Gaucher Disease: A First Reported Adult Case in Indonesia.

A 44-year-old female presented with a distended abdomen and fatigue. On physical examination, prominent splenomegaly was found. The laboratory investigations revealed pancytopenia and decreased albumin-globulin ratio. The abdominal ultrasonography revealed splenomegaly, cholelithiasis, and cystitis, and the bone survey showed osteopenia. Differential diagnoses included leukemia, multiple myeloma, and myelofibrosis therefore bone marrow puncture was performed. However, histopathologic examination found Gaucher-like cells in the bone marrow aspiration. The finding of CD68 positivity in Gaucher-like cells by using the immunohistochemistry staining supporting Gaucher disease. To confirm the diagnosis, an examination of glucocerebroside substrate from the patient's blood plasma was performed. Glucosylsphingosine, a deacylated form of glucosylceramide, was markedly elevated. Therefore, the diagnosis of Gaucher disease was confirmed. This is the first reported adult Gaucher case diagnosed in Indonesia.

Is it possible to predict a disease course prone to macrophage activation syndrome at systemic juvenile idiopathic arthritis diagnosis?

OBJECTIVES: Macrophage activation syndrome (MAS) is a severe complication of systemic juvenile idiopathic arthritis (SJIA). We aimed to compare the characteristics of SJIA patients who developed MAS in the disease course to those who never experienced MAS. METHODS: Patients with SJIA were included. The features of the patients at the time of SJIA diagnosis were compared. Multivariate logistic regression and ROC analyses were used while evaluating factors associated with MAS. RESULTS: Overall, 126 SJIA patients (M/F:1.17) were included. Eighty-six (68.2%) never had MAS. At the time of SJIA diagnosis, age was younger; the duration of fever was longer; rash, hepatomegaly, and splenomegaly were more frequent and arthralgia/arthritis was less common among patients who had MAS in the follow-up than those who never had MAS. Also, white blood cell, neutrophil, and platelet counts and fibrinogen were lower, while transaminases, lactate dehydrogenase, triglyceride (TG), and ferritin levels were higher among patients with MAS than those without MAS. The multivariate regression analysis disclosed age at symptom onset, duration of fever, platelet count, TG and ferritin levels as independent MAS predictors. For ferritin level/platelet count (F/P) ratio at the time of SJIA diagnosis, a threshold of ≥1.1 performed best to predict a MAS-prone disease course with a sensitivity of 90% and a specificity of 82.6%. CONCLUSION: The F/P ratio at the time of SJIA diagnosis may be a promising biomarker to predict MAS-prone disease course in SJIA. Determining MAS-prone patients at the time of SJIA diagnosis could assist physicians while tailoring SJIA treatment individually. Key points • Systemic juvenile idiopathic arthritis (SJIA) patients with macrophage activation syndrome (MAS) differ from SJIA patients who never have MAS, at the time of SJIA diagnosis. • It could be possible to predict a MAS-prone disease course at the time of SJIA diagnosis. • The ferritin/platelet ratio is a promising biomarker for predicting MAS-prone SJIA disease course.

Fever of unknown origin and splenomegaly: a case report of visceral leishmaniasis diagnosed by metagenomic next-generation sequencing.

Visceral leishmaniasis (VL) is a parasitic disease caused by Leishmania spp., which is transmitted by sandflies. As China is not the main epidemic area and VL has complex and atypical clinical manifestations, it is easily misdiagnosed or even missed in clinical practice. Without prompt and efficient treatment, the mortality rate of VL is extremely high; therefore early diagnosis of VL is crucial. Herein we describe a case of fever and splenomegaly of unknown origin, which was finally diagnosed as VL by metagenomic next-generation sequencing.

GAU-PED study for early diagnosis of Gaucher disease in children with splenomegaly and cytopenia.

