Clinical spectrum of Cryopyrin-associated Periodic Syndrome associated with a single nucleotide variant of the NLRP3 gene in a Puerto Rican family

Cryopyrin-associated Periodic Syndromes (CAPS) are a group of autoinflammatory disorders of varying degrees of severity that include familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID, or as Chronic Infantile Neurological, Cutaneous, and Articular (CINCA). There is one case per one million inhabitants in the United States. Cryopyrinopathies arise from mutations in the NOD-like receptor protein 3 (NLRP3) gene, which assembles with the cysteine protease caspase-1 to form the NLP3 and releases several proinflammatory cytokines, including IL-1β. An autosomal dominant GOF mutation of the NLRP3 gene causes the overproduction of IL-1β, inducing excessive inflammation and even permanent organ damage. We describe a Puerto Rican family of three with Cryopyrin-associated Periodic Syndrome and varying degrees of severity that received Canakinumab. A 40-year-old mother and her two sons, ages 26 and 20, presented for an evaluation of cold-induced maculopapular rash, arthralgia, and lower extremity swelling. Their symptoms initially presented at birth and continued into their adulthood. The episodes started briefly after exposure to cool temperatures and lasted hours to days. High fevers and chills often accompany episodes. They all presented with chronic leukocytosis and high inflammatory laboratory values. The oldest son showed the most intense, enduring flares and severe complications. At age 1, he was diagnosed with neuroblastoma of the right adrenal gland and achieved remission with a combination of surgical resection, chemotherapy, and radiotherapy. He subsequently required multiple hospitalizations due to episodes of high fevers as a child. He also developed severe leptomeningeal inflammation at age 12 and underwent an exploratory craniotomy that yielded normal findings. The three family members underwent genetic testing two decades after the children were born, revealing a heterozygous missense mutation. They had a single nucleotide variant of the NPL3 gene c.913G>A (p. Asp305Asn) that has been linked to CAPS. Severe inflammatory neurologic symptoms and familial cold urticaria were the clues for the diagnostic suspicion of CAPS. IL-1β antagonists have been demonstrated to be effective in substantially reducing inflammatory markers and thus decreasing inflammation-related signs and symptoms. Residence in the tropics could have contributed to delayed diagnosis.Table 1General characteristics of the Cryopyrin-associated Periodic SyndromesFCASMWSNOMID/CINCAGenes and pattern of inheritanceNLRP3 gene ADNLRP3 gene ADNLRP3 gene ADEpidemiology Age of onset1:1 million.1Infancy1:1 million1Infancy1:1 million1Neonatal/early infancyCutaneous NeurologicUrticaria-like rash Headaches with fever after cold exposureUrticaria-like rash Headaches with fever during flares. Uncommon to have other CNS symptoms. 3Urticaria-like rash Headaches, fever, chronic aseptic meningitis, and high CNS pressure. Many develop mental or cognitive impairment.AuditoryMild hearing lossSensorineural hearing loss starting in adolescenceSensorineural hearing loss from infancy/childhoodOphthalmicConjunctivitis during flaresConjunctivitis during flaresPapilledema, uveitis, iritis, conjunctivitis, and vision lossLymphaticNot notedMay be notedMay have enlarged lymph nodesJointsArthralgiaArthralgia, stiffness, and swelling during flaresArthralgia, stiffness, and swelling during flaresLaboratory valuesHigh ESR, CRP, SAA, and leukocytosis with flaresHigh ESR, CRP, SAA, and leukocytosis with flaresChronically elevated ESR, CRP, SAA, and leukocytosisFCAS, Familial cold autoinflammatory syndrome; MWS Muckle Wells Syndrome; CINCA/NOMID, chronic infantile neurologic, cutaneous, and articular syndrome/neonatal-onset multisystem inflammatory disease.