RESUMEN
The second affiliation of the corresponding author Eda Tahir Turanli was incorrectly published as Istanbul Medeniyet University instead of Istanbul Technical University.
RESUMEN
Systemic autoinflammatory diseases (sAIDs) are a heterogeneous group of disorders, having monogenic inherited forms with overlapping clinical manifestations. More than half of patients do not carry any pathogenic variant in formerly associated disease genes. Here, we report a cross-sectional study on targeted Next-Generation Sequencing (NGS) screening in patients with suspected sAIDs to determine the diagnostic utility of genetic screening. Fifteen autoinflammation/immune-related genes (ADA2-CARD14-IL10RA-LPIN2-MEFV-MVK-NLRC4-NLRP12-NLRP3-NOD2-PLCG2-PSTPIP1-SLC29A3-TMEM173-TNFRSF1A) were used to screen 196 subjects from adult/pediatric clinics, each with an initial clinical suspicion of one or more sAID diagnosis with the exclusion of typical familial Mediterranean fever (FMF) patients. Following the genetic screening, 140 patients (71.4%) were clinically followed-up and re-evaluated. Fifty rare variants in 41 patients (20.9%) were classified as pathogenic or likely pathogenic and 32 of those variants were located on the MEFV gene. We detected pathogenic or likely pathogenic variants compatible with the final diagnoses and inheritance patterns in 14/140 (10%) of patients for the following sAIDs: familial Mediterranean fever (n = 7), deficiency of adenosine deaminase 2 (n = 2), mevalonate kinase deficiency (n = 2), Muckle-Wells syndrome (n = 1), Majeed syndrome (n = 1), and STING-associated vasculopathy with onset in infancy (n = 1). Targeted NGS panels have impact on diagnosing rare monogenic sAIDs for a group of patients. We suggest that MEFV gene screening should be first-tier genetic testing especially in regions with high carrier rates. Clinical utility of multi-gene testing in sAIDs was as low as expected, but extensive genome-wide familial analyses in combination with exome screening would enlighten additional genetic factors causing disease.
Asunto(s)
Pruebas Genéticas , Enfermedades Autoinflamatorias Hereditarias/diagnóstico , Secuenciación de Nucleótidos de Alto Rendimiento , Proteínas Adaptadoras Transductoras de Señales/genética , Adenosina Desaminasa/deficiencia , Adenosina Desaminasa/genética , Adolescente , Adulto , Agammaglobulinemia/diagnóstico , Agammaglobulinemia/genética , Anemia Diseritropoyética Congénita/diagnóstico , Anemia Diseritropoyética Congénita/genética , Proteínas Adaptadoras de Señalización CARD/genética , Proteínas de Unión al Calcio/genética , Niño , Preescolar , Síndromes Periódicos Asociados a Criopirina/diagnóstico , Síndromes Periódicos Asociados a Criopirina/genética , Proteínas del Citoesqueleto/genética , Fiebre Mediterránea Familiar/diagnóstico , Fiebre Mediterránea Familiar/genética , Femenino , Enfermedades Autoinflamatorias Hereditarias/genética , Humanos , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Masculino , Deficiencia de Mevalonato Quinasa/diagnóstico , Deficiencia de Mevalonato Quinasa/genética , Persona de Mediana Edad , Proteínas de Transporte de Nucleósidos/genética , Osteomielitis/diagnóstico , Osteomielitis/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Pirina/genética , Análisis de Secuencia de ADN , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/genética , Adulto JovenRESUMEN
The aim of this study is to present demographic and clinical features, MEFV mutation variations, and treatment response of a large number of pediatric familial Mediterranean fever (FMF) patients from a single tertiary centre. Moreover, we aimed to investigate the current outcome of FMF, namely frequency of amyloidosis in children with FMF. We evaluated 708 FMF patients who were followed up in our clinic and who were under colchicine treatment for at least 6 months. The data were recorded from patient records and also verified by negotiations with patients and parents. The male/female proportion of the cohort was 1.05/1 (n = 362/346). Abdominal pain (89.5%, n = 634) was the most common manifestation of FMF episodes, followed by fever (88.8%, n = 629) and arthritis (40.7%, n = 288). However, arthritis in 23 (8%) of the 288 cases was not self-limited; and they subsequently diagnosed with juvenile idiopathic arthritis in addition to FMF. Homozygote or heterozygote M694V mutation was more frequent in patients with arthritis (63.2%) and chronic arthritis (69.6%) than the whole cohort (53.8%). Erythrocyte sedimentation rate and CRP level were in high levels even during attack-free period in 13.9% (n = 97/697) and 11% (n = 78/670) of the patients, respectively. Proteinuria was found in ten patients (1.4%). Amyloidosis was confirmed by renal biopsy in only two of these cases who were homozygous for M694V and compound heterozygous for M694V/M680I. 47 (6.6%) subjects were considered as colchicine resistant. Homozygote M694V mutation was the most frequent mutation in those resistant cases (63.8%, n = 30), followed by compound heterozygote mutation of M694V/M680I (6.3%, n = 3). Homozygous M694V mutation are still the most frequent mutation and associated with the most severe clinical picture and the worst outcome in Turkish children. M694V genotype seems to be more frequently associated with arthritis as well as with chronic arthritis than other genotypes. Recurrence of FMF episodes as well as amyloidosis could only be managed via strict compliance to colchicine treatment. Frequency of amyloidosis significantly decreased compared to the previous studies. A favorable outcome could be obtained with the anti IL-1 in colchicine-resistant FMF patients.
Asunto(s)
Dolor Abdominal/etiología , Amiloidosis/etiología , Colchicina/uso terapéutico , Fiebre Mediterránea Familiar/complicaciones , Pirina/genética , Moduladores de Tubulina/uso terapéutico , Dolor Abdominal/genética , Adolescente , Amiloidosis/genética , Niño , Preescolar , Fiebre Mediterránea Familiar/diagnóstico , Fiebre Mediterránea Familiar/tratamiento farmacológico , Fiebre Mediterránea Familiar/genética , Femenino , Genotipo , Humanos , Lactante , Masculino , Mutación , Resultado del TratamientoRESUMEN
Pediatric rheumatology includes autoinflammatory monogenic diseases, autoinflammatory multifactorial diseases with complex inheritance, and diseases with uncertain clinical diagnosis or undefined conditions, even though they show signs of autoinflammation. Most of these diseases are systemic; it is important to diagnose patients promptly and definitively and to select proper treatment options based on the diagnoses. Clinical observation and acute-phase responses are usually sufficient for diagnosis; however, genetic analyses can provide supportive data for definite diagnosis and treatment, especially for rare monogenic diseases. As for multifactorial autoinflammatory diseases, susceptibility genes, and factors involved in the etiopathogenesis have not been fully identified. It is possible to identify disease genes and novel diseases, and lead to new treatment options by gene mapping studies and high-throughput screening strategies for multifactorial diseases and conditions with uncertain clinical characteristics. In this review, we discuss the three groups of autoinflammatory diseases and role of genetics in their diagnosis.
