We evaluated a family in the Undiagnosed Disease Network with recurrent, stereotypical fevers, pharyngitis, adenitis and oral ulcers (similar to PFAPA syndrome) beginning in childhood. Symptoms evolved at puberty to include fever, urticaria, angioedema, arthralgias, and conjunctivitis in response to stress. Treatment with standard anti-inflammatory, antihistamine, and immunosuppressive therapies failed to decrease symptoms.
Physical urticaria testing, biopsy of affected skin lesions, and whole exome sequencing (WES) of 5 affected and 1 unaffected family members were done. Peripheral blood mononuclear cells from the proband and her eldest daughter were stimulated with LPS and incubated with MCC950, a selective inhibitor of NLRP3. IL-1 levels in the supernatant were measured by ELISA.
Physical urticaria testing demonstrated cold-induced and vibratory urticaria, with lesions that persisted for >24 hours. Biopsy of urticarial lesions showed a predominantly neutrophilic infiltration and some eosinophils/mast cell degranulation. WES identified heterozygosity for a previously reported Ser728Gly NLRP3 variant in all affected family members, in addition to variants in IL-17A (4/5 members) and C1RLP (4/5 members). Stimulated cells from the proband and her daughter produced similar levels of IL-1 to healthy controls and significantly lower levels of IL-1 compared with a patient with a known CAPS-associated variant in NLRP3. The proband had noteworthy improvement in fever, urticaria, and angioedema episodes on 300mg of daily subcutaneous anakinra.
We observed a kindred with symptoms similar to PFAPA syndrome in childhood and evolution to febrile urticaria/angioedema after puberty, with beneficial treatment response from anakinra. A Mendelian and an alternative polygenic inheritance pattern are possible.