{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T18:50:19Z","timestamp":1792263019480,"version":"4.4.0"},"reference-count":139,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,3,2]],"date-time":"2024-03-02T00:00:00Z","timestamp":1709337600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Clinical findings of hepatomegaly and splenomegaly, the abnormal enlargement of the liver and spleen, respectively, should prompt a broad differential diagnosis that includes metabolic, congestive, neoplastic, infectious, toxic, and inflammatory conditions. Among the metabolic diseases, lysosomal storage diseases (LSDs) are a group of rare and ultrarare conditions with a collective incidence of 1 in 5000 live births. LSDs are caused by genetic variants affecting the lysosomal enzymes, transporters, or integral membrane proteins. As a result, abnormal metabolites accumulate in the organelle, leading to dysfunction. Therapeutic advances, including early diagnosis and disease-targeted management, have improved the life expectancy and quality of life of people affected by certain LSDs. To access these new interventions, LSDs must be considered in patients presenting with hepatomegaly and splenomegaly throughout the lifespan. This review article navigates the diagnostic approach for individuals with hepatosplenomegaly particularly focusing on LSDs. We provide hints in the history, physical exam, laboratories, and imaging that may identify LSDs. Additionally, we discuss molecular testing, arguably the preferred confirmatory test (over biopsy), accompanied by enzymatic testing when feasible.<\/jats:p>","DOI":"10.3390\/jcm13051465","type":"journal-article","created":{"date-parts":[[2024,3,4]],"date-time":"2024-03-04T04:36:21Z","timestamp":1709526981000},"page":"1465","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Hepatomegaly and Splenomegaly: An Approach to the Diagnosis of Lysosomal Storage Diseases"],"prefix":"10.3390","volume":"13","author":[{"given":"Teodoro","family":"Jerves Serrano","sequence":"first","affiliation":[{"name":"Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6210-4214","authenticated-orcid":false,"given":"Jessica","family":"Gold","sequence":"additional","affiliation":[{"name":"Division of Genetics, Department of Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A.","family":"Cooper","sequence":"additional","affiliation":[{"name":"Willink Biochemical Genetics Laboratory, St Mary\u2019s Hospital, Manchester University NHS Foundation Trust, Manchester M13 9WL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather J.","family":"Church","sequence":"additional","affiliation":[{"name":"Willink Biochemical Genetics Laboratory, St Mary\u2019s Hospital, Manchester University NHS Foundation Trust, Manchester M13 9WL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen L.","family":"Tylee","sequence":"additional","affiliation":[{"name":"Willink Biochemical Genetics Laboratory, St Mary\u2019s Hospital, Manchester University NHS Foundation Trust, Manchester M13 9WL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6471-6743","authenticated-orcid":false,"given":"Hoi Yee","family":"Wu","sequence":"additional","affiliation":[{"name":"Willink Biochemical Genetics Laboratory, St Mary\u2019s Hospital, Manchester University NHS Foundation Trust, Manchester M13 9WL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun Young","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Human Genetics, Department of Pediatrics, Cincinnati Children\u2019s Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0148-6332","authenticated-orcid":false,"given":"Karolina M.","family":"Stepien","sequence":"additional","affiliation":[{"name":"Salford Royal Organization, Northern Care Alliance NHS Foundation Trust, Adult Inherited Metabolic Diseases Department, Salford M6 8HD, UK"},{"name":"Division of Cardiovascular Sciences, University of Manchester, Manchester M13 9PL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.amjmed.2018.09.012","article-title":"How Strongly Do Physical Examination Estimates and Ultrasonographic Measurements of Liver Size Correlate? 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