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Home , Hepatomegaly, Hepatosplenomegaly, Jaundice, Splenomegaly

| Case Presentation | No. 01-2018 | A 7 year old girl with and massive Mohammad Mizanur Rahman, Md. Mehedhi Hasan Shourov, Debashish Saha, Md. Abdul Ali Miah and S. M. Motahar Hossain

Article Info Presentation of Case advised to get her admitted into the children ward for further management. In the child Departet of Heatology, Ared Dr. Md. Mehedhi Hasan Shourov: A 7 year old ward, patient and her parents were thoroughly Fores Istitute of , Dhaka Catoet, Dhaka, Bagladesh MMR, girl reported to the child outpatient department interviewed and the child was re-examined. MMHS; Departet of Bioheistry, of a military hospital in Chittagong (South-East The indoor ordered initial routine Dhaka Catoet, Dhaka, Bagladesh part of Bangladesh) Cantonment with the com- investigations such as complete blood count, DS; Departet of Mediie, Co- plaints of generalized weakness, loss of appe- peripheral blood film examination, ied Military Hospital, Dhaka, Bagla- desh MAAM, SMMH tite, gradual distention of the and parasite, immuno-chromatographic test for weight loss. malaria, random blood sugar, function tests, routine and microscopic examina- The child was reasonably well and performing tion. After getting the results of all investi- For Correspondene: all her daily activities at her own 1 year before. Mohaad Mizaur Raha gations, child specialists sat together, reviewed She was also going to the school regularly and iza@yahoo.o her history, physical findings and the results of was worried when her parents noticed the all investigations so far received, discussed the Reeied: Otoer distension of her abdomen and reluctant to take case in details and decided to refer the patient Aepted: Jauary food adequately. The child also developed Aailale Olie: Marh to a tertiary care military hospital at Dhaka for weakness and witnessed weight loss. At that further evaluation, proper diagnosis and time, there was no history of fever, , management. ISSN: - Olie , hematemesis and melena. She never - Prit got admitted into the hospital in the past. She In mid June 2015, the patient got admitted into DOI: ./suj.i. was immunized as per national immunization the child ward of a tertiary care military schedule and her milestones of development hospital, Dhaka. The attending child specialist were age proportional. The patient is the first re-examined the patient and reviewed all the Keyords: Aeia; Lier; Splee child of non-consanguineous parents, with investigations performed in Chittagong from normal per vaginal delivery and her only other where the case was referred. The pediatrician Cite this artile: sister who is one year of age is apparently also advised to repeat all the investigations so Raha MM, Shouro MMH, Saha D, normal. There were no of far done and added some other investigations Miah MAA, Hossai SMM. A year old mental retardation and her neurological func- girl ith aeia ad assie hepato- such as immunochromatographic test for Kala- spleoegaly. Bagaadhu Sheikh tions were intact. She did not receive any blood azar, Mantoux test, serum lipid profile, serum Muji Med Ui J. ; : -. transfusion. As her father has been serving in profile, electrophoresis, X-ray Chittagong as a vehicle driver, so the whole chest (P/A view), skull (A/P and lateral view), family was residing in Chittagong though their knee joint (A/P and lateral view), ultrasono- Copyright: The opyright of this artile is retaied permanent residence is in Lalmonirhat (North- graphy and computed tomography of whole y the authors [Atriutio CC-By .] West part of Bangladesh). abdomen and bone marrow examination. On the basis of history, physical findings and On examination in the child outpatient Depart- investigations done at Chittagong, a provisional Aailale at: ment, the patient was found moderately anemic diagnosis was made. .aglajol.ifo and had massive hepatosplenomegaly. There A Joural of Bagaadhu Sheikh Muji were no stigmata of chronic liver . Medial Uiersity, Dhaka, Bagladesh Examination of the alimentary system revealed non-tender distended abdomen. Liver was Provisional Diagnosis palpable about eight centimeters from the right Hereditary costal margin in mid clavicular line. 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. Dr Mohammad Mizanur Rahman: This 7 year old There were no evidences of ascities. No abnor- child had a history of , weight loss, mality was detected on examination of the generalized weakness, gradual distension of the cardiovascular, respiratory, nervous and mus- abdomen, moderate anemia and long standing culoskeletal systems. The attending physician painless massive hepatosplenomegaly. These 50 BSMMU J 2018; 11: 49-54

