engleski

New ATM variants and a rare association of juvenile idiopathic arthritis and ataxia- telangiectasia: coincidence or relationship?

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder caused by biallelic pathogenic variants in ATM (ataxia telangiectasia mutated) gene. A-T has a variable presentation, including cerebellar ataxia, telangiectasia, gradually developing cerebellar degeneration, immunodeficiency, predilection for cancer occurrence and radiation sensitivity. Juvenile idiopathic arthritis (JIA) is an autoimmune disorder, believed to be of a polygenic nature, encompassing all arthritis of unknown aetiology occurring in children under the age of 16. Objectives: We present a patient diagnosed with a rare association of JIA and A-T which with identified two likely pathogenic ATM variants. Methods: We obtained all patient’s records from the Department of Paediatrics, UHC Zagreb. Genomic analysis was done using singleton whole exome sequencing (WES). Results: Our patient is a male with suspected ataxia telangiectasia and JIA. His older sister suffers from cerebral palsy (due to complications of premature birth). He was diagnosed with ataxia at 3 years of age. Brain MRI performed at the age of 15 years revealed pontocerebellar hypoplasia and laboratory testing showed selective IgA deficiency, decrease in proportion of lymphocytes and progressive elevation of alpha fetoprotein concentration. Genetic testing excluded Friedrich ataxia and spinocerebellar ataxia. Cytogenetics analysis detected mosaic translocation (7 ; 14) suggestive of chromosomal instability. These findings were clinically suggestive of A-T. Regarding the JIA, the patient first noticed swelling of the fifth finger of the right foot at 13 years of age. Two years later the metacarpophalangeal joint of the thumb of his left hand started to swell and finally his left knee. MRI revealed chronic effusion, oedema and a popliteal cyst in the left knee. MRI of the right foot detected erosive changes followed with the expansion of the soft tissue and bone. Ultrasound of hands, left knee and feet confirmed chronic inflammatory changes. Based on these features the patient was diagnosed with JIA and treated with nonsteroidal anti- inflammatory drugs (NSAIDs). Due to the chronic character of JIA and having in mind the concomitant disease, low doses of methotrexate were initiated alongside NSAIDs, after which a stable improvement followed. Genomic analysis using WES identified two likely pathogenic ATM variants: NM_000051.3 (ATM_v001): c.8305T>C, p. (W2769R) and c.5293C>T, p.(Q1765Ter) confirming the A-T diagnosis. Analysis of the familial segregation of the identified variants is underway to ascertain the phase of the variants and identify heterozygous relatives at increased risk of cancer. Conclusion: To the best of our knowledge, this is the second reported case of an association between JIA and typical A-T in the literature. A compelling phenomenon is that the only prior described case was identified in the same geographical region. Further analysis of these case with the rare association between A-T and JIA may help us explore and understand the possible role of the ATM gene in development of JIA.

juvenile idiopathic arthritis ; ataxia-telangiectasia ; ATM variants

Objavljeno u Pediatric Rheumatology 2019, 17(Suppl 1):P2123