Haematology Watch, Vol 3, Issue 1.
CASE REPORTCASE REPORT
A YOUNG BOY HAVING FEVER, ORGANOMEGALY, AND GREY HAIR
Mehmood-ul-Hasan
A young child of 10 presented on 28th Sep, 2010 with fever and cough for 15 days.
Hx:
Has taken antibiotic but got no benefit. Mother gave history of normal developmental milestones.
One brother died after recurrent infections and hepatosplenomegaly.
Examination:
Greyish brittle hair
Pulse: 125/min
BR: 55/min
Temp.: 102 F
B.P.: 90/60 mm Hg
Jaundice
Albinism
Enlarged tonsils.
Bilateral cervical lymphadenopathy
Liver: 9 cm BCM (below costal margin)
Spleen: 7 cm BCM
His laboratory investigation revealed:
Complete blood count:
TLC: 5.33 K/ul
RBC: 4.32 M/ul
Hb: 9.2 g/dl
Hct: 30%
MCV: 69.4 fl
MCH: 21.3 pg
MCHC: 30.7 g/dl
Plt: 113 K/ul
ANC: 0.47 K/ul
ALC: 4.05 K/ul
AMC: 0.75 K/ul
AEC: 0.01 K/ul
ABC: 0.05 K/ul
Chemistry:
S. Bilirubin 21 (< 17 µmol/l)
S. ALT: 79 (< 45 U/l)Alk. Phos.: 351 (65-306 U/l)
Culture:
Throat Swab culture: Normal throat flora
As his CBC revealed bicytopenia, and he had organomegaly, a peripheral blood morphology report and lymph node FNAC (fine needle aspiration cytology) was advised suspecting Leukaemia/Lymphoma.
TLC: 4.94 K/ul
RBC: 3.58 M/ul
Hb: 7.7 g/dl
Hct: 25 %
MCV: 70 fl
MCH: 21.5 pg
MCHC: 30.7 g/dl
Plt: 51 K/ul
ANC: 2.06 K/ul
ALC: 2.26 K/ul
AMC: 0.58 K/ul
AEC: 0 K/ul
ABC: 0.04 K/ul
Fig. 1 A. Peripheral morphology x40 Objective. Leishman stained.
Fig. 1 B & C: x100 Showing abnormal granules in lymphocyte and neutrophil.
Peripheral blood morphology:
Aniso+
Poikilo+
Micro+
Hypo+
Reticulocytes: 1.5%
NRBC/100 WBC: 15
[Corrected TLC:
For 100 WBC=15 NRBC
For 4940 WBC=(15/100)(4940)
=741 NRBC
Corrected TLC: 4940-741=4199/uL]
No platelet clumps seen. Thrombocytopenia.
Opinion: Bicytopenia.No abnormal cells seen. Abnormal Intracellular inclusions in leukocytes.
FNAC showed Reactive lymph node.
Monospot test was negative.
As his blood cell counts were decreasing progressively, a bone marrow examination was advised.
Fig. 2 A Bone marrow apirate. X4 Objective. Leishman stained.
Fig. 2 B & C. x40 Objective. Leishman stained.
Fig. 2 C. Showing absence of iron. Perl's stain.
Bone Marrow Aspiration report:
Site: PSIS
Aspiration: Easy
Cellularity: Increased
Myelopoiesis: Left shift with toxic granulation and inclusions
Erythropoiesis: Normoblastic
M:E : 3:1
Megakaryopoiesis: Increased
Abnormal cells: Haemophagocytosis and Histiocytes reactive
Iron: Absent
Opinion: Reactive marrow showing marked haemophagocytosis, with giant inclusion bodies predominantly in myeloid precursor cells consistent with Chediak-Higashi Syndrome.
Fig. 3 A. Bone Marrow trephine biopsy. x4 objective.
Fig. 4 B. Bone marrow trephine biopsy. x40 Objective.
Bone marrow trephine biopsy showed no evidence of lymphoma/leukaemia.
Coagulation tests:
Bleeding time: 2 min 15 sec
PT: 16 sec (Control: 12 sec)
APTT: 34 sec (Control: 30 sec)
As bleeding time was normal, platelet function tests were not performed.
Viral Serology:
HB sAg: Negative
Anti-HCV Ab: Negative
Chemistry:
S. Bilirubin: 70 (< 17 µmol/L)
S. ALT: 130 (< 45 U/L)
Alk. Phos.: 1910 (65-306 U/L)
S. Urea: 3.6 (3.3 – 8.3 mmol/L)
S. Creatinine: 80 (60 – 156 µmol/L)
S. Na: 142 (136 – 145 mmol/L)
S. K: 4.4 (3.4 – 5.0 mmol/L)
S. Cl: 102 (98 – 106 mmol/L)
Hair were taken from the patient which showed following appearance compared to control normal man:
Fig. 4 A. Control hair showing normal pigmentation.x40 Objective.
