Chédiak-Higashi Syndrome

Chédiak-Higashi syndrome (CHS) is an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancedisorder caused by mutations affecting a lysosomal trafficking regulator protein. This protein plays a crucial role in the inability of neutrophils to kill phagocytosed microbes. Patients with CHS exhibit recurrent pyogenic infections, easy bleeding and bruising, and neurologic manifestations. The syndrome is also associated with oculocutaneous albinism Oculocutaneous albinism Albinism refers to a group of inherited disorders that result in the disruption of melanin production, causing hypopigmentation and visual impairment. The condition is classified according to the clinical phenotype. Oculocutaneous albinism results in hypopigmentation of the skin, eyes, and hair. Ocular albinism affects only the eyes. Albinism. The diagnosis is made based on analysis of the patient’s blood or bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow smear and genetic testing. The treatment of choice is allogeneic hematopoietic cell transplantation.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Epidemiology

  • Incidence: < 1 in 1 million people
  • < 500 cases reported worldwide
  • Most patients die before 10 years of age.

Etiology

  • Mode of inheritance: autosomal recessive
  • Gene: mutations in CHS1 (or LYST) gene
    • Encodes for a lysosomal trafficking regulator, which plays a role in trafficking materials into lysosomes
    • The exact role lysosomal trafficking regulator proteins play in killing off microbes in lysosomes is unknown.

Pathophysiology

  • Disruption in lysosomal function, maintenance, and trafficking → failure in phagolysosome formation → phagocytosed bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview are not destroyed by lysosomal enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
  • Additional effects:
    • Impaired chemotaxis
    • Melanocytes are unable to transfer melanin to keratinocytes → albinism Albinism Albinism refers to a group of inherited disorders that result in the disruption of melanin production, causing hypopigmentation and visual impairment. The condition is classified according to the clinical phenotype. Oculocutaneous albinism results in hypopigmentation of the skin, eyes, and hair. Ocular albinism affects only the eyes. Albinism
    • ↓ Platelet storage granules → impaired platelet aggregation → bleeding

Clinical Presentation

General signs and symptoms

Signs and symptoms that usually appear soon after birth include the following:

  • Oculocutaneous albinism Albinism Albinism refers to a group of inherited disorders that result in the disruption of melanin production, causing hypopigmentation and visual impairment. The condition is classified according to the clinical phenotype. Oculocutaneous albinism results in hypopigmentation of the skin, eyes, and hair. Ocular albinism affects only the eyes. Albinism (nonpigmented skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin, eyes, and hair)
  • Lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy
  • Gingivitis and periodontal disease
  • Oral ulcers
  • Bleeding:
    • Mucosal bleeding (e.g., gingival, epistaxis)
    • Easy bruising
  • Immunodeficiency: 
    • Severe and recurrent pyogenic sinopulmonary infections
    • Common organisms:
      • Staphylococcus Staphylococcus Staphylococcus is a medically important genera of Gram-positive, aerobic cocci. These bacteria form clusters resembling grapes on culture plates. Staphylococci are ubiquitous for humans, and many strains compose the normal skin flora. Staphylococcus aureus (most common)
      • Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus
      • Fungi Fungi Fungi belong to the eukaryote domain and, like plants, have cell walls and vacuoles, exhibit cytoplasmic streaming, and are immobile. Almost all fungi, however, have cell walls composed of chitin and not cellulose. Fungi do not carry out photosynthesis but obtain their substrates for metabolism as saprophytes (obtain their food from dead matter). Mycosis is an infection caused by fungi. Mycology: Overview
  • Late-onset neurological manifestations:
    • Central and peripheral neuropathies
    • Sensory loss
    • Muscle weakness
    • Parkinsonism
    • Cerebellar ataxia
    • Cognitive impairment
Hypopigmented eyes chediak-higashi syndrome

Hypopigmented eyes and eyelashes in a patient with oculocutaneous albinism Oculocutaneous albinism Albinism refers to a group of inherited disorders that result in the disruption of melanin production, causing hypopigmentation and visual impairment. The condition is classified according to the clinical phenotype. Oculocutaneous albinism results in hypopigmentation of the skin, eyes, and hair. Ocular albinism affects only the eyes. Albinism:
This may be seen in Chédiak-Higashi syndrome.

Image: “Eyes from a patient with OCA1A” by Karen G et al. License: CC BY 2.0

Accelerated phase

Chédiak-Higashi syndrome (CHS) can progress to the accelerated phase or lymphoma-like syndrome, where defective WBCs divide uncontrollably and undergo metastasis. Signs and symptoms include:

  • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
  • Jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice
  • Hepatosplenomegaly
  • Lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy
  • Pancytopenia
  • Abnormal bleeding
  • Profound immunodeficiency
  • Organ failure

Diagnosis

  • Peripheral blood smear: giant azurophilic granules can be seen in 
    • Neutrophils
    • Eosinophils
    • Granulocytes
  • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones marrow smear:
    • Shows “giant inclusion bodies” in leukocyte precursor cells 
    • Granules are peroxidase positive and contain lysosomal enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes.
  • Microscopic examination of hair:
    • Clumped melanin granules that are larger than those found in normal hairs 
    • Bright and polychromatic refringence pattern
  • Genetic testing for mutations in the LYST gene
  • Supporting laboratory evaluation:
    • Neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia 
    • Hypergammaglobulinemia

