Hematology

Chediak-Higashi syndrome

Chédiak-Higashi syndrome

What every physician needs to know:

Chédiak-Higashi syndrome (CHS) is a rare, autosomal recessive disorder characterized by severe immunodeficiency with frequent bacterial infections, bleeding tendency, decreased pigmentation of hair and eyes (partial albinism), photophobia, nystagmus, progressive neurologic dysfunction, and heightened risk for hemophagocytic histiocytic (HLH) syndrome. Failure of normal granule morphogenesis, resulting in overtly large granules and abnormal lysomal trafficking is the primary molecular defect in CHS patients.

All granule bearing cells are affected resulting in giant, yet defective lysosomes, melanosomes, platelet dense granules, and T cell and NK (natural killer) cell cytolytic granules. Patients have mutations in the CHS1/LYSTgene. The syndrome has two distinct phases, stable and accelerated. CHS patients can be managed with prophylactic antibiotics during the stable phase. However, CHS patients are prone to develop an accelerated phase typified by HLH. Allogeneic stem cell transplantation is the only curative option; however, neurologic dysfunction persists and often progresses after transplant.

Are you sure your patient has Chediak-Higashi syndrome? What should you expect to find?

Patients with CHS usually present with:

  • Moderate neutropenia, absolute neutrophil count (ANC) less than 1,000/uL and neutrophil dysfunction characterized by defects in chemotaxis, degranulation, and bactericidal activity

  • Frequent, recurrent, and potentially life-threatening bacterial infections. Recurrent gingivitis and peridonitis, pneumonia, and skin infections are common

  • Oculocutaneous albinism arising from failure of dispersal of melanin in the skin and retina. Complaints of photosensitivity and decreased visual acuity are common

  • Easy bruising and/or bleeding, despite normal platelet counts

  • Demonstration of giant peroxidase-positive lysosomal granules in the blood or bone marrow myeloid cells

  • Predisposition to HLH as a consequence of the lack of NK cell cytolytic activity

Beware of other conditions that can mimic Chediak-Higashi syndrome:

Griscelli's syndrome

Griscelli's syndrome (GS) is a rare autosomal recessive syndrome characterized by pigment dilution of the skin, a silver-gray sheen of the hair with large clumps of hair pigment within the hair shafts, and the accumulation of abnormal and large melanosomes in the center of melanocytes. Three types of GS have been identified.

  • Type 1 patients have albinism and neurologic impairment with mutations in the MY05A gene

  • Type 2 patients have albinism and immune defects often leading to HLH due to a mutation in RAB27A

  • Type 3 patients have only albinism with a mutation in the MLPH gene.

None of the GS types have giant granules in their myeloid cells.

Hermansky-Pudlack syndrome, type II

Hermansky-Pudlack syndrome (HPS) type II is a rare autosomal recessive syndrome caused by a mutation in the AP3B1 gene, a gene important in the trafficking of proteins to the lysosome. Clinically, HPS is characterized by albinism, a bleeding diathesis, and neutropenia. It can be distinguished from CHS as the large intracellular granules seen in CHS, are not present in HPS.

Which individuals are most at risk for developing Chediak-Higashi syndrome:

Siblings of CHS patients are most at risk.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Laboratory studies required:

  • Complete blood count with platelets and differential

  • NK cell function studies to assess for impaired cytotoxic capacity

  • Platelet function tests indicating a storage pool defect

  • Peripheral blood or bone marrow for evaluation of giant peroxidase-positive lysosomal granules in the myeloid cells

  • Gene testing for CHS1/LSYT

What imaging studies (if any) will be helpful in making or excluding the diagnosis of Chediak-Higashi syndrome?

Imaging studies do not play a significant role in diagnosing CHS, although directed imaging studies may serve to confirm/characterize infections.

If you decide the patient has Chediak-Higashi syndrome, what therapies should you initiate immediately?

Antibiotics directed at any active infections should be initiated promptly.

More definitive therapies?

The only definitive therapy available for the hematologic manifestations of CHS is allogeneic stem cell transplantation, which should occur prior to the beginning of the accelerated/HLH phase. Unfortunately, stem cell transplant does not correct or prevent progression of the neurologic dysfunction manifested by CHS patients, as most patients have developed neurologic deficits and/or low cognitive abilities prior to diagnosis. Additionally, stem cell transplantation does not correct any of the oculocutaneous albinism phenotypic features.

What other therapies are helpful for reducing complications?

Once the diagnosis CHS is recognized, prophylactic antibiotics, for example, Bactrim, may be of benefit. Antibiotics directed at specific infections should be utilized. Additionally, high-dose ascorbic acid supplementation has been reported in some patients to improve neutrophil function. If the patient enters the accelerated/ HLH phase of the disease, combination treatment with steroids, cyclosporine, and etoposide should be considered until a human leukocyte antigen (HLA) matched allogeneic bone marrow transplantation is identified.

What should you tell the patient and the family about prognosis?

Without allogeneic stem cell transplantation, most patients die of infection and/or complications of the accelerated/HLH phase of CHS in the first or second decade of life.

Patients who do undergo an allogeneic stem cell transplant have been reported to have a 5 year probability of overall survival of 62%, with the highest mortality seen in patients with accelerated phase of disease at the time of transplant. Even in those who survive beyond 5 years post stem cell transplant, neurologic impairment is likely with increasing age.

"What if" scenarios.

What if the patient has a fever?

