Gene mutations and clinical phenotypes in 15 Chinese children with cryopyrin-associated periodic syndrome (CAPS)

Abstract

The aim of our study is to explore the features of clinical manifestations and genetic mutations in Chinese CAPS patients. Fifteen confirmed patients with CAPS were enrolled. The onset time ranges from 2 days after birth to 6 years and 1 month. Recurrent urticaria rash (93.3%) with fever (100%) were two dominant characteristics of these patients that were presented as either acute or chronic process. Systemic involvements were found in all patients except for one with only rash and fever. The top three symptoms were fever (100%), rash (93.3%) and myalgia (76%). Other clinical manifestations include arthritis (11 cases), lung involvement (seven cases), optical dysfunction (seven cases), nerve deafness (six cases), nervous system involvement (five cases), hepatomegaly, splenomegaly and lymphadenectasis (five cases). Also, four patients had heart involvement and one patient suffered kidney involvement. The laboratory inflammation index such as leukocyte counts, platelet counts, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum amyloid A (SAA) and fibrinogen (FIB) increased significantly at initial stage, but decreased after therapy. As for gene mutation detection, Twelve out of 15 patients were confirmed with mutation in NLRP3, including 11 mutant site: c1789A<G, c.1703T<A, c.913G<A, c.1710G<C, c.1057G<T, c.2335C<T, c.932TvC, c.296G<C, c.663C<T, t.1702T<A, 299G<A. Mutation sites c.1703T<A, c.2335C<T, c.296G<C, c.663C<T, and 299G<A were newly identified. The association between gene mutation and clinical manifestation shows that D305N was highly associated with severe organs involvements, and therefore, the time of therapy and regimen were critical for the prognosis of disease. As the largest cohort study of Chinese CAPS patients, we confirmed that all patients presented typical clinical manifestations, identified five new mutation sites on NLRP3 and analyzed the correlation between the genotypes and phenotypes. We also raise concerns for one case with serious conditions that only had two nonsense mutations (c.663C<T and t.1702T<A) detected.

Cryopyrin‐associated periodic fever syndrome in children: A case‐based review

“…Three out of 20 patients were hypospermic in a British case series . A Chinese case series looked into the effect of genotype on the severity of symptoms, but they did not find any but one mutation ( D305N ) as highly associated with severe organ involvement . Some of the patients had pulmonary, cardiac, hepatic or renal involvement, but the exact disease pathology in the tissues was not described.…”

The Role of Nucleic Acid Sensing in Controlling Microbial and Autoimmune Disorders

“…In contrast, autoimmunity generally refers to disorders that originate from defects in the innate immune system but require adaptive immune components such as lymphocyte influx or T and B-cell responses. A classic group of autoinflammatory disorders are the cryopyrin-associated periodic syndromes (CAPS), also known as familial cold autoinflammatory syndrome (FCAS), which result from gain-of-function mutations in the NLRP3 / CIAS1 gene (Cordero et al, 2018; Hoffman et al, 2001; Kanneganti et al, 2006; Li et al, 2017a). On the other hand, classic autoimmune disorders include Aicardi–Goutières syndrome (AGS), and although several mutations in AGS patients are rooted in innate immune dysfunction, AGS has both autoimmune and autoinflammatory components.…”

Cryopyrin-Associated Periodic Syndrome (CAPS) Caused by c.943A>G Variant of NLRP3 Gene: Clinical Case

“…CAPS включают семейный холодовой аутовоспалительный синдром (familial cold autoinflammatory syndrome, FCAS), синдром Мак ла-Уэллса (Muckle-Wells syndrome, MWS) и хронический младенческий нервно-кожно-артикулярный синдром/младенческое мультисистемное воспалительное заболевание (chronic infantile onset neurologic cutaneous articular/neonatal onset multisystem inflammatory disease, CINCA/NOMID) [1][2][3]. Все эти заболевания наследуются по аутосомно-доминантному типу и обусловлены вариантами гена NLRP3 (альтернативное написание: NALP3, PYPAF1, CATERPILLER1.1, CIAS1), локализованного на длинном плече хромосомы 1 [4]. Ген NLRP3 кодирует белок криопирин [4].…”

“…Все эти заболевания наследуются по аутосомно-доминантному типу и обусловлены вариантами гена NLRP3 (альтернативное написание: NALP3, PYPAF1, CATERPILLER1.1, CIAS1), локализованного на длинном плече хромосомы 1 [4]. Ген NLRP3 кодирует белок криопирин [4]. Нарушение структуры криопирина при изменении нуклеотидной последовательности гена приводит к нарушению функционирования инфламмасомы -супрамолекулярного комплекса, обеспечивающего превращение проинтерлейкина 1 в активную форму, избыточному образованию интерлейкина 1 и, как следствие, развитию системного воспаления [1,2,5].…”

“…Последнее в настоящее время играет ключевую роль в диагностике CAPS-синдромов. По данным литературы, описаны 177 вариантов гена NLRP3, связанных с различными клиническими фенотипами [3,4,13].…”