Chediak Higashi Syndrome Clinical And Hematological Parameters Biology Essay

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Abstract

Chediak-Higashi syndrome (CHS) is a rare multiorgan disease entity with autosomal recessive inheritance characterized by oculocutaneous albinism, bleeding tendency, recurrent bacterial infections and various neurological symptoms. We report four new cases of Chediak-Hibachi syndrome, presenting to our departments in previous 1 year. All the patients were children ranging from 14 months to 10 years. 3 of the four had history of recurrent infections and admissions. There clinical and hematological features on diagnosis are discussed in our report.

Conclusion: Chediak Higashi Syndrome (CHS) is a rare disorder causing a wide spectrum of symptoms and signs. Diagnosis is delayed until late in the course of the disease and to diagnose early, a high degree of suspicion should be kept in mind with children presenting with recurrent illnesses. Therapeutic decisions are limited in the limited availability of Allogenic Stem Cell Transplant. Genetic counseling and family screening are important in early detection and prevention of the disease.

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Keywords: Chediak-Higashi syndrome, immunodeficiency, hepatosplenomegaly.

Chediak Higashi syndrome; Clinical and Hematological parameters of four cases

Introduction: Chediak Higashi Syndrome (CHS) is a rare autosomal recessive disorder. It has been described in man, mink, cattle and mice1. In humans, it was first described in 1943 by Béguez-César, a Cuban pediatrician and then, by Moises chediak and Ototaka Higashi, who described the hematological menifestations and the presence of peroxidase positive granules in the neutrophils respectively2.

The disease is characterized by recurrent infections, hepatosplenomegaly, neuropathy, ocular and cutaneous albinism, a bleeding tendency and presence of giant and dysfunctional granules in the granulated cells of body. Giant granules from CHS neutrophils originate from azurophil granules which stain positive with the cytochemical stain Myeloperoxidase (MPO)3. Infact, a synonym of CHS is ' Congenital gigantism of Peroxidase granules". Dysfunctional granules are also present in the melanocytes of the skin. These melanocytes fail to transport these giant melanosomes, resulting in pigmentry dilutional effect causing hypopigmentation of the skin, hair and ocular fundi. Neurological menifestations are also linked to a dysfunctional lysosomal trafficking system.

The genetic defect in CHS is in CHS-1/LYST (Lysosomal Trafficking regulator) gene, identified on the chromosome 1q42-434. Various mutations have been found in the this gene5. A high proportion of marriages producing affected children are found to be consanguinous5, 6, 7. LYST gene is thought to be a regulator in vesicle formation and trafficking.

Diagnosis is usually based upon finding of giant MPO positive granules in the Neutrophils of blood and bone marrow2, 6. Other findings may include platelet function disorder, peripheral blood cytopenias and later in the course of disease, a lymphohistiocytic infiltration of the tissues. Intrauterine diagnosis can be done with fetal blood or chorionic villous sampling.

Clinical course of the disease is progressive and outcome before stem cell transplant was invariably fatal, the average survival being 6 years 8. The main treatment modalities include prophylactic antibiotics, administration of ascorbic acid and recently, Hematopoietic Stem Cell Transplant (HSCT). The latter appears to have cured the hematological menifestations of the disease but not the non hematological 9, 10, 11. Those patients who do not succumb to infection, end up in the ' Accelerated Phase' characterized by lymphoma like lymphohistiocytic infiltration of liver, spleen, lymph nodes and bone marrow.

Approximately 200 cases of CHS have been reported8. To our knowledge only 4 have been have been reported in Pakistan12.

Case report #1:

This is a case of ten years old female child who presented to pediatric emergency with the complaints of pallor, fever & abdominal distension for last six months. She received multiple drugs with several antibiotics but had temporary relief. Fever was intermittent and high grade. Past history was significant; she had episodes of chest infections and multiple abscesses involving the different parts of body at different occasions. There were two old healed infected areas on trunk and limb. She had been treated for repeated episodes of diarrhea and pneumonia in past with oral and injectable antibiotics. There was significant family history for the death of three siblings. All due to unknown causes. Her birth was uneventful. On admission, she was febrile (101 F) pulse of 110/min and R/R of 35/min. The child was anemic with de-pigmented skin rash, while cervical lymph nodes were enlarged. Liver was palpable, one cm below the right costal margin and spleen was huge, palpable 10 cm, crossing the midline and umbilicus (Figure 1). Rest of systemic examination was largely unremarkable.

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Her initial CBC showed Hb of 56gm/l, TLC of 1.1 x 109 /l and Platelets 22 x 10 9/l. Liver function test, BUN and blood sugar were within normal limits.

Bone marrow aspiration showed trilineage hemopoeisis. Myeloid precursors showed giant granules. Giant inclusions were present in myelocytes, neutrophils, monocytes and some lymphocytes. The giant granules in the myeloid cells stained positive for the cytochemical stain Myeloperoxidase. Diagnosis of CHS was made and she was treated with antibiotics, high dose Ascorbic acid. Patient was also given red cell concentrate transfusion. Patient was discharged safely. She is on follow up.

Patient # 2:

This was a 2 years old boy, who presented with a fever and abdominal distension since birth. He was referred to hematology unit to investigate the cause of hepatosplenomegaly. His family history was unremarkable except for consanguinity. His birth history and developmental history was unremarkable. On examination, the child was pale, febrile, with tachycardia. He had silvery grey hair and nystagmus. He had a palpable liver, 2 cm below the costal margin and spleen 3 cm below the costal margin. Other systems were unremarkable on examination. The CBC showed an Hb of 7.7, Platelets 54000 and Total white cell count 7800, Bone marrow aspirate was done and CHS diagnosis was given on the basis of presence of giant granules in the white cells of blood and bone marrow (Figure 2). The granules stained positive for myeloperoxidase (Figure 3). He was started on broad spectrum antibiotics and high doze Ascorbic acid. Genetic counseling was done. He is currently on follow up and free of infections.

