{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:06:30Z","timestamp":1760058390922,"version":"build-2065373602"},"reference-count":19,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T00:00:00Z","timestamp":1743292800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sanofi Spain","award":["2019"],"award-info":[{"award-number":["2019"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diseases"],"abstract":"<jats:p>Introduction: The differential diagnosis of splenomegaly is a complex process that encompasses a wide variety of diseases. Moreover, it is not always standardized and lacks a definitive consensus on which tests should be performed and in what order. Gaucher disease (GD) and acid sphingomyelinase deficiency (ASMD) are lysosomal diseases (LD) that present with splenomegaly, the diagnosis of which requires a high index of suspicion and specific biochemical and genetic techniques. The aim of the project for the education and diagnosis of Gaucher disease and acid sphingomyelinase deficiency (PREDIGA) was to conduct educational training alongside an observational, multicenter, ambispective, cross-sectional, single-cohort study among patients having an enlarged spleen or undergone splenectomy to further assess these subjects to exclude two lysosomal diseases, namely GD and ASMD. Methods: Using dried blood spot (DBS) testing, we identified patients with abnormally low values of the enzymes glucocerebrosidase and acid sphingomyelinase, who then underwent sequencing of the GBA1 and SPMD1 genes, respectively. The study involved 34 hospitals and 52 medical specialists. Results: We identified 220 patients (208 adults and 12 children under 18 years) with cryptogenic splenomegaly or who had undergone splenectomy (12 patients) without having reached a diagnosis. The median age was 11 years (interquartile range [IQR] 3\u201316) in the pediatric population and 51 years (IQR 38\u201365) in the adult population. Lower-than-normal enzyme values were detected in 19 DBSs, confirming eight positive cases, which corresponded to six patients with GD and two with ASMD. The rest of the DBSs with low enzyme activity were not genetically confirmed (58%). We determined that lysosomal diseases accounted for 3.6% of cryptogenic splenomegaly\/splenectomy cases in our setting: 2.7% were GD and 0.9% ASMD, in a ratio of 1 ASMD patient to every 3 GD patients. Lyso-GL1 values in patients with GD were elevated in all but one individual, corresponding to a child diagnosed at 4 months old. The variants detected in the GBA1 gene were consistent with the most frequent variants found in Spain. Discussion\/Conclusion: The development and implementation of this protocol for the education and diagnosis of cryptogenic splenomegaly\/splenectomy, even in asymptomatic patients, constitutes a comprehensive, simple, rapid, and effective screening method for the diagnosis of GD and ASMD.<\/jats:p>","DOI":"10.3390\/diseases13040102","type":"journal-article","created":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T01:59:36Z","timestamp":1743386376000},"page":"102","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Study of Adult and Pediatric Spanish Patients with Cryptogenic Splenomegaly and Splenectomy"],"prefix":"10.3390","volume":"13","author":[{"given":"Marta","family":"Morado Arias","sequence":"first","affiliation":[{"name":"Department of Hematology and Hemotherapy, Hospital Universitario La Paz, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jes\u00fas","family":"Villarrubia Espinosa","sequence":"additional","affiliation":[{"name":"Department of Hematology and Hemotherapy, Hospital Universitario Ram\u00f3n y Cajal, 28034 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isidro","family":"Vitoria Mi\u00f1ana","sequence":"additional","affiliation":[{"name":"Nutrition and Metabolic Disease Unit, Hospital Universitario La Fe, 46026 Valencia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3166-5086","authenticated-orcid":false,"given":"Enrique","family":"Calder\u00f3n Sandubete","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Biomedicine Institute, Hospital Universitario Virgen del Roc\u00edo, 41013 Seville, Spain"},{"name":"Consejo Superior de Investigaciones Cient\u00edficas (CSIC), Centro de Investigaci\u00f3n Biom\u00e9dica en Red Epidemiol\u00f3gica y Salud P\u00fablica de Espa\u00f1a (CIBERESP), 41013 Sevilla, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"V\u00edctor","family":"Quintero","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology-Oncology, Hospital Universitario La Paz, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0451-3597","authenticated-orcid":false,"given":"Miguel \u00c1ngel","family":"Torralba-Cabeza","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Hospital Universitario Lozano Blesa, 50009 Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.blre.2008.10.001","article-title":"Splenomegaly: Investigation, diagnosis and management","volume":"23","author":"Pozo","year":"2009","journal-title":"Blood Rev."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Pelizzo, G., Guazzotti, M., Klersy, C., Nakib, G., Costanzo, F., Andreatta, E., Bassotti, G., and Calcaterra, V. (2018). Spleen size evaluation in children: Time to define splenomegaly for pediatric surgeons and pediatricians. