Farber disease: report of three cases with joint involvement mimicking juvenile idiopathic arthritis.

Farber disease is a rare recessive autosomal disorder presented with three main features of joint involvement, subcutaneous nodules and hoarseness. Hereby we describe three new cases of Farber disease. All three cases were first misdiagnosed as juvenile idiopathic arthritis (JIA) due to the presentation of joint swelling. Addition of hoarseness and subcutaneous nodules to the initial joint swelling questioned the diagnosis of JIA and further evaluations led to the diagnosis of Farber disease. The first case was a 4-year old girl in whom a novel genetic mutation in ASAH1 gene was found. The second patient was a 4-year old girl presented with joint swelling at 7 month of age. The third patient was a 9-month boy complicated with severe respiratory distress. All patients were treated with symptomatic and supportive care. Two cases died due to respiratory ailure and infection, but one patient follow up for 2 years after diagnosis. Farber disease should be considered as differential diagnosis in children with early onset of poly articular involvement with subcutaneous nodules and/or hoarseness.

A cross-sectional quantitative analysis of the natural history of Farber disease: an ultra-orphan condition with rheumatologic and neurological cardinal disease features.

PurposeFarber disease (OMIM 22800) is an ultrarare progressive multisystemic neurodevelopmental storage disorder caused by a deficiency of the lysosomal enzyme acid ceramidase (AC). Hard clinical end points for future clinical trials remain to be defined.MethodsWe quantitatively analyzed published cases with Farber disease (N = 96). The main outcome variables were survival and diagnostic delay. As a potential predictor of survival, the influence of residual AC enzyme activity was investigated. The analysis was performed in compliance with STROBE criteria.ResultsThe median survival period of the study population was 3 years. The median age at disease onset was 3 months, and the median age at diagnosis was 17 months. The median diagnostic delay was 13.75 months. Patients with residual AC activity in fibroblasts at more than 5.1% of the normal level survived significantly longer than patients with residual AC activity below this threshold. In addition, higher residual AC activity was associated with a later onset of symptoms.ConclusionFarber disease onset is in infancy. Diagnostic delay is typically substantial. Our data suggest a phenotype-biomarker association with implications for future clinical and therapeutic trials. In the absence of a prospective multicenter natural-history study protocol, we believe that our modeling approach, based on published case descriptions, is the best and most timely approximation for generalizability.

C26-Ceramide as highly sensitive biomarker for the diagnosis of Farber Disease.

Farber disease (FD) is a rare autosomal recessive disease caused by mutations in the acid ceramidase gene (ASAH1). Low ceramidase activity results in the accumulation of fatty substances, mainly ceramides. Hallmark symptoms at clinical level are periarticular nodules, lipogranulomas, swollen and painful joints and a hoarse voice. FD phenotypes are heterogeneous varying from mild to very severe cases, with the patients not surviving past their first year of life. The diagnostic aspects of FD are poorly developed due to the rarity of the disease. In the present study, the screening for ceramides and related molecules was performed in Farber affected patients (n = 10), carriers (n = 11) and control individuals (n = 192). This study has the highest number of enrolled Farber patients and carriers reported to present. Liquid chromatography multiple reaction mass spectrometry (LC/MRM-MS) studies revealed that the ceramide C26:0 and especially its isoform 1 is a highly sensitive and specific biomarker for FD (p < 0.0001). The new biomarker can be determined directly in the dried blood spot extracts with low sample consumption. This allows for easy sample preparation, high reproducibility and use in high throughput screenings.

Lipogranulomatous subconjunctival nodules: a novel presentation in Blau syndrome.

Blau syndrome is an early-onset granulomatous disease known to affect the skin, joints, and eyes. We report a child with diffuse rash, arthritis, and subconjunctival nodules. Biopsy of the bulbar conjunctiva revealed noncaseating lipogranulomas that lead to a diagnosis of Blau syndrome. To our knowledge, noncaseating lipogranulomas of the conjunctiva have not been reported previously as a presenting finding in Blau syndrome. Although uveitis is the classic manifestation, it is important to broaden the awareness of other ocular signs, as these variations can aid in diagnosis.

Atypical presentation of infantile-onset farber disease with novel ASAH1 mutations.

Farber disease is a very rare autosomal recessive disease caused by mutation of ASAH1 that results in the accumulation of ceramide in various tissues. Clinical symptoms of classic Farber disease comprise painful joint deformity, hoarseness of voice, and subcutaneous nodules. Here, we describe a patient with Farber disease with atypical presentation of early onset hypotonia, sacral mass, congenital heart disease, and dysmorphic face since birth. Severe cognitive disability, failure to gain motor skills, failure to thrive, and joint contractures developed. Using whole-exome sequencing, we identified the compound heterozygote missense mutations of ASAH1 (p.R333C and p.G235R). Because of the diagnostic delay, she underwent sacral mass excision, which revealed enlarged lysosomes and zebra bodies. We report an atypical presentation of Farber disease with her pathology and associated genetic defect. This case expands the phenotypic spectrum of Farber disease to include novel mutations of ASAH1, which pose a diagnostic challenge. We also discuss the clinical utility of whole-exome sequencing for diagnosis of ultra-rare diseases. © 2016 Wiley Periodicals, Inc.

Brief Report: Peripheral Osteolysis in Adults Linked to ASAH1 (Acid Ceramidase) Mutations: A New Presentation of Farber's Disease.

