Gaucher's disease is a rare lipid storage disorder, affecting one in 40,000-200,000 people and results from a genetic deficiency of the enzyme glucocerebrosidase (glucosylceramidase). We report a 10-year old Iranian girl with chief complaint of anemia from 8 years ago, managed for iron deficiency anemia. The patient had hepatomegaly associated with huge splenomegaly which was confirmed by sonography. No skeletal disorder was found. Bone marrow aspiration revealed typical Gaucher cells. Low level of β-glucocerebrosidase enzyme activity confirmed the Gaucher disease. The patient is now under treatment with CEREZIME, a recombinant DNA modified form of glucocerebrosidase with good condition. © 2008 Asian Network for Scientific Information

Davarian, A.

Mirbehbahani, N.B.

Pakistan Journal of Biological Sciences

Golestan University of Medical Sciences Repository

Pakistan Journal of Biological Sciences 11 (7): 1063-1065, 2008 ISSN 1028-8880 © 2008 Asian Network for Scientific Information Gaucher Disease: A 10 Year Old Girl with Anemia and Huge Spelenomegaly (A Case Report) 1Ali Davarian and 2Narges Beigom Mirbehbahani 1Faculty of Medicine, Gargan University of Medical Sciences, Gargan, Iran 'Department of Oncology, Faculty of Medicine, Gargan University of Medical Sciences, Gargan, Iran Abstract: Gaucher's disease is a rare lipid storage disorder, affecting one in 40,000-200,000 people and results from a genetic deficiency of the enzyme glucocerebrosidase (glucosylceramidase ). We report a 10-year old Iranian girl with chief complaint of anemia from 8 years ago, managed for iron deficiency anemia. The patient had hepatomegaly associated with huge splenomegaly which was confirmed by sonography. No skeletal disorder was found. Bone marrow aspiration revealed typical Gaucher cells. Low level of P-glucocerebrosidase enzyme activity confinned the Gaucher disease. The patient is now under treatment with CEREZI1.1E, a recombinant DNA modified form of glucocerebrosidase with good condition. Key words: Anemia, huge splenomegaly, Gaucher disease, @-glucocerebrosidase INTRODUCTION Gaucher's disease is the most common lipid storage disorder known and results from a genetic deficiency of the enzyme glucocerebrosidase (glucosylceramidase). Enzyme deficiency results m accwnulation of glucocerebroside within the reticuloendothelial system. It may present with delayed stanturoponderal growth, a cutaneomucous pallor hepatosplenomegaly, bone marrow suppression and bone lesions (Rachid et al., 2005; Morales, 1996). The blood count formula showed anemia with major thrombocytopenia. The myelogram was poor and the osteomedullar biopsy showed the presence of Gaucher's cells. The diagnosis has been confirmed by enzymatic dosage (Leucocytar P-glucosidase). Gaucher's disease is classified into three types: type 1 (non-neuronopathic), type 2 (acute neuronopathic) and type 3 (subacute neuronopathic). Of the three, type 1 is the most conunon, affecting one in 40,000-200,000 people and having a high prevalence among Ashkenazi Jews, affecting one in 450-1500 (Fumic et al., 2004). In 1991, enzyme treatment became available with the marketing of alglucerase, a placentally derived modified form of glucocerebrosidase. In 1994, a recombinant DNA modified form of glucocerebrosidase, known as imiglucerase, was developed to replace alglucerase. Most published data on enzyme therapy are with alglucerase in patients with type 1 disease. A dosage regimen of 60 units kg-1 every 2 weeks for moderate to severe ill patients has been effective in reducing hepatosplenomegaly, improving anemia and thrombocytopenia, as well as improving weight gain and growth in children and increasing vigor and self-esteem in adults. Bone involvement is often slow to respond to therapy although pain is frequently improved. Controversy exists as to whether lower dosage regimens are as effective. The role of enzyme therapy in the rarer neuronopathic subtypes remams to be determined, but initial reports have been disappointing (Morales, 1996; Butters, 2007; Starzyk eta!., 2007). CASE REPORT The patient was a 10 year old girl, third child of her family, result of C/S. Their parents were non-consanguineous and healthy. Their ethnic was KORD, non-jewish and other child are healthy. Her mother didu't use any drug during this pregnancy. The patient managed for iron deficiency anemia for the firs two years of her life. Easy bruising and paleness with decreased appetite were her chief complaint on her first visit to oncologist on 1385/8/24. CBC was taken, revealed WBC ~ 4300 µL _, (N ~ 45%, L ~ 52%, E ~ 3%), RBC ~ 4,190,000µL-',Hb~10.9mg dL_,, MCV ~78.28 fl, Flt = 52,000 mL - 1. Biochemistry revealed calcium = 9.1 mg dL-l and normal liver function. On physical examination, pale conjunctiva, clear lungs, Nl heart sound Corresponding Author: 	 Ali Davari.an, No.151- Farhangian Township, Shahidbeheshti Ave, Postal Code 49148-18955, Gorgan City, Golestan Province, Iran Tel: +989113710978 Fax: +98 (171) 4421657/4425165 1063 Pak. J. Biol. Sci., 11 (7): 1063-1065, 2008 Fig. 1: Bone marrow aspirate shows typical Gaucher cells ----+ 40 x view were found. No abnormal ophta1moscopic findings were found. N eurologic exam was normal. Anthropometric measures were: wt = 25 kg (< 25th percentile), Ht = 133cm(<10th percentile) andHc = 50.5. The liver edge was palpable 6 cm below the subxiphoid process and 4 cm below the right costal margin. Huge splenomegaly was also found. Other findings were n01TI1al. Liver parenchymawa<> n01TI1al in ultrasonography (US) and the liver s ize was 10 mm which was larger than normal. Also, hemogen and normal echo spleen was found with 184 mm length which was categorized