Farber Disease

Farber disease (Farber lipogranulomatosis) is a rare autosomal recessive lysosomal storage disorder due to biallelic variants in ASAH1, with deficiency of acid ceramidase and accumulation of ceramide. It classically causes painful swollen joints, subcutaneous nodules and a hoarse voice, and ranges from fatal infantile disease to mild forms. Allelic variants cause spinal muscular atrophy with progressive myoclonic epilepsy.

Pathophysiology. Acid ceramidase hydrolyses ceramide into sphingosine and fatty acid. Deficiency leads to ceramide storage and a granulomatous inflammatory response with macrophage infiltration of joints, skin, larynx and other organs.

Severity depends on residual enzyme activity.

Haemophagocytic lymphohistiocytosis can complicate severe disease.

• Painful, swollen joints with contractures, usually of the hands, wrists and ankles
• Subcutaneous nodules over joints and pressure points
• Hoarse or weak cry from laryngeal involvement, with stridor and airway obstruction
• Failure to thrive and recurrent chest infections
• Hepatosplenomegaly and lymphadenopathy
• Neurological disease in the severe forms: hypotonia, regression and seizures
• Macular cherry red spot in some
• Progressive respiratory failure
• Haemophagocytic lymphohistiocytosis with fever, cytopenias and raised ferritin
• Attenuated forms: arthritis and nodules with little neurological disease

• Acid ceramidase activity in leukocytes or fibroblasts: markedly reduced.
• ASAH1 sequencing with deletion and duplication analysis.
• Ceramide measurement in plasma, urine or cells shows raised levels.
• Biopsy of a nodule: foamy histiocytes with Farber bodies on electron microscopy.
• Laryngoscopy and chest imaging.
• Brain MRI and EMG when neurological disease or weakness is present.
• Ferritin, triglycerides, fibrinogen and blood count to assess for haemophagocytic lymphohistiocytosis.

Differential diagnosis.

• Juvenile idiopathic arthritis
• Spinal muscular atrophy with progressive myoclonic epilepsy (ASAH1)
• Mucolipidosis, mucopolysaccharidosis and other storage disorders with joint contractures
• Infantile systemic hyalinosis
• Multicentric reticulohistiocytosis

• Pain and joint disease: paracetamol 15 mg/kg every 6 hours (maximum 60 mg/kg daily; adults 1 g up to four times daily, maximum 4 g) and ibuprofen 10 mg/kg every 8 hours (maximum 30 mg/kg daily). Add prednisolone 0.5 to 1 mg/kg daily for severe inflammation, and gabapentin 5 mg/kg at night increasing to 15 mg/kg three times daily for neuropathic pain. Physiotherapy and splints for contractures.
• Airway: laryngeal assessment, and tracheostomy for severe obstruction.
• Haemophagocytic lymphohistiocytosis: specialist haematology treatment with dexamethasone 10 mg/m2 daily and etoposide 150 mg/m2 twice weekly in the first 2 weeks.
• Haematopoietic stem cell transplantation: can reduce nodules, pain and joint disease in patients without major neurological involvement, and is not expected to correct established brain disease.
• Enzyme replacement therapy: recombinant acid ceramidase is under development, with no licensed product.
• Seizures: levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily. Provide a rescue plan: buccal midazolam 0.3 mg/kg (maximum 10 mg) for a seizure lasting over 5 minutes.
• Feeding and nutrition: dietitian input and gastrostomy for failure to thrive.
• Respiratory care: vaccination, chest physiotherapy and prompt antibiotics.
• Palliative care: early involvement in the infantile neurological form.
• Genetic counselling: a 25% recurrence risk in each pregnancy, with prenatal diagnosis by enzyme assay or variant testing.

Special groups.

• Children with fever, cytopenias and high ferritin: evaluate urgently for haemophagocytic lymphohistiocytosis.

Monitoring. Pain, joints and airway at each visit. Blood count and ferritin every 3 to 6 months, and neurological review every 6 months.

Referral and escalation. Refer to clinical genetics, metabolic medicine, rheumatology and haematology. Emergency for stridor, respiratory failure or suspected haemophagocytic lymphohistiocytosis.