral immunity

SCID common symptoms

marked decrease in circulating T cells
poorly functioning B cells
hypogammaglobinemia

gamma chain deficiency

most common form of SCID
caused by mutations in the IL2RG gene located at Xq13.1

adenosine deaminase

a key component of the metabolic breakdown of adenosine triphosphate and RNA

Wiskott-Aldrich Syndrome

- a rare X-linked diseased caused by one of more than 400 mutations in the WAS gene
- T cells are decreased, B, T and NK cells, neutrophils and monocytes are dysfunctional
- risk of bleeding due to thrombocytopenia and small abnormal platelets

22q11 Syndromes

- microdeletion in chromosome 22q11.2
- 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

Bruton Tyrosine Kinase Deficiency

a primary immunodeficiency disease characterized by reductions in all serum immunoglobulin isotypes and profoundly decreased or absent B cells

Chediak-Higashi Syndrome

- rare autosomal recessive disease of immune dysregulation
- mutation in the CHS1 LYST gene on chromosome 1q42.1-2 that encodes for a protein that regulates the morphology and function of lysosome-related organelles
- giant lysosomal granules in granulocytes, monocytes and lymphocytes
- fused granules

Pseudo-Chediak-Higashi

-cytoplasmic inclusions that resemble the fused lysosomal granules
- reported in patients with acute myeloid leukemia, chronic myeloid leukemia and myelodysplastic syndrome (MDS)

Congenital Defects of Phagocytes/ Congenital Neutropenias

- rare group of genetic diseases characterized by low neutrophil count
- 24 genes identified that causes CN

Leukocyte Adhesion Disorders (Defects of Motility)

- inability of neutrophils and monocytes to move from circulation to the site of inflammation (extravasation)

Defects of Respiratory Burst/ Chronic Granulomatous Disease

- rare condition caused by the decreased ability of neutrophils to undergo a respiratory burst after phagocytosis of foreign organisms

60%

How many percent is X-linked recessive for CGD?

40%

How many percent is autososomal recessive for CGD?

Chronic Granulomatous Defects

- caused by mutations in genes responsible for proteins that make up the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase

life-threatening catalase-positive bacterial and fungal infections

CGD patients are prone to what?

WHIM syndrome (warts, hypogammaglobulinemia, infections and myelokathexis syndrome)

- a defect in intrinsic and innate immunity
- results from mutation in the CXCR4 gene located at 2q22
- patients experience recurrent bacterial infections and are highly susceptible to human papillomavirus (HPV) infection, which leads to warts, can be widespread and resistant to treatment

Pelger-Huet Anomaly/True or Congenital PHA

- characterized by decreased nuclear segmentation and distinctive coarse chromatin clumping pattern
- affects all leukocytes
- a result of a mutation in the lamin B-receptor gene
- pince-nez morphology with the nuclei attached by a thin filament

Pseudo or Acquired Pelger-Huet Anomaly

- associated with severe bacterial infections, HIV, TB and mycoplasma pneumonia

True PHA

- all WBC lineages can be affected in terms of nuclear shape and chromatin structure

Pseudo-PHA

- phenomenon is restricted to neutrophils

Neutrophil Hypersegmentation

- neutrophils have more than 5 lobes
- often associated with megaloblastic anemia
- can also be seen in MDS where they represent a form of dysplasia

Alder-Reilly Anomaly

- a rare inherited disorder characterized by granulocytes (monocytes & lymphocytes less often) with large, darkly staining metachromatic cytoplasmic granules
- Reilly bodies also found in mucopolysaccharidoses

May-Hegglin Anomaly

- characterized by variable thrombocytopenia, giant platelets and large Dohle body-like inclusions in neutrophils, eosinophils, basophils and monocytes
- caused by mutation in the MYH9 gene on chromosome 22q12-13
- patients are mostly asymptomatic but a few have mild bleeding tendencies related to the degree of thrombocytopenia