For temperatures greater than 38.3°C, patients with an ANC less than 1,000/uL should be urgently evaluated by a physician. Blood cultures and urine cultures should be obtained, broad-spectrum antibiotics administered, and the patient should be admitted for observation for at least 48 hours to confirm negative cultures. Additional work-up should be dictated by the patient's presenting symptoms.

What if the patient is bleeding, for example, has a prolonged nosebleed?

For patients who exhibit bleeding manifestations, such as prolonged nosebleeds, local pressure and topically vasoconstriction medications should be provided in an attempt to avoid platelet transfusion if possible (to minimize the negative impact of pre-stem cell transplant transfusion exposure). Major bleeding episodes may require platelet transfusion.

What if the patient does not have oculocutaneous albinism, could the patient still have CHS?

The degree of albinism is variable in patients with CHS, so even patients without overt albinism may still have the diagnosis. Hair color may range from grey to white and skin pigmentation may be lighter only as compared to siblings, depending on ethnic background.

Pathophysiology

The pathologic hallmark of CHS is the development of large intracellular granules and abnormal lysosome trafficking. The abnormalities in the intracellular granules affect multiple cell types such as the myelin sheath in neurons, melanosomes in melanocytes, dense granules in platelets and T lymphocytes, and NK cells' cytolytic granules.

The defective granules result in clinical manifestations of progressive neurologic deficits, oculocutaneous albinism, bleeding diathesis, and immunodeficiency. Patients have mutations in the CHS1/LYST gene which leads to abnormal fusion of intracellular granules and defective membrane targeting of many of the proteins present in secretory lysosomes.

What other clinical manifestations may help me to diagnose Chediak-Higashi syndrome?

Patients with CHS frequently have evidence of partial oculocutaneous albinism on examination, as well as oral ulcers, peridonitis, and/or gingivitis on inspection of their oropharynx. Frequent skin and upper respiratory infections, plus bruising/bleeding may also be evident.

As CHS is heritable, it is important to ask about any other affected family members. Inquiring about photosensitivity, vision problems, bruising/bleeding manifestations, oral health, early loss of dentition, frequent infection, sudden death from overwhelming infection, and neurologic dysfunction can be helpful. Additionally, confirming if the patient has any full-siblings for potential HLA typing is useful in thinking about stem cell transplant as a treatment option.

What other additional laboratory studies may be ordered?

No additional studies are routinely required.

What’s the evidence?

Dessinioti, C, Stratigos, AJ, Rigopoulos, D, Katsambas, D. "A review of genetic disorders of hypopigmentation: lessons learned from the biology of melanocytes". Exp Derm. vol. 18. 2009. pp. 741-749.

[In this review, the authors summarize the basic concepts of melanocyte biology and discuss how molecular defects in melanocytes development and function can result in the development in the hypopigmentary hereditary skin diseases.]

Haddad, E, Le, Deist, Blanche, S. "Treatment of Chédiak-Higashi syndrome by allogeneic bone marrow transplantation: report of 10 cases". Blood. vol. 85. 1995. pp. 3328-3333.

[The authors describe the outcome of bone marrow transplantation in 10 children with the Chédiak-Higashi syndrome and point out that fully matched donors are required to prevent patients from progressing to the accelerated phase.]

Eapen, M, DeLaat, CA, Baker, KS. "Hematopoietic cell transplantation for Chédiak-Higashi syndrome". Bone Marrow Transplant. vol. 39. 2007. pp. 411-415.

[The authors reviewed outcomes of allogeneic bone marrow transplantation from the International Blood and Transplant Registry in 35 children with Chédiak-Higashi syndrome. Overall survival with bone marrow transplantation was 62% prior to patients entering the accelerated phase, but was significantly less if patients were transplanted in the accelerated phase. In this study, appropriately matched unrelated donors proved to be a suitable alternative to those patients without a matched sibling.]

Tardieu, M, Lacroix, C, Neven, B. "Progressive neurologic dysfunction 20 years after allogeneic bone marrow transplantation for Chédiak-Higashi syndrome". Blood. vol. 106. 2005. pp. 40-42.

[The authors describe three patients with Chédiak-Higashi syndrome who underwent allogeneic bone marrow transplantation who did not progress to the accelerated phase, but progressive neurologic deterioration occurred, indicating that bone marrow transplantation is ineffective in preventing cerebellar ataxia and peripheral neuropathy.]

Boxer, LA, Watanabe, AM, Rister, M. "Correction of leukocyte function in Chédiak-Higashi syndrome by ascorbate". N Engl J Med. vol. 295. 1976. pp. 1041-1045.

[The article demonstrates the utility of oral ascorbate to correct the neutrophil motility defects.]

Blood. vol. 57. 1981. pp. 856-865.

[The authors confirmed the benefit of ascorbate on neutrophil function.]

Kritzler, RA, Terner, JY, Lindenbaum, K. "Chédiak-Higashi syndrome: Cytologic and serum lipid observations in a case and family". Am J Med. vol. 36. 1964. pp. 583-94.

[This paper confirmed the autosomal recessive inheritance pattern in Chédiak-Higashi syndrome and identified that giant pigmentary granules could occur outside of the hematopoetic system.]

Windhorst, DB, Xelickson, AS, Good, RA. "A human pigmentary dilution based on a heritable subcellular structural defect: the Chédiak-Higashi syndrome". J Invest Dermatol. vol. 50. 1968. pp. 9-18.

[The article points out that the pigmentary anomaly of Chédiak-Higashi syndrome is related to poor dispersion of giant melanin granules rather than impaired melanin synthesis.]
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