Hereditary

This category encompasses several rare, inherited disorders that affect the morphology and/or function of leukocytes, and have been listed in the WHO classification

Hereditary Anomalies of Leukocytes

Definition: A group of inherited disorders characterized by distinct morphological or functional abnormalities in leukocytes
Key Features
- Present from Birth: These abnormalities are present from birth and persist throughout life
- Typically Benign: Most are asymptomatic and do not cause significant clinical problems
- Recognizable Morphology: They are recognized by their distinctive morphological features on the peripheral blood smear
- Genetic Basis: Caused by mutations in specific genes
Importance of Recognition: Crucial for laboratory personnel to recognize these anomalies to avoid misdiagnosis of more serious conditions, such as myelodysplastic syndromes (MDS) or acute leukemia

Specific Hereditary Anomalies

Here’s a breakdown of the key hereditary anomalies, including their genetic basis, morphological features, clinical significance, and laboratory findings:

Pelger-Huët Anomaly (PHA)

Definition: A benign inherited disorder characterized by a high percentage of neutrophils with bilobed or unsegmented nuclei (hyposegmentation)
Genetic Basis:
- Autosomal dominant inheritance
- Most commonly caused by a mutation in the Lamin B Receptor (LBR) gene on chromosome 1q42.13
Pathophysiology: Mutation in LBR gene disrupts normal neutrophil nuclear segmentation. Remember that this is one of the later steps in maturation!
Morphological Features
- Increased number of neutrophils with bilobed or unsegmented nuclei
- Nuclei have a “pince-nez” or “dumbbell” shape
- Normal chromatin condensation
- Cells otherwise appear normal, and typically don’t have other qualitative features
- May see occasional unsegmented neutrophils (band forms)
- All neutrophils are affected (uniformity of findings)
Clinical Significance
- Benign and Asymptomatic: Does not cause any health problems
- Importance of Recognition: Must be distinguished from pseudo-Pelger-Huët anomaly, which is associated with more serious conditions like MDS
Laboratory Findings
- CBC: Normal WBC count
- Peripheral Blood Smear:
  - Increased percentage of neutrophils with bilobed or unsegmented nuclei
  - Normal neutrophils with 3-4 lobes may be present, but are less common than bilobed cells
  - Lack of toxic granulation or other dysplastic features
- Reticulocyte Count
- Family Testing: Not required for diagnosis but may be done to confirm hereditary nature of the abnormality
How to Distinguish From Pseudo-Pelger-Huët Anomaly: A “true” PHA usually occurs in all cell lines, is always present, and exhibits cells that are still properly shaped

May-Hegglin Anomaly (MHA)

Definition: A rare autosomal dominant disorder characterized by:
- Large, pale-blue inclusions (Döhle bodies) in neutrophils, eosinophils, basophils, and monocytes
- Thrombocytopenia (low platelet count)
- Giant Platelets (megathrombocytes)
Genetic Basis: Caused by mutations in the MYH9 gene, which encodes nonmuscle myosin heavy chain IIA
Pathophysiology
- Abnormal Myosin Heavy Chain: Affects normal platelet and leukocyte function
- Döhle Bodies: Consist of aggregates of abnormal myosin heavy chain
- Thrombocytopenia: Results from impaired platelet production and increased platelet destruction
Morphological Features
- Neutrophils, Eosinophils, Basophils, and Monocytes: Contain large, pale-blue, spindle-shaped or round inclusions (Döhle bodies)
- Platelets: Thrombocytopenia with giant platelets
- Easy to see on PBS at 40X lens strength
Clinical Features
- Mild to moderate bleeding tendencies:
  - Easy bruising
  - Nosebleeds
  - Prolonged bleeding after cuts or surgery
- Most patients are asymptomatic
Laboratory Findings
- CBC:
  - Thrombocytopenia (platelet count often between 50-100 x 10^9/L)
  - Normal WBC count
- Peripheral Blood Smear:
  - Döhle-like inclusions in neutrophils, eosinophils, basophils, and monocytes
  - Giant platelets (macrothrombocytes)
Treatment
- Usually supportive
- Avoid aspirin and other antiplatelet agents
- Platelet transfusions may be necessary for severe bleeding
- Desmopressin may be helpful in some cases
- Genetic counseling

