Study of Chediak-Higashi Syndrome

• ClinicalTrials.gov Identifier: NCT00005917
• Recruitment Status: Recruiting
• First Posted: June 19, 2000
• Last Update Posted: May 23, 2023
• Sponsor: National Human Genome Research Institute (NHGRI)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Human Genome Research Institute (NHGRI) )

Study Description

Brief Summary:

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.

Condition or disease
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 Design

• Study Type: Observational
• Estimated Enrollment: 60 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Investigations Into Chediak-Higashi Syndrome and Related Disorders
• Actual Study Start Date: September 10, 2002

Groups and Cohorts

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

Outcome Measures

Primary Outcome Measures :

1. Delineate the clinical and laboratory findings of CHS and its variants. [ Time Frame: 4-5 days every 1-2 years ]
   Delineate the clinical and laboratory findings of CHS and its variants.

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 1 Month to 70 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• 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.@@@

Criteria

• 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.

Contacts and Locations

Contacts

Contact: Wendy J Introne, M.D.; (301) 451-8879; wi2p@nih.gov

Locations

United States, Maryland

National Institutes of Health Clinical Center; Recruiting

Bethesda, Maryland, United States, 20892

Sponsors and Collaborators

National Human Genome Research Institute (NHGRI)

Investigators

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

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

• Responsible Party: National Human Genome Research Institute (NHGRI)
• ClinicalTrials.gov Identifier: NCT00005917
• Other Study ID Numbers: 000153; 00-HG-0153
• First Posted: June 19, 2000
• Last Update Posted: May 23, 2023
• Last Verified: March 9, 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: .This data will be deidentified.
• Supporting Materials: Study Protocol
• Time Frame: While the study is open.
• Access Criteria: All data sharing will be approved by the NHGRI Tech Transfer Office.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Human Genome Research Institute (NHGRI) ):

Albinism; Giant Granules; Infection; Melanosomes; Platelet Storage Pool Defect; Natural History

Additional relevant MeSH terms:

Chediak-Higashi Syndrome; Syndrome; Disease; Pathologic Processes; Albinism; Eye Diseases, Hereditary; Eye Diseases; Phagocyte Bactericidal Dysfunction; Leukocyte Disorders; Hematologic Diseases; Primary Immunodeficiency Diseases; Genetic Diseases, Inborn; Immunologic Deficiency Syndromes; Immune System Diseases