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Farber lipogranulomatosis

ORPHA333
Synonym(s) Ceramidase deficiency
Farber disease
Prevalence <1 / 1 000 000
Inheritance Autosomal recessive
Age of onset Infancy
Neonatal
Childhood
Antenatal
ICD-10
  • E75.2
OMIM
UMLS
  • C0268255
  • C2936785
MeSH
  • C537075
  • D055577
MedDRA -

Summary

Farber disease is a rare sphingolipid disorder characterized by a spectrum of clinical signs ranging from the classical triad of painful and progressively deformed joints, subcutaneous nodules, and progressive hoarseness (due to laryngeal involvement) that presents in infancy, to varying phenotypes with respiratory and neurologic involvement.

Approximately 80 cases have been reported worldwide in the literature to date.

A high clinical variability is seen between patients. The classic phenotype presents at around 3-6 months of age with painful, swollen and stiff joints of the hands and feet, prominent subcutaneous nodules over pressure points, and progressive hoarseness leading to aphonia due to vocal cord infiltration. Patients can also develop cardiac, pulmonary and neurological defects. Progressive neurological deterioration can be marked in some forms with seizures, paraparesis and developmental delay. The most severe neonatal form presents at birth with hydrops fetalis, lethargy, and failure to thrive, as well as hepatosplenomegaly, rapid neurological deterioration, and granulomatous infiltrations to various other organs (i.e. liver, spleen, lungs). Milder forms have also been described with no neurological defects and a longer life-expectancy. In some patients, the disease manifests in childhood as a spinal muscular atrophy associated with progressive myoclonic epilepsy in the absence of subcutaneous nodules.

Farber disease is caused by mutations in the N-acylsphingosine amidohydrolase (ASAH1) gene (8p22) which encodes acid ceramidase, a lysosomal enzyme that hydrolyzes ceramide into sphingosine and free fatty acid. A deficient activity of this enzyme leads to an accumulation of ceramide in most tissues.

Diagnosis is based on clinical and laboratory findings by assaying the activity of acid ceramidase in peripheral blood leucocytes, cultured lymphoid cells or cultured skin fibroblasts. Alternatively, diagnosis can be performed by determining ceramide concentration in cultured cells or tissues or by studying lysosomal ceramide catabolism in cultured living cells. Identification of mutations in the ASAH1 gene by molecular genetic testing usually allows for diagnostic confirmation.

Differential diagnoses include juvenile idiopathic arthritis, stiff skin syndrome and lethal restrictive dermopathy (see these terms). Encephalopathy due to prosaposin deficiency (see this term) should also be excluded.

Prenatal diagnosis by DNA testing is possible in families with a known disease-causing mutation. Alternatively, prenatal diagnosis can be performed by measuring acid ceramidase activity in cultured amniotic fluid cells or chorionic villi.

Farber disease is inherited in an autosomal recessive manner. Genetic counseling is possible.

There is currently no effective specific therapy for Farber disease and symptomatic treatment is based on analgesics, corticotherapy, and plastic surgery. However, allogeneic hematopoietic stem cell transplantation provides a promising approach for patients with limited neurological involvement.

The prognosis varies, with some patients dying within the first few days of life (severe neonatal form) and others living until adolescence or early adulthood (milder forms).

Expert reviewer(s)

  • Pr Thierry LEVADE
  • Dr Jeffrey MEDIN

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