BACKGROUND: Gaucher disease (GD) diagnosis can be delayed due to non-specific symptoms and lack of awareness, leading to unnecessary procedures and irreversible complications. GAU-PED study aims to assess GD prevalence in a high-risk pediatric population and the presence, if any, of novel clinical or biochemical markers associated with GD. MATERIALS AND METHODS: DBS samples were collected and tested for ß-glucocerebrosidase enzyme activity for 154 patients selected through the algorithm proposed by Di Rocco et al. Patients showing ß-glucocerebrosidase activity below normal values were recalled to confirm the enzyme deficiency with the gold standard essay on cellular homogenate. Patients tested positive at the gold standard analysis were evaluated through GBA1 gene sequencing. RESULTS: 14 out of 154 patients were diagnosed with GD, with a prevalence of 9.09% (5.06-14.78%, CI 95%). Hepatomegaly, thrombocytopenia, anemia, growth delay/deceleration, elevated serum ferritin, elevated Lyso-Gb1 and chitotriosidase were significantly associated with GD. CONCLUSIONS: GD prevalence in a pediatric population at high-risk appeared to be higher compared to high-risk adults. Lyso-Gb1 was associated with GD diagnosis. The algorithm proposed by Di Rocco et al. can potentially improve the diagnostic accuracy of pediatric GD, allowing the prompt start of therapy, aiming to reduce irreversible complications.

A Three-Step Screening Procedure for Early Identification of Children at High Risk of Hemophagocytic Lymphohistiocytosis.

PURPOSE: The first step in diagnosing hemophagocytic lymphohistiocytosis (HLH) is to suspect its presence and then order the appropriate diagnostic tests. The development of screening procedures for HLH could facilitate early diagnosis. In this study, we evaluated the utility of fever, splenomegaly, and cytopenias as screening criteria for identifying pediatric HLH at an early stage, built a screening model using commonly measured laboratory parameters, and developed a step-wise screening procedure for pediatric HLH. METHODS: The medical records of 83,965 pediatric inpatients, including 160 patients with HLH, were collected retrospectively. The utility of fever, splenomegaly, hemoglobin level, and platelet and neutrophil counts at hospital admission as screening criteria for HLH was evaluated. For HLH patients who might be missed by screening based on the presence of fever, splenomegaly, and cytopenias, a screening model using common laboratory parameters was developed. Following that, a three-step screening procedure was then developed. RESULTS: The criteria of cytopenias affecting two or more lineages plus fever or splenomegaly had a sensitivity of 51.9% and a specificity of 98.4% for identifying HLH in pediatric inpatients. Our screening score model comprises six parameters: splenomegaly, platelet count, neutrophil count, albumin level, total bile acid level, and lactate dehydrogenase level. The use of the validation set had a sensitivity of 87.0% and a specificity of 90.6%. A three-step screening procedure has been developed: Step 1: Is fever or splenomegaly present? (Yes: risk for HLH should be considered, go to Step 2; No: less likely HLH); Step 2: Are cytopenias affecting at least two lineages? (Yes: consider HLH; No: go to Step 3); Step 3: Calculate the screening score. Is the sum of the score greater than 37? (Yes: consider HLH; No: less likely HLH). The overall sensitivity and specificity of the three-step screening procedure were 91.9% and 94.4%, respectively. CONCLUSION: A significant proportion of pediatric HLH patients present at the hospital without having all three symptoms: fever, splenomegaly, and cytopenias. Our three-step screening procedure, utilizing commonly available clinical and laboratory parameters, can effectively identify pediatric patients who may be at high risk for HLH.

[Misdiagnosis of Gaucher disease in real life: Retrospective study of the French Gaucher's disease registry]. / Les erreurs diagnostiques de la maladie de Gaucher dans la vraie vie : étude rétrospective du Registre français de la Maladie de Gaucher.

INTRODUCTION: Gaucher disease is an autosomal recessive genetic disorder. It is caused by a deficiency of the lysosomal enzyme, glucocerebrosidase which leads to an accumulation of glucosylceramide in the macrophages. Splenomegaly, hepatomegaly, cytopenias (anemia, thrombocytopenia) and bone disorders are the main symptoms. The diagnosis is often delayed, leading to unnecessary investigations and treatments, and delaying the specific treatment. The primary objective of our study was to establish, in patients who had a diagnostic delay of more than one year, the reported misdiagnoses before the final diagnosis. The secondary objectives were to investigate the risk factors associated with error and delayed diagnosis. METHODS: Retrospective study including patients with Gaucher disease from the French Gaucher Disease Registry. Collection of data by a single investigator from a standardized form. RESULTS: Among 83 patients with a known diagnostic delay, 13 patients (15 %) had one or two misdiagnoses. These included osteo-articular diagnoses (osteomyelitis, osteoarthritis, arthritis, osteochondritis, rheumatic fever, n=8), haematological diagnoses (gestational thrombocytopenia, immunological thrombocytopenia, n=4), infectious diagnoses (visceral leishmaniasis, mononucleosis, n=2) and hemochromatosis. The osteo-articular and infectious diagnoses concerned the child and the adolescent while the haematological diagnoses and the hemochromatosis concerned the adult. No factors were found associated with misdiagnoses. Patients with a diagnostic delay greater than one year were less likely to have hepatosplenomegaly as the first symptom. CONCLUSION: There is a risk of diagnostic error related to phenotypic heterogeneity and lack of specificity of Gaucher disease symptoms. This study helps to better identify the misdiagnoses associated with Gaucher disease.

