| ObjectiveX-linked immunoglobulinemia(XLA)was first reported in 1952 by Dr.Bruton of the US navy.It has been more than 60 years and is also known as Bruton's disease.The maximum number of XLA cases reported by foreign single centers was 1111.According to the morbidity in foreign countries,there are at least 4000 pediatric patients in China.Domestic data revealed that there were 174 cases in Shanghai,23 cases in Chongqing,and17 cases in Beijing respectively.In addition,sporadic cases were also reported in other regions.However the data in Northwestern China are relatively scant.Therefore,there are still a large number of children with XLA in China who have not been clearly diagnosed,let alone received standardized intravenous immunoglobulin(IVIG)replacement therapy.In this study,Bruton tyrosine kinase(BTK)gene test was performed on the children who were highly suspicious of XLA,and the clinical characteristics and genetic mutations were analyzed,so as to accumulate more cases and enrich the clinical data of XLA and improve the understanding of XLA by the majority of grassroots pediatric clinicians in northwest China.MethodsFrom September 2016 to September 2018,male infants with repeated infection who were admitted to the outpatient and inpatient department of rheumatology and immunology department of Xi'an Children's Hospital were screened out after relevant immune function evaluation.With the consent of parents,the BTK gene test was performed by Sanger sequencing technology to make clear the diagnosis of XLA.All XLA patients received IVIG replacement therapy and long-term follow-up regularly after diagnosed.Finally,clinical data of XLA children were collected for analysis,such as age of onset,age of diagnosis,clinical manifestations,family history,past history,auxiliary examinations,IVIG replacement treatment,and follow-up and so on.Result1.General clinical data of children with XLAThe study initially screened 2680 children with recurrent infection,and finally 10 children were included in the study.Eight of them(n=8,80%)were from Shaanxi province and two(n=2,20%)from Gansu province.The median age of onset was 25 months(10~72 months),the median age at diagnosis was 78.5 months(25~144 months),and themedian diagnostic period was 46 months(15~125 months).10 cases(n=10,100%)of clinical manifestations were mainly respiratory tract infections,9 cases(n=9,90%)were diagnosed with pneumonia,and 1 case(n=1,10%)were diagnosed with digestive tract infection.9 cases(n=9,90%)of pneumonia complicated with pleural effusion or atelectasis in 2 cases(n=2,20%),with bloodstream infection in 3 cases(n=3,30%),with secondary neutropenia in 1 case(n=1,10%),with anemia in 3 cases(n=3,30%),with otitis media in 3 cases(n=3,30%),with thrush in 2cases(n=2,20%),with central nervous system infection in 1 case(n=1,10%).In addition to interferon in 1 case(n=1,10%),the other 9 cases(n=9,90%)were treated with more than three generations of cephalosporin or broad-spectrum antibiotics.There were 5 cases(n=5,50%)with combined antibiotics,including 4 cases(n=4,40%)with combined cephalosporins and macrolides,1 case(n=1,10%)of pneumonia complicated with central nervous system infection,and treatment with special grade antibiotics vancomycin and meropenem to enhance anti-infection.Eight of them(n=8,80%)were poor in constitution and susceptible to respiratory tract infection;1 case(n=1,10%)was hospitalized for hand,foot and mouth disease(HFMD)for 2 times;the other case(n=1,10%)had normal constitution.Among the 8 cases(n=8,80%)with poor physique,3 cases(n=3,30%)had lymph node,chest and knee synovium operation before XLA diagnosis.2.Immunological function examination of XLA children:The median serum IgG was 0.33g/L(0.33~3.05g/L).The median serum IgM was0.16g/L(0.04~0.24g/L).The median serum IgA was 0.07g/L(0.04~0.24g/L).Peripheral blood mature B lymphocytes are absent in 9 cases(n=9,90%).3.The results of genetic testing in children with XLAAmong the 10 gene mutations,there were 6 cases(n=6,60%)of missense mutation,2 cases(n=2,20%)of frameshift mutation,1 case(n=1,10%)of nonsense mutation,and 1case(n=1,10%)of splicing site mutation.Exon was involved in all the 10 cases(n=10,100%),including 1 case(n=1,10%)of exon 2,1 case(n=1,10%)of exon 9,1 case(n=1,10%)of exon 12,and 2 cases(n=2,20%)of exon 14,2 cases(n=2,20%)of exon 15 patients and 3 cases(n=3,30%)of exon 18.Gene mutation was located in PH region ofBTK protein structure region(Pleckstrinhomolog)in 1 case(n=1,10%),SH3region(Srchomolgy3)in 1 case(n=1,10%),SH2 region(Srchomolgy2)in 1 case(n=1,10%),and TK(Kinase)region in 7 cases(n=7,70%).In the 10 cases(n=10,100%),their mothers' corresponding exon test of BTK gene was performed at the same time,among which 9 cases(n=9,90%)had disease-causing gene in their mothers,and 1 case(n=1,10%)had spontaneous mutation.One case(n=1,10%)of gene mutation site has not been reported in the literature.One case(n=1,10%)had a history of male death in his family.One family made a plan to give birth to a child again,at 26 weeks of gestation,the mother(BTK pathogenic gene carrier)was instructed in the antenatal BTK gene testing,and no pathogenic genes were found.All the 10 cases(n=10,100%)received IVIG replacement therapy after diagnosis,they have been followed up regularly till now,the frequency of severe infection was significantly reduced,the quality of life was significantly improved,and the family financial burden was greatly reduced.Conclusion1.BTK gene test showed 7 cases of mutation in TK region,among which 1 case(c.1751-TTCTAGGGGTT)was not reported in the literature.2.For male infants with repeated severe and special site infection,especially those with related past history,family history should make early identification,actively conduct immune function screening,and make clear diagnosis by genetic testing if necessary.3.Give genetic counseling to families with XLA children who plan to give birth to their children again,and guide prenatal diagnosis to achieve prenatal and postnatal care and reduce the economic burden of society and families.4.The treatment of children with XLA is not limited to the immunology department,so as to improve the understanding of XLA among more primary pediatric physicians and some subprofessional pediatric physicians(Such as otolaryngology department,Infection department,intensive care department),and realize the multidisciplinary cooperative diagnosis and treatment mechanism for rare diseases in the future. |
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