# SplenoMegaly study (SMS): exploring the etiologies for 'unexplained' splenomegalies in the real world

G. Denis, Louis Terriou, T. Sené, R. Costello, M. Michaud, A. Lagadec, F.

Bauduer, L. Sanhes, C. Rose, G. Urbanski, et al.

► To cite this version:

G. Denis, Louis Terriou, T. Sené, R. Costello, M. Michaud, et al. SplenoMegaly study (SMS): exploring the etiologies for 'unexplained' splenomegalies in the real world. Orphanet Journal of Rare Diseases, 2025, Orphanet J. Rare Dis., 20 (285), 10.1186/s13023-025-03768-3. doi:10.1186/s13023-025-03768-3

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# SplenoMegaly study (SMS): exploring the etiologies for "unexplained" splenomegalies in the real world

Guillaume Denis¹*, Louis Terriou², Thomas Sené³, Regis Costello⁴, Martin Michaud⁵, Audrey Lagadec⁶, Frédéric Bauduer⁷,⁸, Laurence Sanhes⁹, Christian Rose¹⁰†, Geoffrey Urbanski¹¹,¹²,¹³ and Marc G. Berger¹⁴

**Abstract**

**Background** The predominant etiologies of splenomegaly (SM) are readily discernible through routine clinical assessments, yet in numerous instances, the etiological basis remains elusive. Subsequent diagnostic steps are not consensual and are challenging for physicians due to miscellaneous causes and non-specific symptoms. This study aimed to estimate the prevalence of Gaucher disease (GD) and other etiologies in patients presenting with unexplained splenomegaly (SM) after exclusion of first intention-diagnoses (e.g., portal hypertension, hematological malignancy, hemolytic anemia, and infection) based on basic physical examination, patient interview, and routine biological exams (e.g., full blood count, liver enzymes, and reticulocyte count). Additionally, the study aimed to describe the diagnostic tests performed and the most frequent associations observed. This French prospective, observational, multicenter, longitudinal SMS study enrolled 505 patients from September 2015 to April 2020, aged ≥ 15 years, referred to hematology or internal medicine departments, with a diagnostically confirmed SM (spleen length ≥ 13 cm). SM was defined as unexplained when routine clinical and biological tests were negative. Patients were followed up until an etiology was identified or up to 18 months after inclusion.

**Results** An etiology of SM was found in 223 (44.5%) of 501 patients with follow up. Patients with explained SM were older, had a larger spleen, and had altered biological parameters compared with patients with unexplained SM. There was a higher prevalence of non-malignant diseases than hematological malignancies (27.1% vs. 17.0%). Overall, lysosomal storage diseases (LSDs) were diagnosed in 10 patients (2.0%), including 4 patients with GD (0.8%).

**Conclusions** A list of potential predictive factors for the main diagnostic categories was identified that could optimize the diagnostic strategy for unexplained SM. This study provides new insights into exploring SM in the real world and proposes clinical and biological factors associated with specific etiologies.

**Clinical trial registration** NCT04430881.

Full list of author information is available at the end of the article

<footnote>†Christian Rose contributed equally to this work and Author deceased.</footnote>

<footnote>*Correspondence:
Guillaume Denis
guillaume.denis@ght-atlantique17.fr</footnote>
## Background

Splenomegaly (SM) is defined as an abnormal enlargement of the spleen. SM is a rare condition in the general population, with an estimated incidence of 0.3% of admissions in United States (US) hospitals [1] and 2% of the total US population [2]. In clinical practice, it could be discovered during a physical examination or in an imaging setting, such as ultrasound or computerized tomography (CT). Defining SM remains a source of debate, due to variability in the shape and size of the spleen according to physiological conditions, height, sex, age, and ethnic origin [3]; however, it is commonly accepted that a clearly palpable SM and/or a maximal length of ≥13 cm determined by radiological investigation could be considered as a criterion to define SM [4, 5].

The mechanism of splenic enlargement varies depending on the underlying cause, of which the most frequently reported in previous studies are hematological (16–66%), liver (9–41%), and infectious diseases (9–36%) in Europe and the US [1, 6, 7]. In 4–10% of patients, congestive or inflammatory diseases are observed, while primary splenic diseases are reported in 1–6% of cases. One to eight% of cases remain idiopathic or are associated with other underlying conditions. However, for cases of SM where no obvious etiology is found through questioning, clinical examination, and basic investigation, other diagnoses need to be investigated.

As no recommendations on the basic exploratory workup or the progression of complementary examinations have been established, the evaluation strategy is particularly influenced by the specialization of the physicians taking care of the patient. Given the large spectrum of underlying diseases sharing several signs and symptoms, differential diagnosis typically requires stepwise investigations, including a patient interview, a clinical examination, and routine biological tests [8, 9, 10].

After ruling out most common diagnoses, a significant but variable proportion of patients remain without any diagnosis (2–25%) [1, 6, 7], and a splenectomy for diagnostic purposes may even be performed in cases of non-obvious etiology reaching up to 12% of patients [1]. A French-based study focusing on a limited number of splenectomies performed for diagnostic purposes underlines its postoperative value in the diagnosis of lymphoid malignancies [11]. However, in such cases, determining a diagnosis before resorting to splenectomy is certainly a challenge as delayed diagnosis is detrimental to the progression of certain diseases. Splenectomy, however, exposes patients to postoperative complication rates varying from 20 to 52% (postoperative mortality rates were around 1.4–1.8%) [12, 13, 14] as well as the aggravation of underlying diseases, such as Gaucher disease (GD), thalassemia, Hodgkin lymphoma, or primitive myelofibrosis.

Notably, studying the prevalence of etiologies in patients with unexplained SM would help the medical community prioritize investigations toward identifying the causes. To the best of the authors' knowledge, there are no published data focusing on the etiology of unexplained SM. The prevalence of these rarer etiologies in patients with unexplained SM is not yet known. In a more in-depth stage of etiology research, it is logical to incorporate the search for rare diseases, such as lysosomal storage diseases (LSDs). LSDs are heterogeneous, inherited, metabolic diseases characterized by the abnormal accumulation of substrates in the cells of various organs due to enzyme dysfunctions [15, 16]. GD, one of the most prevalent LSDs, is caused by a deficiency of glucocerebrosidase, which occurs due to GBA gene mutation [15]. Diagnosis of GD by testing glucocerebrosidase activity is the gold standard, but the rarity and non-specificity of some phenotypic aspects of the heterogeneous nature of GD impede the diagnostic approach and may lead to mis- or underdiagnosis. Patients then encounter inappropriate procedures and severe complications, including irreversible bone disease (e.g., osteonecrosis and pathological fractures). Therefore, early diagnosis before the occurrence of irreversible complications underpins the management guidelines of GD, can minimize the emotional and financial burden encountered by patients, and thus, improve the quality of life of these patients [17–19]. This is to be considered for all the rarer etiologies of unexplained SM. In this context, the Splenomegaly Study (SMS) aimed at estimating the prevalence of GD and other etiologies in patients presenting with unexplained SM after exclusion of first intention-diagnoses (e.g., portal hypertension, hematological malignancy, hemolytic anemia, and infection) based on basic physical examination, patient interview, and routine biological exams (e.g., full blood count, liver enzymes, and reticulo-cyte count). Additionally, the study aimed to describe the diagnostic tests performed and the most frequent associations observed.

