title: Brief Report: Peripheral Osteolysis in Adults Linked to ASAH1 (Acid Ceramidase) Mutations: A New Presentation of Farber's Disease.
abstract: To establish a diagnosis and provide counseling and treatment for 3 adult patients from one family presenting with peripheral osteolysis.
  
  
  
  Following clinical and radiographic assessment, exome sequencing, targeted gene resequencing, and determination of enzyme activity in cultured fibroblasts were performed.
  
  
  
  The proband (age 40 years) had a history of episodic fever and pain in childhood that subsided around puberty. He and 2 of his older sisters (ages 58 and 60 years, respectively) showed adult-onset progressive shortening of fingers and toes with redundancy of the overlying skin. Radiographs showed severe osteolysis of the distal radius and ulna, carpal bones, metacarpal bones, and phalanges. Sequencing of the known genes for recessively inherited osteolysis, MMP2 and MMP14, failed to show pathogenic mutations. Exome sequencing revealed compound heterozygosity for mutations c.505T>C (p.Trp169Arg) and c.760A>G (p.Arg254Gly) in ASAH1, the gene coding for acid ceramidase. Sanger sequencing confirmed correct segregation in the family, and enzyme activity in fibroblast cultures from the patients was reduced to ∼8% of that in controls, confirming a diagnosis of Farber's disease.
  
  
  
  Our findings indicate that hypomorphic mutations in ASAH1 may result in an osteoarticular phenotype with a juvenile phase resembling rheumatoid arthritis that evolves to osteolysis as the final stage in the absence of neurologic signs. This observation delineates a novel type of recessively inherited peripheral osteolysis and illustrates the long-term skeletal manifestations of acid ceramidase deficiency (Farber's disease) in what appear to be the oldest affected individuals known so far.
authors.affiliation: Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Luisa
authors.initials: L
authors.lastname: Bonafé
authors.affiliation: Kariminejad-Najmabadi Pathology and Genetics Centre, Tehran, Iran.
authors.forename: Ariana
authors.initials: A
authors.lastname: Kariminejad
authors.affiliation: University of Lausanne, Lausanne, Switzerland.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: University of Lausanne, Lausanne, Switzerland.
authors.forename: Beryl
authors.initials: B
authors.lastname: Royer-Bertrand
authors.affiliation: Centre Hospitalier Universitaire de Toulouse, INSERM UMR1037, and Université Toulouse III Paul-Sabatier, Toulouse, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Garcia
authors.affiliation: Tehran Medical Genetics Laboratory, Tehran Welfare Organization, Tehran, Iran.
authors.forename: Shokouholsadat
authors.initials: S
authors.lastname: Mahdavi
authors.affiliation: Kariminejad-Najmabadi Pathology and Genetics Centre, Tehran, Iran.
authors.forename: Bita
authors.initials: B
authors.lastname: Bozorgmehr
authors.affiliation: International Skeletal Dysplasia Registry and University of California, Los Angeles.
authors.forename: Ralph L
authors.initials: RL
authors.lastname: Lachman
authors.affiliation: Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Lauréane
authors.initials: L
authors.lastname: Mittaz-Crettol
authors.affiliation: Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Belinda
authors.initials: B
authors.lastname: Campos-Xavier
authors.affiliation: Amrita Institute of Medical Sciences and Research Center, Cochin, India.
authors.forename: Sheela
authors.initials: S
authors.lastname: Nampoothiri
authors.affiliation: Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Sheila
authors.initials: S
authors.lastname: Unger
authors.affiliation: University of Lausanne, Lausanne, Switzerland.
authors.forename: Carlo
authors.initials: C
authors.lastname: Rivolta
authors.affiliation: Centre Hospitalier Universitaire de Toulouse, INSERM UMR1037, and Université Toulouse III Paul-Sabatier, Toulouse, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Levade
authors.affiliation: Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
mesh_terms: D055573:Acid Ceramidase / Q000235:genetics*; D000328:Adult; D055577:Farber Lipogranulomatosis / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010014:Osteolysis / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype
chemical_list: C526693:ASAH1 protein, human; D055573:Acid Ceramidase