A diagnostic score for molecular analysis of hereditary autoinflammatory syndromes with periodic fever in children

Abstract

Objective. To identify a set of clinical parameters that can predict the probability of carrying mutations in one of the genes associated with hereditary autoinflammatory syndromes.Methods. A total of 228 consecutive patients with a clinical history of periodic fever were screened for mutations in the MVK, TNFRSF1A, and MEFV genes, and detailed clinical information was collected. A diagnostic score was formulated based on univariate and multivariate analyses in genetically positive and negative patients (training set). The diagnostic score was validated in an independent set of 77 patients (validation set).Results. Young age at onset (odds ratio [OR] 0.94, P ‫؍‬ 0.003), positive family history of periodic fever (OR 4.1, P ‫؍‬ 0.039), thoracic pain (OR 4.6, P ‫؍‬ 0.05), abdominal pain (OR 33.1, P < 0.001), diarrhea (OR 3.3, P ‫؍‬ 0.028), and oral aphthosis (OR 0.2, P ‫؍‬ 0.007) were found to be independently correlated with a positive genetic test result. These variables were combined in a linear score whose ability to predict a positive result on genetic testing was validated in an independent data set. In this latter set, the diagnostic score revealed high sensitivity (82%) and specificity (72%) for discriminating patients who were genetically positive from those who were negative. In patients with a high probability of having a positive result on genetic testing, a regression tree analysis provided the most reasonable order in which the genes should be screened.Conclusion. The proposed approach in patients with periodic fever will increase the probability of obtaining positive results on genetic testing, with good specificity and sensitivity. Our results further help to optimize the molecular analysis by suggesting the order in which the genes should be screened.

Concerted action of wild-type and mutant TNF receptors enhances inflammation in TNF receptor 1-associated periodic fever syndrome

“…Another class of mutations, exemplified by R92Q and P46L missense mutations, occurs in 1-5% of the general population (and for P46L, in up to 10% of a West African population) (9,10). These two variants are more likely to be functional polymorphisms thought to synergize with other abnormalities to cause a milder form of TRAPS with low penetrance (11).…”

Results of molecular genetic screening of mutations in the NLRP3, TNFRSF1A, and MVK genes in patients with autoinflammatory diseases and systemic juvenile arthritis

“…Экс-пертами в области изучения АВЗ для их идентификации предложены алгоритмы диагностики, включающие клини-ческие классификационные критерии, рекомендации по лечению [15][16][17][18][19]. Разработаны также диагностический счет для определения степени риска наличия АВЗ и показания для проведения молекулярно-генетического анализа [20]. Поскольку одних клинических данных для диагностики АВЗ не всегда достаточно, современные методы генетиче-…”

Autoinflammatory diseases in Pediatrics

“…It is not uncommon that with overlapping symptoms or with partial or atypical clinical forms that prevent a precise clinical diagnosis, the testing of disease responsible genes help to make a diagnosis. Flow charts have been developed as a guidance or screening tool to know which genes to test, 54 but testing is not recommended if there are no highly indicative symptoms, because their interpretation may not be conclusive or mutations with incomplete penetrance may be found, which usually do not require treatment.…”