Genotype-phenotype relationship in childhood autoinflammatory diseases

GENOTYPE-PHENOTYPE RELATIONSHIP IN CHILDHOOD AUTOINFLAMMATORY DISEASES Objective: 40 cases with no mutation in MEFV gene, directed with FMF and autoinflammatory disease pre-diagnosis to Pediatric Rheumotology and General Pediatrics polyclinics of Pediatrics in Medical School of Aegean University have been aimed to be assessed with New Generation Sequencing (NGS) in terms of other auto-inflammatory diseases (Tumor Necrosis Factor 1 Associated Periodic System (TRAPS), Hyperimmunoglobulobin D Syndrome (HIDS), Cryopyrine Associated Periodic Syndrome (CAPS), Pyogenic Arthritis, Pyoderma Gangrenosum and Acne Syndrome (PAPA) ). This study is a cross-sectional and controlled study. Material and Method: 40 cases and their parents involved in the study were interviewed and survey form was filled in (including onset age of disease, symptoms accompanying the attacks, family history, received treatment, information of examinations performed in attack period). 2 cc blood was taken from each case into EDTA tube. New Generation Sequencing method was used for genetic analysis. The obtained results were assessed according to databases. The research data were analyzed in SSPS statistical program. The conditions of P < 0.05 were accepted as statistically significant. Findings: Mutation was detected in 16 of the 40 cases involved in the study. In cases with mutation positive, the average age of the disease onset was detected to be 7.1 ± 4.6, average year of delayed diagnosis to be 4.1 ± 3.9, in cases with mutation negative, the average age of disease onset was detected to be 5.2 ± 4.6. Family history was observed to be 37.5% in mutation positive cases and to be 16.6% in mutation negative cases. The most common symptoms accompanying the attacks in each group were fever, arthralgia and abdominal pain. Aphtha and maculopapular rash were determined to be significantly higher in mutation negative cases than mutation positive cases (p = 0.003, p = 0.03). Acute phase reactant levels taken in the attack period in mutation positive cases were seen to be higher than mutation negative cases even though not statistically significant. 7 cases detected with NLRP3 gene mutation were included in CAPS case group. In 5 of 7 patients Q703K mutation, in 1 of them V198M and in 1 of them I313V mutation were detected. The average age of disease onset was 6.5 ± 3.8 in these cases. The most common symptoms accompanying the attacks were fever, arthralgia, abdominal pain, and rash (86%, 71%, 43%, and 43%, respectively). 6 cases detected with MVK gene mutation were included in HIDS case group. S52N mutation was found in 5 and V377I mutation was found in 1 of 6 patients. The average age of disease onset in these cases was 8.4 ± 5.1. The most common symptoms accompanying the attacks were arthralgia, gastralgia and rash (100%, 50% and 50%, respectively). 2 cases detected with TNFRSF1A gene mutation were included in TRAPS case group. In one of the two patients C52Y mutation and in the other one R92Q mutation were found out. The average age of disease onset in these cases were 7.7 ± 8.8. The most common symptoms accompanying the attacks were fever, abdominal pain and arthralgia (100%, 50%, 50% respectively). 1 cases detected with A372V mutation in PSTPIP1 gene was included in PAPA case group. This case of ours the disease onset of whom was 2 years had one day lasting attacks accompanied by fever, abdominal pain, arthralgia. Discussion and conclusion: This study is the first cross sectional and controlled study made on auto-inflammatory diseases in Turkey. 4 of the mutations found in our study were definite pathogenic (V377I, C52Y, I313V, A372V), 3 of them were low penetrance mutations (Q703K, V198M, R92Q), and 1 of them was the mutation with uncertain significance (S52N). The fact that in our mutation positive patient group, the disease onset age was older than the cases in literature, their clinical findings were lighter, and there were not serious neurological involvement and musculoskeletal involvement was thought to be associated with the fact that low penetrance mutations were found in most of our patients (12 patients). In examining 5 cases detected with Q703K mutation and 5 cases detected with S52N mutation, the disease onset age and clinical symptoms in cases with the same mutation were observed to be different from one another, and mutations were observed to have changeable penetrance, and the same mutation were observed to cause different clinical picture (asymptomatic - severe attack) in different cases because of heterogeneous phenotype they created. In cases having applied with repetitive fever, arthralgia and abdominal pain complaints, referred with FMF pre-diagnosis, but not detected with mutation in MEFV gene, other auto-inflammatory diseases must be considered despite the low incidence rate, and prospective genetic examination must be carried out for it in the event of clinical suspect.