Clinical Analysis Of 11 Cases With Congenital Neutropenia

Objective We summarized the diagnosis,treatment,follow-up experience of 11 cases with congenital neutropenia(CN)to improve the knowledge on CN.Methods(1)Clinical and laboratory data of the propositus and other family members were collected.(2)Targeted exon gene-trap and the second generation sequencing including more than 500 pathogenic genes that related to CN such as ELANE,HAX1,GFI1,CSF3 R,WAS,G6PC3,SLC37A4,LYST,AK2,SBDS and so on,which were carried out to detect the mutational gene sequence.Sanger sequencing was performed on the patient and other family members for verification.Additionally,we conducted pathogenicity analysis.(3)Patients' therapeutic effect,drug side-effect with recombinant human granulocyte colony stimulating factor treatment were followed up.(4)All the collected data was analyzed and managed by using SPSS20.0 statistical software and Microsoft Office Excel 2010.Results(1)11 patients(4 males and 7 females)with CN were taken for this research.The age of onset is between 0.5 to 6 months,the average age of onset is 4.23±2.0 months;the diagnosed age is between 3.5 to 77 months,the average diagnosed age is 22.36±20.89 months.From the result,CN patients need around 18.13 months to be diagnosed after the onset.(2)All patients got infections every month,and it was found that recurrent pneumonitis,ulceration of the mouth,diarrhea,infections of the upper respiratory tract,and otitis media are the common clinical features of CN.An average rate of 54.5%,18.2%,9.1%,18.2% had recurrent infection once a week,once every two weeks,once every three weeks,once every four weeks respectively.Most of the cases have multiple hospitalization records: 63.6%,18.2%,9.1% of the patients admitted to the hospital monthly,every two months,every three months,and 1 case had no multiple hospitalization record.(3)Blood counts need to be performed at least 2 times per week over four weeks: the ANC of all patients was less than 0.5×109/L for at least three times;ANC decreased periodically in 5 cases which diagnosed as cyclic neutropenia.Otherwise,there're 6 cases of the ANC were remained below 0.5×109/L,which diagnosed SCN.However,the Lymphocyte count,hemoglobin,and platelet count were normal in all cases and the full blood count of the 11 patients' family members appeared to be normal as well.(4)Bone marrow cell morphology: The bone marrow shows a maturation arrest of neutrophil precursors at an early stage with few cells of the neutrophilic series beyond the promyelocyte.The absolute numbers of promyelocyte?myelocyte and metamyelocyte are slightly increased.Otherwise the absolute numbers of banded neutrophils and segmented granulocyte are decreased,and erythrocytic,megakaryocyte series are normal.(5)8 cases were on genetic detection,and 2 cases were abnormal,case 1: SLC37A4 homozygous mutation,the parents are the pathogenic gene carriers.case 8: carrying FANCB gene,hemizygous,the mutation site of the father is negative,while the mother is heterozygous.There were no positive pathogenic genes in other 6 cases.(6)Treatment and follow-up:(1)when ANC<0.5×109/L or the patient has obvious infection with ANC<1.0×109/L,the SCN patients need rhG-CSF treatment;When the ANC stay in the minimum value per cycle or getting obvious infection with ANC<1.0×109/L,the CyN patients need rhG-CSF treatment.Initially administration at 5ug/kg.day;Blood counts must be obtained 24 hours after administration of rhG-CSF,and according to the increase or decrease of ANC,calibrate the rhG-CSF dose to keep ANC averages between 1.0×109/L to 2.0×109/L.If the infection is severe,antibiotics must be added to the treatment.(2)Health education.10 patients were treated with low-dose rh G-CSF(5ug/kg.d),and 24 hours after treatment,the ANC rose to normal(ANC > 1×109/L),with no obvious side effect.The frequency of getting infection was lower than before: There are no cases of having recurrent infection in neither every week nor every two weeks,both 20% of cases had recurrent infection once every three and four weeks,while the remaining 60% of the cases only had recurrent infection in more than four weeks.As a result of treating patients with rhG-CSF,the frequency of hospitalization had decreased-----The rate of hospitalization during follow-up was 0%.Conclusions(1)The clinical manifestations of congenital neutropenia are not specific,mainly on recurrent infection.The diagnosis of the disease is always delayed mostly due to lack of knowledge about the disease.On the emergence of recurring infections and having neutropenia since birth,clinicians should consider the possibility of congenital neutropenia by investigating the full blood counts and bone marrow cytomorphology for clinical diagnosis.(2)We divided these 11 patients into 5 CyN and 6 SCN by monitoring ANC,which can guide us to use rhG-CSF.(3)8 patients were checked by using targeted exon gene-trap and the second generation sequencing for CN genetic diagnosis,only 2 cases had the pathogenic genes,so we plan to perform the whole genome sequencing?MLPA for genetic diagnosis.(4)Most patients responded well to recombinant human granulocyte colony stimulating factors with lesser adverse reactions,which could significantly reduce the recurrent infection and hospitalization frequency.However,patients who did not insist using or respond to recombinant human granulocyte colony stimulating factor therapy can have severe infection even can result to death.