A 7 year old girl with anemia and massive hepatosplenomegaly

This article has no abstract. The first 100 words appear below: A 7 year old girl reported to the child outpatient department of a military hospital in Chittagong (South-East part of Bangladesh) Cantonment with the complaints of generalized weakness, loss of appe-tite, gradual distention of the abdomen and weight loss. The child was reasonably well and performing all her daily activities at her own 1 year before. She was also going to the school regularly and was worried when her parents noticed the distension of her abdomen and reluctant to take food adequately. The child also developed weakness and witnessed weight loss. At that time, there was no history of fever, jaundice, vomiting, hematemesis and melena.

On examination in the child outpatient Department, the patient was found moderately anemic and had massive hepatosplenomegaly.There were no stigmata of chronic liver disease.Examination of the alimentary system revealed non-tender distended abdomen.Liver was palpable about eight centimeters from the right costal margin in mid clavicular line.Spleen was also palpable about 18 cm from the left costal margin in mid clavicular line.Both liver and spleen were non-tender, firm in consistency and have smooth surface with regular margin.There were no evidences of ascities.No abnormality was detected on examination of the cardiovascular, respiratory, nervous and musculoskeletal systems.The attending physician advised to get her admitted into the children ward for further management.In the child ward, patient and her parents were thoroughly interviewed and the child was re-examined.The indoor physician ordered initial routine investigations such as complete blood count, peripheral blood film examination, malaria parasite, immuno-chromatographic test for malaria, random blood sugar, liver function tests, urine routine and microscopic examination.After getting the results of all investigations, child specialists sat together, reviewed her history, physical findings and the results of all investigations so far received, discussed the case in details and decided to refer the patient to a tertiary care military hospital at Dhaka for further evaluation, proper diagnosis and management.
In mid June 2015, the patient got admitted into the child ward of a tertiary care military hospital, Dhaka.The attending child specialist re-examined the patient and reviewed all the investigations performed in Chittagong from where the case was referred.The pediatrician also advised to repeat all the investigations so far done and added some other investigations such as immunochromatographic test for Kalaazar, Mantoux test, serum lipid profile, serum iron profile, hemoglobin electrophoresis, X-ray chest (P/A view), skull (A/P and lateral view), knee joint (A/P and lateral view), ultrasonography and computed tomography of whole abdomen and bone marrow examination.On the basis of history, physical findings and investigations done at Chittagong, a provisional diagnosis was made.

Differential Diagnosis
Dr Mohammad Mizanur Rahman: This 7 year old child had a history of anorexia, weight loss, generalized weakness, gradual distension of the abdomen, moderate anemia and long standing painless massive hepatosplenomegaly.These

Tropical splenomegaly syndrome
Tropical splenomegaly syndrome, also known as hyper-reactive malarial syndrome, occurs due to frequent assault of malaria infection over a long period leading to immunological over stimulation. 1his condition is most prevalent in many malarious zones of the tropics including Uganda, Nigeria, New guinea and Congo as well as Indian subcontinent. 2Tropical splenomegaly syndrome is described by massive splenomegaly, hepatomegaly, marked elevations in serum IgM levels (more than 1000 IU/ mL), antimalarial antibodies and a good clinical response to antimalarial therapy with regression of splenomegaly, elevation of hemoglobin level and decreasing serum IgM level. 3Tropical splenomegaly syndrome is not the result of active malarial infection, though it appears that malaria is primarily responsible for tropical splenomegaly syndrome.
A peripheral smear for malaria parasite is usually negative and the malarial pigment is not found in the biopsy material from the liver and spleen.The continual presence of malarial antigen leads to an aberrant host response resulting in a reactive and relatively benign lymphoproliferative disorder that affects the liver and spleen, seems more likely to be the pathogenesis of tropical splenomegaly syndrome. 4The condition may show the characters of severe hypersplenism including anemia and thrombocytopenia. 5As the patient presented with long standing painless massive hepatosplenomegaly and moderate anemia, these features are, therefore, suggestive of tropical splenomegaly syndrome but no past history of malaria as well as not residing in the malarial hyperendemic zone disfavors the diagnosis of tropical splenomegaly syndrome.

Chronic visceral Leishmaniasis
Leishmaniasis is a parasitic disease caused by Leishmania donovani complex (comprising L. donovani, L. infantum, L. chagasi) that spread to people through the bite of the female phlebotomine sandfly. 6eishmania infection in human is caused by more than 20 species of Leishmania.The risk factors which may predispose to such infections include: Poverty, malnutrition, deforestation and urbanization.