Clinical insights from Wolman disease: Evaluating infantile hepatosplenomegaly.

There is a broad differential diagnosis of infantile hepatosplenomegaly, with some etiologies being debilitating and treatable. A structured approach to history, examination, and laboratory and radiographic findings is important in diagnosis. Herein, we present a case of Wolman disease presenting as hepatosplenomegaly in an infant. This case details important learning points to help distinguish the diagnosis of Wolman disease from other conditions with overlapping clinical features, such as hemophagocytic lymphohistiocytosis (HLH). The advent of enzyme replacement therapy has dramatically changed the natural history of Wolman disease, and this child showed remarkable improvement with treatment. This child was later found to have extensive adenopathy with retroperitoneal lymph node biopsy demonstrating diffuse infiltration by lipid-laden macrophages, fatty deposits, cholesterol crystals, and calcifications. Similar to the collection of characteristic cells in other lysosomal storage disorders, we postulate that this is characteristic of underlying Wolman disease. We conclude with a summary of learning points from this presentation on infantile hepatosplenomegaly, pertinent to the geneticist, pediatrician, and pediatric subspecialists.

Visceral leishmaniasis: A leucaemia mimicker: A case report.

Visceral Leishmaniasis (VL) is endemic in the northeast part of India, principally Bihar, Jharkhand, Uttar Pradesh, and West Bengal. We report a case of VL from the non-endemic Himalayan region of Kashmir. A 25-year-old female presented with a history of fever, generalized weakness, loss of appetite for one month. On clinical examination, there was hepatosplenomegaly and pancytopenia. There was no travel history to any VL endemic areas. Bone marrow examination revealed an amastigote form of Leishmania Donovan. Nested polymerase chain reaction (PCR) confirmed diagnosis. The patient was treated with 6 mg/kg liposomal amphotericin B, for ten days and improved clinically. Our case reveals that VL is expanding towards non-endemic regions of India, and physicians should remember the differential diagnosis of VL in a patient presenting with fever, pancytopenia, and hepatosplenomegaly.

[Splenic lymphoma, diagnosis and treatment]. / Lymphomes spléniques : diagnostic et prise en charge.

Some common clinical situations, such as splenomegaly or lymphocytosis, or less common, such as autoimmune hemolytic anemia, cold agglutinin disease, or cryoglobulinemia can lead to the diagnosis of splenic lymphoma. Splenic lymphoma is rare, mainly of non-hodgkinian origin, encompassing very different hematological entities in their clinical and biological presentation from an aggressive form such as hepato-splenic lymphoma to indolent B-cell lymphoma not requiring treatment such as marginal zone lymphoma, the most frequent form of splenic lymphoma. These entities can be challenging to diagnose and differentiate. This review presents different clinical and biological manifestations suspicious of splenic lymphoma and proposes a diagnosis work-up. We extended the strict definition of splenic lymphoma (lymphoma exclusively involving the spleen) to lymphoma thant can be revealed by a splenomegaly and we discuss the differential diagnosis of splenomegaly.

Mujer de 66 años con nódulos cutáneos recurrentes, esplenomegalia, anemia hemolítica y neumonía organizada / A 66-year-old woman with recurrent skin nodules, splenomegaly, hemolytic anemia, and organizing pneumonia

We present the case of a women previously diagnosed with nodularpanniculitis (biopsy compatible with neutrophilic dermatosis) andmultifactorial anemia with signs of hemolysis and splenomegaly,who refers reappearance of painful nodules in extremities and general syndrome. The differential diagnosis of the coexistence of these alterations is proposed, with the subsequent solution of the case. (AU)

Presentamos el caso de una mujer con diagnóstico previo de paniculitis nodular con biopsia compatible con dermatosis neutrofílicay anemia multifactorial con componente hemolítico asociada a esplenomegalia, que consulta por reaparición de nódulos dolorososen extremidades y síndrome general. Se plantea el diagnóstico diferencial de la aparición conjunta de estas alteraciones y posteriorresolución del caso clínico. (AU)

Volumetric Splenomegaly in Patients With Polycythemia Vera.

