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Internal Medicine

Chediak-Higashi syndrome (CHS)

Extremely rare autosomal recessive immunodeficiency disorder leading to a decrease in phagocytosis.

  • Type of primary immunodeficiency

Salient features:

CHINA
  • Chediak-Higashi
  • Immunodeficiency
  • Neurologic manifestations
  • Oculocutaneous albinism
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(2020) Inherited Innate Immunodeficiencies (Immunology) Flashcards | Memorang. Retrieved February 07, 2020, from https://www.memorangapp.com/flashcards/29949/Inherited+Innate+Immunodeficiencies/

History:

Chediak-Higashi syndrome (CHS) was first described by Beguez-Cesar in 1943 in 3 siblings bearing the main clinical features of neutropenia and abnormal granules in leukocytes. Subsequently, Steinbrinck reported another case in 1948. Chediak, a Cuban haematologist, reported another case in 1952; [3] and in 1954, Higashi, a Japanese paediatrician, described a series of cases and found maldistribution of myeloperoxidase in neutrophilic granules of affected patients.


Classification

  • Classic CHS: Classic, early-onset form
  • Atypical CHS: Attenuated, later-onset form

Pathophysiology

Defect in long arm of chromosome 1:

  • Lysosomal trafficking regulator (LYST)
  • Chediak-Higashi syndrome  (CHS1) gene

Disruption of protein synthesis & storage and secretory functions of lysosomal granules
(of leukocytes, fibroblasts, dense bodies of platelets, azurophilic granules of neutrophils, and melanosomes of melanocytes)

Enlarged vesicles and non-functional lysosomes


Clinical features

Clinical quartet:

Clinically it is characterized by occulocutaneous albinism, photophobia, silver-grey hypopigmented hair and recurrent pyogenic infections particularly of the skin, respiratory tract and gastrointestinal tract due to functional abnormality of neutrophils.
  1. Partial oculocutaneous albinism
  2. Immunodeficiency
  3. Bleeding defects
  4. Peripheral neuropathy

Partial oculo-cutaneous albinism (OCA):

Decrease in skin & retinal pigments.
  • Silver/blonde hair with albinism

Other ophthalmologic symptoms:

  • Photophobia
  • Increasing red reflex
  • Horizontal/rotating nystagmus

Immunodeficiency: Recurrent infections

  • Organisms: Bacterial and fungal infections with staphylococcal, streptococcal, pneumococcal, and beta-hemolytic species being the most predominant
  • Sites: Skin and upper respiratory tract infections

Bleeding tendency (mild): Platelet-type

  • Epistaxis, mucosal or gum bleeding, and easy bruising

Neurologic manifestations (late symptom):

  • Peripheral neuropathy (M/C)
  • Sensory loss
  • Muscle weakness
  • Cerebellar ataxia
  • Cognitive impairment
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a, b Silvery gray hair and hypopigmentation of skin of the patient. Light microscopic examination of hair shaft of the patient (c) compared to normal hair (d) | Patne, S. C., Kumar, S., Bagri, N. K., Kumar, A., & Shukla, J. (2013). Chédiak-higashi syndrome: a case report. Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion, 29(2), 80–83. doi:10.1007/s12288-011-0130-y

Accelerated phase (85%):

Hemophagocytic lymphohistiocytosis associated with multi-organ inflammation characterized by fever, hepatosplenomegaly, lymphadenopathy, neutropenia, anaemia, and sometimes thrombocytopenia. It is caused by the inappropriate stimulation of the macrophages in the bone marrow and the lymphoid organs that leads to phagocytosis of blood cells and production of a large number of pro-inflammatory cytokines.
  • 90% mortality

Diagnosis

Complete blood count (CBC):

  • Neutropenia

Genetic testing:

  • LSYT & CSH1 genes

Peripherla blood smear (PBS):

  • Characteristic giant cytoplasmic granules in granulocytes
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Chédiak-Higashi Sindrome giant azurophilic granules in peripheral blood. A – Eosinophil; B – Lymphocyte; C – Neutrophil; D – Monocyte | de Azambuja, A. P., do Nascimento, B., Comar, S. R., Loth, G., Ribeiro, L. L., Bonfim, C., … Malvezzi, M. (2011). Four cases of Chédiak-Higashi syndrome. Revista brasileira de hematologia e hemoterapia, 33(4), 315–316. doi:10.5581/1516-8484.20110084

Bone marrow biopsy (FNAC):

  • Giant inclusion bodies in leukocyte precursors
  • Terminal phase: Non-malignant lymphohistiocytic infiltration of multiple organs (pseudolymphoma).
rbhh-33-315-g02
Chédiak-Higashi Sindrome giant azurophilic granules in bone marrow. A – Neutrophil and Monocyte; B – Neutrophils | de Azambuja, A. P., do Nascimento, B., Comar, S. R., Loth, G., Ribeiro, L. L., Bonfim, C., … Malvezzi, M. (2011). Four cases of Chédiak-Higashi syndrome. Revista brasileira de hematologia e hemoterapia, 33(4), 315–316. doi:10.5581/1516-8484.20110084

Hair/skin biopsy:

  • Clumped melanin granules

Differential diagnosis:

  • Oculocutaneous albinism
  • Hermansky Pudlak syndrome (specifically HPS-2)
  • Cross syndrome
  • Griscelli disease

Management

Supportive management:

  • High-dose vitamin C
  • G-CSF (for neutropenia)
  • Antimicrobial treatment (for infection)
  • Dental hygeine
  • Platelet transfusion (for severe bleeding)

Definitive treatment: Allogeneic hematopoietic stem cell transplantation (HSCT)

  • M/effective if performed before accelerated phase

Accelerated phase:

  • Combination therapy: Etoposide, dexamethasone, and cyclosporine

Summary:

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