[Genetic mosaicism in Systemic Auto-Inflammatory Diseases: A review of the literature]. / Mosaïcisme génétique dans les maladies auto-inflammatoires : revue de la littérature.

Systemic auto-inflammatory diseases (SAIDs) are disorders associated with deregulation of innate immunity in which patients present classically with systemic inflammatory manifestations, in particular fever, skin-mucosal rashes, arthromyalgia and abdominal pain, with an increase in blood biomarkers of inflammation. At the time of their discovery, these diseases were associated with constitutional mutations in genes encoding proteins involved in innate immunity, and it was then considered that they had to begin in childhood. This dogma of constitutional mutations in SAIDs is no longer so unquestionable, since 2005 several cases of mosaicism have been reported in the literature, initially in cryopyrinopathies, but also in other SAIDs in patients with obvious clinical phenotypes and late onset of disease expression, in particular in the VEXAS syndrome (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic Syndrome) and very recently in MEVF gene. Next-generation sequencing techniques are more sensitive than Sanger for detecting mosaicisms. So, when a clinical diagnosis seems obvious but no constitutional mutation is found by low-depth genetic analysis, it is useful to discuss with expert geneticists whether to consider another genetic approach in a child or an adult. This modifies the situations in which clinicians can evoke these diseases. This review provides an update on mosaicism in SAIDs.

[Autoinflammatory diseases associated with RIPK1 mutations: A review of the literature]. / Revue de la littérature sur les maladies auto-inflammatoires associées aux mutations du gène RIPK1.

Autoinflammatory diseases related to RIPK1 mutations have been recently described. Two distinct clinical phenotypes have been reported and depend on the type and location of the mutation. When the mutation is recessive with loss of function, patients develop a combined phenotype of immune deficiency with recurrent bacterial and fungal infections and signs of early inflammatory bowel disease, non-erosive polyarthritis and growth retardation. On the other hand, when the mutation is dominant, gain of function, the manifestations are only auto-inflammatory with extensive lymphoproliferation, oral lesions such as aphthosis or ulcers, abdominal pain and hepatosplenomegaly. The mutations described for the dominant form affect only the cleavage site of caspase 8 and the clinical phenotype is called CRIA for Cleavage-Resistant RIPK1-Induced Autoinflammatory syndrome. The recessive form is severe and life-threatening requiring hematopoietic stem cell transplantation while the dominant form responds well to interleukin-6 receptor antagonists. Thus, RIPK1 mutations can induce various clinical manifestations with two distinct phenotypes. Although still rare, because of their recent description, these diseases can be suspected by an internist, in front of recurrent digestive features and will be increasingly diagnosed in the future through the integration of this gene in the diagnostic chips dedicated to autoinflammatory diseases and early inflammatory bowel diseases, using next generation sequencing.