## Methods

### Study design

The SMS was a prospective, observational, multicenter, longitudinal study conducted across 87 active centers in France. The study was approved by the ethics committee (CPP Ouest IV, France) and performed in accordance with the Declaration of Helsinki. Patients or their legal representatives, if applicable, signed an informed consent form prior to participating in the study.

### Patient selection and procedures

Patients who consented to participate in the study were recruited between September 2015 to April 2020 based on the following inclusion criteria: age ≥ 15 years,
<figure><img src="image_3.png" /><figcaption>**Fig. 1** Disposition of patients. <sup>a</sup>Patients could have several reasons of non-inclusion. <sup>b</sup>Obvious diagnoses included portal hypertension, hemolytic anemia, or hematological malignancy. <sup>c</sup>Including Gaucher disease, *n* = 1; unknown origin *n* = 5. SM, splenomegaly</figcaption></figure>

<table><caption>**Table 1** Baseline demographics and clinical characteristics stratified by group</caption><thead><tr><th>Category</th><th>Parameter</th><th>Explained SM (n=223)</th><th>Still unexplained SM (n=278)</th><th>p-value</th><th>Total (N=501)</th></tr></thead><tbody><tr><td>Females</td><td>n (%)</td><td>93 (41.7)</td><td>100 (36.0)</td><td>0.190</td><td>193 (38.5)</td></tr><tr><td>Males</td><td>n (%)</td><td>130 (58.3)</td><td>178 (64.0)</td><td></td><td>308 (61.5)</td></tr><tr><td>Age at inclusion, years</td><td>Mean (SD)</td><td>55.5 (18.9)</td><td>47.6 (19.0)</td><td>&lt;0.001</td><td>51.1 (19.4)</td></tr><tr><td></td><td>Median</td><td>60.0</td><td>45.0</td><td></td><td>51.0</td></tr><tr><td></td><td>Min; Max</td><td>16; 94</td><td>17; 91</td><td></td><td>16; 94</td></tr><tr><td>BMI, kg/m<sup>2</sup></td><td>N</td><td>217</td><td>262</td><td>0.194</td><td>479</td></tr><tr><td></td><td>n (%)</td><td>12 (5.5)</td><td>7 (2.7)</td><td></td><td>19 (4.0)</td></tr><tr><td></td><td>[18.5–30]</td><td>159 (73.3)</td><td>189 (72.1)</td><td></td><td>348 (72.7)</td></tr><tr><td></td><td>&gt; 30</td><td>46 (21.2)</td><td>66 (25.2)</td><td></td><td>112 (23.4)</td></tr><tr><td>Spleen length, cm</td><td>N</td><td>223</td><td>278</td><td>&lt;.001<sup>a</sup></td><td></td></tr><tr><td></td><td>Mean (SD)</td><td>16.4 (3.1)</td><td>15.3 (2.0)</td><td></td><td>15.8 (2.6)</td></tr><tr><td></td><td>Median</td><td>15.7</td><td>15.0</td><td></td><td>15.0</td></tr><tr><td></td><td>Min; Max</td><td>13; 30</td><td>13; 25</td><td></td><td>13; 30</td></tr><tr><td>Spleen length, cm</td><td></td><td></td><td></td><td>&lt;.001<sup>b</sup></td><td></td></tr><tr><td></td><td>n (%)</td><td>164 (73.5)</td><td>249 (89.6)</td><td></td><td>413 (82.4)</td></tr><tr><td></td><td>n (%)</td><td>59 (26.5)</td><td>29 (10.4)</td><td></td><td>88 (17.6)</td></tr><tr><td>SM according to SplenoCalc<sup>c, d</sup></td><td>N</td><td>219</td><td>268</td><td>.411<sup>b</sup></td><td>487</td></tr><tr><td></td><td>n (%)</td><td>191 (87.2)</td><td>241 (89.9)</td><td></td><td>432 (88.7)</td></tr><tr><td></td><td>Not confirmed</td><td>12 (5.5)</td><td>15 (5.6)</td><td></td><td>27 (5.5)</td></tr><tr><td></td><td>Size out of range</td><td>16 (7.3)</td><td>12 (4.5)</td><td></td><td>28 (5.7)</td></tr><tr><td>Spleen structure</td><td>N</td><td>195</td><td>235</td><td>0.001</td><td>430</td></tr><tr><td></td><td>Homogeneous</td><td>162 (83.1)</td><td>220 (93.6)</td><td></td><td>382 (88.8)</td></tr><tr><td></td><td>Heterogeneous</td><td>33 (16.9)</td><td>15 (6.4)</td><td></td><td>48 (11.2)</td></tr></tbody></table>

BMI, body mass index; SD, standard deviation; SM, splenomegaly

<sup>a</sup>Wilcoxon–Mann–Whitney test (for quantitative variables)

<sup>b</sup>Pearson's Chi<sup>2</sup> test (for qualitative variable) was conducted with a significance level of 5%

<sup>c</sup>SplenoCalc<sup>a</sup> application, which calculates approximate percentiles of an individual's spleen size

<sup>d</sup>Height was not available for 14 patients
referred to a hematology or internal medicine depart-
ment, and presenting with an unexplained SM con-
firmed by an ultrasound or CT scan with a maximal
spleen length ≥ 13 cm. Patients with spleen size ≥ 18 cm
were defined under massive SM. Unexplained SM was
considered when a first clinical workup based on patient
interview, physical examination, and routine biological
tests (including hemogram and reticulocyte count, clot-
ting test, liver enzymes, bilirubin, protein electrophore-
sis, erythrocyte sedimentation rate [ESR], and C-reactive
protein [CRP]) was negative or inconclusive for the phy-
sicians to reach the underlying disease. Patients with
portal hypertension, hemolytic anemia, hematological
malignancy, or known diagnosis of GD based on clinical
examination, patient interview, and previous initial bio-
logical tests were excluded. Furthermore, a center could
not enroll > 10% of the total study population to avoid
overrepresentation of certain etiologies.

After the first visit, the last visit for each patient took
place when an etiology was identified or 18 months after
inclusion, whichever occurred first. All examinations and
tests conducted for diagnostic purposes were under each
physician's responsibility. Since there is no clinical gold
standard for the precise definition of SM, the SplenoCalc®
application (published after the start of the study) was
used retrospectively, adjusting for patient's sex and height
[20].