findings are relatively common in such a child in Table I Bangladesh and there are several differential diag- noses. However, findings such feature in a child of Laboratory data this age particularly in Bangladesh and Indian Subcontinent can help to narrow the list of the Variable Reference range, In the children ward, possible causes. Therefore, I will first focus on my Children (6–12 years)¶ Dhaka differential diagnosis. Hemoglobin (g/dL) 11.5–15.5 7.4 Hematocrit (L/L) 0.4–0.5 0.2 Tropical syndrome RBC (x1012/L) 4.0–5.2 2.5 Tropical splenomegaly syndrome, also known as Mean cell volume (fl) 77–95 69 hyper-reactive malarial syndrome, occurs due to White cell count (x109/L) 5.0–13.0 2.2 frequent assault of malaria over a long 1 Differential count (%) period leading to immunological over stimulation. This condition is most prevalent in many malarious Neutrophils 53 44 zones of the tropics including Uganda, Nigeria, Lymphocytes 39 47 New guinea and Congo as well as Indian subconti- Monocytes 04 04 nent.2 Tropical splenomegaly syndrome is described Eosinophils 02 05 by massive splenomegaly, , marked Basophils <1-2 00 elevations in serum IgM levels (more than 1000 IU/ Blasts 00 00 mL), antimalarial and a good clinical response to antimalarial with regression of count (x109/L) 170–450 65 splenomegaly, elevation of hemoglobin level and Peripheral blood film decreasing serum IgM level.3 Tropical spleno- ICT for malaria Negative megaly syndrome is not the result of active malarial ICT for Kala-azar Negative infection, though it appears that malaria is primari- Normal ly responsible for tropical splenomegaly syndrome. A peripheral smear for malaria parasite is usually Random plasma sugar 5.3 mmol/L negative and the malarial pigment is not found in Urine R/M/E Normal the biopsy material from the liver and spleen. The Mantoux test Negative continual presence of malarial antigen leads to an Serum lipid profile High serum triglycer- aberrant host response resulting in a reactive and ide (193 mg/dL); relatively benign lymphoproliferative disorder that low serum cholesterol affects the liver and spleen, seems more likely to be Serum iron profile Normal the pathogenesis of tropical splenomegaly syn- 4 Hb electrophoresis Normal drome. The condition may show the characters of severe hypersplenism including anemia and throm- Bone marrow study Suggestive of Gaucher bocytopenia.5 As the patient presented with long disease standing painless massive hepatosplenomegaly and ¶ Reference values are affected by many variables, including the demographics and the moderate anemia, these features are, therefore, laboratory methods used. The ranges used at the Armed Forces Institute of Pathology suggestive of tropical splenomegaly syndrome but (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 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 is a parasitic disease caused by Leish- mania donovani complex (comprising L. donovani, L. infantum, L. chagasi) that spread to people through the bite of the female phlebotomine sandfly.6 Leishmania infection in human is caused by more than 20 species of Leishmania. The risk factors which may predispose to such include: Poverty, malnutrition, deforestation and urbanization.7 In about 98 countries, 4 to 12 million people are infected and two million new cases are infected each year. Between 20 and 50 thousand deaths occur in every year. About 200 million people are residing in areas such as Asia, Africa, south and central America and southern Europe where Figure 1: Leishman stained bone marrow slide showing Gaucher cell (indicated by leishmaniasis is common.8 More than 90% of the arrow) World's cases of are in India,

