Indian Journal of Pathology and Microbiology

ORIGINAL ARTICLE
Year
: 2011  |  Volume : 54  |  Issue : 3  |  Page : 547--551

Clinico-hematological profile of Chediak-Higashi syndrome: Experience from a tertiary care center in south India


Arun Roy, Rakhee Kar, Debdatta Basu, S Srivani, Bhawana Ashok Badhe 
 Department of Pathology, JIPMER, Puducherry, India

Correspondence Address:
Rakhee Kar
Hematology Section, Department of Pathology, JIPMER, Puducherry - 605 006
India

Abstract

Introduction: Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder characterized by partial ocular and cutaneous albinism, increased susceptibility to pyogenic infections, the presence of large lysosomal-like organelles in most granule-containing cells and a bleeding tendency. The abnormal granules are most readily seen in blood and marrow leukocytes, especially granulocytes; and in melanocytes. Other clinical features include silvery hair, photophobia, horizontal and rotatory nystagmus and hepatosplenomegaly. Materials and Methods: The clinico-hematological profile of a series of 5 cases of CHS encountered at JIPMER Hospital with diagnostic work-up done in the Department of Pathology over the last 6 years is presented. The diagnostic work-up included complete hemogram with peripheral smear, bone marrow examination, skin and liver biopsies. Results: The age of the patients ranged from 5 months to 3 years. All patients had silvery hair and partial albinism and presented with fever and recurrent chest infection. Two patients were stable. Three patients were in accelerated phase; of them, 1 patient with associated hemophagocytic syndrome had a rapidly fulminant course. Peripheral blood smear showed anomalously large granules in the leukocytes. Skin biopsy showed sparse, coarse melanin pigment in the epidermis, and liver biopsy done in 2 patients with accelerated phase showed portal lymphohistiocytic aggregates. Conclusions: The diagnostic hallmark of CHS is the occurrence of giant inclusion bodies (granules) in the peripheral leukocyte and their bone marrow precursors. The case series is being presented because of the rarity of CHS and varied spectrum of clinical and hematological presentation.



How to cite this article:
Roy A, Kar R, Basu D, Srivani S, Badhe BA. Clinico-hematological profile of Chediak-Higashi syndrome: Experience from a tertiary care center in south India.Indian J Pathol Microbiol 2011;54:547-551


How to cite this URL:
Roy A, Kar R, Basu D, Srivani S, Badhe BA. Clinico-hematological profile of Chediak-Higashi syndrome: Experience from a tertiary care center in south India. Indian J Pathol Microbiol [serial online] 2011 [cited 2020 Mar 29 ];54:547-551
Available from: http://www.ijpmonline.org/text.asp?2011/54/3/547/85090


Full Text

 Introduction



Chediak-Higashi syndrome (CHS) was first described by Beguez-Cesar in 1943 in 3 siblings bearing the main clinical features of neutropenia and abnormal granules in leukocytes.[1] Subsequently Steinbrinck reported another case in 1948. [2] Chediak, a Cuban hematologist, reported another case in 1952; [3] and in 1954, Higashi, a Japanese pediatrician, described a series of cases and found maldistribution of myeloperoxidase in neutrophilic granules of affected patients. [4]

CHS is a rare, autosomal recessive multi-systemic disorder characterized by hypopigmentation of the skin, eyes and hair; prolonged bleeding times; easy bruisability; recurrent infections; abnormal NK cell function; and peripheral neuropathy. [5] The presence of giant peroxidase-positive lysosomal-like organelles most readily seen in blood and marrow leukocytes is clinically diagnostic. Other clinical features include silvery hair, photophobia, horizontal and rotatory nystagmus and hepatosplenomegaly.

Approximately 85% of affected individuals develop the accelerated phase, a lymphoproliferative infiltration of the bone marrow and reticuloendothelial system. [6]

 Materials and Methods



The clinico-hematological profile of a series of 5 cases of CHS encountered at JIPMER Hospital with diagnostic work-up done in the Department of Pathology over the last 6 years is presented. The diagnostic work-up included complete hemogram with peripheral smear examination. Some cases, in addition, underwent bone marrow aspiration, skin biopsy and liver biopsy.

