MISSENSE MUTATION IN NLRP12 ASSOCIATED WITH AN ATYPICAL PERIODIC FEVER SYNDROME

Abstract

Introduction NLRP12 encodes for the protein NALP12, which regulates NF-Kβ activation. Mutations in this gene are associated with familial cold autoinflammatory syndrome type 2 (FCAS2), which presents with fever, joint pain, and urticarial rash upon exposure to cold temperatures. Few patients with NLRP12 related autoinflammatory disease have been identified, therefore there is little data on the phenotypic presentation of this syndrome. Case Description A 10-year-old African American boy presented to the ED with a 9-day history of fever and worsening stomatitis. Parents reported recurrent episodes of fever, oral ulcers, and joint pain lasting for 4-8 weeks. He was febrile, and exam demonstrated severe, hemorrhagic stomatitis. Labwork revealed elevated inflammatory markers. An extensive workup was negative. He was subsequently treated with methylprednisone and gradually improved. Sequencing showed a heterozygous variant of uncertain significance in NLRP12: c.193G>C (p.Gly65Arg). He was scheduled for outpatient evaluation but was lost to follow up. Several months later, he presented again to the ED with similar symptoms. As his clinical presentation and genetic testing made an NLRP12-associated autoinflammatory disorder likely, he was treated with anakinra. His symptoms dramatically improved within days. He was transitioned to prophylactic IL-1 blockade with canakinumab, which has prevented further attacks. Discussion This patient presented with episodes of fevers, stomatitis, and joint pain, which suggested an autoinflammatory syndrome. Genetic testing demonstrated a mutation in NLRP12, leading to successful treatment with IL-1 inhibition. This case expands the clinical phenotype of patients with NLRP12 mutations, as he lacked typical associated features of FCAS2. NLRP12 encodes for the protein NALP12, which regulates NF-Kβ activation. Mutations in this gene are associated with familial cold autoinflammatory syndrome type 2 (FCAS2), which presents with fever, joint pain, and urticarial rash upon exposure to cold temperatures. Few patients with NLRP12 related autoinflammatory disease have been identified, therefore there is little data on the phenotypic presentation of this syndrome. A 10-year-old African American boy presented to the ED with a 9-day history of fever and worsening stomatitis. Parents reported recurrent episodes of fever, oral ulcers, and joint pain lasting for 4-8 weeks. He was febrile, and exam demonstrated severe, hemorrhagic stomatitis. Labwork revealed elevated inflammatory markers. An extensive workup was negative. He was subsequently treated with methylprednisone and gradually improved. Sequencing showed a heterozygous variant of uncertain significance in NLRP12: c.193G>C (p.Gly65Arg). He was scheduled for outpatient evaluation but was lost to follow up. Several months later, he presented again to the ED with similar symptoms. As his clinical presentation and genetic testing made an NLRP12-associated autoinflammatory disorder likely, he was treated with anakinra. His symptoms dramatically improved within days. He was transitioned to prophylactic IL-1 blockade with canakinumab, which has prevented further attacks. This patient presented with episodes of fevers, stomatitis, and joint pain, which suggested an autoinflammatory syndrome. Genetic testing demonstrated a mutation in NLRP12, leading to successful treatment with IL-1 inhibition. This case expands the clinical phenotype of patients with NLRP12 mutations, as he lacked typical associated features of FCAS2.