Periodic Fever Syndromes Panel

Periodic Fever Syndromes (PFS) (also known as monogenic autoinflammatory syndromes) is a collective group of disorders highlighted by recurrent fever and inflammatory episodes. Fever episodes can range from hours up to ~ 2 weeks with recurrences ranging from several bouts per month to a few per year. PFS frequently involve inflammation of the skin, serous membranes, joints, lymph nodes, gastrointestinal tract, and nervous system. Onset of PFS occurs during the first year of life or early childhood with only familial mediterranean fever (FMF) and tumor necrosis factor receptor-associated periodic syndrome having cases of adult onset described. In severe cases, development of amyloidosis may occur. PFS are caused by aberrant inflammasome activation leading to heightened interleukin 1 levels and innate immune dysregulation. Differential diagnosis of individual PFS is important for employing appropriate therapeutics such as colchicine to treat FMF or antibiotics for cyclic neutropenia. PFS may mirror other immune dysfunction disorders such as cyclic neutropenia and SCID due to recurrent fever bouts, but unlike those disorders, bouts are not a result of recurrent infections (Caso et al. 2013; Touitou et al. 2013).

Disorders tested in this PFS panel include familial mediterranean fever/FMF, familial cold autoinflammatory syndrome/FCAS, muckle-wells syndrome/MWS, chronic infantile neurological cutaneous articular syndrome/CINCA, tumor necrosis factor receptor-associated periodic syndrome/TRAPS, mevalonate kinase deficiency/MKD, NLRP12 associated autoinflammatory disorder, pyogenic arthritis pyoderma gangrenosum and cystic acne syndrome/PAPA, Majeed syndrome, cyclic neutropenia, pediatric granulomatous arthritis/PGA, CANDLE syndrome, DITRA syndrome, CARD14 mediated psoriasis/CAMPS, and TNFAIP3-mediated early onset autoinflammatory disease (Sanchez et al. 2013).

Autosomal dominant PFS disorders include TRAPS (TNFRSF1A), FACS (NLRP3), MWS (NLRP3), CINCA (NLRP3), NLRP12 associated autoinflammatory disorder (NLRP12), PAPA (PSTPIP1), CAMPS (CARD14), TNFAIP3-mediated early onset inflammatory disease, PGA (NOD2), and cyclic neutropenia (ELANE). Autosomal recessive PFS disorders include FMF (MEFV), MKD (MVK), CANDLE (PSMB8), DITRA (IL36RN) and majeed syndrome (LPIN2) (Caso et al. 2013; Sanchez et al. 2013).

See individual test descriptions for additional information on the molecular biology of each gene product.

Analytical sensitivity for detection of causative variants in the MEFV, MVK, NLRP3, NLRP12, TNFRSF1A, LPIN2, ELANE, and PSTPIP1 is >95% as gross deletions have not been reported. Clinical sensitivity is variable. In patients diagnosed with familial mediterranean fever, an identifiable pathogenic variant in the MEFV gene was found in 70-80% of cases (Aksentijevich et al. 1999). In patients with biochemical evidence of impaired mevalonate kinase activity and suspected Hyper-IgD syndrome or mevalonic aciduria, causative variants in the MVK gene were found ~95% of cases (Mandey et al. 2006; Bader-Meunier et al. 2011). In tumor necrosis factor receptor-associated periodic syndrome patients, causative variants in the TNFRSF1A gene are found in 40-50% of familial and ~5% of sporadic cases (Aksentijevich et al. 2001; Dode et al. 2002). Causative variants in NLRP3 have been identified in >85% of patients with familial cold autoinflammatory syndrome and ~60% of patients with chronic infantile neurological cutaneous articular syndrome (Aksentijevich et al. 2007; Aksentijevich et al. 2002). Clinical sensitivity for detection of ELANE causative variants in patients with cyclic neutropenia varies with two reports finding causative variants in 31 of 81 and 21 of 24 patients respectively (Dale et al. 2000; Bellanne-Chantelot et al. 2004). In an international registry for pediatric granulomatous diseases, 75 individuals were assessed for pathogenic variants in the NOD2 gene. In this cohort, 45 symptomatic patients had a pathogenic variant in the NOD2 gene. Of these 45 individuals, 22 were familial (Blau syndrome) and 23 were sporadic (Early Onset Sarcoidosis) form of PGA (Rosé et. al. 2009)

Clinical sensitivity cannot be estimated for pyogenic arthritis pyoderma gangrenosum and cystic acne syndrome, Majeed syndrome, CANDLE, DITRA, TNFAIP3-mediated early onset autoinflammatory disease, CAMPS and NLRP12-associated autoinflammatory disorder because only a small number of cases have been reported.

Thus far, no gross deletions or duplications have been reported in the ELANE, CARD14, NOD2, PSMB8, NLRP3, NLRP12, PSTPIP1, LPIN2, TNFRSF1A, IL36RN, or MEFV genes (Human Gene Mutation Database). A gross deletion involving exon 1 of TNFAIP3 has been reported in one patient with Sjögren's syndrome (Nocturne et al. 2013). Deletions in the MVK gene have been reported in three cases, but account for less than 5% of all cases of mevalonate kinase deficiency (Takada et. al. 2003; Cuisset et. al. 2001; Zhang et. al. 2015).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).