Unravelling variants in Farber disease: diagnostic and prenatal challenges in atypical presentations

Abstract Farber disease (FD; OMIM #228000), also known as Farber's lipogranulomatosis, is a rare lysosomal storage disease caused by acid ceramidase deficiency. Clinically, FD is typically identified by a triad of symptoms: subcutaneous nodules, joint pain, and voice hoarseness. However, diagnosing mild or attenuated variants can be difficult, as some symptoms may be absent or overlooked. In such cases, genetic testing is essential for confirming the diagnosis and enabling prenatal diagnosis. Case presentation A couple presented with a history of losing two children at 1.5 years of age, both of whom exhibited severe developmental delay, hypotonia, weak cry, and progressive skin lesions. Neither child underwent genetic testing, and no DNA samples were preserved. Subsequent parental carrier screening identified a heterozygous variant of uncertain significance (VUS) in the ASAH1 (N-Acylsphingosine Amidohydrolase 1) (OMIM #613468) gene in both parents. Exome sequencing was later performed on the couple’s third affected child, revealing compound heterozygous variants in the ASAH1 gene, consistent with those found in the parents. This case presented with atypical manifestations of FD, necessitating comprehensive investigations, including laboratory tests, radiological assessments, genetic analysis, and histopathological examination of skin biopsy samples. These findings led to the identification of likely pathogenic mutations in ASAH1 . Based on these results, prenatal diagnosis was successfully conducted in the couple's fourth pregnancy. Conclusion This case illustrates the challenges of diagnosing FD when atypical presentations and genetic variants of uncertain significance are involved. The absence of classic symptoms like subcutaneous nodules and the presence of an ASAH1 gene variant complicated the diagnosis and delayed options for prenatal diagnosis in future pregnancies. It underscores the critical role of genetic testing and the need to reclassify VUS through detailed genotype–phenotype correlations to enhance diagnostic accuracy and support timely interventions.