Metabolic diseases, such as lysosomal acid lipase deficiency (LAL-D), should be considered in the differential diagnosis of hepatosplenomegaly in infants, according to a recently published case report in the American Journal of Medical Genetics.

The differential diagnosis for infantile hepatosplenomegaly is very broad, including malignant, infectious, hematologic, and metabolic causes. However, many metabolic diseases, such as LAL-D and mucopolysaccharidosis type 1, are not routinely considered in newborn screenings.

The present case involved a 2-month-old dizygotic twin girl with a history of abdominal distension, fever, failure to thrive, and constant vomiting. Physical examination revealed an enlarged abdomen due to hepatosplenomegaly.

Continue Reading

Furthermore, the patient had no dysmorphic features or skeletal abnormalities, and newborn screening was normal. Laboratory findings included elevated liver enzymes, acute phase reactants, cholesterol, and triglycerides, as well as microcytic anemia without an appropriate reticulocyte response.

Read more about LAL-D epidemiology

Due to initial concerns about underlying malignancy, a bone marrow aspirate with flow cytometry was performed, revealing no infiltrative neoplastic processes. However, the aspirate did contain lipid-laden macrophages. Further workup to exclude malignancy, including chest, abdominal, and pelvic imaging, was unremarkable. 

After ruling out oncologic and infectious causes, the attending physicians were highly suspicious of metabolic disease and thus measured blood lysosomal acid lipase activity, which was found to be absent. A next-generation sequencing panel identified 2 variants in LIPA: a pathogenic variant and a variant of uncertain significance, which was considered sufficient for a diagnosis of the Wolman disease form of LAL-D.

The patient showed significant improvement after the initiation of enzyme replacement therapy, with improved growth and development.

Approximately 2 years after diagnosis, the patient presented with fever, anemia, and abdominal distension. Abdominal computed tomography revealed extensive adenopathy involving the mesentery, aorta, vena cava, and pancreas.

Although there was a concern for malignancy, a biopsy revealed diffuse infiltration by lipid macrophages, cholesterol crystals, and fatty deposits, which was consistent with LAL-D. After further treatment, new imaging studies revealed a reduction in lymphadenopathy. The patient continues to thrive, and her well-being has significantly improved.

“When infectious and malignant causes are excluded or unlikely, a careful evaluation of treatable inborn metabolic disorders is critical,” the authors wrote.


Hannah WB, Ryan K, Pendyal S, et al. Clinical insights from Wolman disease: evaluating infantile hepatosplenomegaly. Am J Med Genet A. Published online August 16, 2022. doi:10.1002/ajmg.a.62923