Are You Confident of the Diagnosis?
What you should be alert for in the history
Extensive depigmentation of the skin and hair present since birth; alteration in eye pigmentation resulting in photosensitivity and decreased visual acuity; and recurrent severe bacterial infections especially in the respiratory tract and skin, may be features of the history. In some patients, periodonotitis has been reported, as have mild coagulation defects often manifesting as bruising, mucosal bleeding, and petechiae.
Characteristic findings on physical examination
Hair color may range from grey to white depending on the ethnic background of the patient. Often hair displays a silvery sheen. Skin pigment dilution may not be appreciated unless compared with that of family members.
Expected results of diagnostic studies
On peripheral blood smear, peroxidase-positive giant inclusions in polymorphonuclear neutrophils, and to a lesser extent in lymphocytes, are diagnostic of Chediak-Higashi syndrome (CHS). Light microscopy of hair shafts shows irregular distribution of large and small pigment clumps. Sequence analysis of the LYST gene identifies mutations in approximately 70% of affected individuals.
Other diseases characterized by both so-called partial albinism and immunodeficiency should be distinguished from CHS. Griscelli Syndrome, type 2, presents with hypopigmented hair and hemophagocytic lymphohistiocytosis. Hermansky-Pudlak syndrome, type 2, displays cutaneous albinism, decreased visual acuity, prolonged bleeding, neutropenia and recurrent infections. The presence of cytoplasmic inclusions in leukocytes is diagnostic for CHS.
Who is at Risk for Developing this Disease?
Chediak-Higashi syndrome is a rare autosomal recessive disease.
What is the Cause of the Disease?
Mutations of the CHS1/LYST gene, located on chromosome 1q42, are the cause of CHS.
The function of the CHS1/LYST gene product is not yet completely understood. The CHS1 protein is predicted to be a cytosolic protein with a role in vesicular transport. Indeed, CHS is characterized by massive cytoplasmic lysosomal and nonlysosomal inclusions in granule-containing cells. Melanocytes containing giant melanosomes that do not get distributed to keratinocytes seem to be the cause of hypopigmentation.
Neutropenia and natural killer cell activity and T-cell cytotoxicity, chemotaxis and bactericidal killing by granulocytes and monocytes, result in immunodeficiency. Platelets in CHS patients contain abnormal platelet dense bodies that seem to be delayed in secretion resulting in increased bleeding times. Neurons contain cytoplasmic inclusions resembling enlarged lysosomes.
Systemic Implications and Complications
Patients who survive infections usually develop life-threatening, accelerated phases of hemophagocytic lymphohistiocytosis, typically triggered by Epstein-Barr virus infection, within the first or second decade. The accelerated phase is characterized by macrophage and T-cell activation with lymphohistiocytic infiltration of liver, spleen, lymph nodes, central nervous system and bone marrow. This is the most common cause of death in CHS patients.
Transient remissions are reported after treatment with etoposide, corticosteroids and supportive care; relapses are frequent and are increasingly resistant to treatment. Treatment for CHS is hematopoietic stem cell transplantation (HSCT). Patients who have survived into their third decade after HSCT develop neurologic involvement with weakness, ataxia, sensory deficit and progressive neurodegeneration. It is not expected that HSCT would prevent neurologic deficit.
Antibiotics are effective in controlling recurrent infections but do not prevent the other complications of CHS including bleeding, hemophagocytic syndrome or neurologic involvement. The bleeding diathesis usually does not require treatment.
The accelerated phase may be controlled with etoposide, corticosteroids and supportive care. HSCT should be performed before the occurrence of the accelerated phase.
Optimal Therapeutic Approach for this Disease
Hematopoietic stem cell transplantation is the therapeutic option of choice for CHS. Mortality is higher in patients with accelerated phase CHS at transplantation and for recipients of alternate related donor HSCT. An unrelated donor may be a suitable alternative for patients without an HLA-matched sibling.
All patients must be referred to an hematologist for adequate treatment and follow-up.
Unusual Clinical Scenarios to Consider in Patient Management
Atypical phenotypes include subtle or absent hypopigmentation, mild infections or severe infections that become less frequent later in life, subtle bleeding manifestations with reduced platelet-dense bodies, progressive neurologic involvement in adults with peripheral neuropathy, balance abnormalities, and tremor.
What is the Evidence?
Zhao , H, Boissy , YL, Abdel-Malek , Z, King , RA, Nordlund , JJ, Boissy , RE. “On the analysis of the pathophysiology of Chediak-Higashi syndrome: defects expressed by cultured melanocytes”. Lab Invest . vol. 71. 1994. pp. 25-34. (Defects in melanosome transfer in CHS.)
de Beer , HA, Anderson , R, Findlay , GH. “Chediak-Higashi syndrome in a ‘Black’ child”. S Afr Med J . vol. 60. 1981. pp. 108-12. (Role of ethnic background on clinical expression of CHS.)
Valenzuela , R, Morningstar , WA. “The ocular pigmentary disturbance of human Chediak-Higashi syndrome: a comparative light- and electron-microscopic study and review of the literature”. Am J Clin Pathol . vol. 75. 1981. pp. 591-6. (Ophthalmologic features of CHS.)
Apitz-Castro , R, Cruz , MR, Ledezma , E, Merino , F, Ramirez-Duque , P, Dangelmeier , C. “The storage pool deficiency in platelets from humans with the Chediak-Higashi syndrome: study of six patients”. Br J Haematol . vol. 59. 1985. pp. 471-83. (.Platelets dense granules defects in CHS.)
Eapen , M, DeLaat , CA, Baker , KS, Cairo , MS, Cowan , MJ, Kurtzberg , J. “Hematopoietic cell transplantation for Chediak-Higashi syndrome”. Bone Marrow Transplant . vol. 39. 2007. pp. 411-5. (Excellent article on treatment of CHS.)
Aslan , Y, Erduran , E, Gedik , Y, Mocan , H, Yildiran , A. “The role of high dose methylprednisolone and splenectomy in the accelerated phase of Chediak–Higashi syndrome”. Acta Haematol . vol. 96. 1996. pp. 105-7. (Management of accelerated phase.)
Fukuda , M, Morimoto , T, Ishida , Y, Suzuki , Y, Murakami , Y, Kida, K. “Improvement of peripheral neuropathy with oral prednisolone in Chediak–Higashi syndrome”. Eur J Pediatr . vol. 159. 2000. pp. 300-1. (Management of peripheral neuropathy.)
Tardieu , M, Lacroix , C, Neven , B, Bordigoni , P, de Saint Basile , G, Blanche, S. “Progressive neurologic dysfunctions 20 years after allogeneic bone marrow transplantation for Chediak–Higashi syndrome”. Blood . vol. 106. 2005. pp. 40-2. (Neurologic sequelae of CHS.)
Westbroek , W, Adams , D, Huizing , M, Koshoffer , A, Dorward , H, Tinloy , B. “The severity of cellular defects in Chediak Higashi syndrome correlate with the molecular genotype and clinical phenotype”. J Invest Dermatol. vol. 127. 2007. pp. 2674-7. (Genotype/phenotype correlation.)
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