as huge splenomegaly. Based on clinical and US findings, Bone Marrow Aspiration (BMA) was done for ruling out malignancy. BMA revealed moderate cellularity with normal eiythroid, lymphoid and myeloid series, but increa<>ed number of megakaryocytes and large lipid storage cells resembling Gaucher cells (Fig. 1 ). The diagnosis wa<> established by p-glucocerebrosida<>e activity level a<>say (1.4 mcmol/L/h, notmal: 2.1-5.3) in peripheral leukocytes which was done by the help of UNESCO organization in Argentina The patient is now under Enzyme Replacement Therapy (ER.1) by CEREZY1v!E with good condition. DISCUSSION Our case was referred by anemia and complete blood count showed bicytopenia and hepatosplenomegaly, confumed by abdominal sonography. Splenomegaly and bicytopenia were two important s igns with multiple differential diagnosis. Reticiloendothelial system hyperplasia, immune heperplasia, extramedullaiy hematopoiesis, intra or extracellular depositions and benign or malignant cellular infiltrations are the most causes ofsplenomegaly. On the other hand, primaiy bone marrow disease such as myelofibrosis, leukemia and lymphoma, also systemic disease such as hypersplenism, sarcoidosis, SLE and fol ate deficiency can potentially lead to cytopenia w ith cellular bone marrow. So, in order to approach to our case and rull-in causes, bone marrow aspintion was done, showed typical Gaucher cells (Kasperet al., 2005; Barton etaJ., 1991). Gaucher disease is mainly due to mutations in the gene-encoding acid P-glucosida<>e (GBA), located on chromosome 1 at position q21 (Phillip and Poplack, 1998). This disease severely impairs quality of life because of hematologic or skeletal complications, physical limitations and psychosocial problems for both patients and their families (Barnevel et al., 1983). Gauche1's disea<>e, type 1 should be cons idered when unexplained spleno- and hepatomegaly, anemia, thrombocytopenia, or skeletal disease are present, particularly in combination. In our case, all of the so called s ings except skeletal problems were found. Lack of awareness and ofwidespread availability of the enzyme assay has as yet limited its application in clinical practice and led to many cases of Gauchet's disease being diagnosed by bone marrow and liver biopsy (Ch arrow et aJ., 2000). The diagnosis of Gaucher disease is established by an assay for P-glucocerebrosida<>e enzyme activity in peripheral leukocytes (Niederau and Haussinger, 2000). In our case, enzymatic diagnosis in dried blood spots on filter paper which has been previously discussed by Chamoles et al. (2002), showed serum level of 1.4 mcmol/L/h (Normal range: 2.1-5.3) for the P-D­glucosidase activity, which was lower than normal range. The treatment of type 1 Gaucher disease ha<> dramatically improved with the development of Enzyme Replacement Therapy (ERT) (Chamoles et al., 2002). In previous studies, ERT has been shovvn to prevent progressive manifestations of Gaucher disease, as well as ameliorating specific features of the disease (Lin et al., 2006; Zimran et al., 1995; Weinreb et al., 2002). The study by Weinreb et al. (2002) found a 20-30% decrease in liver volume within 1-2 years after beginning ERT, with a reduction of30-40% by 5 years. A case report describes an experience of using recombinant enzyme by Masood and Ali (2006) in a child who was diagnosed as a ca<>e of Gaucher disea<>e at the age of 3 years. Regular enzyme replacement therapy has resulted in marked improvement in his hemoglobin level, absolute neutrophil count, plmelets and physical growth. In the study of Grigorescu Sido et al. (2007), enzyme replacement therapy administered for 18 months in Romanian patients with Gaucher disease type I led to a marked improvement in haematological parameters and hepato- and splenomegaly. In the majority of patients no further progress of bone disease was observed'. 1064 Pak. J. Biol. Sci., II (7): 1063-1065, 2008 Our patient suffered from hepatomegaly, with the liver edge palpable 6 cm below the subxiphoid process and 4 cm below the right costal margin before ERT, which we expect to decrease after treatment initiation. CONCLUSION Enzyme replacement therapy is available for the treatment of type 1 Gaucher's disease, resulting in clinical improvement with enhanced quality of life within the first year of treatment, although improvement in bone disease can take longer. Doses of 60 units kg-1 every 2 weeks are of clinical benefit to patients with moderate to severe disease. A number of lower dosage regimens have been evaluated in small groups of patients, with satisfactory clinical responses occurring in some of these patients. ACKNOWLEDGMENTS We appreciate the laboratory of Dr. Mariana Blanco, Argentina, for enzyme assay. We are indebted to Mr. Rahim Davarian and Mrs. 0. Shirinbeik Mohajer for their leading suggestions. REFERENCES Bamevel, RA, W. Keijz.er, F.P. Tegelaers, E.I. Ginns, A. Geurts and RO. van Kessel et al., 1983. Assignment of the gene coding for hwnan P­glucocerebrosidase to the region q21-q31 of chromosome 1 using monoclonal antibodies. Hurn. Genet, 64 (3): 227-231. Barton, N.W., RO. Brady, J.M. Dambrosia, AM. Di Bisceglie, S.H. Doppelt, S. C. Hill and HJ. Mankin et al., 1991. Replacement therapy for inherited enzyme deficiency: Macrophage-targeted glucocerebrosidase for Gaucher's disease. N. Engl. J. Med, 324 (21) 1464-1470. Butters, T.D., 2007. Gaucher disease. Curr. Opin. Chem. Biol, 11 (4) 412-418. Charuoles, NA , M. Blanco, D. 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Gaucher disease: A 10 year old girl with anemia and huge spelenomegaly (a case report)

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