Farber disease in infancy resembling juvenile idiopathic arthritis: identification of two new mutations and a good early response to allogeneic haematopoietic stem cell transplantation

Sir, Farber disease is a rare lysosomal storage disorder, caused by a deficiency of acid ceramidase (N-acylsphingosine deacylase) [1], that could mimic JIA. The disease presents with different frameworks and is often rapidly progressive, including death [2]. Current management is supportive. We describe the case of a Caucasian infant born at term to healthy, unrelated parents. The first symptoms appeared at 3 months, with contractures, pain during movement and flexor hypertonus. At 6 months he developed painful joint swelling, particularly the interphalangeal and metacarpal joints (Fig. 1A) and failure to thrive. At 7 months, swelling of the knees, elbows, ankles and wrists was observed. The fingers were held fixed at the interphalangeal joints. Blood tests showed anaemia (haemoglobin 8.7 g/dl), increased inflammatory marker levels [ESR 89 mm/h, CRP 4.18 mg/dl (normal <0.5) and lactate dehydrogenase (LDH) 1098–1336 IU/l]. Infectious serological tests and culture were negative. Bone marrow aspirate, chest radiograph, US of the abdomen, echocardiography and dermatological and neurological examinations were normal. The hands of the patient (A) At the age of 6 months with joint swelling. (B) At the age of 12 months with subcutaneous and periarticular erythematous nodules. (C) At the age of 14 months with increased nodules. (D) Two months after bone marrow transplant. A diagnosis of JRA was made and the patient was treated with i.v. steroids and indomethacin and subsequently with oral steroids and MTX. Despite therapy, at 12 months the infant showed persistent elevation of inflammatory markers (ESR 85 mm/h and CRP 7.06 mg/dl, while procalcitonin was negative). Symptoms included joints with fixed antalgic posture in flexion/adduction of all four limbs. Subcutaneous erythematous nodules appeared at the PIP and MCP joints (Fig. 1B) and symmetrically at the auricles and over the malleolus and elbow. The size of the nodules ranged from 3 to 11 mm. Hoarseness became evident. Ophthalmoscopic examination, EMG and electroencephalogram were all normal. Skeletal X-ray demonstrated severe osteoporosis. At 13 months, biopsy specimens was taken from a periarticular nodule of the finger and from a skin nodule on the ear. Microscopic examination of subcutaneous and periarticular tissue showed an accumulation of macrophages and foamy histiocytes with broad cytoplasm arranged in clusters. Immunohistochemical analysis confirmed the histiocytic nature (CD68+). The histochemical reaction for periodic acid–Schiff–periodic acid–Schiff diastase was negative. Diagnosis was established by the analysis of ceramide metabolism in cultured fibroblasts. The ceramide content in cultured skin fibroblasts was markedly elevated (22.87 nM/mg; 15-fold above control), consistent with Farber disease. Analysis of the ASAH1 gene (NM_177924.3) by direct sequencing of the exons and the adjacent intronic sequences identified the presence in combined heterozygosis of a 2 bp deletion (c.410-411delAT) with the subsequent creation of a premature stop codon in position 137 (p.Tyr137Xfs) and a missense mutation (c.704G>A), that leads to the substitution of amino acid glycine in position 235 with the amino acid aspartic acid (p.Gly235Asp). Both mutations found have never been previously published. To date, at least 20 different disease-related mutations have been described. Six new mutations in the ceramidase gene were identified in a 2001 study in Germany [3]. Currently a genotype–phenotype correlation cannot be proposed for this disorder. At 14 months the size of the nodules increased from 8 to 15 mm (Fig. 1C). The child was standing with support, neurologically appropriate for his age, without evidence of respiratory infection. At 18 months, as no matched related donor was available, after informed consent was obtained, our patient underwent bone marrow transplant (BMT) from an unrelated HLA-identical donor. The intervention was chosen on the basis of the rapid progress of the disease and the highly unfavourable prognosis described in the absence of any intervention, even though we were aware that the long-term neurological outcome was unpredictable. He received 5.7 × 108 nucleated cells/kg after a myeloablative preparative regimen combining i.v. thiotepa (12 mg/kg), treosulfan (14 g/m2) and fludarabine (160 mg/m2). The clinical post-transplant course was unremarkable, complicated only by grade I–II mucositis. No symptoms or signs of acute or chronic graft-vs-host disease or transplant-related organ toxicity were observed. Persistent haematopoietic full-donor chimerism was demonstrated in the blood cells by PCR analysis of short tandem repeat markers (STR-PCR) from day +20 until day +60. Two months after the BMT the subcutaneous skin nodules substantially decreased in size (Fig. 1D) and the number of joints with limited motion decreased significantly, leading to a dramatic improvement in motor activity. His hoarseness has completely resolved. Inflammatory markers (ESR, leucocyte count, CRP, LDH), which are checked regularly, are normal. Ten months from BMT, he is growing along the third percentile and has some gains in cognitive and language neurodevelopment. The graft is stable, with a mixed chimerism of 40% donor cells, as determined by STR-PCR. In conclusion, despite the limited experience [4–6], the results obtained support the potentially curative role of allogeneic haematopoietic stem cell transplantation in patients with Farber’s disease with normal cognitive development. Early diagnosis and treatment are essential to optimize outcome. It is highly possible that improvements in knowledge of enzymic therapy coupled with emerging pharmacological treatments influencing ceramide metabolism [7] could allow for further and promising therapeutic options. Elevated inflammatory markers and joint swelling may help characterize Farber’s disease earlier. Disclosure statement: The authors have declared no conflicts of interest.