Background: Lysosomal storage diseases (LSDs) are a genetically and clinically heterogeneous group of inborn errors of metabolism caused by variants in genes encoding lysosomal hydrolases, membrane proteins, activator proteins, or transporters. These disease-causing variants lead to enzymatic deficiencies and the progressive accumulation of undegraded substrates within lysosomes, disrupting cellular function across multiple organ systems. While classical phenotypes typically manifest in infancy or early childhood with severe multisystem involvement, a combination of advances in molecular diagnostics [particularly next-generation sequencing (NGS)] and improved understanding of disease heterogeneity have enabled the identification of attenuated forms characterised by residual enzyme activity and later-onset presentations. These milder phenotypes often evade early recognition due to nonspecific or isolated symptoms, resulting in significant diagnostic delays and missed therapeutic opportunities. Objectives/Methods: This study characterises the clinical, biochemical, and molecular profiles of 10 adult patients diagnosed with LSDs, all representing attenuated forms, and discusses them alongside a narrative review. Results: Enzyme activity, molecular data, and phenotypic assessments are described to explore genotype–phenotype correlations and identify diagnostic challenges. Conclusions: These findings highlight the variable expressivity and organ involvement of attenuated LSDs and reinforce the importance of maintaining clinical suspicion in adults presenting with unexplained cardiovascular, neurological, ophthalmological, or musculoskeletal findings. Enhanced recognition of atypical presentations is critical to facilitate earlier diagnosis, guide management, and enable cascade testing for at-risk family members.

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.

Wolman disease (WD) is a lethal disorder defined by the deficiency of the lysosomal acid lipase enzyme. Patients present with intestinal failure, malnutrition, and hepatosplenomegaly. Enzyme replacement therapy (ERT) with dietary substrate reduction (DSR) significantly improves survival. We sought to determine the outcomes of two siblings with WD treated after the onset of symptoms (sibling 1) and presymptomatic (sibling 2). A chart review was conducted on two siblings with WD treated with ERT and DSR at 4 months of age (sibling 1) and immediately after birth (sibling 2) to determine clinical outcomes based on survival, laboratory results, growth, dietary records, and gut biopsies. Sibling 1 presented with hepatosplenomegaly and liver dysfunction and developed hemophagocytic lymphohistiocytosis despite treatment. She received a bone marrow transplant at 8 months of age but died at 13 months. Sibling 2 is alive at 16 months of age with height, weight, and MUAC above the 95th centile, fully orally fed, with no gastrointestinal symptoms, normal liver function, and normal oxysterols. Sibling 2 duodenal biopsies show normal villus architecture with no foamy macrophage infiltration. Initiation of treatment prior to the onset of symptoms can prevent clinical manifestations and increase survival. The divergent trajectory in these siblings raises the question of WD’s candidacy for newborn screening.