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0202741"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"15","DOI":"10.5694\/j.1326-5377.1986.tb113733.x","article-title":"A palpable spleen is not necessarily enlarged or pathological","volume":"145","author":"Arkles","year":"1986","journal-title":"Med. J. Aust."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Suttorp, M., and Classen, C.F. (2021). Splenomegaly in Children and Adolescents. Front. Pediatr., 9.","DOI":"10.3389\/fped.2021.704635"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Curovic Rotbain, E., Lund Hansen, D., Schaffalitzky de Muckadell, O., Wibrand, F., Meldgaard Lund, A., and Frederiksen, H. (2017). Splenomegaly\u2014Diagnostic validity, work-up, and underlying causes. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0186674"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1111\/ejh.12596","article-title":"Splenomegaly Gaucher Disease study group. A multicentre observational study for early diagnosis of Gaucher disease in patients with Splenomegaly and\/or Thrombocytopenia","volume":"96","author":"Motta","year":"2016","journal-title":"Eur. J. Haematol."},{"key":"ref_7","first-page":"78","article-title":"Splenomegaly in 2505 patients at a large university medical center from 1913 to 1995. 1913 to 1962: 2056 patients","volume":"169","year":"1998","journal-title":"West. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/j.gtc.2018.04.009","article-title":"Splenomegal: A combined clinical and Radiologic approach to differential diagnosis","volume":"47","author":"Sjoberg","year":"2018","journal-title":"Gastroenterol. Clin. N. Am."},{"key":"ref_9","first-page":"330","article-title":"Acid sphingomyelinase deficiency and Gaucher disease in adults: Similarities and differences in two macrophage storage disorders","volume":"65","author":"Eskes","year":"2024","journal-title":"JIMD Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.ejim.2022.11.028","article-title":"Similarities and differences between Gaucher disease and acid sphingomyelinase deficiency: An algorithm to support the diagnosis","volume":"108","author":"Capellini","year":"2023","journal-title":"Eur. J. Intern. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"107563","DOI":"10.1016\/j.ymgme.2023.107563","article-title":"Importance to include differential diagnostics for acid sphingomyelinase deficiency (ASMD) in patients suspected to have to Gaucher disease","volume":"139","author":"Oliva","year":"2023","journal-title":"Mol. Genet. Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"207","DOI":"10.5045\/br.2022.2022089","article-title":"Early diagnosis of Gaucher disease in Korean patients with unexplained splenomegaly: A multicenter observational study","volume":"57","author":"Do","year":"2022","journal-title":"Blood Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1186\/s13023-023-02797-0","article-title":"Screening for lysosomal diseases in a selected pediatric population: The case of Gaucher disease and acid sphingomyelinase deficiency","volume":"18","author":"Vici","year":"2023","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1186\/s13023-023-02760-z","article-title":"GAU-PED study for early diagnosis of Gaucher disease in children with splenomegaly and cytopenia","volume":"18","author":"Pession","year":"2023","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Giacomarra, M., Colomba, P., Francofonte, D., Zora, M., Caocci, G., Diomede, D., Guiffrida, G., Fiori, L., Montanari, C., and Sapuppo, A. (2024). Gaucher Disease or Acid Sphingomyelinase Deficiency? The Importance of Differential Diagnosis. J. Clin. Med., 13.","DOI":"10.3390\/jcm13051487"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.1373\/clinchem.2004.035907","article-title":"Direct multiplex assay of lysosomal enzymes in dried blood spots for newborn screening","volume":"50","author":"Li","year":"2004","journal-title":"Clin. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Motta, I., Consoni, D., Stroppiano, M., Benedetto, C., Cassinerio, E., Tappino, B., Ranalli, P., Borin, L., Facchini, L., and Patriarca, A. (2021). Predicting the probability of Gaucher disease in subjects with splenomegaly and thrombocytopenia. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-82296-z"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1006\/bcmd.2002.0535","article-title":"High prevalence of the 55-bp deletion (c.1263del55) in exon 9 of the glucocerebrosidase gene causing misdiagnosis (for homozygous N370S (c.1226A > G) mutation) in Spanish Gaucher disease patients","volume":"29","author":"Torralba","year":"2002","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.ymgme.2022.03.001","article-title":"The diagnosis and management of Gaucher disease in pediatric patients: Where do we go from here?","volume":"136","author":"Weinreb","year":"2022","journal-title":"Mol. Genet. Metab."}],"container-title":["Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-9721\/13\/4\/102\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:05:46Z","timestamp":1760029546000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-9721\/13\/4\/102"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,30]]},"references-count":19,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["diseases13040102"],"URL":"https:\/\/doi.org\/10.3390\/diseases13040102","relation":{},"ISSN":["2079-9721"],"issn-type":[{"type":"electronic","value":"2079-9721"}],"subject":[],"published":{"date-parts":[[2025,3,30]]}}}