An Overview of Disease and Health Research Vol. 5

Background: Farber Disease (FD; OMIM #228000) is a rare lysosomal storage disorder caused by mutations in the ASAH1 gene leading to acid ceramidase deficiency. It classically presents in infancy with a triad of subcutaneous nodules, painful joints, and hoarseness. However, atypical or attenuated phenotypes lacking one or more hallmark features can complicate diagnosis, delaying appropriate management and genetic counseling.

Case Presentation: We report an atypical familial case of FD in which two children exhibited severe developmental delay, hypotonia, progressive skin lesions, joint stiffness, and neuroregression, but lacked subcutaneous nodules. Magnetic Resonance Imaging (MRI) revealed cerebral atrophy. Genetic testing in the parents identified heterozygous Variants of Uncertain Significance (VUS) in ASAH1: c.1042-2A>C (intron 12) and c.457+4A>G (intron 6). A third affected child showed similar clinical features, and exome sequencing confirmed compound heterozygosity for the same variants. Functional studies, including Reverse Transcription Polymerase Chain Reaction (RT-PCR), demonstrated exon skipping and abnormal splicing, leading to the reclassification of both variants as likely pathogenic. A skin biopsy supported the diagnosis of a lysosomal storage disorder, though without classic lipogranulomas. Based on these findings, prenatal testing was successfully offered in a subsequent pregnancy.

Conclusion: This case highlights the diagnostic challenges of atypical Farber Disease and the importance of integrating genetic testing, functional validation, and clinical correlation to reclassify VUS. Early diagnosis and variant interpretation enabled accurate reproductive counseling and prenatal diagnosis. The report underscores the value of preserving DNA samples, especially in rare diseases with evolving phenotypic presentations.