E70 A new mutation of uncertain significance in Farber disease

Abstract Introduction Farber disease is a rare autosomal recessive lysosomal storage disorder. It is caused by a mutation in the ASAH1 gene, which results in a deficiency of acid ceramidase and subsequently an accumulation of ceramide in various tissues. The manifestations are diverse and the cardinal symptoms of the Farber disease triad include subcutaneous nodules, joint pain and hoarseness. Aims To recall the clinical features of this rare disease in order to avoid a late diagnosis and to inform about the identification of a novel mutation in a Moroccan patient known until now as a mutation of uncertain significance in the acid ceramidase gene. Method About a clinical case reported retrospectively with a prospective follow-up. Results We report the case of a fourteen-year-old boy born from healthy, consanguineous Moroccan parents after an uneventful pregnancy and delivery. He had normal development until the age of 9 months. The first symptoms appeared at the end of the first year of life with joint stiffness, hoarseness, subcutaneous nodules, blepharitis resulting in amblyopia, dental enamel defect, gingival hyperplasia, and severe failure to thrive, without any visceral manifestations. Routine laboratory investigations revealed normal hydroelectolytic, glycemic, hepatic, renal, and thyroid status. Standard radiography revealed diffuse bone demineralization, laryngoscopy showed laryngeal dyskinesia, echocardiography and abdominal ultrasound were normal. Biopsy of a nodule revealed hyalinosis deposition leading initially to the hypothesis of systemic hyalinosis. The diagnosis of Farber disease was suspected at the age of eight and definitively confirmed at the age of fourteen after a genetic study of ASAH1 revealing a novel compound homozygous mutation in exon 3 c.194T>G (p.Leu65Trp) whose significance was considered uncertain to date with an acid ceramidase enzyme assay that showed a markedly reduced leucocyte acid ceramidase activity, consistent with a homozygous status for acid ceramidase deficiency. Treatment with analgesics based on paracetamol and nonsteroidal anti-inflammatory drugs, with iron, calcium and vitamin D supplements was prescribed. Physiotherapy was recommended but was very difficult as the child is so painful. Discussion and Conclusion Farber disease is a rare condition with only about 200 cases identified worldwide. It is caused by mutations in the ASAH1 gene. The disease has a wide range of clinical presentations, and this case report highlights the challenge of diagnosis, with a long delay due to lack of awareness of the disease among clinicians. Furthermore, this case describes a novel homozygous mutation in the ASAH1 gene: c.194T>G (p.Leu65Trp) of the ASAH1 gene in a Moroccan patient, expanding the phenotypic spectrum of the disease. Genetic testing should be considered in patients with a clinical presentation consistent with the disease, supplemented by an acid ceramidase enzyme assay in case of doubt as was done in our patient. To date, there is no cure for Farber disease, and treatment is symptomatic and supportive. However, early diagnosis and appropriate management can help improve the quality of life for patients and their families. This case highlights the importance of further research in order to develop more effective treatments for this rare condition. Clinical trials are planned in the close future. Ethics The patient and his family members provided informed consent for publication of indirectly identifiable data.