**Endpoints and assessments**

The primary endpoint of the study was to determine the percentage of patients with GD among those with unexplained SM. GD diagnosis was based on peripheral blood leukocyte β-glucocerebrosidase enzyme activity of < 30% of the normal value. Secondary endpoints included the percentage of patients with etiologies other than GD. This included any disease that could be considered in the differential diagnosis of unexplained SM, such as infection, hematological, congestive, inflammatory, neoplastic, infiltrative, and benign tumors, immune and iron deficiencies, and other miscellaneous rare causes. The percentage of patients with each etiology and the percentage of patients with an unknown diagnosis at the end of the study were estimated. The exploratory endpoint included the percentage of patients presenting with certain symptoms, including thrombocytopenia (platelet count < 150 G/L), anemia (below the sex-adjusted normal range), a history of bone pain, monoclonal or polyclonal gammopathy, and cholelithiasis.

**Statistics**

Statistical analyses were performed by International
Clinical Trials Association Project Management (ICTA
PM) using SAS® software (version 9.4; SAS Institute, NC,
USA). The sample size was determined in terms of pre-
cision (half-length of 95% confidence interval [CI]) to
describe the expected percentage of patients diagnosed
with rarest diseases, such as GD. Based on literature

<figure><img src="image_4.png" /><figcaption>**Fig. 2** Patient symptomatology stratified by group (N = 501). NS, non-significant; SM, splenomegaly. Pearson's Chi² test was conducted with a significance level of 5%</figcaption></figure>
and medical health information databases, the poten-
tial number of patients in the concerned population was
estimated between 5,000 and 10,000 based on the PMSI
database [21]. With an expected rate of GD diagnosis at
4% and a precision of 1.6% in the concerned population,
500 patients were required to be enrolled in the study.

Univariate and multivariate logistic regressions were
performed to identify predictive factors for obtaining a
diagnosis and each of the identified etiologies. Univari-
ate regressions were performed (for diagnostic catego-
ries with ≥ 25 patients). Otherwise, multivariate logistic
regressions were performed when sample size was suffi-
cient (i.e., > 45 patients). For multivariate logistic regres-
sions, a stepwise procedure with a 10% threshold for the
input and a 10% threshold for the output of the variables
was used to select the variables in the final model [22].
Quantitative variables were compared using Mann–
Whitney–Wilcoxon test or Student's t-test. Qualitative
variables were compared using Chi² test or Fisher's exact
test. All tests were two-sided and type 1 error was set at
5%.

Results

Study populations and baseline characteristics

From September 2015 to April 2020, 521 patients were
screened in 87 centers. Active investigators were inter-
nists (52.3%), hematologists (45.5%), nephrologists
(1.1%), and general practitioners (1.1%) who were prac-
ticing mainly in general hospitals (57.5%) distributed
throughout Metropolitan France. A total of 505 patients
met all eligibility criteria and were enrolled in the study,
of which 501 continued follow-up visits up to 18 months
after inclusion (Fig. 1). The median (range) number of
included patients per site was 3.0 (1–50).

At inclusion, the total population (N=501, median [range] 51.0 [16–94] years) comprised 61.5% of male patients, with 23.4% of patients having a body mass index > 30 kg/m². The median (range) spleen length was 15.0 [13; 30] cm, with massive SM (spleen length ≥ 18 cm) observed in 17.6% of patients and heterogeneous SM structure in 11.2% of patients (Table 1). The relevant medical/surgical history per system organ class according to diagnosis at the follow-up visit is presented in Additional file 1, Supplementary Table 1. A previous history of SM was found in 72 patients (14.7%) and was associated with unexplained SM when compared to explained SM (18.5% vs. 10.1%, *p* = .010).

According to SplenoCalc® application, SM was con-
firmed in 432 of 487 (88.7%) patients and invalidated in
5.5% without any statistical difference between patients
with or without a final diagnosis (p =.411). Of note, it
could not be determined in 5.7% of patients because their
height was outside the application standards.

A precise diagnosis was reached in 223 (44.5%) of
patients, with a median (min, max) duration between
inclusion and diagnosis of 4.9 (0, 17) months. Com-
pared to patients with still unexplained SM, patients who
received a diagnosis were significantly older (median age:
60.0 vs. 45.0 years, *p* <.001), had more often a massive SM
(spleen size ≥ 18 cm, 26.5% vs. 10.4%, *p* <.001), and had a
heterogeneous spleen structure (16.9% vs. 6.4%, *p* = .001).
In addition, patients with explained SM displayed more
frequently altered biological test results (Additional file 1,
Supplementary Table 2), including lower platelet count;
a greater proportion of patients presented with throm-
bocytopenia (platelet count < 100 G/L in 23.3% vs. 11.9%
of patients, *p* = .001), lower median hemoglobin levels
(12.5 g/dL vs. 14.0 g/dL, *p* <.001; abnormal in 61.4% vs.
33.5% of patients), lower leukocyte levels (abnormal ≤ 1.5
G/L in 29.1% vs. 18.3% of patients, *p* = .004), higher
median CRP levels (5.0 mg/L vs. 3.5 mg/L, *p* = .005;
abnormal [≥6 mg/L] in 46.9% vs. 33.2% of patients,
*p* = .003), and higher median gamma-glutamyl transferase
(γ-GT) levels (36.0 UI/L vs. 29.0 UI/L, *p* = .007; abnormal
in 35.3% vs. 25.6% of patients, *p* = .022). No differences
were found in other liver function parameters (aspartate
aminotransferase and alanine aminotransferase).

Patients with an explained SM showed significantly
more general symptoms, specifically asthenia, fever, pru-
ritus, and others, and digestive symptoms at inclusion
than patients with still unexplained SM (Fig. 2). Fever
is part of the category of general symptoms, along with
fatigue and pruritus. Hematological symptoms corre-
sponded to purpura, petechiae, hemorrhage, lymphade-
nopathy, and other related conditions. Osteoarticular or
other symptoms were not significantly different between
the study groups.

Prevalence of identified etiologies

The etiologies identified were divided into hematological malignancies and non-malignant disease with a prevalence of 17% and 27.1%, respectively. The most prevalent ones were lymphoid malignancies, immunological disorders, myeloid malignancies, portal hypertension, infectious diseases, and red blood cell disorders (Fig. 3; Additional file 1, Supplementary Table 3). None of the patients had cholelithiasis.

Ten patients were identified with LSDs (prevalence, 2.0%): 4 patients with GD, 3 patients with acid sphingo-myelinase deficiency (ASMD) type B disease, 2 patients with Niemann–Pick type C disease, and 1 patient with Fabry disease. The prevalence of GD was 0.8% of the total included patients (n = 505), corresponding to 4 patients (2 male and 2 female patients; Additional file 1, Supplementary Table 4). All patients had thrombocytopenia, with platelet levels < 150 G/L (from 77 G/L to 101 G/L); Case 1 described a 35-year-old male presenting with bone pain,
<figure><img src="image_5.png" /><figcaption>**Fig. 3** Prevalence of identified etiologies for SM (N = 505). ASMD, acid sphingomyelinase deficiency; NPC, Niemann–Pick type C; SM, splenomegaly</figcaption></figure>

Case 2 described a 27-year-old female presenting with mild anemia (hemoglobin: 11.0 g/dL), Case 3 described a 17-year-old female with no other relevant clinical symptoms than thrombocytopenia, and Case 4 described a 62-year-old male with polyclonal gammopathy.