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differentiation and the t (9:22) (q34:q:11) leading to Table II formation of BCR-ABL fusion gene. Chronic mye- loid is uncommon in childhood, accoun- Report of enzyme assay ting for only 2 to 5% of all . It has incidence of <1 case per 1,00,000 population youn- Beta–glucocerebrosidase value (nmol/hour/mg) Remarks ger than 20 years of age per year.16 Chronic myeloid >4 Normal activity leukemia accounts less than 10% of all leukemias 2–4 Possibility of carrier under the age of 20 years and 7–20% of all leukemias seen at all ages. After the age of 60 years <2 Deficient activity it is very rare and occasionally occurs in children.17 Patient value 0.56 nmol/hour/mg About 50 years ago, two forms of chronic myeloid leukemia were described in children. One had the Bangladesh, Nepal, Sudan, and Brazil.9 Visceral typical features of chronic myeloid leukemia of leishmaniasis, which is usually caused by L. adulthood and appeared in children after the age of donovani, is the most serious form and potentially 4 years; the another type affected children in bet- fatal if untreated and is characterized by fever, ween 1 and 4 years of age and presented as massive splenomegaly, hepatomegaly and anemia.10 myelomonocytic proliferation associated with Visceral leishmaniasis is diagnosed in the hemato- hemorrhage, infection, and logy laboratory by direct visualization of LD body . The prognosis of the later group is invariably in aspirates from the bone marrow, spleen and poor.18 The hallmark of juvenile type chronic nodes.11 In this case, moderate anemia and myeloid leukemia is the absence of Philadelphia massive hepatosplenomegaly favor the diagnosis of chromosome. Philadelphia chromosome is rarely chronic visceral leishmaniasis but absence of fever, seen in children.19, 20 Chronic myeloid leukemia is anorexia and residing in an area where leishma- divided into three phases: Chronic, accelerated and niasis is uncommon are the features against visceral blast phase. Approximately 85% of patients with leishmaniasis. chronic myeloid leukemia are in chronic phase at the time of diagnosis. During chronic phase patient Chronic may be completely asymptomatic or may have is the disease of the liver hypermetabolic symptoms such as fatigue, increa- lasting over a period of six months characterized by sed sweating and loss of appetite, weight loss and progressive destruction and regeneration of liver sometimes with features indicative of hepato- parenchyma resulting in fibrosis, and in splenomegaly.21, 22 Massive splenomegaly, weight some cases .12 In day to loss and the presence of moderate anemia in this day clinical practice in Bangladesh, patients with patient was in favor of the diagnosis of chronic chronic liver disease is commonly encountered. No myeloid leukemia but age of the patient, hepato- age is immune for chronic liver disease and often megaly and absence of hyper-metabolic symptoms causes prolonged morbidity and is an important were the features against the diagnosis of chronic cause of premature death.13 There are many myeloid leukemia. conditions and causes of chronic liver disease, Lysosomal storage among which B and virus are the most important etiological factors. Besides these, Lysosomal storage diseases are genetically inherited non-alcoholic hepatic steatosis and autoimmune metabolic disorders resulting from defects in lyso- hepatitis also contribute to the development of somal function usually as a consequence of deficien- chronic liver disease.14 Patients with chronic liver cy of a single enzyme required for the metabolism disease clinically may present with ascities, features of lipids, glycoproteins or mucopolysaccharides. of hypersplenism with or without splenomegaly, Individually lysosomal storage diseases occur with anemia, jaundice, bleeding manifestations and other incidences of less than 1:100,000. However, as a stigmata of chronic liver disease (palmar erythema, group the incidence is 1:5,000–1: 10,000. Most of the nail clubbing, spider nevi).15 Moderate anemia and lysosomal storage diseases are usually inherited in splenomegaly are in favor of chronic liver disease autosomal recessive fashion and results from but massive hepatomegaly, absence of ascities, different gene mutations that translate into a jaundice and stigmata of chronic liver disease deficiency of enzyme activity and therefore they all oppose the diagnosis of chronic liver disease. share common biochemical characteristic– an abnormal accumulation of substances within the Chronic myeloid leukemia lysosome. The lysosomal storage diseases are Chronic myeloid leukemia is a clonal stem cell generally classified by the nature of the primary myeloproliferative disorder almost exclusively stored material involved and can be broadly broken occurring in adults with peak incidence in between into lipid storage disorders (such as Gaucher 40 and 60 years of age. It is characterized by a disease, Niemann Pick disease), mucopolysaccha- proliferation of myeloid cells of all stages of ridoses (Hunter and ), glycogen

