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 Table of Contents  
Year : 2023  |  Volume : 14  |  Issue : 2  |  Page : 171-175

Challenges in the diagnosis of gaucher disease with multiple splenic lesions

Department of Medicine, College of Medicine, Qassim University, Buraidah, Qassim; Dr. Sulaiman Al Habib Medical Group, Riyadh, Saudi Arabia

Date of Submission05-Jun-2023
Date of Decision02-Jul-2023
Date of Acceptance17-Jul-2023
Date of Web Publication27-Jul-2023

Correspondence Address:
Dr. Ahmad Alshomar
Department of Medicine, College of Medicine, Qassim University, Buraidah 51452
Saudi Arabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/joah.joah_36_23

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The progressive nature, multisystem involvement, and delayed diagnosis of Gaucher disease (GD) make it a challenging disorder. Herein, we report the clinical and genetic findings of a patient with GD of Saudi-Arab ethnicity. In this case, a young patient was discovered to have hepatosplenomegaly and whose radiological image revealed an unusual presentation of multiple nodular lesions in the spleen that were initially thought to represent benign hemangiomas. He had a splenectomy with a liver biopsy, which revealed features consistent with GD. The activity of β-glucocerebrosidase in dry blood spots was below its cutoff value. Molecular genetic analysis of the glucosylceramidase beta gene confirms the diagnosis. Enzyme replacement therapy was initiated.

Keywords: Gaucher disease, gaucheroma, Saudi Arabia, splenomegaly, thrombocytopenia

How to cite this article:
Alshomar A. Challenges in the diagnosis of gaucher disease with multiple splenic lesions. J Appl Hematol 2023;14:171-5

How to cite this URL:
Alshomar A. Challenges in the diagnosis of gaucher disease with multiple splenic lesions. J Appl Hematol [serial online] 2023 [cited 2023 Sep 27];14:171-5. Available from: https://www.jahjournal.org/text.asp?2023/14/2/171/382414

  Introduction Top

Gaucher disease (GD) is among the most prevalent autosomal recessive lysosomal storage disorders worldwide.[1] It is caused by an inborn error in glycosphingolipid metabolism. A mutation in the glucosylceramidase beta (GBA) gene on chromosome 1q22 causes a reduction in the activity of the β-glucocerebrosidase enzyme, leading to the accumulation of glucocerebroside (glucosylceramide) inside the macrophages. Gaucher cells are macrophages that have been accumulating glycolipids and lipids, and their systemic accumulation inside the reticuloendothelial system causes a variety of presentations such as hepatosplenomegaly, abdominal discomfort, bony pain, anemia, and thrombocytopenia.[2],[3],[4] Gaucher et al., a French dermatologist, initially described the condition in a 32-year-old woman with hepatosplenomegaly in 1882.[5]

GD has been reported in all ethnic groups, but Ashkenazi Jews have a prevalence of 118 per 100,000, compared to 1.33–1.75 per 100,000 among the general population.[4],[6] There are no published statistics on the prevalence of GD in Saudi Arabia. Nevertheless, we anticipated that the prevalence would be higher in Saudi Arabia compared to Western countries due to strong consanguinity.[7]

There are three types of GD that share the same enzyme defect, although their manifestations vary. It has been described and recognized based on clinical signs, age of onset, and neurological involvement.[8] The most common type of GD is type 1 (adult nonneuropathic), which is characterized by visceral involvement such as hepatosplenomegaly, cytopenia, and bone disease. Even though type 1 spares the nervous system, recent research has demonstrated that this type is more prone to Parkinson's disease and peripheral neuropathy.[9],[10] The most severe form is type 2 (infantile acute neuropathic). It has a 2-year life expectancy and is characterized by neurological impairment that begins within the first 6 months of life.[11] Type 3 (juvenile subacute neuropathic) manifests as a gradual, progressive neurological disease that typically results in early death in children and young adults.

Gaucheroma is a rare presentation of GD, in which an aggregate of Gaucher cells forms in different organs, most commonly the spleen and liver. The literature reports that 20% of GD patients develop Gaucheroma.[12],[13],[14]

The finding of reduced B-glucocerebrosidase activity in peripheral leukocytes in a patient with clinical symptoms compatible with GD establishes the diagnosis. Molecular analysis to detect the mutation will further confirm the diagnosis. Treatment aims for GD to alleviate symptoms, prevent further damage, and enhance the patient's general health and quality of life. GD can be effectively treated with enzyme replacement therapy (ERT). Early ERT reverses both visceral and hematological signs of GD and reduces skeletal symptoms, resulting in a higher quality of life.[15]

Herein, we report the clinical and genetic findings of a patient with GD in Saudi Arabia. In this case, a young patient was discovered to have incidental hepatosplenomegaly and whose radiological image revealed an unusual presentation of multiple nodular lesions in the spleen that were initially thought to represent benign hemangiomas. He had a splenectomy with a liver biopsy, which revealed features consistent with GD. The radiological features likely represent a splenic Gaucheroma.