## Tests and examinations

For patients with explained SM, investigators could report a maximum of 3 tests that led to the diagnosis; this was reported for 86.1% of patients. The most performed examinations for explained SM were various organ biopsies (48.0% of patients), imaging (38.1% of patients), and flow cytometry (18.4% of patients; Additional file 1, Supplementary Table 5). Bone marrow trephine biopsy (BMTB) was the most frequent type of biopsy performed in 52.3% of patients with explained SM. In total, 112 patients had BMTB, 56 had an explained SM and 56 had no diagnosis. 25.1% of patient with explained SM had BMTB. Among patients with explained SM, the most frequently performed association of tests was BMTB and molecular biology (performed in 6.3% of patients (n = 14), including 9 patients who only had these 2 examinations). The other most frequent test associations were BMTB with flow cytometry or bone marrow examination (each performed in 5.8% of patients).

For patients with still unexplained SM, all tests performed were considered to establish a diagnosis. In consequence, the median (range) number of tests and examinations performed in those patients was 13.0 (0–51) per patient. The most frequent test categories were imaging (77.8%), biology (91.8%), serology (88.2%), and autoimmunity (69.0%) (Additional file 1, Supplementary Table 5). Thus, as the method of collection was not similar, no comparison could be drawn between those patients and patients with explained SM.

In addition, most patients (80.2%) underwent a β-glucocerebrosidase activity assay to test for GD, and the prevalence of type 1 GD was 1.0% in those patients (n = 402). However, among patients with still unexplained SM (n = 278), 22.3% were not tested for GD. Diagnostic splenectomy was performed for 6 (2.5%) and 16 (7.2%) patients in the still unexplained SM and explained SM subgroups, respectively, with at least one relevant medical/surgical history in 4/6 (66.6%) patients with still unexplained SM and 12/16 (75.0%) patients with explained SM. A history of metabolism and nutrition disorders and nervous system disorders was reported for 2 (33.3%) patients in the still unexplained SM group who underwent diagnostic splenectomy.

## Predictive and associated factors to splenomegaly diagnostic categories

The following predictive factors were associated with higher odds of being diagnosed with lymphoid malignancies (compared to reference categories): hypogamaglobulinemia, massive SM, heterogeneous spleen structure, lymphocytes, presence of a monoclonal peak, older age at inclusion, and biopsy exploration (Fig. 4 A).

High CRP levels, constitutional, and osteoarticular symptoms, and biopsy exploration, were significantly associated with higher odds of having an accurate diagnosis of autoimmune or inflammatory disorders than the reference categories (Fig. 4 B). On the contrary, patients treated in institutions other than university hospitals were significantly less likely to be diagnosed with autoimmune or inflammatory disorders.

Older age at inclusion, massive SM, high platelets counts, and lactate dehydrogenase levels, biopsy exploration, and BMTB exploration were all significantly associated with higher odds of being diagnosed with myeloid
A

<table><thead><tr><th>Lymphoid malignancies (N = 453)</th><th>Lymphoid malignancies (n = 48)</th><th>No lymphoid malignancies (n = 405)</th><th>OR [95% CI]</th><th>p-value</th></tr></thead><tbody><tr><td>Gamma-globulin level &lt;8 g/L (vs 8-13.5 g/L)</td><td>24 (50.0%)</td><td>65 (16.0%)</td><td>4.78 [2.11; 10.83]</td><td>.0002</td></tr><tr><td>Splenic length ≥18 cm (vs &lt;18 cm)</td><td>25 (52.1%)</td><td>57 (14.1%)</td><td>4.63 [2.22; 9.66]</td><td>&lt;.0001</td></tr><tr><td>Heterogeneous spleen structure (vibomogeneous)</td><td>12 (25.0%)</td><td>35 (8.6%)</td><td>2.75 [1.14; 6.64]</td><td>.0240</td></tr><tr><td>Lymphocytes &gt;3.3 G/L (vs 1.1-3.3 G/L)</td><td>5 (10.4%)</td><td>11 (2.7%)</td><td>6.14 [1.45; 26.04]</td><td>.0139</td></tr><tr><td>Monoclonal peak (yes vs no)</td><td>11 (22.9%)</td><td>23 (5.7%)</td><td>3.40 [1.22; 9.50]</td><td>.0196</td></tr><tr><td>Age at inclusion ≥65 yrs (vs &lt;65 yrs)</td><td>26 (54.2%)</td><td>111 (27.4%)</td><td>2.12 [1.03; 4.33]</td><td>.0402</td></tr><tr><td>Biopsy (yes vs no)</td><td>33 (68.8%)</td><td>146 (36.0%)</td><td>2.59 [1.24; 5.43]</td><td>.0117</td></tr></tbody><tfoot><tr><td colspan="5">p-value of the Hosmer-Lemeshow test = .672.</td></tr></tfoot></table>

B

<table><thead><tr><th>Autoimmune disorders (N = 414)</th><th>Autoimmune disorders (n = 46)</th><th>No autoimmune disorders (n = 368)</th><th>OR [95% CI]</th><th>p-value</th></tr></thead><tbody><tr><td>CRP levels ≥6 mg/L (vs &lt;6 mg/L)</td><td>30 (65.2%)</td><td>132 (35.9%)</td><td>2.32 [1.15; 4.69]</td><td>.0186</td></tr><tr><td>Hypergammaglobulinemia (yes vs no)</td><td>15 (32.6%)</td><td>50 (13.6%)</td><td>1.91 [0.89; 4.11]</td><td>.0970</td></tr><tr><td>Constitutional symptoms (yes vs no)</td><td>33 (71.7%)</td><td>149 (40.4%)</td><td>2.28 [1.09; 4.76]</td><td>.0280</td></tr><tr><td>Osteoarticular symptoms (yes vs no)</td><td>15 (32.6%)</td><td>49 (13.3%)</td><td>3.61 [1.66; 7.85]</td><td>.0012</td></tr><tr><td>Non-university hospital (yes vs no)</td><td>13 (28.3%)</td><td>203 (55.2%)</td><td>0.27 [0.13; 0.56]</td><td>.0005</td></tr><tr><td>Biopsy (yes vs no)</td><td>28 (60.9%)</td><td>138 (37.5%)</td><td>2.43 [1.22; 4.84]</td><td>.0112</td></tr></tbody><tfoot><tr><td colspan="5">p-value of the Hosmer-Lemeshow test = .315.</td></tr></tfoot></table>