Hb electrophoresis Normal
Bone marrow study Suggestive of Gaucher disease ¶ Reference values are affected by many variables, including the demographics and the laboratory methods used.The ranges used at the Armed Forces Institute of Pathology (AFIP) are for children (6-12 years) who do not have medical conditions that could affect the results.They may, therefore, not be appropriate for all patients Bangladesh, Nepal, Sudan, and Brazil. 9Visceral leishmaniasis, which is usually caused by L. donovani, is the most serious form and potentially fatal if untreated and is characterized by fever, massive splenomegaly, hepatomegaly and anemia. 10isceral leishmaniasis is diagnosed in the hematology laboratory by direct visualization of LD body in aspirates from the bone marrow, spleen and lymph nodes. 11In this case, moderate anemia and massive hepatosplenomegaly favor the diagnosis of chronic visceral leishmaniasis but absence of fever, anorexia and residing in an area where leishmaniasis is uncommon are the features against visceral leishmaniasis.

Chronic liver disease
Chronic liver disease is the disease of the liver lasting over a period of six months characterized by progressive destruction and regeneration of liver parenchyma resulting in fibrosis, cirrhosis and in some cases hepatocellular carcinoma. 12In day to day clinical practice in Bangladesh, patients with chronic liver disease is commonly encountered.No age is immune for chronic liver disease and often causes prolonged morbidity and is an important cause of premature death. 13There are many conditions and causes of chronic liver disease, among which hepatitis B and hepatitis C virus are the most important etiological factors.Besides these, non-alcoholic hepatic steatosis and autoimmune hepatitis also contribute to the development of chronic liver disease. 14Patients with chronic liver disease clinically may present with ascities, features of hypersplenism with or without splenomegaly, anemia, jaundice, bleeding manifestations and other stigmata of chronic liver disease (palmar erythema, nail clubbing, spider nevi). 15Moderate anemia and splenomegaly are in favor of chronic liver disease but massive hepatomegaly, absence of ascities, jaundice and stigmata of chronic liver disease oppose the diagnosis of chronic liver disease.

Chronic myeloid leukemia
Chronic myeloid leukemia is a clonal stem cell myeloproliferative disorder almost exclusively occurring in adults with peak incidence in between 40 and 60 years of age.It is characterized by a proliferation of myeloid cells of all stages of differentiation and the t (9:22) (q34:q:11) leading to formation of BCR-ABL fusion gene.Chronic myeloid leukemia is uncommon in childhood, accounting for only 2 to 5% of all leukemias.It has incidence of <1 case per 1,00,000 population younger than 20 years of age per year. 16Chronic myeloid leukemia accounts less than 10% of all leukemias under the age of 20 years and 7-20% of all leukemias seen at all ages.After the age of 60 years it is very rare and occasionally occurs in children. 17bout 50 years ago, two forms of chronic myeloid leukemia were described in children.One had the typical features of chronic myeloid leukemia of adulthood and appeared in children after the age of 4 years; the another type affected children in between 1 and 4 years of age and presented as myelomonocytic proliferation associated with hemorrhage, infection, lymphadenopathy and skin rash.The prognosis of the later group is invariably poor. 18The hallmark of juvenile type chronic myeloid leukemia is the absence of Philadelphia chromosome.Philadelphia chromosome is rarely seen in children. 19,20 hronic myeloid leukemia is divided into three phases: Chronic, accelerated and blast phase.Approximately 85% of patients with chronic myeloid leukemia are in chronic phase at the time of diagnosis.During chronic phase patient may be completely asymptomatic or may have hypermetabolic symptoms such as fatigue, increased sweating and loss of appetite, weight loss and sometimes with features indicative of hepatosplenomegaly.21, 22 Massive splenomegaly, weight loss and the presence of moderate anemia in this patient was in favor of the diagnosis of chronic myeloid leukemia but age of the patient, hepatomegaly and absence of hyper-metabolic symptoms were the features against the diagnosis of chronic myeloid leukemia.