Lysosomal Storage Diseases

- a group of more than 50 inherited enzyme deficiencies resulting from mutations in genes that code for the production of lysosomal enzymes
- causes cell dysfunction, cell death and a range of clinical symptoms

Mucopolysaccharidoses

- family of inherited disorders of mucopolysaccharide or glycoaminoglycan degradation
- caused by deficient activity of an enzyme necessary for the degradatio of dermatan sulfate, heparan sulfate, keratan sulfate and/or chondroitin sulfate

Gaucher Disease

- the most common of the lysosomal lipid storage diseases
- an autosomal recessive disorder caused by a defect or deficiency in the catabolic enzyme B-glucocerebrosidase (gene located at 1q21-q22) which is necessary for glycolipid metabolism

Niemann-Pick Disease

- characterized by an accumulation of fat in cellular lysosomes of vital organs which impairs function
- deficiency of lysosomal hydrolase enzyme acid sphingomyelinase (ASM)

Normal Absolute Neutrophil Count

2-7.7x10^9/L

Neutrophilia

- occur as a result of catecholamine-induced shift in neutrophils from the marginal pool
- as a result of increase in bone marrow production
-accompanied by left shift
- greater than 7.0x10^9/L in adults
- 8.5x10^9/L in children

Leukemoid reaction

- refers to a reactive neutrophilic leukocytosis greater than 50x10^9/L with a shift to the left
- usually caused by acute and chronic infections, metabolic disease or inflammation or occur as part of an inflammatory response to malignancy

Leukoerythroblastic reaction

simultaneous presence of immature neutrophils, nucleated red blood cells, and teardrop red blood cells

Neutropenia

- decrease in the ANC to less than 2.0x10^9/L in white adults
- 1.3x10^9/L in black adults

Agranulocytosis

refers to a neutrophil count of less than 0.1x10^9/L

What are causes of neutropenia?

1. increased rate of removal or destruction of peripheral blood neutrophils
2. fewer neutrophils released from the bone marrow to the blood because of decreases production or ineffective hematopoiesis, where neutrophils are present in the bone marrow but not released into circulation because they are defective
3. decreased ratio of circulating versus marginal pool of neutrophils
4. a combination of these

Eosinophilia

defined as absolute eosinophil count greater than 0.4x10^9/L

What are some causes of eosinophilia?

- parasitic infections
- allergic reactions, asthma, rhinitis, urticaria and atopic dermatitis, scabies, scarlet fever, HIV, primary biliary cirrhosis, hepatitis, autoimmune disorders, drug reactions and hematologic neoplasms

Eosipenia

absolute eosinophil count of less than 0.09x10^9/L
- reported in autoimmune diseases, steroid therapy, stress, sepsis and acute inflammatory states

Basophilia

- defined as an absolute count of greater than 0.15x10^9/L
- associated with chronic myeloid leukemia, allergic rhinitis, hypersensitivity to drugs or foods, chronic infections, hypothyroidism, chronic inflammatory conditions, radiation therapy and bee stings

Monocytosis

- absolute monocyte count greater than 1.0x10^9/L in adults
- greater than 3.5x10^9/L in neonates

Monocytosis is often the first sign of recovery of?

after myelosuppression

Monocytopenia

- defined as an absolute monocyte count of less than 0.2x10^9/L

Children between 2 weeks and 8-10 years of age have lower absolute lymphocyte counts than adults.

FALSE
- higher absolute lymphocyte count than adults

Lymphocytosis in children

- greater than 10.0x10^9/L

Lymphocytosis in adults

- greater than 5.0x10^9/L

T or F: Newborns have lymphocyte counts equal to adults.

TRUE

Lymphocytopenia

- defined as an absolute count of less than 2.0x10^9/L in children
- less than 1.0x10^9/L in adults

Primary immunodeficiency disorders

- a group of inherited diseases of the innate or adaptive immune system that often result in severe clinical manifestations

What are examples of severe combined immune deficiency that is characterized by defects in cellular and humoral immunity?

yc deficiency and adenosine deaminase (ADA)

Wiskott-Aldrich Syndrome

- a combined immunodeficiency disease with numerous hematologic and clinical findings and increased risk for leukemic transformation.