C

<table><thead><tr><th>Myeloid malignancies (N = 501)</th><th>Myeloid malignancies (n = 35)</th><th>No myeloid malignancies (n = 466)</th><th>OR [95% CI]</th><th>p-value</th></tr></thead><tbody><tr><td>Age at inclusion ≥65 yrs (vs &lt;65 yrs)</td><td>20 (57.1%)</td><td>130 (27.9%)</td><td>3.45 [1.71; 6.94]</td><td>.0005</td></tr><tr><td>Splenic length ≥18 cm (vs &lt;18 cm)</td><td>12 (34.3%)</td><td>76 (16.3%)</td><td>2.68 [1.28; 5.61]</td><td>.0091</td></tr><tr><td>Platelets (G/L)</td><td></td><td></td><td></td><td>.0001</td></tr><tr><td>&lt;150 vs [150; 450]</td><td>13 (37.1%)</td><td>203 (43.6%)</td><td>0.98 [0.46; 2.06]</td><td></td></tr><tr><td>&gt;450 vs [150; 450]</td><td>5 (14.3%)</td><td>4 (0.9%)</td><td>19.04 [4.68; 77.49]</td><td></td></tr><tr><td>LDH ≥250 UI/L (vs &lt;250 UI/L)</td><td>18 (60.0%)</td><td>164 (38.5%)</td><td>2.40 [1.13; 5.10]</td><td>.0235</td></tr><tr><td>Biopsy (yes vs no)</td><td>25 (71.4%)</td><td>157 (36.8%)</td><td>4.30 [2.01; 9.18]</td><td>.0002</td></tr><tr><td>BMTB (yes vs no)</td><td>23 (65.7%)</td><td>89 (20.8%)</td><td>7.28 [3.49; 15.20]</td><td>&lt;.0001</td></tr></tbody></table>

D

<table><thead><tr><th>Portal hypertension (N = 501)</th><th>Portal hypertension (n = 26)</th><th>No portal hypertension (n = 475)</th><th>OR [95% CI]</th><th>p-value</th></tr></thead><tbody><tr><td>Platelets &lt;150 G/L (vs 150-450 G/L)</td><td>18 (69.2%)</td><td>198 (41.7%)</td><td>3.05 [1.30; 7.15]</td><td>.0378</td></tr><tr><td>Abnormal γ-GT (vs normal)</td><td>17 (68.0%)</td><td>124 (28.0%)</td><td>5.47 [2.30; 12.99]</td><td>.0001</td></tr><tr><td>Monoclonal peak (yes vs no)</td><td>5 (19.2%)</td><td>32 (6.9%)</td><td>3.24 [1.14; 9.15]</td><td>.0268</td></tr><tr><td>Liver biopsy (yes vs no)</td><td>10 (38.5%)</td><td>10 (2.3%)</td><td>26.62 [9.71; 73.00]</td><td>&lt;.0001</td></tr></tbody></table>

**Fig. 4** Predictive factors for lymphoid malignancies<sup>a</sup> (A), autoimmune disorders<sup>a</sup> (B), myeloid malignancies<sup>b</sup> (C), and portal hypertension<sup>b</sup> (D). <sup>a</sup>All predictive factors obtained with the multiple regression analyses are presented. Independent variables with *p* <.01 in the univariate regression analysis were introduced in the model. The number of observations used was lower than the sample size because of missing data for some variables. <sup>b</sup>Univariate regression analysis with predictive factors with *p* ≤.05 presented. The observed number of patients with myeloid malignancies and portal hypertension was too low to proceed to a multiple regression analysis through the numerous predictive factors identified. BMTB, bone marrow trephine biopsy; CI, confidence interval; CRP, C-reactive protein; γ-GT, gamma-glutamyl transferase; LDH, lactate dehydrogenase; OR, odds ratio; vs., versus; yrs, years
malignancies (compared to the reference categories; Fig. 4C).

Low platelet levels, abnormal γ-GT levels, presence of a monoclonal peak, and liver biopsy exploration were all significantly associated with higher odds of having a diagnosis of portal hypertension (compared to the reference categories; Fig. 4D).

## Discussion

The SMS is the first real-life observational study to investigate the etiologies of “unexplained” SM and confirm the diagnostic challenges these patients face. During the study, a significant proportion (44.5%) of patients with unexplained SM, who had undergone investigations for varying durations prior to the study, ultimately received a diagnosis through further investigations. However, 55.5% of 501 patients remained without diagnosis within 18-month follow-up. Several explanations can be proposed. First, the observational methodology prevented a predefined diagnosis approach such that physicians were not directed in their workup and patients could refuse some invasive examinations (e.g., BTMB). We found that 5.6% of these patients with a maximal spleen length ≥ 13 cm was not true SM, by using the height and sex weighting of SplenoCalc® application, but invalidated SM in a similar proportion in subgroup with or without a final diagnosis as the calculation limit designates women < 155 cm or ≥ 180 cm in height as well as men < 160 cm in height, as having an out-of-bound size that does not allow the determination of spleno-megaly. Moreover, the follow-up time was limited, and some additional cases were diagnosed after the end of the study. Finally, patients who had SM of unknown origin and did not feel unwell were younger, with few clinical symptoms and biological abnormalities. Conversely, older patients with massive SM or heterogenous structure were more likely to be diagnosed.

Extensive medical workup is challenging for physicians as many signs and symptoms are common to various conditions. This long medical course was confirmed by data observed in this study, considering the variety and high number of tests and examinations performed. Indeed, undiagnosed patients underwent an average of 14 tests and examinations. The most frequent tests were related to imaging, biology, and serology, both for patients with explained and unexplained SM. However, notably, biopsies were more frequently performed in diagnosed than undiagnosed patients, with BMTB being the most frequent and relevant. Only 9 imaging-guided percutaneous spleen biopsies were reported compared to 16 hepatic ones. This low splenic biopsy rate reflects the French practice indicating concern for hemorrhagic risk [23, 24]. Although a meta-analysis found a high performance for diagnosis and a quite low hemorrhagic complication

rate of approximately 1.3% compared to kidney biopsies [25]. Diagnostic splenectomy was performed in 22 (4.8%) patients, of whom 16 contributed directly to the diagnosis, which was mainly lymphoid malignancies (75.0% of them). Previous studies reported that among patients who underwent a splenectomy for any reason, diagnostic splenectomy was performed in 9.2% [11] to 12% [1] of patients with SM. The lower observed splenectomy rate in the current study could be explained by the modification of clinical practice in France where few surgical actions are performed for diagnostic purposes due to safety reasons [23, 24].