Alder-Reilly Anomaly

Definition: A rare, inherited anomaly characterized by large, intensely staining granules in all types of leukocytes (neutrophils, lymphocytes, monocytes, eosinophils, and basophils)
Genetic Basis
- Autosomal recessive inheritance
- Caused by a deficiency in certain lysosomal enzymes involved in the degradation of mucopolysaccharides
Pathophysiology
- Lysosomal Storage Disorder: Deficiency of lysosomal enzymes leads to the accumulation of undigested mucopolysaccharides in lysosomes
- Granule Formation: The accumulated mucopolysaccharides form large granules that are visible in the cytoplasm of leukocytes
Morphological Features
- Large, intensely staining azurophilic (purple-red) granules in all types of leukocytes
- Granules are typically larger and more prominent than normal granules
- Distinction from Toxic Granulation: Alder-Reilly granules are present in all types of leukocytes, while toxic granulation is usually limited to neutrophils
Associated Conditions: Mucopolysaccharidoses (MPS), a group of inherited metabolic disorders:
- Hurler syndrome (MPS IH)
- Hunter syndrome (MPS II)
- Sanfilippo syndrome (MPS III)
- Morquio syndrome (MPS IV)
Clinical Features
- Related to Mucopolysaccharidoses
- Skeletal abnormalities
- Mental retardation
- Hepatosplenomegaly
- Corneal clouding
Laboratory Findings
- CBC: May be normal
- Peripheral Blood Smear:
  - Large, intensely staining granules in all types of leukocytes
- Bone Marrow Examination:
  - May show storage cells containing mucopolysaccharides
- Enzyme Assays:
  - Demonstrate deficiency of the specific lysosomal enzyme that is affected in the particular mucopolysaccharidosis
- Genetic Testing:
  - Can confirm the diagnosis and identify the specific mutation
Treatment
- Supportive care for the underlying mucopolysaccharidosis
- Enzyme replacement therapy is available for some MPS disorders
- Hematopoietic stem cell transplantation (HSCT) may be considered in some cases

Chédiak-Higashi Syndrome (CHS)

Definition: A rare autosomal recessive disorder characterized by:
- Giant granules in leukocytes, melanocytes, and other cells
- Partial albinism (skin and hair)
- Recurrent bacterial infections
- Neurological abnormalities
Genetic Basis: Caused by mutations in the LYST (also known as CHS1) gene, which regulates lysosomal trafficking
Pathophysiology
- Abnormal Lysosomal Trafficking: Defective LYST protein disrupts the normal fusion and trafficking of lysosomes and other organelles
- Giant Granule Formation: Leads to the formation of abnormally large granules in various cell types, including leukocytes, melanocytes, and nerve cells
- Impaired Function: The giant granules impair the normal function of these cells, leading to the clinical manifestations of the syndrome
Morphological Features
- Neutrophils, Eosinophils, Basophils, Monocytes, and Lymphocytes: Contain giant granules that stain with Wright-Giemsa stain
- The granules are often irregular in shape and size
Clinical Features
- Partial Albinism: Light skin and hair color due to abnormal melanosomes
- Recurrent Bacterial Infections: Due to impaired neutrophil chemotaxis and killing
- Neurological Abnormalities: Peripheral neuropathy, seizures, developmental delay
- Accelerated Phase: Some patients develop an accelerated phase characterized by uncontrolled lymphocyte proliferation, hepatosplenomegaly, lymphadenopathy, and pancytopenia
Laboratory Findings
- CBC:
  - May be normal or show neutropenia, thrombocytopenia, or anemia
- Peripheral Blood Smear:
  - Giant granules in leukocytes (neutrophils, eosinophils, basophils, monocytes, and lymphocytes)
  - Large platelets may be present
- Bone Marrow Examination:
  - May show giant granules in hematopoietic cells
- Microscopy of Skin and Hair:
  - Melanocytes contain large, abnormal melanosomes
- Genetic Testing:
  - Can confirm the diagnosis by identifying mutations in the LYST gene
Treatment
- Supportive Care:
  - Antibiotics to treat infections
  - Antiviral medications (e.g., acyclovir) for viral infections
- Hematopoietic Stem Cell Transplantation (HSCT):
  - The only curative treatment
  - Most effective if performed early in life, before the development of severe neurological complications
- Other Therapies:
  - Ascorbic acid (vitamin C) may improve some aspects of immune function
  - Interferon-gamma may reduce the frequency of infections

Laboratory Evaluation

Complete Blood Count (CBC) with Differential
- Used to assess the number and types of leukocytes in the blood
Peripheral Blood Smear Examination
- The most important test for identifying hereditary anomalies of leukocytes
- Careful examination of the smear morphology is essential for accurate diagnosis
Special Stains
- May be used to highlight specific features of the cells
Flow Cytometry Immunophenotyping
- Can be used to identify cell surface markers
Genetic Testing
- Used to confirm the diagnosis and identify the specific gene mutation

Key Terms

Hereditary Anomaly: An inherited disorder characterized by distinct morphological or functional abnormalities
Pelger-Huët Anomaly: Neutrophils with bilobed or unsegmented nuclei
May-Hegglin Anomaly: Döhle-like inclusions in leukocytes, thrombocytopenia, and giant platelets
Alder-Reilly Anomaly: Large granules in all leukocytes
Chédiak-Higashi Syndrome: Giant granules in leukocytes, partial albinism, and recurrent infections
Peripheral Blood Smear: A blood sample spread thinly on a slide for microscopic examination
Lysosomal Storage Disorder: A group of inherited metabolic disorders characterized by the accumulation of undigested materials in lysosomes

Plasma Cell

PLT Production