 Results



The age of the patients at presentation ranged from 5 months to 3 years, and 2 were male and 3 were female. All patients had silvery hair [Figure 1]a, partial albinism [Figure 1]b, photophobia and light sensitivity. The presenting symptoms warranting hospitalization were fever and recurrent chest infection in all cases. In addition, 3 patients had sinus infection, skin infection and pneumonia. Neurological involvement in the form of cerebellar tremor and incoordination was seen in 2 patients, and one of them had nystagmus and peripheral neuropathy. On examination, 4 patients had hepatosplenomegaly, 3 had lymphadenopathy and 3 had bleeding manifestation in the form of petechie. Stunting and growth retardation was seen in 3 cases. The clinical presentation is summarized in [Table 1].{Table 1}{Figure 1}

Hemogram and peripheral smear evaluation were done in all cases. At presentation, all patients had anemia, 4 had thrombocytopenia, 3 had leukocytosis and 2 had leucopenia. All the cases showed anomalously large granules in leukocytes [Figure 2]a and b. The peripheral smear findings strongly supported the possibility of CHS. In addition, in 2 cases (case nos. 3 and 5), smear findings were suggestive of microangiopathic hemolytic anemia, possibly due to sepsis-associated disseminated intravascular coagulation (DIC). Bone marrow aspiration done in 2 cases (case nos. 3 and 4) showed erythroid hyperplasia and presence of abnormal large granules in the immature myeloid precursor cells [Figure 2]c. Marrow lymphocytosis (25%) was seen in case no. 3.{Figure 2}

Liver and skin biopsies were available in 2 cases (case nos. 4 and 5; postmortem, in case no. 5). In both the cases, skin biopsy showed sparse but coarse granular brown pigment in the basal layer [Figure 2]d, which was confirmed to be melanin by Masson Fontana. In addition, case no. 5, in which biopsy was taken from ulcer edge, showed parakeratosis and ulceration of lining epithelium with underlying dense granulation tissue. Dermis also showed dense lymphohistiocytic infiltrate [Figure 2]e. Liver biopsy in both the cases showed portal lymphohistiocytic aggregates [Figure 2]f, which were positive for CD3 [Figure 2]g and CD68 [Figure 2]h on immunostaining. In addition, case no. 5 also exhibited kupffer cell hyperplasia; few of these cells showed evidence of hemophagocytosis. The investigation findings are summarized in [Table 2].{Table 2}

Two patients (case nos. 1 and 2) were discharged after symptomatic treatment and were lost to follow-up. Three patients (case nos. 3, 4 and 5) had an accelerated course of disease. Two patients (case nos. 3 and 4) died after 5 days of admission due to fulminant infection. One patient (case no. 5) died within 48 hours of admission due to rapidly fulminating course complicated by the presence of hemophagocytic syndrome and sepsis-associated DIC.

 Discussion



Chediak-Higashi syndrome, a rare autosomal recessive disorder, was described over 50 years ago. The pathological hallmark of CHS is the presence of massive lysosomal inclusion in leukocytes, fibroblasts and melanocytes, formed through a combined process of fusion, cytoplasmic injury, and phagocytosis due to a microtubular defect. Recent studies showed that lysosomes function as calcium-regulated secretory compartments and may play an important role in membrane resealing. Lysosomal exocytosis triggered by membrane wounding is defective in human CHS and beige mouse fibroblasts, and this defect may be central to the CHS phenotype. [7]

Numerous cases of CHS have been reported to result from mutation in the lysosomal trafficking regulator LYST or CHS1 gene located on chromosome 1q42-43.[8] The LYST protein is a very large cytoplasmic protein (425 kD). However, LYST mutation cannot be identified in all CHS patients, suggesting the existence of causative defects in other genes. Several studies led to the suggestion that the enlarged lysosomes found in CHS cells result from abnormalities in membrane fusion, which could occur during the biogenesis of the lysosomes. This LYST protein has been hypothesized to interact with attachment proteins on lysosomes (v-SNAREs), with the mutated protein leading to indiscriminate interactions with v-SNARE and yielding uncontrolled fusion of lysosomes with each other. [9] Various CHS clinical phenotypes have been correlated with molecular genotypes, where loss-of-function mutations are associated with severe early-onset CHS characterized by fatal infections and hemophagocytic lymphohistiocytosis; whereas missense mutations are associated with milder, late-onset CHS with slowly progressive neurological impairment, or an adolescent form with infections but no hemophagocytic lymphohistiocytosis. [10]

Increased susceptibility to infection - especially in skin and respiratory tract, as seen in our cases; and, less commonly, in gastrointestinal tract - is due to the defective function of neutrophils (due to defective fusion of phagosomes and lysosomes in phagocytes, defective chemotaxis and decreased bactericidal activity). [11] The average age at manifestation is 5.85 years (1.62 years in our series), and most patients die before the age of 10 years.