BACKGROUND: Non-palpable splenomegaly in patients with polycythemia vera (PV) has seldom been addressed. In this retrospective study, we evaluated non-palpable, volumetric splenomegaly defined based on age- and body surface area (BSA)-matched criteria in patients with PV diagnosed according to the 2016 World Health Organization diagnostic criteria. METHODS: Patients with PV who underwent abdominal computed tomography (CT) and who had palpable splenomegaly at diagnosis from January 1991 to December 2020 at Chungnam National University Hospital were enrolled. The spleen volume of each patient was determined by volumetric analysis of abdominal CT and adjusted for the patient's age and BSA. Then the degree of splenomegaly was classified as no splenomegaly, borderline volumetric splenomegaly, overt volumetric splenomegaly, or palpable splenomegaly. RESULTS: Of the 87 PV patients enrolled, 15 (17.2%) had no splenomegaly, whereas 17 (19.5%), 45 (51.7%), and 10 (11.5%) had borderline volumetric, overt volumetric, and palpable splenomegaly, respectively. The degree of splenomegaly did not affect the cumulative incidence of thrombotic vascular events (10-year incidence: 7.7%, 0%, 22.3%, and 50.7%, respectively, P = 0.414). By contrast, splenomegaly tended to adversely affect myelofibrotic transformation (10-year cumulative incidence: 0%, 0%, 7.1%, and 30.3%, respectively, P = 0.062). Moreover, the cumulative incidence of myelofibrotic transformation was significantly higher in patients with overt volumetric or palpable splenomegaly than those with no or borderline volumetric splenomegaly (10-year incidence: 0% vs. 10.3%, respectively; 15-year incidence: 0% vs. 26.3%, respectively, P = 0.020). Overall survival (OS) differed among patients with different degrees of splenomegaly (15-year OS: 100%, 78.6%, 71.7%, and 51.9%, respectively, P = 0.021). CONCLUSION: The degree of splenomegaly, including volumetric splenomegaly, based on age- and BSA-matched reference spleen volumes at diagnosis reflects disease progression in PV patients. Therefore, volumetric splenomegaly should be evaluated at the time of diagnosis and taken into consideration when predicting the prognosis of patients with PV.

Diagnostic and management strategies for Myeloproliferative Neoplasm-Unclassifiable (MPN-U): An international survey of contemporary practice.

Myeloproliferative Neoplasm-Unclassifiable (MPN-U) is defined as an MPN that fails to meet the diagnostic criteria for any of the other defined classical or 'non-classical' MPNs. The reported incidence is variable, dependent on appropriate recognition, and the clinical course can be highly variable ranging from an indolent disorder through to an aggressive disease course with a significant risk of thrombosis, bulky splenomegaly, and debilitating symptom burden. Clinicians frequently manage these conditions according to the clinical concerns e.g. splenomegaly akin to the phenotype, but no evidence base exists. Currently, there are no widely accepted guidelines to deal with both the diagnostic work up and subsequent clinical management of this entity. We hence surveyed major International MPN centres to gain an understanding of common challenges in MPN-U management in 2021 and aid identification of considerable practice variations where harmonisation would be desirable. Such information is vital to support future consensus guidelines in addition to informing further collaborative studies.

[Pancytopenia and B-symptoms - an unexpected souvenir?] / Panzytopenie und B-Symptomatik ­ unerwartetes Souvenir?

HISTORY: The 79-year-old patient was admitted with recurring fever, weight loss, night sweat, a decrease in physical capacity and hematomas of the extremities. FINDINGS: The patient presented with pancytopenia, elevated CRP and impaired renal function. A splenomegaly was evident in abdominal sonography. A bone marrow aspiration was performed. DIAGNOSIS: Histopathologic examination revealed a visceral Leishmaniasis. The diagnosis was confirmed by PCR from peripheral blood. THERAPY AND COURSE: After initiation of liposomal amphotericin B haematopoiesis recovered and CRP decreased. Initially the renal function deteriorated with prolongated improvement in the course of therapy. CONCLUSIONS: Pancytopenia and corresponding symptoms are suspect for visceral Leishmaniasis also in patients supposed to be immunocompetent with travel history of endemic regions.