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storage disorders (Pompe disease) and muco- Discussion lipidoses.23, 24 Lysosomal storage diseases affect mostly children and they often die at younger and Dr. Rahman: It is now an established and settled unpredictable age. The symptoms of lysosomal issue that Gaucher disease is a genetic disorder. storage disease vary, depending on the particular Genetic disorders in children are not that rare any- disorder and other variables like the age of onset, more, almost in every block on every street we see and can be mild to severe. They can include syndromic child with some form of genetic disor- developmental delay, movement disorders, sei- ders. Many of the general people don't understand zures, dementia, deafness and/or blindness. Some the reason behind their unusual appearance and people with lysosomal storage disease have massive behavior. Also most people thought that genetic hepatosplenomegaly, pulmonary and cardiac prob- studies are dead end investigations with no possible lems and bones that grow abnormally.25 Gaucher treatment. But this is not fact as the treatment is and Niemann Pick diseases are the most important available for some genetic diseases such as Gaucher cause of massive hepatosplenomegaly in children. disease, Pompe disease, Hurler syndrome, Febry As this patient presented with long standing pain- disease, , mucoplosaccharidoses less massive hepatosplenomegaly, moderate anemia type VI and Niemann Pick disease, type I.26 without fever, no past history of malaria as well as About 1 in 100 people in the United States are no neurodegenerative regression and involvement carriers of the gene for type I Gaucher disease of musculoskeletal system, among the lysosomal which is the most common type. The month storage diseases, Gaucher disease is the most likely October marks as the National Gaucher's Disease diagnosis. Awareness month in the United States.27 Dr. Mahbuba Sultana: After two days I got the results Each type of Guacher disease has been linked to the of the laboratory and radiological investigations particular mutations. There are about 80 known which were sent after getting admitted into the mutations, grouped into three main types. military hospital, Dhaka. The results of the labo- N370S homozygote is responsible for type I ratory investigations are shown in Table I. Gaucher disease, also called the "non-neuropathic" Radiological and imaging investigations revealed type and occurs mainly in Ashkenazi Jews, about normal chest skiagram and X-ray of the skull and 100 times the occurrence in the general population. knee were normal. Ultrasonogram and computed The median age at diagnosis is 28 years of age and tomography of the whole abdomen showed moder- the life expectancy is mildly decreased. Type II (one ately enlarged liver and hugely enlarged spleen. or two alleles L444P) is characterized by neurologi- Bone marrow examination depicted a hypercellular cal problems among small children. The enzyme is marrow with increased M:E ratio. Erythropoiesis hardly released into the lysosomes. The prognosis is and granulopoiesis were depressed. Megakaryo- poor. Most of them die before the age of three. Type cytes were normal. Marrow is heavily infiltrated III (also one or two copies of L444P, possibly with numerous large cells having fibrillary delayed by protective polymorphisms) occurs in cytoplasm morphologically resemble Gaucher cell Swedish patients. This group develops the disease (Figure 1). Bone marrow examination was carried somewhat later, but most of them die before their out by Dr. Rahman who also informed that the bone 30th birthday.28 marrow aspirate was also stained with Periodic Acid Schiff (PAS) stain which gave strong positivity Gaucher disease is suggested based on the overall suggesting the diagnosis of Gaucher disease. Dr. clinical picture which was present in this patient. Rahman also gave advice to perform leucocyte acid Initial screening test is serum chitotriosidase. This beta-glucocerebrosidase assay, DNA analysis for enzyme assay is simple. The enzyme chitotriosidase GBA gene, plasma chitotriosidase assay and serum has proved to be very useful for screening as well as ferritin and lipid profile measurement. To confirm monitoring Gaucher's disease activity in response to the diagnosis of Gaucher disease, I