Lifting the Lid on CAPS: Uncovering Genetic Anticipation in Cryopyrin-Associated Periodic Syndrome

Abstract

Cryopyrin-associated periodic syndrome (CAPS) is a spectrum of autoinflammatory conditions comprising three subtypes: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal onset multisystem inflammatory disease (NOMID).1 Symptoms include urticaria, fever, arthralgias, conjunctival injection, and headaches, which can occur spontaneously or during periods of cold/stress.2 Complications include permanent sensorineural hearing loss (SNHL), chronic aseptic meningitis, systemic amyloidosis, developmental delay, seizures, and chronic arthropathy.3 CAPS is treated with inhibition of interleukin (IL)-1 which can reduce symptoms and prevent progression of complications including hearing loss, CNS inflammation, and renal disease from amyloidosis.3,4.Here, we present a five-year-old boy who developed unexplained arthralgias, SNHL, increased intracranial pressure, atrophic retinal nerve fiber layer, and painful urticaria. Laboratory testing showed elevated inflammatory markers and neutrophil count. Genetic testing showed a heterozygous variant in the NLRP3 gene that was previously reported in a patient with NOMID. Interestingly, his mother had similar history of arthralgia, aseptic meningitis, SNHL, and recurrent aphthous ulcers, while his maternal grandmother had a history of SNHL and arthralgia. The mother and grandmother had similar elevations in inflammatory markers and neutrophils. Both were found to have the same variant in NLRP3 as the index patient and were diagnosed with CAPS/NOMID. The histories suggested a degree of genetic anticipation, for the child’s symptoms were most severe, while his mother had moderate symptoms and his grandmother was relatively mildly affected. Notably, neither the mother nor grandmother had signs of kidney disease to suggest amyloidosis. All three family members were started on canakinumab injections. The child’s arthralgias and mother’s symptoms improved, and flares have decreased in frequency. The grandmother has not yet received therapy long enough to assess for improved symptoms.CAPS is a group of autoinflammatory disorders with autosomal dominant inheritance, quality-of-life-limiting symptoms, and potential life-long complications. CAPS should be suspected and screened for in relatives of affected individuals. This familial case demonstrates a pattern of increased severity of CAPS symptoms with each subsequent generation from grandmother to grandchild suggestive of genetic anticipation. Early diagnosis and initiation of anti-IL-1 therapy is important to prevent progression and complications.