Lysosomal storage diseases
Lysosomal storage diseases are genetically inherited metabolic disorders resulting from defects in lysosomal function usually as a consequence of deficiency of a single enzyme required for the metabolism of lipids, glycoproteins or mucopolysaccharides.Individually lysosomal storage diseases occur with incidences of less than 1:100,000.However, as a group the incidence is 1:5,000-1: 10,000.Most of the lysosomal storage diseases are usually inherited in autosomal recessive fashion and results from different gene mutations that translate into a deficiency of enzyme activity and therefore they all share common biochemical characteristic-an abnormal accumulation of substances within the lysosome.The lysosomal storage diseases are generally classified by the nature of the primary stored material involved and can be broadly broken into lipid storage disorders (such as Gaucher disease, Niemann Pick disease), mucopolysaccharidoses (Hunter and Hurler syndrome), glycogen

Discussion
Dr. Rahman: It is now an established and settled issue that Gaucher disease is a genetic disorder.Genetic disorders in children are not that rare anymore, almost in every block on every street we see syndromic child with some form of genetic disorders.Many of the general people don't understand the reason behind their unusual appearance and behavior.Also most people thought that genetic studies are dead end investigations with no possible treatment.But this is not fact as the treatment is available for some genetic diseases such as Gaucher disease, Pompe disease, Hurler syndrome, Febry disease, Hunter syndrome, mucoplosaccharidoses type VI and Niemann Pick disease, type I. 26 About 1 in 100 people in the United States are carriers of the gene for type I Gaucher disease which is the most common type.The month October marks as the National Gaucher's Disease Awareness month in the United States. 27ch type of Guacher disease has been linked to the particular mutations.There are about 80 known mutations, grouped into three main types.N370S homozygote is responsible for type I Gaucher disease, also called the "non-neuropathic" type and occurs mainly in Ashkenazi Jews, about 100 times the occurrence in the general population.
The median age at diagnosis is 28 years of age and the life expectancy is mildly decreased.Type II (one or two alleles L444P) is characterized by neurological problems among small children.The enzyme is hardly released into the lysosomes.The prognosis is poor.Most of them die before the age of three.Type III (also one or two copies of L444P, possibly delayed by protective polymorphisms) occurs in Swedish patients.This group develops the disease somewhat later, but most of them die before their 30th birthday.Juvenile chronic myeloid leukemia is an old term which was described about 50 years ago.Now the term Juvenile chronic myelomonocytic leukemia is used. 18.Mahfuz: Should we consider bone marrow transplantation as one of the effective mode of treatment?
Dr. Lutfunnahar Khan: Successful bone marrow transplantation cures the non-neurological manifestation of the disease as it introduces monocyte population with active beta-glucosidase activity.But the procedure carries significant risk and is rarely performed in Gaucher disease. 31. Syed Zoherul Alam: What are the radiological findings you expect in Gaucher disease?
Dr. Rahman: Most patients with type I Gaucher disease have radiological evidence of skeletal involvement including an early change, Erlenmeyer flask deformity of the distal femur.In patients with symptomatic bone disease, lytic lesions can develop in the long bones, ribs and pelvis and osteosclerosis may be evident at an early age. 32

Final Diagnosis
Gaucher disease

Figure 1 :
Figure 1: Leishman stained bone marrow slide showing Gaucher cell (indicated by arrow)

Table I Laboratory data
Serum lipid profileHigh serum triglyceride (193 mg/dL); low serum cholesterolSerum iron profile Normal

Table II Report of enzyme assay
32zyme replacement therapy is now available and if the enzyme is given intravenously, it can dramatically decrease the liver and spleen size, reduce the skeletal abnormalities and reverse other manifestations but the cost is very high.Due to low incidence of the disease, this drug has become an orphan drug in many countries.30Dr.S. M. Motahar Hossain: The incidence of type I Gaucher disease is gradually increasing, giving a prevalence of one in 40,000.Among Ashkenazi Jews, the rate of carriers is considerably higher, at roughly one in 15.Type I Gaucher disease is most common and its prognosis is also good if ERT can be given.However, successful bone marrow transplantation in the treatment of Gaucher disease may cure the disease but the procedure carries significant risk and is now rarely considered in the treatment of Gaucher disease.Why type II and type III are more serious than type I Gaucher disease?Dr Rahman: The amount of residual enzyme (betaglucocerebrosidase) activity determines the disease subtype and severity.In type II and III Gaucher disease, the mutations responsible for this type of disease express the very low level of enzyme activity.32Dr.Hossain: Did this patient develop hypersplenism?Dr.Mohammad Shahidul Islam: This patient develops the features of secondary hypersplenism such as pancytopenia, massive splenomegaly and hypercellular bone marrow.Dr.Haque Mahfuz: Why didn't you include juvenile chronic myeloid leukemia as one of the differential diagnosis?Dr.Shourov: I have included chronic myeloid leukemia as one of the differential diagnosis.
31Dr.Mehedi (Trainee in Surgery): What is the pathogenesis of bone deformity in Gaucher disease?