Lysosomal Acid Lipase Deficiency (LAL-D) comprises a spectrum of rare autosomal recessive lipid storage disorders, including Wolman disease and Cholesteryl Ester Storage Disease (CESD). These conditions are caused by pathogenic variants in the LIPA gene, encoding lysosomal acid lipase (LAL), a key enzyme responsible for hydrolyzing cholesterol esters and triglycerides into free fatty acids, free cholesterol, and glycerol within lysosomes (1). Complete or near-complete deficiency in LAL activity leads to systemic lipid accumulation, predominantly in the liver, spleen, and vascular endothelium. Clinical manifestations of LAL-D range from rapidly progressive severe disease to more slowly progressing milder phenotypes (2,3). To date, genotype–phenotype correlations remain poorly defined, except for the LIPA (NM_000235.3):c.894G>A (p.Gln298=) splice variant which has been extensively characterized (4).

Wolman disease, the severe, early-onset form, presents in infancy with significant hepatosplenomegaly, intestinal malabsorption, and adrenal calcifications, typically leading to death within the first six months of life. In contrast, CESD follows a milder course, presenting later in childhood or adolescence with hepatomegaly, mixed hyperlipidemia, elevated transaminases, and progressive liver dysfunction, including fibrosis and potential progression to cirrhosis (3,5).

Suspicion for LAL-D usually arises in patients presenting with hepatomegaly, persistently elevated transaminases, and a characteristic dyslipidemia—marked by elevated total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides, and low high-density lipoprotein cholesterol (HDL-C) (6). Definitive diagnosis is established by demonstrating reduced LAL enzymatic activity or molecular identification of pathogenic variants in the LIPA gene (6). The therapeutic landscape for LAL-D has evolved significantly following the FDA approval of sebelipase alfa, a recombinant LAL enzyme that reduces lipid accumulation and improves clinical symptoms. However, long-term outcomes and optimal enzyme replacement therapy (ERT) protocols remain under active investigation (7), Currently, ERT remains the only available treatment for LAL-D (8).

Prompt and precise diagnosis paired with early therapeutic intervention is critical to prevent disease progression and enhance patient quality of life (8).

This article describes the first documented case in Mexico of CESD with continuous follow-up, diagnosed at age 13 due to short stature and hypercholesterolemia. After four years of ERT, we highlight clinical outcomes and underscore the importance of early diagnosis and personalized therapeutic management.