Autosomal recessive disorder characterized by immunodeficiency, platelet dysfunction, and partial oculocutaneous albinism. It may present with axonal and demyelinating types of peripheral neuropathy that can be associated with central nervous system disorders.
Chediak-Steinbrinck-Higashi Syndrome; Beguez Cesar Syndrome.
First described in 1943 by Antonio Beguez Cesar, a Cuban pediatrician. Walter Steinbrinck, a German physician, Alexander Moises Chediak, a Cuban physician, and Otokata Higashi, a Japanese pediatrician, reported their findings in 1948, 1952, and 1953, respectively.
Approximately 500 cases have been described worldwide. A significant proportion of patients is of Spanish or South American descent.
Autosomal recessive and caused by mutations in the lysosomal trafficking regulator gene (LYST or CHS-1) that has been mapped to chromosome 1q42.3. Defective melanosome transfer is a secondary phenomenon of the primary defect affecting the LYST-protein, which is crucial for vesicle trafficking, membrane dynamics, and receptor signaling. Parental consanguinity is a risk factor. The majority of patients with CHS presents with severe disease in childhood. These patients have a functionally null-mutant LYST allele, whereas patients with onset in adolescence or adulthood have missense-mutant alleles that most likely encode CHS1 polypeptides with partial function.
The combination of recurrent and/or severe infections with pathological platelet aggregation tests and ophthalmologic anomalies (ie, nystagmus, strabismus, loss of binocular vision, photophobia, macular hypoplasia, and decreased iris pigmentation and visual acuity) should trigger further evaluations for CHS. Partial tyrosinase-positive oculocutaneous albinism with formation of giant melanosomes suggests that melanin is not distributed evenly. Giant peroxidase-filled lysosomal granules can be detected in leukocytes, lymphocytes, natural killer cells, Schwann cells, and in certain cells of liver, spleen, pancreas, and kidneys. In fact, the diagnosis depends on the presence of these giant lysosomal granules found in neutrophils and bone marrow cells. Prenatal diagnosis is possible on amniotic fluid cells.
Hypopigmentation affects the skin, hair, and eyes. In addition to these features of partial oculocutaneous albinism, patients with CHS show marked susceptibility to infections. The neutrophils are predominately affected, and the coalescence of their lysosomes to form giant granules seems to inhibit neutropoiesis and lead to intramedullary granulocyte destruction clinically detected as neutropenia. Furthermore, the content of proteases in neutrophils (particularly elastase and cathepsin G) is severely decreased. This neutrophil defect leads to decreased chemotaxis and incomplete degranulation and in combination with abnormalities of lymphocytes, natural killer cells, and monocytes results in an ineffective immune system. Death often occurs in the first decade of life as a result of overwhelming infection/sepsis or bleeding. However, survival into the second and third decade has been reported in milder cases. Approximately 85% of affected patients will develop a progression to an accelerated, lymphoma-like phase that can occur at any age ...