II year Postgraduate - CPA Chennai · —ChediakHigashi Syndrome presenting in Accelerated phase...

Dr.P.Subramani

II year Postgraduate

SRMCDr.Latha RavichandranProfessorDepartment of pediatrics

Dr.Julius Xavier ScottProfessorDepartment of pediatric hematooncology

Sri Ramachandra University, Porur.

CASE HISTORY

— 3 months old, Girl infant

— History of hypopigmentation over the skin x 1 month

— Recurrent respiratory tract infection x 1 month

— Fever x 3 days

— Loose stools x 2 days

GENERAL EXAMINATION

— Febrile (Temp 100.3 F).— Vitals stable

— Anthropometry:— Normal

— Pallor present.— Blond hair

— Intermittent areas of skin hypopigmentation over face, trunk and limbs— Cervical and axillary lymph nodes palpable.

SYSTEMIC EXAMINATION— Spleen 3 cm below left costal margin.

Liver 1 cm below right costal margin.

Other systems- NAD.

PROBLEM LIST

Fever

Splenohepatomegaly

Hypopigmentation

Blond hair

Recurrent infections

DIFFERENTIAL DIAGNOSISDD RULED OUT

1. IEM Urine for metabolic screening :NEGATIVE

2. TORCH infection TORCH panel: NEGATIVE

3. Immunodeficiency Immunoglobulin Assay : NORMAL

Further workup was planned.

INVESTIGATIONS

INVESTIGATION REPORT

Hb 6.6g/dl

Total count 5900/cu.mm

Lymphocytes 81

MCV 75

Platelets 60,000

RFT/serumelectrolytes

Normal

LFT/coagulation profile

Normal

INVESTIGATION REPORT

Uric acid 2

LDH 735

DCT NEGATIVE

Serum ferritin 2734

Triglycerides 323mg/dl

CXR and XraySkull,USG abdomen

Normal

INVESTIGATIONSINVESTIGATION REPORT

Hb 6.6g/dl

Total count 5900/cu.mm

L 81

PCV 19.2

MCV 75

Platelet 60,000

BUN 15

S.Creatinine 0.5

Peripheral smear Microcytic,thromocytopenic

INVESTIGATION REPORT

Serum electrolytes NORMAL

Uric acid 2

PT/PTT/INR NORMAL

LDH 735

S.G.O.T 146

S.G.P.T 70

DCT NEGATIVE

TOTAL BILIRUBIN 0.87

CXR NAD

HLH CRITERIA OUR CASE— Fever

— Splenomegaly

— Cytopenia ( more than or 2 cell lineages)

— Hypertriglyceridemia/

Hypofibrinogenemia

— Hyperferritinemia

— Low/Absent NK cell activity

— Hemophagocytosis

— Elevated soluble CD25

— Fever

— Splenomegaly

— Bicytopenia

— Hypertriglyceridemia -323mg/dl

— Hyperferritinemia- 2734

HLH – ?Familial? Secondary to infection

SUSPICION OF HLH

HLHHypo

pigmentation

Blond hair

Recurrent infection

MISSING LINK

?

PERIPHERAL SMEARRBC:

•Microcytic hypochromic with anisocytosis

WBC:•Few reactive lymphocytes

•Few lymphocytes showing large abnormal granules

PLATELET COUNT:•Thrombocytopenia

HLH

Hypo

Pigment

\Blond hair

CHSAccelerated

phase

Recurrent infections

PS- Granules

BONE MARROW SKIN BIOPSY

1. Hemophagocyte2. Large Granules

1. Irregulary arranged large melanosomes.

MANAGEMENT— Control infection

— IV Piperacillin/Tazobactum, Amikacin

— Stepped up to Meropenem

— IV fluconzole

— To find the source of infection— Blood &Urine C/S- NO GROWTH

Further Treatment Plan….— Ophthalmology evaluation : Not suggestive of occular

albinism

— Parents were counselled about the prognosis

— Genetic counselling given.

— Planned to continue IV antibiotics for a week

— Dexamethasone + Etoposide and intravenous immunoglobulin thrice weekly (HLH 2004 PROTOCOL)

— Referral to transplant physician

— Parents were not willing for any further approach of treatment and wanted to continue with the conservative plan of management.

— Child succumbed to illness 2 days post discharge.

CHEDIAK HIGASHI SYNDROME— Rare autosomal recessive disorder characterized by Ø Recurrent pyogenic infections,

Ø Partial oculocutaneous albinism,

Ø Progressive neurologic abnormalities,

Ø Mild coagulation defects,

Ø A lymphoma-like accelerated phase

— Less than 500 cases have been reported worldwide.

