A Case Of CRIA Syndrome Caused By Mutation Of RIPK1 Gene In A Child And Literature Review

Objective:The clinical and genetic data of a child with Cleavage-resistant RIPK1-induced autoinflammatory(CRIA)syndrome were collected,relevant literature at home and abroad were searched,and the characteristics of the disease were summarized.It is hoped that early identification,early diagnosis and reasonable treatment of such autoinflammatory diseases can be carried out,so as to improve the long-term prognosis.Methods:A child with recurrent fever onset and clinically suspected autoinflammatory disease was selected.The clinical data of the child was summarized and analyzed retrospectively.At the same time,the next-generation sequencing technology was used to sequence the genes of the child and his immediate family members to find possible pathogenic genes and conduct family verification.According to the clinical characteristics of the children and the results of genetic testing,the keywords and subject terms of"RIPK1 gene,periodic fever,autoinflammatory diseases,autoinflammatory diseases,AIDs"were respectively published in CNKI,Wanfang database and biomedical literature database(Pub Med)for data retrieval,and the retrieval time was set from January 2000 to January 2023.Summarize the clinical manifestations,gene mutation characteristics and treatment methods of patients with CRIA syndrome,and summarize the characteristics of the disease.Results:1.Case report:The patient was a female,3 years and 8 months old,who was admitted to the hospital for the first time on December 6,2020 due to intermittent fever for 3 years.The child developed fever for the first time at the age of 7 months.Oral antipyretics can reduce the temperature.The fever lasted for 2 days and the body temperature returned to normal.After that,the fever occurred once every 3-4 weeks.1～2days body temperature can be normal.After the child was 1 year old,the frequency of fever increased compared with the previous one.She had fever once in about 7-10 days,intermittently accompanied by transient rash,no convulsions,no joint swelling and pain,and blood routine leukocytes increased during fever(12.79-16.73×10~9/L),mainly neutrophils,CRP30.95～192mg/L,erythrocyte sedimentation rate 42～50mm/1h,oral antipyretics,cold medicine,body temperature can be normal within 1～2 days.When he was 3 years old and 5 months old(August 2020),she visited the outpatient clinic of our hospital due to repeated fever.Considering the possibility of autoinflammatory diseases,genetic testing was improved,and he was given oral treatment with thalidomide for 2months.The interval between fevers was longer than before.Inpatient for further treatment.Admission examination:T36.2℃,P 90 beats/min,R 25 beats/min,HT 92cm(P3),WT13Kg(P3),BP:99/69mm Hg.The mind is clear and the mental response is OK.Mild malnutrition.The face was unremarkable,and several swollen lymph nodes were palpable on both sides of the neck,the largest one was about 2×1cm,firm in texture,movable,and without tenderness.Cardiopulmonary examination showed no obvious abnormalities.The abdomen was soft,the ribs of the liver were not palpable,and the spleen was 1.5 cm below the ribs,and the texture was tough without tenderness.Neurological examination was unremarkable.Auxiliary examination:blood routine showed white blood cell count 8.44×10~9/L,neutrophils 4.36×10~9/L,CRP 4.07mg/L,erythrocyte sedimentation rate 14mm/1h,cytokine IL-6 6.02pg/ml(0～5.4pg/ml),IFN-β30.05pg/ml(0～23.1pg/ml),brain MRI showed no obvious abnormalities.The results of genetic testing showed that there was c.970G>A,p.D324N heterozygous mutation(spontaneous mutation)in the RIPK1 gene(autosomal dominant inheritance).A definite diagnosis of CRIA syndrome was made.Oral thalidomide was continued,and the IL-6antagonist tocilizumab was added.After the first dose,the fever interval was extended to10-14 days,and the fever peak dropped below 38°C.No re-fever,stable condition,gradually prolonging the interval between the administration of tocilizumab,and currently taking medication every 8 weeks,the child has no fever,no repeated rash,and the height and weight are rapidly catching up.2.Literature review:A total of 4 literatures with relatively complete clinical data and genetic information reported at home and abroad have been retrieved so far,including1 Chinese literature and 3 English literatures.A total of 19 patients with CRIA syndrome came from 9 families.The systematic summary of the data is as follows:(1)Clinical data:Among the 19 patients,18 patients(95%)presented with periodic fever.16 patients(84.2%)had enlarged lymph nodes,9 patients(47.3%)had oral ulcers,42.1%(8 patients)had hepatosplenomegaly,and 8 patients(42.1%)had arthralgia,Other clinical manifestations include anemia(31.6%),headache(26.3%),abdominal pain(26.3%),diarrhea(5.3%),rash(5.3%),etc.(2)Genetics Information:The disease is autosomal dominant.The causative gene is the RIPK1 gene.There are 3 mutation sites in total,including 6 mutation forms.9 patients have c.970G>C(p.D324H)mutation.Other mutation forms include:c.962T>G(p.L321R)(4 cases),c.970G>A(2 cases),c.971A>G(p.D324G)(2 cases),c.970G>T(p.D324Y)(1case),c.9701A>T(p.D324V)(1 case).The mutation types of RIPK1 gene in 19 patients were all missense mutations.(3)Treatment and follow-up data:Seven patients received non-steroidal anti-inflammatory drugs when they had a fever,and 4 patients(57.1%)could reduce their fever.Ten patients received glucocorticoid therapy for fever,and 9 patients(90%)could control their body temperature.Eleven patients received colchicine treatment,among which 3 cases(27.3%)had prolonged fever intervals and lower heat peaks after treatment,and the remaining 8 patients had no response to colchicine treatment.Nine patients received IL-6 antagonist treatment,and fever was completely controlled in 5 patients(55.6%).Another 6 patients were treated with IL-1 antagonists and 5 patients were treated with TNF antagonists,both of which failed to completely control the patients’febrile symptoms.There are no reports of deaths in the retrieved literature.Conclusions:(1)The patient in this study were diagnosed with CRIA syndrome based on clinical manifestations,laboratory tests and genetic test results.The c.970G>A(p.D324N)heterozygous mutation of RIPK1 gene was reported for the first time.(2)CRIA syndrome is a newly recognized inflammasome disease,clinically characterized by periodic fever,oral ulcers,hepatosplenomegaly,lymphadenopathy,and arthralgia.IL-6 antagonists have a better therapeutic effect on some patients.(3)For children with young onset age,recurrent and periodic fever,systemic symptoms and multisystem inflammatory manifestations,and elevated inflammatory indicators(leukocytes,neutrophils,CRP,ESR)during the attack,autoinflammatory diseases need to be considered If possible,relevant examinations and genetic testing need to be further improved to confirm the diagnosis.