  Case Report Top

A 29-year-old man of Saudi-Arab ethnicity presented to hematology clinic with a 2-year history of abdominal discomfort and fatigue. He denies B-symptoms, palpable masses, a skin rash, joint pain, jaundice, or neurological symptoms. He has a history of forearm fractures resulting from low-energy trauma when he was 15 years old. He denied a family history of a similar presentation. He was not on medication or drinking alcohol.

On the examination, his vitals were intact, and he looked well. He was not pale or jaundiced. Hepatosplenomegaly was present on palpation of the abdomen. The liver was palpable at 5 cm below the right costal edge, while the spleen was palpable at 6 cm below the left costal margin. The cardiopulmonary examination was unremarkable. Lymph nodes were not palpable. The neurological examination was intact.

The initial workup revealed mild thrombocytopenia with platelet counts of 114 × 103/UL and leukopenia with white blood cells of 3.4 × 103/UL [Table 1]. A peripheral blood film revealed normocytic, normochromic red blood cells, mild thrombocytopenia, and leukopenia. There were no immature or abnormal cells. Abdominal ultrasound revealed an enlarged spleen, measuring 16.2 cm × 5.8 cm without focal abnormalities. The liver is enlarged, measuring 17 cm. Hemoglobin electrophoresis revealed no evidence of hemoglobinopathy.
Table 1: Laboratory data

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There are many common potential differential diagnoses for hepatosplenomegaly and bicytopenia, which include infectious causes (such as viral hepatitis and infective endocarditis), malignancy (such as lymphoma and leukemia), inflammatory (such as systemic lupus erythematosus), and congestive (such as liver cirrhosis and heart failure). Viral hepatitis, Schistosoma serology, and antinuclear antibodies were negative.

An echocardiogram demonstrated normal systolic and diastolic functions with a normal ejection fraction. There were no valvular heart diseases.

A contrast-enhanced computed tomography scan of the chest, abdomen, and pelvis showed moderate hepatomegaly without focal lesions. The longest dimension of the liver was 21 cm. There was moderate-to-severe splenomegaly, with the longest dimension measuring 19 cm. There were multiple hypodense, heterogeneous, nodular-enhancing lesions noted in the spleen, varying in size. Most of the lesions were isodense to splenic parenchyma in the delayed phase. The differential for the described findings was likely due to splenic hemangiomatosis [Figure 1].
Figure 1: A coronal computed tomography scan shows hepatosplenomegaly with multiple hypodense, heterogeneous nodular lesions of different sizes in the spleen (highlighted in white arrow)

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Plain and contrast magnetic resonance imaging of the abdomen and pelvis showed moderate hepatosplenomegaly, with the liver measuring 21 cm and the spleen measuring 19 cm. There was no suspicion of a focal liver lesion. Multiple T2-bright lesions in the spleen, the largest measuring 3.5 cm with progressive enhancement, likely represent benign hemangiomas [Figure 2].
Figure 2: Coronal T2 magnetic resonance imaging reveals hepatosplenomegaly with multiple hyperintense splenic lesions, the largest measuring 3.5 cm (highlighted in white arrow)

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We initially assumed that multiple splenic hemangiomatosis was the culprit for splenomegaly that accompanied the patient's bicytopenia. As a result, the patient underwent a total splenectomy under laparoscopy in addition to a liver biopsy. The result showed marked expansion of splenic red pulp, with a large number of histiocytes showing finely fibrillar cytoplasm (wrinkly paper-like). The liver biopsy shows scattered histiocytic aggregates in the sinusoid with similar histologic features to the histiocytes in the spleen. The histocytes were positive for periodic acid–Schiff (PAS) with diastase (PAS-D) stains but negative for iron staining. The Gomori methenamine silver, Ziehl–Neelsen, and FITE special stains revealed no microorganisms. The differential diagnosis includes GD, other lysosomal storage disorders, infection, and myeloid neoplasms.

Bone marrow aspiration revealed normal trilineage hematopoiesis in number and morphology. A few macrophages with an onion-skin appearance (Gaucher cells) were seen. There was no increase in blasts or hemophagocytic activity. A bone marrow trephine biopsy revealed cellular marrow with all hematopoietic elements well represented. It shows patchy infiltration by macrophages (Gaucher cells). Flow cytometry of the bone marrow aspirate revealed no evidence of clonal cells. The overall picture was consistent with lysosomal storage disease, most likely GD.

The reason why we delay bone marrow biopsy and aspiration before splenectomy is because we find multiple hypodense nodular-enhancing lesions in the spleen, thought to be likely due to splenic hemangiomatosis.