— First case in India reported in 1982

— *Chediak-Higashi syndrome. Kaplan J, De Domenico I, Ward DM

— Curr Opin Hematol. 2008;15(1):22.

PATHOGENESIS• Mutation in the lysosomal trafficking

regulator (CHS1/LYST) gene at 1q42

• Abnormal organellar protein trafficking

• Aberrant fusion of vesicles

• Failure to transport lysosomes to the appropriate site of action

Altered lysosomes/granules are found in all cell types in CHS, and are the hallmark of the disease

*Identification and mutation analysis of the complete gene for Chediak-Higashi syndrome. Nagle DL, Karim MA, Woolf EA, Holmgren L. Nat Genet. 1996;14(3):307.

RECURRENT INFECTIONS

HYPOPIGMENTATION

MILD BLEEDING DIATHESIS

Defective neutrophilchemotaxis, degranulation

and bactericidal activity.

Giant granules – Interfere with the cells ability to traverse the narrow passages between endothelial cells into tissue.

Impaired NK cell function

Pathologic aggregation and uneven distribution of

melanosomes

Impaired Platelet Aggregation

CLINICAL MANIFESTATIONS

— Partial oculocutaneousalbinism

— Hepatosplenomegaly and lymphadenopathy.

— Gingivitis, oral ulcerations, and periodontal disease.

— Recurrent pyogenicinfections

— Mild coagulation defect

— Ocular manifestations include photophobia, decreased visual acuity, nystagmus, and strabismus.

About 10 percent of patients survive early childhood despite serious infections, but develop severe, debilitating neurologic

manifestations in adolescence and early adulthood

DIAGNOSIS— Peripheral blood smear for the classic large granules

in all nucleated giant cells.

— Examination of skin melanocytes reveals giant melanosomes.

— Genetic testing for mutations in the CHS1/LYST gene.

— Light microscopy of hair shafts shows small aggregates of clumped pigmentation that are irregularly distributed.

— CHS can be diagnosed prenatally by examining amniotic or chorionic villus cells for enlarged lysosomes.

ACCELERATED PHASE— Lymphohistiocytic infiltration of virtually all organ

systems .

— Even more profound immune deficiency.

— Patients present with fever, increased hepatosplenomegaly and lymphadenopathy, and worsened pancytopenia and bleeding.

— This phase occurs in more than 80 percent of patients and is usually lethal.

MANAGEMENT— Supportive

— High dose Ascorbic acid improves the clinical status in stable phase- Controversy.

— IV antibiotics for infections.

— CURATIVE THERAPY : Stem Cell Transplant

MANAGEMENTINITIAL 8 WEEKS CHEMOTHERAPY

•Etoposide•Dexamethasone

•IT Methotrexate

(after 2 weeks when progressive neurological symptoms)

FAMILIAL

PERSISTANTNon-Familial

RESOLVEDNon-Familial

Stop Therapy

Re activation

HSCT

Accelerated Phase : HLH 2004 protocol.

— Chediak Higashi Syndrome presenting in Accelerated phase— Tanzeel Imran, Lybna Zafar, Madeeha Rehan— Journal of college of Physicians and surgeons Pakistan 2012

— A 2 year old boy presented with high grade fever, cough, swelling of neck and abdominal distention. pallor, hepatosplenomegaly significant cervical lymphadenopathy,enlarged axillary and inguinal lymph nodes. He also had silver hair and partial cutaneous albinism since birth.

— Bone marrow aspirate also revealed prominent histiocytes and haemophagocytosis. On the basis of his clinical presentation, peripheral blood film and bone marrow aspirate findings, the diagnosis of Chediak-Higashi syndrome was established.

— Unfortunately patient expired after 24 days of hospital stay.

— Chédiak-higashi Syndrome: An Accelerated Phase With Hereditary Elliptocytosis

— Abu Sharif M. A. Islam, MD; Zakaria M. Hawsawi, MD;

— Annals of Saudi Medicine, Vol 21, Nos 3-4, 2001

— 2 year-old male, blond hair and patchy cutaneoushypopigmentation, H/O recurrent Respiratory tract infections. Blood reports revealed features of HLH.

— Peripheral smear, Bone marrow confirmed Chediak Higashi Syndrome.

— Bone marrow transplantation was performed. Boy clinically well.

— Chediak higashi can present with — Oculo Cutaneous albinism, — Splenomegaly, — Lymphadenopathy, — Fever and H/O recurrent infections.

— Carefully examined peripheral smear can clinch the diagnosis.

— Accelerated phase of CHS presents as HLH.

— Since the disease is usually lethal in the first decade, its early detection may facilitate early BMT, which is the only curative approach.

THANK YOU !!THANK YOU !!