Information on the following diseases can be found in the Related Disorders section of this report:

• Griscelli Syndrome (Chediak-Higashi Like Syndrome)
• Hermansky-Pudlak Syndrome
• Albinism

The symptoms of CHS are apparent during early infancy. The hair is typically blond or light brown with a silvery tint. Affected children may be abnormally sensitivity to light (photosensitivity) and exhibit rapid, involuntary, eye movements (nystagmus).

More important and more serious are the affects of CHS on the patient’s immune and nervous systems.

Symptoms involving the nervous system include an unsteady posture and walk (ataxia) and lack of sensation in the arms and legs (peripheral neuropathy), leading to obvious signs of physical weakness and disability. Symptoms involving the immune system include a predisposition to bruising and bleeding (bleeding diathesis), susceptibility to recurrent infections and a tendency to develop a lymphoma-like malignancy of the blood.

Children with Chediak-Higashi syndrome often have abnormally low levels of white blood cells (leukocytes) and platelets (thrombocytopenia) and may be susceptible to frequent bacterial and fungal infections of the skin, respiratory tract, and/or mucous membranes. These infections are frequently accompanied by abnormally high fever. Children with this disorder may bruise easily and tend to bleed excessively when injured. Organs of the body including the lungs, brain, kidneys, adrenal glands, and/or liver may have impaired function in some cases. Children with this disorder may be susceptible to cancers of the blood (leukemia) and lymphatic system (lymphoma).

Advanced symptoms of CHS may include general muscle weakness, poor growth, tingling or burning sensations in the arms and legs (peripheral neuropathy), the inability to coordinate movement (ataxia), skin ulcerations, an abnormally enlarged liver or spleen (hepatomegaly or splenomegaly), and/or enlarged lymph nodes (lymphadenopathy).
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Chediak-Higashi syndrome is inherited as an autosomal recessive genetic trait. The responsible gene has been mapped to chromosomal locus 1q42.1-q42.2 and is known as CHS1.

The abnormal gene affects the “traffic patterns” of proteins within the cells. Proteins (or enzymes) that are meant to go from one part of the cell to another are either misdirected or fail to be transported.

For example, a granule in which the skin pigment (melanin) is made is interfered with so that the pigment cannot be transported to the appropriate skin cell. Similarly, a defect in the transport of part of a white blood cell (wbc) renders the cell helpless in killing infective agents like viruses or bacteria and causing the immune problems.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 1q42.1” refers to band 42.1 on the long arm of chromosome 1. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are determined by the combination of genes for a particular trait which are on the chromosomes received from the father and the mother.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
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Chediak-Higashi syndrome is a very rare disorder that affects males and females in equal numbers. It is usually obvious at birth or shortly thereafter. There does not appear to be a higher risk for any particular ethnic or racial group.
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Symptoms of the following disorders can be similar to those of Chediak- Higashi syndrome. Comparisons may be useful for a differential diagnosis:

Griscelli syndrome, also known as Chediak-Higashi-Like syndrome, is a rare inherited disorder characterized by partial albinism and abnormalities of platelets and white blood cells. The symptoms are similar to those of CHS but without the severe immune abnormalities. If the immune system is involved, the consequences are far milder than in CHS. The CHS-like symptoms include a lack of color in the hair and eyes, abnormal sensitivity to light (photosensitivity), and rapid involuntary eye movements (nystagmus). On laboratory analysis, the white blood cells appear different from those of people with Chediak- Higashi syndrome. The relationship between these two disorders is not fully understood.

Hermansky-Pudlak syndrome is a rare inherited disorder characterized by lack of skin pigmentation (albinism), abnormal red blood cells, and the excessive storage of a fatty substance (ceroid) in various parts of the body. The symptoms of Hermansky-Pudlak syndrome include the lack of color in the skin, hair, and eyes, impaired vision, and excessive bleeding. Fatty deposits of ceroid in the lungs, intestines, heart, and/or kidneys may cause impaired function in many organs of the body. Frequently the first symptoms of Hermansky-Pudlak syndrome in a child include easy bruising, bleeding gums, nosebleeds, and excessive bleeding after surgery or injury. (For more information on this disorder, choose "Hermansky-Pudlak" as your search term in the Rare Disease Database.)