In SMS, the main etiologies of SM were non-malignant diseases (combining autoimmune or inflammatory disorders, portal hypertension, infectious diseases, and marginally LSDs) with a total prevalence of 27.1%, while hematological disorders have usually been reported as the main cause of SM [1, 7, 11]. Even if infectious diseases are much less frequent than in the past decade (they represented 16–36% in the American study), they are still present (4.8%) and need to be ruled out, especially tuberculosis [1]. It is noteworthy that various red blood cell disorders, mainly inherited, come to light as isolated SM (2%); thus, hemolysis has to be carefully searched, even without anemia. Among hematological neoplasms, lymphomas were the leading cause with splenic marginal zone lymphoma (18/49) being the most prominent B-cell-derived lymphoma (Additional file 1, Supplementary Table 6). In myeloid neoplasms, primary or secondary myelofibrosis is most common (14/35). Indeed, in some cases, the analysis of white blood cells and blood films failed to provide convincing results, and other examinations were warranted, such as chromosomal microarray familial testing, karyotype, next-generation sequencing (NGS), and BMTB.

A total of 10 (2.0%) patients were diagnosed with LSDs, including 4 with GD (representing a prevalence of 0.8%). The prevalence of GD was lower in SMS study than previously described [26, 27]. Indeed, the expected rate of patients with GD was 4.0%, and in a recent study, the prevalence of GD was reported at 3.3% in patients with SM and/or thrombocytopenia [26].

Patients from this cohort were younger than in the current study (mean age, 46.9 years vs. 51.0 years). Above all, the higher GD prevalence in the study from Motta et al. [26] could be explained by the study design, which was in favor of enriching the population with patients with GD: patients needed to have ≥ 1 other sign or symptom of GD (based on Mistry P's algorithm [28]) in addition to SM or thrombocytopenia, compared to SMS study wherein no specific patients were targeted (all patients with unexplained SM could be included). Nevertheless, this prevalence at the end of SMS study is higher than the incidence of new cases of GD observed in real
life by the French MG expert group (in the order of 2–6
per year for the whole of Metropolitan France. However,
GD prevalence could be underestimated in the SMS
study since some patients with GD could not be included
because the β-glucocerebrosidase enzyme activity assay
had already been performed before enrollment. Patients
with still unexplained SM who may have LSD could also
not be excluded at the end of the study as 22.3% of them
were not tested for GD or ASMD. This is also the rea-
son these data support that an enzymatic assay for LSD,
such as β-glucocerebrosidase and acid sphingomyelin-
ase for GD and Niemann–Pick disease, respectively [29],
be systematically performed in patients presenting with
unexplained SM. In addition, the descriptive analysis of
the 4 patients with GD showed patients with very hetero-
geneous clinical symptoms and thus, also highlighted the
relevance of a systematic screening for GD by appropri-
ate enzymatic tests in patients with SM and thrombocy-
topenia (platelet levels < 150 G/L) because no clear and
specific clinical profile can be drawn for these patients.

Unlike GD and ASMD, where SM is frequent (80% and 60%, respectively), SM is not frequent in Fabry disease (α-galactosidase A congenital deficiency). Nevertheless, SM has been yet described, and the spleen enlargement was due to high blood splenic flow and globotriaosylceramide (Gb3) and Lyso-Gb3 endothelial cell accumulation [30].

SM may be consecutive to mild portal hypertension
noted in approximately 5% of cases and clinicians may
be suspicious of that especially if patients have meta-
bolic syndrome and/or the observed risk factors. Mild
thrombocytopenia and high γ-GT levels are intuitive but
monoclonal gammopathy seems also associated as it is
well-known in cirrhosis. In this setting, the patient may
be referred to a hepatologist for more explorations such
liver biopsy.

Compared to patients with still unexplained SM after
the follow-up period, patients with explained SM were
significantly older, with a larger and heterogeneous
spleen, more severe symptoms, and altered biological
parameters. Therefore, more severe clinical symptoms
made it easier for physicians to establish a diagnosis by
facilitating diagnostic orientation. This confirms again
the difficulty in diagnosing patients with a wide range of
symptoms less characteristic of a particular etiology.

Site representativeness was not assessed, but to pre-
vent any selection bias, a large sample of physicians was
invited to participate in the study (> 3,700 physicians,
representing around 80% of targeted French physicians).
Physicians targeted for participation were internists or
hematologists considering the possible etiologies asso-
ciated with SM [21]. In adherence to the protocol, no
selection of site was performed according to physicians'

specialty or region of practice; the study was proposed to
all responders.

The study is constrained by the limited sample size of
patients diagnosed with GD (n=4). It should be noted
that univariate and multivariate logistic regression anal-
yses could not be conducted to establish the predictive
significance of diagnostic criteria for GD, as defined by
Mistry P (including thrombocytopenia, anemia, history
of bone pain, early onset of mono- or polyclonal gam-
mopathy in patients < 30 years, along with cholelithiasis)
could not be performed [28]. Despite this, a descriptive
analysis of the patients revealed that some of the diag-
nostic criteria, such as young age, were present in all
patients except for one who was 62 years old, with all but
1 patient experiencing thrombocytopenia (platelet lev-
els < 100 G/L; 1 patient had a platelet level of 101 G/L),
1 patient having anemia, and 1 patient suffering from
bone pain. Polyclonal gammopathy was found in the old-
est male patient, and no patients had cholelithiasis. The
clinical symptoms of these 4 patients with GD were het-
erogeneous, underscoring the importance of systematic
screening for GD in patients with SM and thrombocyto-
penia (platelet levels < 150 G/L).

The diagnostic strategy for SM should be optimized; to
assist physicians in making a possible diagnosis, a list of
potential predictive factors has been identified through
exploratory analyses. These results could help physicians
to be more attentive to particular symptoms and suggest
better management in terms of cost and time, and fewer
invasive examinations, leading to relief for patients if ade-
quate treatment can be implemented more quickly. These
exploratory predictive factors are concrete elements to
help practitioners in their approach when investigating
unexplained SM. In addition, the use of new technolo-
gies, such as NGS panel, might help physicians reduce
diagnostic delay for patients presenting with unexplained
SM [31]. Indeed, several targeted sequencing panels
have been developed for lymphoid, myeloid, rare blood
cell disorders, or LSD [32, 33]. The NGS approach repre-
sents a valuable alternative to biochemical assays, mainly
because a broader spectrum of diseases can be moni-
tored in one single test in a shorter time.

Conclusion

In conclusion, patients with an apparent idiopathic SM
could reach a precise diagnosis in approximately 44.5% of
cases. The use of the SplenoCalc® application published
since the start of this study means that certain diagnoses
of moderate SM can be ruled out and thus, the calcula-
tion should be used more widely.

Patients with explained SM were older and had a larger
spleen and altered biological parameters compared to
those with SM remaining unexplained at the end of the
study. Interestingly, non-malignant diseases were more
prevalent compared to hematological malignancies. The prevalence of rare disease was high: 10 patients were diagnosed with LSD, including 4 with GD (prevalence, 0.8%). These data support that an enzymatic assay for LSD should be systematically performed in patients with unexplained SM, especially before splenectomy, particularly because of the risk of aggravating the underlying disease [14, 34]. This study also allowed to define a potential list of predictive factors for the main diagnostic categories of unexplained SM, providing useful new information to optimize the diagnostic strategy of SM.

## Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s13023-025-03768-3.

Supplementary Material 1

### Acknowledgements

The authors dedicate this manuscript to the memory of Professor Christian Rose from the Department of Oncology and Hematology, Saint Vincent de Paul Hospital, Lille, France, who was the first principal coordinator of the study but sadly passed away. The authors would like to thank all study investigators (Christian Agard, Florence Dalbies, Bénédicte Hivert, Mathieu Jouvray, Sébastien Humbert, Yazid Arkam, Diane Cerutti, Pascal Hutin, Philippe Genet, Maya Hacini, François Maurier, Isabelle Leduc, Hervé Maisonneuve, Pascale Cony-Makhoul, Omar Benbrahim, Marie-Anne Bouldouyre, Sylvie Cailleres, Jean-Paul Kisterman, Laurent Ghandi Damaj, Amélie Servettaz, Gilles Blaison, Thierry Weitten, Elisabeth Brottier-Mancini, Alain Zannetti, Laurence Bouillet, Kamel Laribi, Marielle Roux-Sauvat, Katell Le Du, Isabelle Grulois, Mathieu Puyade, Vanessa Leguy-Seguin, Adrien Bigot, Sten De Witte, Esther Noel, Ali Abdessamad Hachemi, Moumini Kone, Arsène Mekinian, Jean-Baptiste Picque, Bérengère Cador, Chloé Stavris, Jean-François Viallard, Philippe Audeguy, Adrian Hij, Elena Catalina Enache, Charles Quinquenet, Loïc Garçon, Véronique Perronne, Philippe Quittet, Alain Saad, Maria Diaz-Ghanem, Cyril Faure, Alfred Mahr, Hervé Levesque, Loïc Fouillard, Marly Barry, Nadia Baati, Olivier Allangba, Sophie Dupire, Jean-Marie Cournac, Gaëlle Olivier, Julie Graveleau, Patrick Mercié, Sondess Hadj-Khelifa, Seyef Eddine Kadi, Liazid Bencharif, Emilie Berthoux, Caroline Besson, Sylvain Choquet, Léopold Adelaïde, Arnaud Saint-Lezer, Claire Pouteil Noble, Mohamed El Hadi Djerad, Mathilde Roumier, Ruxandra Burlacu, Roland Jaussaud, Véronique Dorvaux, Nicolas Rouanes, Jean-François Brantus, Boris Bienvenu, Hugo Gonzalez, and Bachra Choufi) and the International Clinical Trials Association (ICTA) - CRO for their contribution in the development of this manuscript. Scientific writing support was provided by Krishna Aswal and Subhasri Ghosh of Sanofi.

### Author contributions

All the authors contributed to the interpretation of this work and critically reviewed the article for important intellectual content. FB, MGB, RC, CR, LS, and GD contributed to the ideation and design of the study. GU and MM significantly contributed to recruitment of patients for this study.

### Funding

This study was sponsored by Sanofi.

### Data availability

Data are available at request from the corresponding author.

### Declarations

#### Ethics approval and consent to participate

The study was approved by the independent scientific committee (CPP Ouest IV, France) and performed in accordance with the Declaration of Helsinki and applicable laws. Patients (or legal representatives, if applicable) signed an informed consent form prior to participating in the study.

### Consent for publication

Consent for publication was obtained from all authors.

### Competing interests

**DG:** Received honoraria and/or research support from Sanofi. **LT:** Received honoraria and/or research support from Sanofi. **TS:** Received honoraria from Sanofi for lectures. **RC:** Received honoraria and/or research support from Genzyme/Sanofi, Sandoz, Novartis, and BeiGene. **MM:** Received travel grants and speaker honoraria from Amicus, Genzyme/Sanofi, and Shire/Takeda. **AL:** Employe of Sanofi and may hold shares and/or stock options in the company. **FB:** Novartis, Sanofi, Octapharma, and Incyte. **CR:** Received reimbursement of expenses and honorarium for lectures from Sanofi and Shire. **GU:** Received honoraria from Sanofi and Novartis for lectures. **MGB:** Received honoraria from Sanofi and Takeda for scientific board lectures. **LS:** None.

### Author details

Received: 28 May 2024 / Accepted: 4 May 2025

Published online: 06 June 2025

### References

1. O'Reilly RA. Splenomegaly in 2,505 patients at a large university medical center from 1913 to 1995. 1963 to 1995: 449 patients. West J Med. 1998;169(2):88-97.

2. Chapman J, Goyal A, Azevedo AM. Splenomegaly. StatPearls. Treasure Island (FL): StatPearls publishing copyright © 2023. StatPearls Publishing LLC.; 2023.

3. Srisajjakul S, Prapaisilp P, Laorratkul N. Normal Splenic volume assessment on CT in 426 adults. Siriraj Med J. 2012;64:43-6.

4. Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. Recommendations for initial evaluation, staging, and response assessment of hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-68.

5. Kucybała I, Ciuk S, Tęczar J. Spleen enlargement assessment using computed tomography: which coefficient correlates the strongest with the real volume of the spleen? Abdom Radiol (NY). 2018;43(9):2455-61.

6. Curovic Rotbain E, Lund Hansen D, Schaffalitzky de Muckadell O, Wibrand F, Meldgaard Lund A, Frederiksen H. Splenomegaly - Diagnostic validity, work-up, and underlying causes. PLoS ONE. 2017;12(11):e0186674.

7. Swaroop J, O'Reilly RA. Splenomegaly at a university hospital compared to a nearby County hospital in 317 patients. Acta Haematol. 1999;102(2):83-8.

8. Abramson JS, Kotton CN, Elias N, Sahani DV, Hasserjian RP. Case records of the Massachusetts general hospital. Case 8-2008. A 33-year-old man with fever, abdominal pain, and pancytopenia after renal transplantation. N Engl J Med. 2008;358(11):1176-87.