An Unexpected Finding of Hepatosplenomegaly in a Pediatric Patient.

Gaucher disease (GD) is a rare autosomal recessive metabolic disorder. It is characterized by a deficiency of lysosomal glucocerebrosidase, which results in the accumulation of glycosphingolipid substrates, primarily glucosylceramide, in the phagocyte system. In GD Type 1, the liver, spleen, and bone marrow are typically affected. We report the case of a 7-year-old female with GD Type 1 who presented with hepatosplenomegaly detected incidentally following a motor vehicle accident. She was found to have concomitant thrombocytopenia and Erlenmeyer flask deformities of her lower limbs. Diagnosis was made on the basis of very low leukocyte ß-glucocerebrosidase activity and elevated plasma chitotriosidase. DNA mutation studies revealed both c.1226A>G and c.116_1505 deletion (exons 3-11). The patient is currently managed with biweekly intravenous imiglucerase (Cerezyme) replacement therapy. She demonstrated resolution of thrombocytopenia and hepatosplenomegaly at 2-year follow-up. Physicians must consider this rare diagnosis in children presenting with hepatosplenomegaly to prompt timely management.

Splenomegaly: Diagnosis and Management in Adults.

Splenomegaly can be due to several mechanisms but is almost always a sign of a systemic condition. Patient habits, travel, and medical conditions can increase risk of splenomegaly and suggest etiology. Symptoms can suggest infectious, malignant, hepatic, or hematologic causes. Physical examination will typically reveal splenomegaly, but abdominal ultrasonography is recommended for confirmation. Physical examination should also assess for signs of systemic illness, liver disease, and anemia or other hematologic issues. The most common causes of splenomegaly in the United States are liver disease, malignancy, and infection. Except for apparent causes such as infectious mononucleosis, basic laboratory analysis and ultrasonography are the first-line steps in determining etiology. Malaria and schistosomiasis are common in tropical regions, where as many as 80% of people may have splenomegaly. Management of splenomegaly involves treating the underlying disease process. Splenectomies and spleen reduction therapies are sometimes performed. Any patient with limited splenic function requires increased vaccination and prophylactic antibiotics for procedures involving the respiratory tract. Acute infections, anemia, and splenic rupture are the most common complications of splenomegaly, and people with splenomegaly should refrain from participating in contact sports to decrease risk of rupture.

Comparison of the clinical features and outcome of children with hemophagocytic lymphohistiocytosis (HLH) secondary to visceral leishmaniasis and primary HLH: a single-center study.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of excessive inflammation. We aimed to describe the clinical and laboratory findings of HLH patients secondary to Visceral leishmaniasis (VL) and their treatment outcome during a 4-year follow-up period compared to primary HLH. METHOD: Forty children with primary HLH confirmed by genetic study and 20 children with HLH secondary to VL confirmed by a blood or bone marrow polymerase chain reaction from 2014 to 2018 in Shiraz, Fars province, Southern Iran, were enrolled. RESULTS: The median age at diagnosis was 11.5 months (range 1-170), and 56.7% were male. Fever and splenomegaly were the most frequent clinical presentations. 93.3% of the subjects had an HScore > 169, which had a good correlation with HLH-2004 criteria (r = 0.371, P = 0.004). Patients with primary HLH experienced more thrombocytopenia (P = 0.012) and higher alanine transaminase (P = 0.016), while patients with VL-associated HLH had higher ferritin (P = 0.034) and erythrocyte sedimentation rate (P = 0.011). Central nervous system (CNS) involvement occurred in 38.3% of patients. The mortality rate was higher in patients with CNS disease (61% vs. 35%, P = 0.051). The 3-yr overall survival rate was 35.9%. (24% in primary HLH and 100% in VL-associated HLH, P < 0.001). In Cox regression analysis, platelet count < 100,000/ µ l (hazard ratio 4.472, 95% confidence interval 1.324-15.107, P = 0.016) correlated with increased mortality in patients with primary HLH. CONCLUSION: VL is a potential source of secondary HLH in regions with high endemicity. Treatment of the underlying disease in VL-associated HLH is sufficient in most cases, with no need to start etoposide-based chemotherapy.