A majority (85%) of patients with CHS develop an accelerated phase of the disease, characterized by fever, jaundice, hepatosplenomegaly, lymphadenopathy, pancytopenia, coagulopathy and neurological abnormalities. [12] It may occur shortly after birth or may be delayed for years and is usually fatal either due to infection or hemorrhage. In the accelerated phase, erythrocyte and granulocyte survival may be shortened. [13] During this phase, diffuse mononuclear cell (lymphohistiocytic) infiltrate into the organs is seen on histology. [14] Accelerated phase was seen in 3 of our cases (case nos. 3, 4 and 5); case no. 3 showed marrow lymphocytosis, case no. 4 showed portal lymphohistiocytic aggregate and case no. 5 showed lymphohistiocytic aggregates in skin and liver biopsies. All 3 of these children had a fatal outcome. One of these cases (case no. 5) was clinically suspected to be associated with hemophagocytic syndrome. However, the child had a rapidly fatal course and could not be investigated further. Postmortem liver biopsy showed evidence of hemophagocytosis, which is in concurrence with other studies which have shown a strong association between LYST gene mutation and familial hemophagocytic lymphohistiocytosis (FHL). [15]

Close differential diagnoses of CHS are Griscelli syndrome and Hermansky-Pudlak syndrome. Griscelli syndrome is a rare disorder defined by partial ocular and cutaneous albinism, variable cellular and humoral immunodeficiency, variable neurologic involvement and development of the accelerated phase. Hermansky-Pudlak syndrome is a disorder of ocular and cutaneous albinism, bleeding diathesis and deposition of ceroid lipofuscin in various organs. These patients are however not predisposed to recurrent infections. In contrast to CHS, both Griscelli and Hermansky-Pudlak syndromes lack the giant granules seen in CHS. [14]

 Conclusions



CHS is a rare disease with varied spectrum of clinical presentation and investigation findings. During routine hematological work-up, presence of large coarse granules in leukocytes in the peripheral blood smear should raise the possibility of CHS in adequate clinical context.

References

1Beguez-Cesar A. Neutropeneia cronica maligna familiar con granulaciounes atipicas de los leucocitos. Bol Soc Cubana Pediatr 1943;15:900-22.
2Steinbrinck W. Uber eine neue granulations anomalie der leukocyten. Dtsch Arch Klin Med 1948;193:577-81.
3Chediak MM. New leukocyte anomaly of constitutional and familial character. Rev Hematol 1952;7:362-7.
4Higashi O. Congenital gigantism of peroxidase. Tohoku J Exp Med 1954;59:315-22.
5Ward DM, Shiflett SL, Kaplan J. Chediak-Higashi syndrome: A clinical and molecular view of a rare lysosomal storage disorder. Curr Mol Med 2002;2:469-77.
6Introne WJ, Westbroek W, Golas GA, Adams D. Chediak-Higashi Syndrome. In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors. Gene Reviews. Seattle (WA): University of Washington, Seattle; 1993-2009 Mar 3 [Last updated on 2010 Jul 27].
7Huynh C, Roth D, Ward DM, Kaplan J, Andrews NW. Defective lysosomal exocytosis and plasma membrane repair in Chediak-higashi/beige cells. Proc Natl Acad Sci USA 2004;101:16795-800.
8Barrat FJ, Auloge L, Pastural E, Lagelouse RD, Vilmer E, Cant AJ, et al. Genetic and physical mapping of the Chediak-Higashi syndrome on chromosome 1q42-43. Am J Hum Genet. 1996;59:625-32.
9Tchernev VT, Mansfield TA, Giot L, Kumar AM, Nandabalan K, Li Y, et al. The Chediak-Higashi protein interacts with SNARE complex and signal transduction protein. Mol Med 2002;8:56-64.
10Karim MA, Suzuki K, Fukai K, Oh J, Nagle DL, Moore KJ, et al. Apparent genotype-phenotype correlation in childhood, adolescent, and adult Chediak-Higashi syndrome. Am J Med Genet 2002;108:16-22.
11Boxer LA, Smolen JE. Neutrophil granule constituents and their release in health and disease. Hematol Oncol Clin North Am 1988;2:101-34.
12Blume RS, Bennet JM, Yankee RA, Wolff SM. Defective granulocyte regulation in the Chediak-Higashi syndrome. N Engl J Med 1968;279:1009-15.
13Blume RS, Wolff SM. The Chediak-Higashi syndrome: Studies in four patients and a review of the literature. Medicine 1972;51:247-80.
14Introne W, Boissy RE, Gahl WA. Clinical, molecular and cell biological aspects of Chediak-Higashi syndrome. Mol Genet Metab 1999;68:283- 303.
15Rubin CM, Burke BA, Mckenna RW, McClain KL, White JG, Nesbit ME, et al. The accelerated phase of Chediak-Higashi syndrome: An expression of virus associated hemophagocytic syndrome. Cancer 1985;56:524-30.