Patient # 3:

This 2 and half year old female child presented to the pediatric unit with complaints of failure to thrive, recurrent fever and throat infection and discharge from the ear. Other aspects of history were unremarkable. On examination, the child was pale. Her heart rate was 122/ minute and respiratory rate was 38/ minute. She had thin grayish hair. She had a palpable liver 3 cm below the costal margin and spleen 6 cm below the costal margin. Examination of HEENT showed enlarged hyperemic tonsils, and bilateral cervical lymph nodes. Other systems were unremarkable on examination. The CBC showed an Hb of 66 gm/l, Total white cell count 12.9 x 109 and Platelets 55 x 109. Bone marrow aspiration was performed. Microscopic examination showed hypercellular marrow with giant granules in the myeloid series. These granules were MPO positive. A diagnosis of CHS was made and treatment started with broad spectrum antibiotics and high dose ascorbic acid. Patient became afebrile and was discharged. She is on follow up.

Patient # 4:

This 14 month old boy presented to the pediatric unit with trivial history of fever and vomiting. He had a previous admission in the same unit for chest infection. Rest of the history features were unremarkable. On examination, the patient had thin grey hair. Liver was palpable 2 cm below the costal margin while spleen was palpable 3 cm below the costal margin. There was no lymphadenopathy or any significant systemic examination finding. CBC showed Hb: 100 g/l, Total white cell count 7.8 x 10 9 /l and Plt: 55 x 10 9 /l. Bone marrow aspiration cytology was performed. The bone marrow was hypercellular. Myeloid cells showed giant granules in the cytoplasm in bone marrow and peripheral blood. A diagnosis of chediak-Higashi syndrome was made. The patient was given treatment for infection. Genetic counseling was done and patient discharged on high dose ascorbic acid.

The patient was admitted again for fever and severe chest infection. He had a similar clinical and hematological picture. He was treated with I.V Imepinem and discharged afebrile.

Discussion:

CHS is a fatal disease of infancy and childhood. The clinical course is charachterized by recurrent infections and partial albinism. The other menifestations include neuropathy and platelet function defects.

Generally, disorders of neutrophil function include defects of adhesion, movement, chemotaxis, phagocytosis and killing. The defects may be intrinsic to neutrophils or extrinsic, congenital or acquired. All these disorders show vulnerability to infections. Chediak Higashi syndrome has been categorized as one of the congenital intrinsic disorders of phagocyte function, resulting from defects in phagocytosis or killing. Other disorders of the category include Chronic Granulomatous Disease (CGD). The disorder is inherited as an autosomal recessive trait and is more common in families of affected individual7.

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The pathogenesis of this disorder is due to formation of larger and fewer than normal granules in the phagocytes. These are thought to be abnormal primary granules in the neutrophils. There is a belief that normal primary granules and formed but these fuse later on in the course of myelopoeisis. The abnormal granules are seen less frequently in erythroid component. Decreased dense bodies are seen in megakaryocytes and platelets on electron microscopy, although the granules appear normal by light microscopy. This leads to platelet function defect and a bleeding tendency13. In our cases, only patient 1 had history of purpura. If that was due to functional defect or thrombocytopenia, could not be decided.

In one series, age at diagnosis varied from 2 months to 10 years (median, 32 months). Hypopigmentation of the skin was noticed in all but one patient, and thin hair with silvery tint was observed in all patients. Ocular symptoms including photophobia and/or hypopigmentation of iris and retina and/or nystagmus were noticed in all patients except one. Three patients had severe neurologic manifestations, Neutropenia (less than 1 x 10 9 /L) was present in seven patients, and the five patients tested had reduced granulocyte chemotaxis. All patients had typical enlarged granulations in blood leukocytes. Thrombocytopenia (< 150 x 10 9 /L) and anemia (< I00 g/L) were also noted. 8 patients had accelerated phase on diagnosis9.

In our patients, the median age at diagnosis was 27 months. (table 1), three patients had recurrent infections including those of the skin and respiratory tract.

Cutaneous menifestations are common and include partial albinism, photophobia etc. In our cases, patient 1 had partial cutaneous albinism and photophobia, patient 2 had nystagmus and albinism, patient 3 and 4 had thin grayish hair.

About 85% of the patients develop an accelerated phase characterized by lymphoma like signs including persistent fever hepatosplenomegaly, lymphadenoathy and lymphohistiocytic infiltration of tissues7. In our cases, all had variable degrees of lymphadenopathy, visceromagaly, and peripheral blood cytopenias, deranged liver enzymes, low fibrinogen levels, and hypertriglyceridemia8. In our cases, patients 1 and 3 had accelerated phase at the diagnosis. All the patients had hepatosplenomegaly.

Prophylactic antibiotics are recommended by a few to prevent recurrent infections. Although there has been no convincing evidence to prove clinical improvement, keeping in view its safety, high dose ascorbic acid is advised to all the patients.

Splenectomy may be beneficial in cases of accelerated phase12. Allogenic bone marrow transplantation is the treatment of choice, and should be performed early from an HLA matched family or unrelated donor. Bone marrow transplant does not alleviate neurological or skin problems. Other treatment modalities in accelereated phase include acyclovir, interferon, vincristine, vinblastine and cholchicine2.