Hepatosplenomegaly

Enlargement of both liver and spleen on exam or imaging. In a genetics differential the question is rarely "is the liver big" but "what is in it"; is the organ enlarging because something is being stored, because cells are infiltrating, because blood is congesting, or because the parenchyma is failing? The age at onset, what is bigger (liver-predominant vs spleen-predominant), and the accompanying neurodevelopmental, ocular, and skeletal findings narrow the work-up quickly.

The first split is what is being stored:

1. Sphingolipids → sphingolipidoses (Gaucher, Niemann-Pick, GM1).
2. Glycosaminoglycans → MPS family.
3. Glycogen → GSD I, III, IV.
4. Lipids in cytoplasm → Wolman / cholesteryl ester storage disease (LIPA).
5. Iron, copper, or other metals → hemochromatosis, Wilson disease.

Then liver-predominant (think GSD, biliary disease, Wilson, α1-AT, urea cycle late-effect) vs spleen-predominant (think Gaucher, ITP, NPB) helps further. Look for the second organ that points to the diagnosis: cherry-red spot, dysmorphism, cardiomyopathy, dystonia, supranuclear gaze palsy.

Sphingolipidoses (spleen often bigger than liver)

• Gaucher disease type 1 (GBA1): Ashkenazi Jewish predominance. Massive splenomegaly + hepatomegaly + thrombocytopenia + bone crises + Erlenmeyer-flask femurs. Treatable with ERT or substrate reduction.
• Gaucher type 3 (neuronopathic): type 1 picture + horizontal supranuclear gaze palsy + progressive myoclonic epilepsy.
• Niemann-Pick disease type A (SMPD1): infantile-onset HSM + cherry-red spot + profound neurodegeneration. Fatal in early childhood.
• Niemann-Pick type B: non-neuropathic; HSM + interstitial lung disease.
• Niemann-Pick type C (NPC1 / NPC2): HSM + vertical supranuclear gaze palsy + cataplexy + progressive neurodegeneration. Filipin staining or cholestane triol.
• GM1 gangliosidosis (infantile): HSM + cherry-red spot + coarse facies + dysostosis.

Mucopolysaccharidoses (liver and spleen plus dysmorphism)

• MPS I (Hurler), II (Hunter), VI (Maroteaux-Lamy), VII (Sly): HSM is part of the package; coarse facies + dysostosis multiplex + corneal clouding (in all but Hunter) dominate. Sanfilippo (MPS III) is the outlier with minimal somatic and severe CNS involvement.

Glycogen storage diseases (liver-predominant)

• GSD I (von Gierke): massive hepatomegaly + fasting hypoglycemia + lactic acidosis + hyperuricemia + hyperlipidemia. The classic "metabolic doll-face."
• GSD III (Cori): hepatomegaly + milder fasting hypoglycemia + myopathy / cardiomyopathy in older patients.
• GSD IV (Andersen): hepatomegaly + cirrhosis from abnormal glycogen structure.
• GSD II (Pompe): hepatomegaly is mild; cardiomyopathy + hypotonia dominate.

Lipid storage in liver / spleen

• Wolman disease (LIPA, infantile): HSM + bilateral adrenal calcifications on imaging + failure to thrive + diarrhea. Rapidly fatal without treatment; ERT (sebelipase alfa) is available.
• Cholesteryl ester storage disease (LIPA, milder): dyslipidemia + hepatomegaly + premature atherosclerosis.

Metals

• Wilson disease (ATP7B): copper accumulation. Hepatomegaly + hepatitis + Kayser-Fleischer rings + neuropsychiatric features in older patients. Low ceruloplasmin, high urinary copper.
• Hereditary hemochromatosis (HFE C282Y homozygote, others): adult presentation. Hepatomegaly + cirrhosis + bronze skin + diabetes + arthropathy + cardiomyopathy. Iron studies are the screen.

Infiltrative / hematologic

• Langerhans cell histiocytosis.
• Leukemia, lymphoma.
• Hereditary spherocytosis (spleen-predominant; jaundice + anemia).

Liver failure / cholestasis presenting with HSM

• Alagille syndrome (JAG1): paucity of intrahepatic bile ducts + cholestatic jaundice + butterfly vertebrae + posterior embryotoxon + peripheral pulmonic stenosis + characteristic face.
• α1-antitrypsin deficiency (ZZ): neonatal cholestasis or childhood/adult liver disease + emphysema later.
• Tyrosinemia type 1, classic galactosemia, hereditary fructose intolerance: acute liver failure pictures with HSM.

Inflammatory / immune

• Familial Mediterranean fever (recurrent serositis, eventual amyloidosis).
• Hemophagocytic lymphohistiocytosis (HLH): primary forms (PRF1, UNC13D, others) present with fever + HSM + cytopenias + hyperferritinemia. A genetic emergency.

1. Liver enzymes, bilirubin, GGT, INR, albumin: characterize the liver functionally.
2. CBC + smear: cytopenias from splenic sequestration, infiltration, or HLH.
3. Ferritin, iron studies: hemochromatosis screen; very high in HLH.
4. Ceruloplasmin, 24-hour urine copper, slit-lamp for KF rings if older child or unexplained transaminitis.
5. α1-antitrypsin level and PI typing.
6. Imaging (US, MRI): characterize the organ, look for adrenal calcifications (Wolman), gallstones, biliary anatomy.
7. Lysosomal enzyme panel in leukocytes: Gaucher (β-glucosidase), Niemann-Pick A/B (acid sphingomyelinase), Pompe (acid α-glucosidase), MPS panel. Many can be batched on a single dried blood spot.
8. Urine GAGs and oligosaccharides if MPS or oligosaccharidosis suspected.
9. Cholestane triol or filipin staining if Niemann-Pick C suspected.
10. Targeted gene panel or exome if the phenotype is unclear.