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Chédiak-Higashi syndrome (CHS) is a rare severe genetic disorder generally characterized by partial oculocutaneous albinism (OCA, see this term), severe immunodeficiency, mild bleeding, neurological dysfunction and lymphoproliferative disorder. A classic, early-onset form and an attenuated, later-onset form (Atypical CHS; see this term) have been described.
ORPHA:167Classification level: Disorder
Exact prevalence is difficult to determine; fewer than 500 cases have been reported. Many patients likely remain undiagnosed because of variability in clinical signs. No gender or ethnic predilection has been found.
Patients with CHS mostly have partial OCA involving the hair, skin, and eyes. Reduced iris pigmentation may be associated with nystagmus, and visual acuity may be impaired. Infections that are predominantly bacterial, but also of viral or fungal origin, begin to occur in infancy and may be severe, affecting primarily the skin and upper respiratory tract. Periodontitis has often been reported. Manifestations of increased bleeding tendency are generally mild and include epistaxis, gum bleeding and easy bruising. Cognitive deficits are often noted in childhood. Most patients develop neurological features by early adulthood as the disease progresses including ataxia, tremor, absent deep-tendon reflexes, and peripheral neuropathy. Some patients have Parkinsonian features with bradykinesia and rigidity. About 85% of CHS patients develop the accelerated phase, a lymphoproliferative disorder which involves fever, anemia, neutropenia, and occasionally thrombocytopenia, as well as lymphadenopathy and hepatosplenomegaly.
Loss-of-function mutations in the LYST lysosomal trafficking regulator gene (1q42.1-q42.2) are associated with the severe, childhood-onset form of CHS. Missense mutations appear to underlie the atypical form.
Diagnosis is suspected in individuals with partial OCA, a history of severe or frequent infections, and minor bleeding tendency. The main criterion is peroxidase-positive giant inclusions in white blood cells identified on the peripheral blood smear. Deficiency of platelet-dense bodies found via whole-mount electron microscopy is also characteristic. Molecular genetic testing supports diagnosis.
Differential diagnoses include oculocutaneous albinism, Hermansky Pudlak syndrome (specifically HPS-2 caused by mutations in AP3B1), Cross syndrome and Griscelli disease (see these terms).
Prenatal diagnosis of CHS is available clinically by amniocentesis or chorionic villus sampling and requires prior identification of the genetic mutation in the family.
CHS follows an autosomal recessive pattern of inheritance. Genetic counseling should be provided to asymptomatic carriers and to affected adults.
Management and treatment
The hematological and immunological manifestations can be treated by allogenic hematopoietic stem cell transplantation (HSCT) upon diagnosis. HSCT is more successful when performed before the accelerated phase, but does not alter progression of neurological dysfunction. Management of the acceleration phase involves combination therapy with etoposide, dexamethasone, and cyclosporine (the same as for familial hemophagocytic lymphohistiocytosis (HLH); see this term). Infections should be treated promptly with antibiotics or antivirals and exposure to infectious agents avoided. Desmopressin can be used for bleeding prophylaxis. Standard therapeutic measures should be adopted to improve visual acuity and to manage neurological manifestations. Patients should use sunscreen and wear protective UV sunglasses.
Without treatment, prognosis is very poor. Primary causes of mortality in the first 10 years of life are development of the accelerated phase and overwhelming infection. Neurologic manifestations occur in individuals despite bone marrow transplantation.