sent the patient’s treatment and may reflect the severity of the blood sample overseas for the estimation of disease. Next laboratory test include glucocerebro- leucocyte acid beta-glucocerebrosidase assay. After sidase enzyme assay. Decreased enzyme levels in two weeks I received the result of enzyme assay the leucocytes is often confirmed by genetic testing. which was markedly diminished (0.56 nmol/hour/ As there are numerous different mutations, mg) and shown in Table II, confirming the sequencing of the beta-glucosidase gene is some- diagnosis of Gaucher disease. times necessary to confirm the diagnosis. Prenatal diagnosis is available and is useful when there is a

known genetic risk factor. A diagnosis can also be Dr. Shourov’s Diagnosis supported by the biochemical abnormalities such as high , angiotensin-converting Gaucher disease enzyme, serum triglyceride and serum ferritin

BSMMU J 2018; 11: 49-54 53 and immunoglobulin level as well as low serum disease, the mutations responsible for this type of cholesterol or by cell analysis showing "crinkled disease express the very low level of enzyme paper" cytoplasm and glycolipid-laden activity.32 macrophages on H and E staining.29 Dr. Hossain: Did this patient develop hyper- I would like to inform that from January 2016 to splenism? July 2017, two cases were diagnosed as Guacher Dr. Mohammad Shahidul Islam: This patient develops disease by morphological examination of bone the features of secondary hypersplenism such as marrow aspirate at the Armed Forces Institute of pancytopenia, massive splenomegaly and hyper- Pathology (AFIP), Dhaka cantonment, Bangladesh. cellular bone marrow. Dr. Abdul Ali Miah: Enzyme replacement therapy is Dr. Haque Mahfuz: Why didn’t you include juvenile now available and if the enzyme is given intra- chronic myeloid leukemia as one of the differential venously, it can dramatically decrease the liver and diagnosis? spleen size, reduce the skeletal abnormalities and reverse other manifestations but the cost is very Dr. Shourov: I have included chronic myeloid high. Due to low incidence of the disease, this drug leukemia as one of the differential diagnosis. has become an orphan drug in many countries.30 Juvenile chronic myeloid leukemia is an old term which was described about 50 years ago. Now the Dr. S. M. Motahar Hossain: The incidence of type I term Juvenile chronic myelomonocytic leukemia is Gaucher disease is gradually increasing, giving a used.18 prevalence of one in 40,000. Among Ashkenazi Jews, the rate of carriers is considerably higher, at Dr. Mahfuz: Should we consider bone marrow roughly one in 15. Type I Gaucher disease is most transplantation as one of the effective mode of common and its prognosis is also good if ERT can treatment? be given. However, successful bone marrow trans- plantation in the treatment of Gaucher disease may Dr. Lutfunnahar Khan: Successful bone marrow cure the disease but the procedure carries signi- transplantation cures the non-neurological manifes- ficant risk and is now rarely considered in the tation of the disease as it introduces monocyte treatment of Gaucher disease.31 population with active beta-glucosidase activity. But the procedure carries significant risk and is Dr. Mehedi (Trainee in ): What is the patho- rarely performed in Gaucher disease.31 genesis of bone deformity in Gaucher disease? Dr. Syed Zoherul Alam: What are the radiological Dr. Shourov: Progressive infiltration of Gaucher cells findings you expect in Gaucher disease? in bone marrow results in thinning of the cortex, pathological fracture, bone pain, bone infarct and Dr. Rahman: Most patients with type I Gaucher osteopenia. These bony changes may result in disease have radiological evidence of skeletal Erlenmeyer flask deformity of the distal femur.32 involvement including an early change, Erlenmeyer flask deformity of the distal femur. In patients with Dr. Asfaque (Trainee in Surgery): What is the fate of symptomatic bone disease, lytic lesions can develop the patient with Gaucher disease if untreated? in the long bones, ribs and pelvis and osteosclerosis may be evident at an early age.32 Dr Md. Monirul Islam: If remain untreated, patient gradually develops bone marrow failure, pulmo- nary disease and nephropathy or glomerulo- nephritis which may lead to death.32 Final Diagnosis Dr Manun Mostafe: What is the mechanism of Gaucher disease development of anemia?

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