DiGeorge syndrome

is a disease characterized by a severe decrease in T cells, physical abnormalities, neurologic psychiatric issues, and hematologic manifestations.

Bruton tyrosine kinase (BTK) deficiency (X-linked agammaglobulinemia)

- results in a profound decrease in B cells, hypogammaglobulinemia, and severe, life-threatening infections

Chédiak-Higashi syndrome

an extremely rare condition affecting various cells in the body where granules fuse within lysosomes, disrupting normal function, leading to a wide range of serious clinical symptoms and early death

congenital neutropenias

manifest early in life as recurrent life-threatening bacterial and fungal infections with increased risk for leukemic transformation.

Leukocyte adhesion disorders

a result of impaired ability of neutrophils and monocytes to move to sites of infection. Clinical findings include recurring severe infections, organomegaly, and neurologic defects

Shwachman-Diamond syndrome

characterized by exocrine pancreatic insufficiency, digestive issues, infections, physical anomalies, neurologic defects, bone marrow failure, and increased risk of leukemia.

Chronic granulomatous disease

failure in the neutrophil respiratory burst after ingestion of organisms. Patients suffer from severe recurrent infections; however, advances in the use of antimicrobial agents have been effective at improving the clinical condition

Which of the following inherited leukocyte disorders is caused by a mutation in the lamin B receptor?
a. Pelger-Huët anomaly
b. Chédiak-Higashi disease
c. Alder-Reilly anomaly
d. May-Hegglin anomaly

a. Pelger-Huët anomaly

Which of the following inherited leukocyte disorders involves mutations in non-muscle myosin heavy-chain IIA?
a. Pelger-Huët anomaly
b. Chédiak-Higashi disease
c. Alder-Reilly anomaly
d. May-Hegglin anomaly

d. May-Hegglin anomaly

Which of the following inherited leukocyte disorders might be seen in Hurler syndrome?
a. Pelger-Huët anomaly
b. Chédiak-Higashi disease
c. Alder-Reilly anomaly
d. May-Hegglin anomaly

c. Alder-Reilly anomaly

Which of the following lysosomal storage diseases is characterized by macrophages with striated cytoplasm and storage of glucocerebroside?
a. Sanfilippo syndrome
b. Gaucher disease
c. Fabry disease
d. Niemann-Pick disease

b. Gaucher disease

The neutrophils in chronic granulomatous disease are incapable of producing:
a. Hydrogen peroxide
b. Hypochlorite
c. Superoxide
d. All of the above

d. All of the above

Individuals with X-linked SCID have a mutation that affects their ability to synthesize:
a. Deaminase
b. Oxidase
c. IL-2 receptor
d. IL-8 receptor

c. IL-2 receptor

An absolute lymphocytosis with reactive lymphocytes suggests which of the following conditions?
a. DiGeorge syndrome
b. Bacterial infection
c. Parasitic infection
d. Viral infection

d. Viral infection

What leukocyte cytoplasmic inclusion is composed of ribosomal RNA?
a. Primary granules
b. Toxic granules
c. Döhle bodies
d. Howell-Jolly bodies

c. Döhle bodies

The expected complete blood cell count (CBC) results for women in active labor would include:
a. High total white blood cell (WBC) count with increased lymphocytes
b. High total WBC count with a slight shift to the left in neutrophils
c. Normal WBC count with increased eosinophils
d. Low WBC count with increased monocytes

b. High total WBC count with a slight shift to the left in neutrophils

The expected complete blood cell count (CBC) results for women in active labor would include:
a. High total white blood cell (WBC) count with increased lymphocytes
b. High total WBC count with a slight shift to the left in neutrophils
c. Normal WBC count with increased eosinophils
d. Low WBC count with increased monocytes

c. Normal WBC count with increased eosinophils