Chediak-Higashi Syndrome

CLINICAL CHARACTERISTICS

Chediak-Higashi syndrome (CHS) is characterized by partial oculocutaneous albinism (OCA), immunodeficiency, a mild bleeding tendency, and late adolescent- to adult-onset neurologic manifestations (e.g., learning difficulties, peripheral neuropathy, ataxia, and parkinsonism). While present in nearly all individuals with CHS, these clinical findings vary in severity. Of note, all individuals with CHS are at risk of developing neurologic manifestations and hemophagocytic lymphohistiocytosis (HLH). Individuals with severe childhood-onset presentations are considered to have "classic" CHS, whereas individuals with milder adolescent- to adult-onset presentations are considered to have "atypical" CHS. Because of the considerable overlap between classic CHS and atypical CHS, the disorder is best understood as a continuum of severe to milder phenotypes, with the universal feature being the pathognomonic giant granules within leukocytes observed on peripheral blood smear.

DIAGNOSIS/TESTING: The clinical diagnosis of CHS is established in a proband with suggestive clinical findings by identification of the pathognomonic giant granules within leukocytes on peripheral blood smear and/or biallelic pathogenic variants in on molecular genetic testing.

MANAGEMENT

The only targeted therapy currently available is hematopoietic stem cell transplantation (HSCT). HSCT can correct the hematologic and immunologic manifestations of CHS but does not appear to protect against the development of neurologic manifestations. Multidisciplinary care is recommended, including specialists in ophthalmology and low vision services, infectious disease for management and prevention, hematology (to manage the bleeding disorder, HSCT, and treatment of HLH), neurology and physiatry, physical therapy, occupational therapy, and (for children) neuropsychology or developmental pediatrics to address educational and emotional needs or (for adults) neuropsychology. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, routinely scheduled follow-up evaluations by the multidisciplinary specialists are recommended. Live vaccines given the risk of infection due to immunodeficiency; all nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen) given the risk of exacerbating the bleeding tendency. It is appropriate to evaluate the older and younger sibs of a proband as early as possible. Early diagnosis may provide the opportunity to perform HSCT prior to the development of HLH. Although data are limited, to date females with CHS report uneventful pregnancy, labor, and delivery. However, because of concerns about bleeding during delivery and the postpartum period, developing a plan prior to delivery to address this issue is recommended.

GENETIC COUNSELING

CHS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.