Albinism is a group of rare inherited disorders characterized by the absence at birth of color (pigmentation) in the skin, hair, and eyes. Albinism is also associated with certain syndromes that cause defects in the eyes (ocular abnormalities). The symptoms of albinism include white or pinkish-white skin. Children with oculocutaneous albinism may experience involuntary rhythmic movements of the eyes (nystagmus), distorted vision due to an irregular cornea (astigmatism), crossed eyes (strabismus), and/or nearsightedness (myopia). (For more information on this disorder, choose "albinism" as your search term in the Rare Disease Database.)
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Diagnosis
The diagnosis of Chediak-Higashi syndrome is usually made on the basis of the presence of ‘giant granules’ in microscopic analysis of white blood cells and red blood cells. The diagnosis is confirmed by bone marrow smears that show ‘giant inclusion bodies’ in the cells that develop into white blood cells (leukocyte precursor cells).

CHS can be diagnosed in an unborn child (prenatally) by examining a sample of hair from a fetal scalp biopsy or testing white blood cells (leukocytes) from a fetal blood sample.

Treatment
Treatment of Chediak-Higashi syndrome is symptomatic. When bacterial or fungal infections occur, they should be vigorously treated with antibiotic or antifungal drugs. Acute viral infections may be treated with the anti-viral drug acyclovir and prednisone. Transfusions of white blood cells (leukocytes) may also be useful in treating some infections. Whole blood transfusions may be necessary if bleeding becomes excessive after injury or surgery. If a blood cancer (lymphoma) develops, standard cancer therapy (i.e., vincristine) is indicated depending on the type and location of the malignancy.

People with Chediak-Higashi Syndrome should avoid exposure to sunlight as much as possible. When affected individuals are exposed to sunlight, sunglasses and creams which contain sunscreens applied to the skin can be helpful. Genetic counseling may be of benefit for people with Chediak- Higashi Syndrome and their families.
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Researchers are studying bone marrow transplantation from a compatible donor (allogenic) and non-compatible donors (non-allogenic) as a possible treatment for severe cases of Chediak-Higashi Syndrome. In this procedure patients receive high doses of chemotherapy, followed by radiation therapy. Then donor bone marrow cells are given intravenously to the patient. It is hoped that this procedure may lead to the improvement of the blood abnormalities and immune deficiencies associated with Chediak-Higashi Syndrome and other immune deficiency disorders such as Wiskott-Aldrich Syndrome. More study is needed to determine the long-term safety and effectiveness of bone marrow transplantation for the treatment of Chediak- Higashi Syndrome.

There are three clinical trials presently under way to study CHS in some detail. One of these trials is sponsored by the National Human Genome Research Institute of the NIH and two others are sponsored by Fairview University Medical Center at the University of Minnesota.

1.Investigations into Chediak-Higashi Syndrome and Related Disorders.

This trial is designed to investigate the underlying cause of Chediak-Higashi syndrome (CHS) and define the full spectrum of medical complications associated with it. The responsible gene will be studied and attempts will be made to identify any other gene(s) that may cause milder forms of the syndrome.

This is an observational study primarily the aim of which is to better understand the ‘natural history’ of the disorder.

For further information, please contact:
Patient Recruitment and Public Liaison Office
National Human Genome Research Institute (NHGRI)
9000 Rockville Pike,
Bethesda, MD 20892

Tel:1-800-411-1222
e-mail:prpl@mail.cc.nih.gov

Study ID Numbers are: 000153; 00-HG-0153


2.Allogenic Bone Marrow Transplantation in Patients with Primary Immunodeficiencies

Chediak-Higashi syndrome is listed among the conditions eligible for enrollment in this trial. Patients accepted in this trial will receive either bone marrow, or umbilical cord blood, transplantation from a family member (matched sibling donor). The trial is intended to cure the immunodeficiencies in those participating and to determine morbidity and mortality of the complications associated with this treatment.

For further information, please contact:
Dr. K. Scott Baker
Study Chair
Fairview University Medical Center
Minneapolis, MN 55455
Email: baker084@umn.edu
Tel:1-612-626-3000

Study ID Numbers are: 199/15104; UMN-MT-1995-26; UMN-MT-9526

3. Pilot Study of Unrelated Donor Hematopoietic Stem Cell Transplantation in Patients with Life Threatening Hemophagocytic Disorders.

