Study of Chediak-Higashi Syndrome

Investigations Into Chediak-Higashi Syndrome and Related Disorders

Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder characterized in its classical form by oculocutaneous albinism, a bleeding diathesis, recurrent infection due to abnormal neutrophil and natural killer cell function, and eventual progression to a lymphohistiocytic infiltration known as the accelerated phase . Death often occurs within the first decade as a result of infection or the development of the accelerated phase; bone marrow transplantation is curative except for the late occurrence of neurological deterioration. The basic defect is unknown, although it probably involves abnormal fusion or trafficking of intracellular vesicles. Patients with classical CHS have their disease due to mutations in the LYST gene, but mildly affected individuals have been reported whose genetic defect has not been defined. It is likely that these variants of CHS have abnormalities in proteins involved in the pathways responsible for vesicle fusion. Since the full clinical spectrum of CHS and its variants has not been characterized, and the underlying defects remain enigmatic, we plan to evaluate this group of patients clinically, biochemically, and molecularly, and perform cell biological studies on their fibroblasts, melanocytes, and transformed lymphoblasts. Routine admissions will be 5 days and may occur every two years, or required by changes in clinical symptomatology.

Study Overview

• Status: Recruiting
• Conditions: Chediak-Higashi Syndrome

Detailed Description

Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder characterized in its classical form by oculocutaneous albinism, a bleeding diathesis, recurrent infection due to abnormal neutrophil and natural killer cell function, and often progression to a lymphohistiocytic infiltration known as the accelerated phase . Death generally occurs within the first decade as a result of infection or the development of the accelerated phase; bone marrow transplantation is curative except for the late occurrence of neurological deterioration. However, our research has identified mildly affected individuals who present primarily with a neurological phenotype characterized by central and peripheral nervous system involvement. In addition, classical cases treated with bone marrow transplant (BMT) and surviving into adulthood usually develop neurological symptoms adding relevance to the study of pathophysiology of this disease outside of the hematological and immune systems. The only gene known to be associated with CHS is LYST; however, there are some patients with CHS in whom mutations have not been found, suggesting locus heterogeneity. A genotype-phenotype correlation had begun to emerge, but recent reports noted exceptions to this correlation. The basic defect is unknown, although it probably involves abnormal fusion or trafficking of intracellular vesicles. With regards to neurologic involvement, LYST likely also plays a role in neuronal axonal transport and neurotransmitter pools. We plan to evaluate individuals with CHS clinically, biochemically, and molecularly, and perform cell biological studies on their fibroblasts, melanocytes, and transformed lymphoblasts. Routine admissions may be 3-5 days and may occur every one to two years, or as required by changes in clinical symptomatology.

• Study Type: Observational
• Enrollment (Estimated): 60

Contacts and Locations

• Study Contact: Name: Wendy J Introne, M.D.; Phone Number: (301) 451-8879; Email: wi2p@nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients entering this study will have clinical features suggestive of CHS. Objective evidence of a platelet storage pool deficiency (e.g., an abnormal secondary aggregation response or absent platelet dense bodies) or of a lysosomal fusion abnormality (e.g., giant cytoplasmic granules in leucocytes) will not be required.@@@

Description

• ELIGIBILITY:

Patients will be between the age of 1 month and 70 years. All patients entering this study will have some degree of oculocutaneous albinism plus either a bleeding diathesis or a history of excessive infections in childhood. Objective evidence of a platelet storage pool deficiency (e.g., an abnormal secondary aggregation response or absent platelet dense bodies) or of a lysosomal fusion abnormality (e.g., giant cytoplasmic granules in leucocytes) will not be required.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Chediak-Higashi Syndrome; Confirmed or suspected patients with Chediak-Higashi Syndrome.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Delineate the clinical and laboratory findings of CHS and its variants.	Delineate the clinical and laboratory findings of CHS and its variants.	4-5 days every 1-2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mutation analysis of the LYST gene will be performed, to further delineate genotype/phenotype correlations and or locus heterogeneity.	Mutation analysis of the LYST gene will be performed, to further delineate genotype/phenotype correlations and or locus heterogeneity.	4-5 days every 1-2 years

Collaborators and Investigators

• Sponsor: National Human Genome Research Institute (NHGRI)
• Investigators: Principal Investigator: Wendy J Introne, M.D., National Human Genome Research Institute (NHGRI)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): September 10, 2002

Study Registration Dates

• First Submitted: June 16, 2000
• First Submitted That Met QC Criteria: June 16, 2000
• First Posted (Estimated): June 19, 2000

Study Record Updates

• Last Update Posted (Actual): January 5, 2024
• Last Update Submitted That Met QC Criteria: January 4, 2024
• Last Verified: July 28, 2023

More Information

Terms related to this study

• Keywords: Infection; Natural History; Albinism; Giant Granules; Melanosomes; Platelet Storage Pool Defect
• Additional Relevant MeSH Terms: Pathologic Processes; Immunologic Deficiency Syndromes; Immune System Diseases; Eye Diseases; Disease; Hematologic Diseases; Genetic Diseases, Inborn; Eye Diseases, Hereditary; Leukocyte Disorders; Phagocyte Bactericidal Dysfunction; Primary Immunodeficiency Diseases; Albinism; Syndrome; Chediak-Higashi Syndrome
• Other Study ID Numbers: 000153; 00-HG-0153

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: .This data will be deidentified.
• IPD Sharing Time Frame: While the study is open.
• IPD Sharing Access Criteria: All data sharing will be approved by the NHGRI Tech Transfer Office.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No