Tandem mass spectrometry from a dry blood spot was done to measure β-glucocerebrosidase and acid sphingomyelinase. The activity of acid sphingomyelinase was above the cutoff value. Thus, there was no indication of Niemann–Pick A/B disease. The activity of β-glucocerebrosidase was below its cutoff value. This was indicative of GD [Table 2]. Molecular genetic analysis of the GBA gene was carried out to confirm the diagnosis. Following DNA extraction from a dried blood spot, polymerase chain reaction amplification, sequencing of all coding exons, and flanking intronic regions took place. Two mutations were detected in the homozygous state: C.152G>T (P. Ser52 IIe). This mutation was a known pathogenic missense mutation that confirms GD.[16]
Table 2: Result of μ-glucocerebrosidase and acid sphingomyelinase

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Dual-energy X-ray absorptiometry scan demonstrated normal bone mineral density.

ERT with imiglucerase infusions was initiated. On follow-up at a 2-month interval after ERT was initiated, the liver was shrunken as per the US abdomen, and blood counts normalized.

  Discussion Top

Our case was similar to that of Alsahli et al., who described a 4-year-old Saudi girl who was discovered to have hepatosplenomegaly, pancytopenia, valvular, and aortic calcification. Based on molecular and enzymatic testing, she was diagnosed with GD type III and died as a result of cardiovascular complications.[17] Jilani et al. also reports a case of type 1 GD similar to ours in a young Tunisian Arab woman who presents with bone pain, pancytopenia, splenomegaly, rib deformation, and upper limb tremor. Molecular genetic analysis of the GBA gene confirmed the diagnosis.[18] Fawaris et al. reported another case of a young Libyan Arab woman who presented with bruises after mild trauma, bone pains, splenomegaly, and thrombocytopenia.[19]

Our patient was a young man who was discovered to have incidental hepatosplenomegaly and whose radiological image revealed an unusual presentation of multiple nodular lesions in the spleen that were initially thought to represent benign hemangiomas. He had a splenectomy with a liver biopsy, which revealed features consistent with GD. The radiological features likely represent a splenic Gaucheroma. The activity of β-glucocerebrosidase was low, and molecular genetic analysis of the GBA gene confirms the diagnosis.

Gaucher cells are not pathognomonic for GD, as can be seen in other hematological malignancies such as leukemia, lymphoma, myelodysplastic syndrome, and multiple myeloma.[20],[21],[22],[23] The diagnosis of GD is confirmed by identifying decreased enzyme activity of β-glucocerebrosidase in the blood. The identification of molecular mutations through targeted DNA analysis provides additional confirmation of the diagnosis, can be useful in genetic counseling, and can identify heterozygous carriers who have not been diagnosed. In addition, the genotype may influence the prognosis.[24]

GD is a complex and rare disorder, with patients experiencing diagnostic delays of up to 10 years. Patients with GD seek the advice of up to eight different subspecialists regarding their condition, with hematologists being the most common.[25] Delays in the identification and management of GD may lead to complications including pathological bone fractures, liver disease, persistent bone pain, growth retardation, life-threatening hemorrhage, and severe sepsis.

The 20-year overall survival (OS) rate for 156 Egyptian patients with GD was 73.3%. A total of 148/156 (94.8%) patients received ERT (imiglucerase). The early age of diagnosis and early start of ERT greatly improved the 20-year OS rate.[26] In the United States, patients with GD have a life expectancy of 68 years, 9 years shorter than the general population.[27]

The differential diagnosis of GD largely relies on the initial clinical presentation. Leukemia, lymphoma, and multiple myeloma at a young age can overlap with GD in certain features, such as hepatosplenomegaly, pancytopenia, gammopathies, splenic lesions on the image, and Gaucher cells in histopathology, resulting in inaccurate or delayed diagnosis.[28] Hemangioma, lymphoma, Gaucheroma, and hepatocellular carcinoma are among the possible differential diagnoses for splenic and hepatic lesions.[12] The features that make GD more likely are the longer duration of clinical presentation, association with bone disease, and family history. The prevalence of hematological malignancies is higher in GD as compared to the general population.[29],[30]

There are challenges and unmet needs in terms of medical care for patients with GD, including failure to recognize the disease in its early stages, resulting in significant delays in diagnosis and an unnecessary splenectomy. As a result, it has been recommended to (1) Enhance the awareness of the disease among internists, general pediatricians, and hematologists; (2) Expedite access to diagnostic enzyme assays using the dried blood spot test and facilitate gaining access to ERT; and (3) provide genetic counseling as a critical component in the care of Gaucher families.

  Conclusion Top

This case highlights the need to consider rare diseases such as GD in the differential diagnosis when dealing with unexplained hepatosplenomegaly and pancytopenia. Furthermore, it highlights the importance of correlating radiological imaging with histopathological findings. It is also important to have a tissue biopsy from the least invasive tissues, such as bone marrow, before proceeding to major surgery, such as a splenectomy.

Ethical approval and consent to participate

No prior ethical approval from the institutional review board (IRB) is required in our institution for single case reports. The patient provided consent on an anonymous basis.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understand that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

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  [Table 1], [Table 2]


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