Chediak-Higashi syndrome is listed among the conditions eligible for enrollment in this trial. The trial is designed to determine the effectiveness of transplanting stem cells from unrelated donors to patients suffering from disorders in which their blood cells are being destroyed. In addition the trial is designed to determine the rate of disease free survival, the rate of occurrence failure of the graft to take, and the rate of occurrence of graft-versus-host disease among these patients.

For further information, please contact:
Dr. K. Scott Baker
Study Chair
Fairview University Medical Center
Minneapolis, MN 55455

Tel:1-612-626-3000

Study ID Numbers are: 199/15106; UMN-MT-1997-08; UMN-MT-9708
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McKusick VA, Ed. ONLINE MENDELIAN INHERITANCE IN MAN (OMIM). The Johns Hopkins University. Chediak-Higashi Syndrome; CHS. Entry Number; 214500: Last Edit Date; 5/8/2002.

TEXTBOOKS
Boxer LA. Chediak-Higashi Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:379.

Frank MM, Austen KF, Claman HN, et al. Eds. Samter’s Immunological Diseases. 5th ed. Little Brown and Company, Boston, MA; 1995:594-95.


REVIEW ARTICLES
Ward DM, Shiflett SL, Kaplan J. Chediak-Higashi syndrome: a clinical and molecular view of a rare lysosomal disorder. Curr Mol Med. 2002;2:469-77.

Shiflett SL, Kaplan J, Ward DM. Chediak-Higashi syndrome: a rare disorder of lysosomes and lysosome related organelles. Pigment Cell Res. 2002;15:251-57.

Huizing M, Anikster Y, Gahl WA. Hermansky-Pudlak syndrome and Chediak-Higashi syndrome: disorders of vesicle formation and trafficking. Thromb Haemost. 2001;86:233-45.

Ward DM, Griffiths GM, Stinchcombe JC, et al. Analysis of the lysosomal storage disease Chediak-Higashi syndrome. Traffic. 2000;1:816-22.

JOURNAL ARTICLES
Yamazaki S, Takahashi H, Fujii H, et al. Split chimerism after allogenic bone marrow transplantation in Chediak-Higashi syndrome. Bone Marrow Transplant. 2003;31:137-40.

Shome DK, Al-Mukharraq H, Mahdi N, et al. Clinicopathological aspects of Chediak-Higashi syndrome in the accelerated phase. Saudi Med J. 2002;23:464-66.

Karim MA, Suzuki K, Fukai K, et al. Apparent genotype-phenotype correlation in childhood, adolescent, and adult Chediak-Higashi syndrome. Am J Med Genet. 2002;108:16-22.

Trigg ME, Schugar R. Chediak-Higashi syndrome: hematopoietic chimerism corrects genetic defect. Bone Marrow Transplant. 2001;27:1211-13.

Delcourt-Debruyne EM, Boutigny HR, Hildebrand HF. Features of severe periodontal disease in a teenager with Chediak-Higashi syndrome. J Periodontol. 2000;71:816-24.

Fukuda M, Morimoto T, Ishida Y, et al. Improvement of peripheral neuropathy with oral prednisolone in Chediak-Higashi syndrome. Eur J Pediatr. 2000;159:300-01.

FROM THE INTERNET
Brooks DG. Chediak-Higashi syndrome. In: Medical Encyclopedia. MEDLINEplus. Last Updated: 17 April 2003. 3pp.
www.nlm.nih.gov/medlineplus/ency/article/001312.htm

Nowicki R, Szarmach H. Chediak-Higashi Syndrome. eMedicine. Last Updated: June 2, 2003. 11pp.
www.emedicine.com/derm/topic704.htm

About CHS. Chediak-Higashi Syndrome Association. nd. var pp.
www.chediak-higashi.org/index2.html

Hermansky-Pudlak and Chediak-Higashi syndrome albinism. Keratin.com. nd. 3pp.
www.keratin.com/as/as019.shtml

Chediak-Higashi syndrome; clinical features; prognosis. nd. 3pp
www.gpnotebook.co.uk/simplepage.cfm?ID=-502923227
www.gpnotebook.co.uk/simplepage.cfm?ID=188022833&linkID=8906&cook=yes
www.gpnotebook.co.uk/simplepage.cfm?ID=-1550188482

Health On the Net Foundation. Last Modified: Mar 28 2003. 2pp.
www.hon.ch/cgi-bin/HONselect?browse+C15.378.553.774.257