Review Question - QID 218386

This young boy who presents with a history of peritonsillar abscess, findings concerning for sepsis (hypotension and fever), albinism (white hair with minimal pigmentation), purulent soft tissue infection (exudative drainage from knee wound), and peripheral blood smear showing eosinophilic granules in neutrophils likely has Chediak-Higashi syndrome.

Chediak-Higashi syndrome is an immunodeficiency syndrome caused by phagocyte dysfunction. A defect in the lysosomal trafficking regulator gene (LYST) causes microtubule dysfunction, leading to problems with phagosome-lysosome fusion. This defect leads to dysfunction of phagocytes and impaired phagocytosis. The LYST gene and transporter mechanism is also implicated in the melanization of melanosomes. Because of these defects, Chediak-Higashi syndrome presents with recurrent pyogenic infections, especially of the skin and soft tissue. Infections with Streptococcus spp. and Staphylococcus spp. are common. Furthermore, dermatologic manifestations are common, and partial albinism may be a presenting sign (e.g., hypopigmentation of skin, eyes, and hair). Other features of the disease include progressive neurodegeneration and peripheral neuropathy. Diagnosis is made by evaluation of a peripheral blood smear, which will show eosinophilic peroxidase-positive giant granules in neutrophils and platelets. Treatment for Chediak-Higashi syndrome includes bone marrow transplant and treatment of infection; however, the prognosis is generally poor and the condition is usually fatal before age 10.

Sharma et al. reviewed the history and current management of Chediak-Higashi syndrome. They reported that there is important molecular interplay between LYST and other proteins that governs the size and number of lysosomes in a cell. They recommended further study into the cellular function of LYST in order to discover therapeutic targets for Chediak-Higashi syndrome.

Incorrect Answers:
Answer 2: Chronic granulomatous disease is a defect in phagolysosome function caused by defects in NADPH oxidase, which decreases the respiratory burst and impairs the function of neutrophils. Patients present with recurrent infections due to catalase positive organisms. This disease does not present with cytoplasmic granules on peripheral blood smear but instead is diagnosed with an abnormal dihydrorhodamine test.

Answer 3: Hyper-IgE syndrome (Job syndrome) is caused by a deficiency in Th17 cells due to a STAT3 mutation. This causes impaired recruitment of neutrophils to the site of infection. This disease would present with cold abscesses (due to impaired recruitment of neutrophils to sites of infection), abnormal dentition, eczema, and elevated IgE.

Answer 4: Leukocyte adhesion deficiency is caused by a defect in the LFA-1 integrin (CD18) protein on phagocytes, which causes impaired migration of phagocytes. This disorder presents with late separation of the umbilical cord and recurrent infection. It is diagnosed by increased numbers of circulating neutrophils and is distinguished from Chediak-Higashi syndrome as the deficiency is in the chemotaxis of neutrophils rather than their functioning.

Answer 5: Myeloperoxidase deficiency causes impaired generation of reactive oxygen species and impairs phagocyte neutralization of bacteria and other pathogens. It most commonly presents with recurrent Candidal infections.

Bullet Summary:
Chediak-Higashi syndrome presents with recurrent infections, albinism, and neurodegeneration and is diagnosed by visualizing eosinophilic granules in neutrophils on peripheral blood smear.