<footnote n="1">¹Department of Internal Medicine and Hematology, Rochefort Hospital, Rochefort, France</footnote>

<footnote n="2">²Department of Internal Medicine and Immunology, Centre de Référence des Maladies Autoimmunes Systémiques Rares du Nord et Nord-Ouest de France (CeRAINO), CHRU, Lille, France</footnote>

<footnote n="3">³Department of Internal Medicine, Clinique Axium, Aix En Provence, France</footnote>

<footnote n="4">⁴Department of Hematology and Cellular Therapy, La Conception Hospital, Marseille, France</footnote>

<footnote n="5">⁵Department of Internal Medicine, Joseph Ducuing Hospital, Toulouse, France</footnote>

<footnote n="6">⁶Medical Department, Sanofi, Gentilly, France</footnote>

<footnote n="7">⁷Department of Hematology, Côte Basque Hospital, Bayonne, France</footnote>

<footnote n="8">⁸College of Health Sciences, University of Bordeaux, Bordeaux, France</footnote>

<footnote n="9">⁹Department of Hematology, Saint Jean Hospital, Perpignan, France</footnote>

<footnote n="10">¹⁰Department of Oncology and Hematology, Saint Vincent de Paul Hospital, Lille, France</footnote>

<footnote n="11">¹¹Department of Internal Medicine and Clinical Immunology, University Hospital Angers, Angers, France</footnote>

<footnote n="12">¹²Department of Orofacial Sciences, School of Dentistry, University of California, San Francisco, CA, USA</footnote>

<footnote n="13">¹³Department of Immunology and Allergology, Hôpitaux Universitaires de Genève, Geneva, Switzerland</footnote>

<footnote n="14">¹⁴Department of Biological Hematology and EA 7453 CHELTER, University Hospital of Clermont-Ferrand and Université Clermont Auvergne, Clermont-Ferrand, France</footnote>
9. Sjoberg BP, Menias CO, Lubner MG, Mellnick VM, Pickhardt PJ. Splenomegaly: A combined clinical and radiologic approach to the differential diagnosis. Gastroenterol Clin North Am. 2018;47(3):643-66.

10. Motyckova G, Steensma DP. Why does my patient have lymphadenopathy or splenomegaly? Hematol Oncol Clin North Am. 2012;26(2):395-408. ix.

11. Maillot J, Malfuson JV, Lazure T, Benoist S, Cremades A, Hornez E et al. Diagnostic splenectomy: characteristics, Pre-Operative investigations, and identified pathologies for 20 patients. J Clin Med. 2021;10(7).

12. Pata G, Damiani E, Tognali D, Solaini L, Watt J, Ragni F. Outcomes of open splenectomy for hematologic malignancy with splenomegaly: a contemporary perspective. Am Surg. 2015;81(4):414-20.

13. Taner T, Nagorney DM, Tefferi A, Habermann TM, Harmsen WS, Slettedahl SW, et al. Splenectomy for massive splenomegaly: long-term results and risks for mortality. Ann Surg. 2013;258(6):1034-9.

14. Kristinsson SY, Gridley G, Hoover RN, Check D, Landgren O. Long-term risks after splenectomy among 8,149 cancer-free American veterans: a cohort study with up to 27 years follow-up. Haematologica. 2014;99(2):392-8.

15. Stirnemann J, Belmatoug N, Camou F, Serratrice C, Froissart R, Caillaud C et al. A review of gaucher disease pathophysiology, clinical presentation and treatments. Int J Mol Sci. 2017;18(2).

16. Rajkumar V, Dumpa V. Lysosomal Storage Disease. StatPearls. Treasure Island (FL)2022.

17. Daykin EC, Ryan E, Sidransky E. Diagnosing neuronopathic gaucher disease: new considerations and challenges in assigning gaucher phenotypes. Mol Genet Metab. 2021;132(2):49-58.

18. Pastores GM, Weinreb NJ, Aerts H, Andria G, Cox TM, Giralt M, et al. Thera- peutic goals in the treatment of gaucher disease. Semin Hematol. 2004;41(4 Suppl 5):4-14.

19. Dardis A, Michelakakis H, Rozenfeld P, Fumic K, Wagner J, Pavan E, et al. Patient centered guidelines for the laboratory diagnosis of gaucher disease type 1. Orphanet J Rare Dis. 2022;17(1):442.

20. Chow KU, Luxembourg B, Seifried E, Bonig H. Spleen size is significantly influenced by body height and sex: establishment of normal values for spleen size at US with a cohort of 1200 healthy individuals. Radiology. 2016;279(1):306-13.

21. Pozo AL, Godfrey EM, Bowles KM. Splenomegaly: investigation, diagnosis and management. Blood Rev. 2009;23(3):105-11.

22. Bagley SC, White H, Golomb BA. Logistic regression in the medical literature: standards for use and reporting, with particular attention to one medical domain. J Clin Epidemiol. 2001;54(10):979-85.

23. Lal A, Ariga R, Gattuso P, Nemcek AA, Nayar R. Splenic fine needle aspiration and core biopsy. A review of 49 cases. Acta Cytol. 2003;47(6):951-9.

24. Liang P, Gao Y, Wang Y, Yu X, Yu D, Dong B. US-guided percutaneous needle biopsy of the spleen using 18-gauge versus 21-gauge needles. J Clin Ultra- sound. 2007;35(9):477-82.

25. McInnes MD, Kielar AZ, Macdonald DB. Percutaneous image-guided biopsy of the spleen: systematic review and meta-analysis of the complication rate and diagnostic accuracy. Radiology. 2011;260(3):699-708.

26. Motta I, Consonni D, Stroppiano M, Benedetto C, Cassinerio E, Tappino B, et al. Predicting the probability of gaucher disease in subjects with splenomegaly and thrombocytopenia. Sci Rep. 2021;11(1):2594.

27. Motta I, Filocamo M, Poggiali E, Stroppiano M, Dragani A, Consonni D, et al. A multicentre observational study for early diagnosis of gaucher disease in patients with splenomegaly and/or thrombocytopenia. Eur J Haematol. 2016;96(4):352-9.

28. Mistry PK, Cappellini MD, Lukina E, Ozsan H, Mach Pascual S, Rosenbaum H, et al. A reappraisal of gaucher disease-diagnosis and disease management algorithms. Am J Hematol. 2011;86(1):110-5.

29. Mokhtariye A, Hagh-Nazari L, Varasteh AR, Keyfi F. Diagnostic methods for lysosomal storage disease. Rep Biochem Mol Biol. 2019;7(2):119-28.

30. Oliveira JP, Valbuena C, Baldaia Moreira A, Fonseca E, Soares C, Leão Teles E, et al. Splenomegaly, hypersplenism and peripheral blood cytopae- nias in patients with classical Anderson-Fabry disease. Virchows Arch. 2008;453(3):291-300.

31. Auteri G, Bartoletti D, Bertuzzi C, Bacci F, Tonini V, Catani L, et al. The diagnos- tic role of next generation sequencing in Uncovering isolated splenomegaly: A case report. Hematol Rep. 2021;13(2):8814.

32. Gheldof A, Seneca S, Stouffs K, Lissens W, Jansen A, Laeremans H, et al. Clini- cal implementation of gene panel testing for lysosomal storage diseases. Mol Genet Genomic Med. 2019;7(2):e00527.

33. Zanetti A, D'Avanzo F, Bertoldi L, Zampieri G, Feltrin E, De Pascale F, et al. Setup and validation of a targeted Next-Generation sequencing approach for the diagnosis of lysosomal storage disorders. J Mol Diagn. 2020;22(4):488-502.

34. Rodeghiero F, Ruggeri M. Short- and long-term risks of splenectomy for benign haematological disorders: should we revisit the indications? Br J Haematol. 2012;158(1):16-29.

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