OBJECTIVE: To establish a diagnosis and provide counseling and treatment for 3 adult patients from one family presenting with peripheral osteolysis. METHODS: Following clinical and radiographic assessment, exome sequencing, targeted gene resequencing, and determination of enzyme activity in cultured fibroblasts were performed. RESULTS: 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. CONCLUSION: 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.

Nervous system involvement in Farber disease.

A 30 months-old boy with Farber disease developed nystagmus 12 months after hematopoietic stem cell transplantation (HSCT). At 40 months, gait ataxia was evident, and brain MRI showed increased size of pericerebellar sulci and 4th ventricle. EMG showed denervation in the tongue and upper limb muscles, consistent with motor neuron disease. HSCT improves the peripheral manifestations of Farber disease, but may not prevent the progressive neurological deterioration.

Molecular basis of acid ceramidase deficiency in a neonatal form of Farber disease: identification of the first large deletion in ASAH1 gene.

Farber disease, also known as Farber's lipogranulomatosis, is a clinically heterogeneous autosomal recessive disease caused by mutations in the ASAH1 gene. This gene codes for acid ceramidase, a lysosomal heterodimeric enzyme that hydrolyzes ceramide into sphingosine and fatty acid. To date, less than 25 distinct mutations have been identified in Farber patients, but no large deletions have yet been reported. In this work, cultured fibroblasts from a Farber patient with the rare neonatal form of Farber disease were studied to elucidate the molecular basis of this extremely severe phenotype. Direct sequencing of ASAH1 genomic DNA revealed the causative heterozygous mutation in the donor splice site consensus sequence of intron 11, g.24491A > G (c.917 + 4A > G), that resulted in the absence of detectable mRNA. Subsequent analysis of ASAH1 mRNA showed total skipping of exons 3 to 5. Long-range PCR and sequencing led to the identification of a gross deletion of ASAH1 gene, g.8728_18197del (c.126-3941_382 + 1358del) predicting the synthesis of a truncated polypeptide, p.Tyr42_Leu127delinsArgfs*10. Accordingly, no molecular forms corresponding to precursor or proteolytically processed mature protein were observed. These findings indicate that any functionally active acid ceramidase is absent in patient cells, underscoring the severity of the clinical phenotype. Molecular findings in the non-consanguineous parents confirmed the compound heterozygous ASAH1 genotype identified in this Farber case. This work unravels for the first time the mutations underlying the neonatal form of Farber disease and represents the first report of a large deletion identified in the ASAH1 gene. Screening for gross deletions in other patients in whom the mutation present in the second allele had not yet been identified is required to elucidate further its overall contribution for the molecular pathogenesis of this devastating disease.

Farber lipogranulomatosis with predominant joint involvement mimicking juvenile idiopathic arthritis.

The case of a 10-year-old boy with Farber lipogranulomatosis with predominant joint involvement, subacute, laryngeal and tongue granulomas, microcytic anemia, elevated ESR and CRP, is presented. The boy had no signs of CNS and internal organ involvement. The disease manifested at 6 months; at 11 months the boy had widespread granulomatous polyarthritis with contractures, and juvenile idiopathic arthritis (JIA) was suggested. All antirheumatic therapies failed. Immunologic assessment revealed elevated serum interleukin-1ß, increased T-helper, NK and CD25-positive cells, and circulating immune complexes. Our case with predominant rheumatologic manifestations illustrates a differential diagnosis of JIA.

Novel biochemical abnormalities and genotype in Farber disease.

Farber disease caused by acid ceramidase deficiency is characterised by a triad of painful and swollen joints, subcutaneous nodules, and laryngeal involvement. A one year old female with overlapping features of the classical and type 5 variants is reported. Sialuria and elevated plasma chitotriosidase were unusual findings. A novel mutation of the ASAH 1 gene was detected from DNA extracted from the umbilical stump.

A simple fluorogenic method for determination of acid ceramidase activity and diagnosis of Farber disease.

Acid ceramidase (aCDase) is one of several enzymes responsible for ceramide degradation within mammalian cells. As such, aCDase regulates the intracellular levels of the bioactive lipid ceramide. An inherited deficiency of aCDase activity results in Farber disease (FD), also called lipogranulomatosis, which is characterized by ceramide accumulation in the tissues of patients. Diagnosis of FD is confirmed by demonstration of a deficient aCDase activity and the subsequent storage of ceramide. Existing methods include extremely complex assays, many of them using radiolabeled compounds. Therefore, the aCDase assay and the in vitro enzymatic diagnosis of FD are still performed in only a very limited number of specialized laboratories. Here, the new fluorogenic substrate Rbm14-12 was synthesized and characterized as a new tool to determine aCDase activity. The resulting optimized assay was performed in 96-well plates, and different fibroblast and lymphoid cell lines derived from FD patients and controls were tested to measure aCDase activity. As a result, the activity in cells of FD patients was found to be very low or even null. This new fluorogenic method offers a very easy and rapid way for specific and accurate determination of aCDase activity and, consequently, for diagnosis of FD.

Disseminated lipogranulomatosis.

Farber disease or disseminated lipogranulomatosis is a rare inherited disorder of lipid metabolism resulting from a defect in ceramide degradation. Because of the feature of nodular swellings around various joints, this may sometimes be confused with juvenile idiopathic arthritis. We report a 4-year-old boy with Farber disease who presented with nodular swellings around the joint, angle of the mouth and conjunctiva, and was subsequently diagnosed to be a case of Farber Disease.