Clinical Observation Of One Case And Literature Review Of Neonatal Diabetes Mellitus

ObjectiveWe summarized the experience of diagnosis,treatment,follow-up and genetic counseling in one case of neonatal diabetes mellitus(NDM)and reviewed literature of NDM to raise awareness of the diseases.Methods1.Clinical and laboratory data of the probands and their family members were collected.2.The pathogenicity gene of the proband was detected by the Next-generation sequencing technology,and the gene sequence of the positive mutation locus was screened out.Sanger sequencing was performed on the patient and other family members for verification.Additionally,the pathogenicity of the mutation site was determined by using online prediction programs Poly Phen2,Provean and Mutation Taser.3.Patient’s height,weight,muscle strength,intelligence,blood glucose,C-peptide,insulin,glycosylated hemoglobin and electrolyte were followed up after glimepiride treatment.4.Experience of diagnosing and treatment of the disease was summarized based on relevant literatures of neonatal diabetes from databases of Wanfang,CNKI,VIP,and Pubmed.Results1.Clinical data: A boy,onset age 2 months and 16 days,initially demonstrated vomiting,fever,polyuria,high levels of glycemia and grape glycosylated hemoglobin,ketoacidosis,low C-peptide,negative anti-islet cell antibody and mild delay in psychomotor development.The baby was treated with intravenous fluids and insulin initially,and then changed to subcutaneous injection of insulin(1-1.6 U/kg/d)for more than two months.During the follow-up,laboratory analyses revealed the following results: poor blood glucose control of 1.5-24.6 mmol/L,C-peptide 0.05 ng/ml,insulin 15.65 pg/ml,glycosylated hemoglobin 9% and positive urine sugar.At five months old,the baby began to apply glimepiride in dosage of 0.49 mg/kg/d,with insulin stopped completely.During follow-up to now,26 months old,his blood glucose level was 4-12 mmol/l,serum insulin was rose to 25.36-187.8 pg/ml,C-peptide was rose to 1.52-3.87 ng/ml,glycosylated hemoglobin was 5.5-6%,urine sugar was negative,with other laboratory indicators were normal.Height and weight of the boy was fell slightly behind children of the same age,with good psychomotor development.2.Homozygous mutation of c.259T>G(p.C87G)was found in ABCC8 gene by Next-generation sequencing technique of clinical penetrance 4000.3.Sanger sequencing showed that heterozygotes mutation of c.259T>G in ABCC8 gene were carried by his parents and elder sister,who were without clinical manifestations of polydrinking,polyfood,polyuria,low C-peptide,hyperglycemia,etc.Poly Phen2,Provean and Mutation Taser bioinformatics analysis revealed the mutation was likely pathogenic.The genetic pattern of the family was consistent with autosomal recessive inheritance.4.91 relevant references were reviewed in this study,which published between 2010 to 2019.Totally 271 patients were enrolled,including 72 TNDM and 199 PNDM.The literature indicated that hyperglycemia and low C-peptide levels were observed in all patients within 6 months old.The majority of islet cell autoantibodies of NDM were negative,and anti-insular cell antibody(ICA)was positive in one PNDM,considering to be associated with a combined autoimmune disease.In TNDM,58% of the patients had intrauterine growth retardation,and mean birth weight was(2.18±0.65)kg.Some TNDM patients were complicated with macroglossia,anemia,patent foramen ovale,inguinal hernia and so on.In PNDM,37.8% of the patients had intrauterine growth retardation,and mean birth weight was(2.52 ± 0.57 kg).52.3% of PNDM patients had diabetes ketoacidosis at the time of onset,which may be consistent with intestinal atresia,cholestasis,liver failure,hypothyroidism and so on.Positive gene mutation sites or chromosome abnormalities were found in258 patients(95.2% of 271 patients).The common mutations were KCNJ11(39.1%,101/258),ABCC8(22.9%,59/258),EIF2AK3(10.9%,28/258),INS(6.6%,17/258),and 6q24(7.4%,19/258),etc.The common mutation sites of101 patients in KCNJ11 gene were R201H(28.7%,29/101),R201C(15.8%,16/101),V59M(12.9%,13/101),E229K(7.9%,8/101),E227K(5.0%,5/101),etc.And 99% of KCNJ11 genes were dominant heterozygous mutation and in which 83.2% patients were PNDM.78.0% of the patients were dominant heterozygous mutation in 58 patients in ABCC8 genes,of which half each of TNDM and PNDM.While all of the patients were PNDM in homozygous mutation or compound heterozygous mutation.136 patients of NDM who used sulfonylureas(SU)therapy in the literature were summarized finally and 90%(121/136)patients of NDM successfully converted to SU therapy.95.0%(77/81)patients of KCNJ11 gene mutation and92.1%(35/38)patients of ABCC8 gene mutation could be successfully switched from insulin to SU therapy to improve the quality of life of patients.Some side effects of SU were found in 12 patients of NDM(8.8%,12/136).The gastrointestinal reactions such as nausea,vomiting,diarrhea,poor appetite were most common(84.6%,11/12),and majority of which were temporary and mild,without affecting SU therapy clinical application in infants.Conclusion1.The c.259T>G(p.C87G)homozygous missense mutation of ABCC8 gene was first reported as a pathogenic mutation of NDM.2.The clinical manifestation and examination results of the child are consistent with PNDM,with autosomal recessive inheritance.The child was successfully treated with glimepiride,and the long-term prognosis still needs further follow-up observation.3.Onset age,birth weight,C-peptide and glycosylated hemoglobin at initial diagnosis combining with clinical manifestations were helpful for preliminary distinguishing TNDM or PNDM.4.Clinical phenotype of NDM is related to mutant genes and mutation sites,and gene detection is helpful for disease diagnosis and prognosis evaluation.