Fig. 4 B. Showing hair of the patient. Note reduced pigmentation.
His eye examination showed hyperpigmentation of iris, and the mother revealed absence of photophobia and photosensitivity, which contrast with the usual features of the disease.
The blood cell counts of the child fell progressively, and Chediak-Higashi Syndrome was dominated by Haemophagocytic Syndrome, thus leading towards death of a patient who spent his last day in uncontrollable epistaxis and seizures.
DISCUSSION
Chédiak–Higashi syndrome is a rare disorder inherited as an autosomal recessive disorder; less than 200 cases are reported. It arises from a microtubule polymerization defect which leads to a decrease in phagocytosis. The decrease in phagocytosis results in recurrent pyogenic infections, partial albinism and peripheral neuropathy.
It is named for the Cuban physician and serologist Alexander Moises Chediak, and the Japanese pediatrician Otokata Higashi. It is a disease with impairedbacteriolysis due to failure of phagolysosome formation. As a result of disordered intracellular trafficking there is impaired lysosome degranulation with phagosomes, so phagocytosed bacteria are not destroyed by the lysosome's enzymes. In addition, secretion of lytic secretory granules by cytotoxic T cells is also affected.
The disease is characterised by large lysosome vesicles in phagocytes (neutrophils), which thus have poor bactericidal function, leading to susceptibility to infections, abnormalities in nuclear structure of leukocytes, anaemia, and hepatomegaly.
The diagnosis is confirmed by bone marrow smears that show "giant inclusion bodies" in the cells that develop into white blood cells (leukocyte precursor cells). CHS can be diagnosed in a fetus (prenatally) by examining a sample of hair from a fetal scalp biopsy or testing white blood cells (leukocytes) from a fetal blood sample.
Chédiak–Higashi syndrome is caused by mutations in the LYST gene. This gene provides instructions for making a protein known as the lysosomal trafficking regulator. Researchers believe that this protein plays a role in the transport (trafficking) of materials into structures called lysosomes. Lysosomes act as recycling centers within cells. They use digestive enzymes to break down toxic substances, digest bacteria that invade the cell, and recycle worn-out cell components. Although the lysosomal trafficking regulator protein is involved in the normal function of lysosomes, its exact role is unknown.
Patients with CHS have light skin and silvery hair, and frequently
complain of solar sensitivity and photophobia. Other signs and symptoms
vary considerably, but frequent infections and neuropathy are common.
The infections involve mucous membranes, skin, and respiratory tract.
Affected children are susceptible to gram-positive and gram-negative
bacteria and fungi, with S. aureus being the most common offending
organism. Neuropathy often begins in the teenage years and becomes the
most prominent problem. Infections in CHS tend to be very serious and
even life-threatening; few patients with this condition live to
adulthood. Same is the case here what we experienced.
Most children with Chédiak–Higashi syndrome ultimately reach a stage of the disorder known as the accelerated phase - the lymphoma-like-syndrome. This severe phase of the disease is thought to be triggered by a viral infection (usually Epstein Barr Virus, EBV). In the accelerated phase, defective white blood cells divide uncontrollably and invade many of the body's organs. The accelerated phase is associated with fever, episodes of abnormal bleeding, overwhelming infections, and organ failure. These medical problems are usually life-threatening in childhood.
Mutations have been found in the CHS1 (also called LYST) gene. The primary defect in this disease is in special granules present in skin pigment cells and certain white blood cells. For example, a granule that contains m
elanin is not made properly in skin, resulting in decreased skin pigmentation. A defect in granules found in certain types of white blood cells causes immune system problems. Albinism is typically partial.
There is no specific treatment for Chédiak–Higashi syndrome. Bone marrow transplants appear to have been successful in several patients. Infections are treated with antibiotics and abscesses are surgically drained when appropriate. Antiviral drugs such as acyclovir have been tried during the terminal phase of the disease. Cyclophosphamide and prednisone have been tried. Vitamin C therapy has improved immune function and clotting in some patients.
There are several manifestations of Chédiak–Higashi syndrome as mentioned above; however, neutropenia seems to be the most common. The syndrome is also associated with oculocutaneous albinism. There was hyperpigmentation of iris in our patient! Associated features are abnormalities in melanocytes (albinism), nerve defects, bleeding disorders. Bleeding time was normal in our patient.
The case report emphasizes the role of a keen examination of peripheral blood morphology, the possibility of variation of presentation, and the benefit of chronological assessment of CBC and other tests (which led to the detection of the accelerated phase by bone marrow aspiration, thus preventing unknown cause of death in this patient).