Management

  • Treatment of choice: allogeneic hematopoietic cell transplantation
  • Supportive management:
    • Treat infections with appropriate antibiotics
    • Routine immunizations
    • Platelet transfusions for serious bleeding
    • Management of the accelerated phase:
      • Corticosteroids
      • intravenous immunoglobulin (IVIG)
      • Chemotherapy (e.g., etoposide, methotrexate)
      • Splenectomy

Differential Diagnosis

  • Leukocyte adhesion deficiency type 1 Leukocyte adhesion deficiency type 1 Leukocyte adhesion deficiency type 1 (LAD1) is an inherited condition in which genetic mutations result in a lack of CD18 expression on neutrophils. These mutations lead to a decrease in the ability of neutrophils to migrate from the blood vessels to the site of injury or infection on recruitment, presenting as recurrent infections and delayed wound healing. Leukocyte Adhesion Deficiency Type 1: an inherited condition resulting in a lack of CD18 expression on neutrophils leading to a decrease in the ability of neutrophils to migrate from the blood vessels. Patients with this condition will have recurrent infections, delayed wound healing Wound healing Wound healing is a physiological process involving tissue repair in response to injury. It involves a complex interaction of various cell types, cytokines, and inflammatory mediators. Wound healing stages include hemostasis, inflammation, granulation, and remodeling. Wound Healing, and an elevated neutrophil count. The deficiency is not associated with oculocutaneous albinism Oculocutaneous albinism Albinism refers to a group of inherited disorders that result in the disruption of melanin production, causing hypopigmentation and visual impairment. The condition is classified according to the clinical phenotype. Oculocutaneous albinism results in hypopigmentation of the skin, eyes, and hair. Ocular albinism affects only the eyes. Albinism. The diagnosis is confirmed with flow cytometry demonstrating a deficiency in CD18. Hematopoietic stem cell transplant is the treatment of choice.
  • Chronic granulomatous disease Chronic Granulomatous Disease Chronic granulomatous disease (CGD), as the name implies, is a chronic disorder that is characterized by granuloma formation. This disorder is a consequence of defective phagocytic cells that are unable to produce bactericidal superoxide because of a defect in nicotinamide adenine dinucleotide phosphate (NADPH), the oxidase responsible for the respiratory burst in phagocytic leukocytes. Chronic Granulomatous Disease: a consequence of defective phagocytic cells. Patients will have recurrent infections, abscesses, and granulomatous lesions of multiple organs. Hypergammaglobulinemia may be seen. The diagnosis is made with neutrophil function testing for superoxide production. Antimicrobial prophylaxis, interferon gamma, granulocyte transfusion, and hematopoietic stem cell transplantation are potential management options.
  • Severe congenital neutropenia Severe congenital neutropenia Severe congenital neutropenia (SCN) affects myelopoiesis and has many different subtypes. SCN manifests in infancy with life-threatening bacterial infections. Severe Congenital Neutropenia: a rare disease resulting from genetic mutations that affect myelopoiesis. The condition manifests in infancy with life-threatening bacterial infections. Neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia is found on laboratory evaluation, often with an elevated monocyte count. A bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow biopsy will also aid in the diagnosis. Management includes granulocyte colony-stimulating factor and hematopoietic stem cell transplantation..
  • Myeloperoxidase deficiency Myeloperoxidase deficiency Myeloperoxidase (MPO) deficiency is an inherited or acquired disorder caused by mutations in the MPO gene on chromosome 17, leading to a deficiency of MPO in neutrophils and monocytes. This deficiency particularly impairs destruction of pathogens in phagolysosomes. Myeloperoxidase Deficiency: an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancedisorder that causes impaired microbial killing by phagocytes. The majority of patients are asymptomatic, while others can have recurrent, severe fungal infections. The diagnosis is made with histochemical staining for myeloperoxidase in neutrophils. There is no specific management for this condition, but patients should be treated for any infections.

References

  1. Nowicki, R.J. (2018). Chediak-Higashi syndrome. In Elston, D.M. (Ed.), Medscape. Retrieved March 23, 2021, from  https://emedicine.medscape.com/article/1114607-overview
  2. Boztug, K. (2021). Chediak-Higashi syndrome. In TePas, E. (Ed.), UpToDate. Retrieved May 3, 2021, from https://www.uptodate.com/contents/chediak-higashi-syndrome
  3. Fernandez, J. (2021). Chediak-Higashi syndrome. [online] MSD Manual Professional Version. Retrieved May 3, 2021, from https://www.msdmanuals.com/professional/immunology-allergic-disorders/immunodeficiency-disorders/ch%C3%A9diak-higashi-syndrome
  4. Ajitkumar, A., Yarrarapu, S.N.S., and Ramphul, K. (2021). Chediak Higashi syndrome. [online] StatPearls. Retrieved May 3, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK507881/

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