Variable outcome in infantile-onset inflammatory bowel disease in an Asian cohort

AIM Infantile-onset inflammatory bowel disease(IO-IBD) with the onset of disease before 12 mo of age, is a different disease entity from childhood IBD. We aimed to describe the clinical features, outcome and role of mutation in interleukin-10(IL-10) and interleukin-10 receptors(IL-10R) in Asian children with IO-IBD. METHODS All cases of IO-IBD, defined as onset of disease before 12 mo of age, seen at University Malaya Medical Center, Malaysia were reviewed. We performed mutational analysis for IL10 and IL10 R genes in patients with presenting clinical features of Crohn's disease(CD).RESULTS Six [13%; CD = 3, ulcerative colitis(UC) = 2, IBDunclassified(IBD-U) = 1] of the 48 children(CD = 25; UC = 23) with IBD have IO-IBD. At final review [median(range) duration of follow-up: 6.5(3.0-20) years], three patients were in remission without immunosuppression [one each for post-colostomy(IBD-U), after standard immunosuppression(CD), and after total colectomy(UC)]. Three patients were on immunosuppression:one(UC) was in remission while two(both CD) had persistent disease. As compared with later-onset disease, IO-IBD were more likely to present with bloody diarrhea(100% vs 55%, P = 0.039) but were similar in terms of an associated autoimmune liver disease(0% vs 19%, P = 0.31), requiring biologics therapy(50% vs 36%, P = 0.40), surgery(50% vs 29%, P = 0.27), or achieving remission(50% vs 64%, P = 0.40). No mutations in either IL10 or IL10 R in the three patients with CD and the only patient with IBD-U were identified.CONCLUSION The clinical features of IO-IBD in this Asian cohort of children who were negative for IL-10 or IL-10 R mutations were variable. As compared to childhood IBD with onset of disease after 12 mo of age, IO-IBD achieved remission at a similar rate.

Valuable clinical indicators for identifying infantile-onset inflammatory bowel disease patients with monogenic diseases

BACKGROUND Infantile-onset inflammatory bowel disease(IO-IBD)occurs in very young children and causes severe clinical manifestations,which has poor responses to traditional inflammatory bowel disease(IBD)treatments.At present,there are no simple and reliable laboratory indicators for early screening IO-IBD patients,especially those in whom the disease is caused by monogenic diseases.AIM To search for valuable indicators for early identifying IO-IBD patients,especially those in whom the disease is caused by monogenic diseases.METHODS A retrospective analysis was performed in 73 patients with IO-IBD admitted to our hospital in the past 5 years.Based on the next-generation sequencing results,they were divided into a monogenic IBD group(M-IBD)and a non-monogenic IBD group(NM-IBD).Forty age-matched patients with allergic proctocolitis(AP)were included in a control group.The clinical manifestations and the inflammatory factors in peripheral blood were evaluated.Logistic regression analysis and receiver operating characteristic(ROC)curve analysis were used to identify the screening factors and cut-off values of IO-IBD as well as monogenic IO-IBD,respectively.RESULTS Among the 44 M-IBD patients,35 carried IL-10RA mutations,and the most common mutations were c.301C>T(p.R101W,30/70)and the c.537G>A(p.T179T,17/70).Patients with higher serum tumor necrosis factor(TNF)-αvalue were more likely to have IBD[odds ratio(OR)=1.25,95%confidence interval(CI):1.05-1.50,P=0.013],while higher serum albumin level was associated with lower risk of IBD(OR=0.86,95%CI:0.74-1.00,P=0.048).The cut-off values of TNF-αand albumin were 17.40 pg/mL(sensitivity:0.78;specificity:0.88)and 36.50 g/L(sensitivity:0.80;specificity:0.90),respectively.The increased ferritin level was indicative of a genetic mutation in IO-IBD patients.Its cut-off value was 28.20 ng/mL(sensitivity:0.93;specificity:0.92).When interleukin(IL)-10 level was higher than 33.05 pg/mL(sensitivity:1.00;specificity:0.84),or the onset age was earlier than 0.21 mo(sensitivity:0.82;specificity:0.94),the presence of diseasecausing mutations in IL-10RA in IO-IBD patients was strongly suggested.CONCLUSION Serum TNF-αand albumin level could differentiate IO-IBD patients from allergic proctocolitis patients,and serum ferritin and IL-10 levels are useful indicators for early diagnosing monogenic IO-IBD.

Dose escalation of adalimumab as a strategy to overcome anti-drug antibodies:A case report of infantile-onset inflammatory bowel disease

BACKGROUND Treatment of infantile-onset inflammatory bowel disease(IO-IBD)is often challenging due to its aggressive disease course and failure of standard therapies with a need for biologics.Secondary loss of response is frequently caused by the production of anti-drug antibodies,a well-known problem in IBD patients on biologic treatment.We present a case of IO-IBD treated with therapeutic drug monitoring(TDM)-guided high-dose anti-tumor necrosis factor therapy,in which dose escalation monitoring was used as a strategy to overcome anti-drug antibodies.CASE SUMMARY A 5-mo-old boy presented with a history of persistent hematochezia from the 10th d of life,as well as relapsing perianal abscess and growth failure.Hypoalbuminemia,anemia,and elevated inflammatory markers were also present.Endoscopic assessment revealed skip lesions with deep colic ulcerations,inflammatory anal sub-stenosis,and deep fissures with persistent abscess.A diagnosis of IO-IBD Crohn-like was made.The patient was initially treated with oral steroids and fistulotomy.After the perianal abscess healed,adalimumab(ADA)was administered with concomitant gradual tapering of steroids.Clinical and biochemical steroid-free remission was achieved with good trough levels.After 3 mo,antibodies to ADA(ATA)were found with undetectable trough levels;therefore,we optimized the therapy schedule,first administering 10 mg weekly and subsequently up to 20 mg weekly(2.8 mg/kg/dose).After 2 mo of high-dose treatment,ATA disappeared,with concomitant high trough levels and stable clinical and biochemical remission of the disease.CONCLUSION TDM-guided high-dose ADA treatment as a monotherapy overcame ATA production.This strategy could be a good alternative to combination therapy,especially in very young patients.

High Prevalence of Genetic Alterations in Infantile-Onset Cardiomyopathy

Background and Method:The genetic cause of infantile-onset cardiomyopathy is rarely investigated.Here,we conducted whole exome sequencing(WES)and mitochondrial DNA(mtDNA)sequencing in eight patients with infantile-onset cardiomyopathy to identify genetic variations.Result:Among these patients,two(25%)had dilated cardiomyopathy(DCMP),two(25%)had left ventricular non-compaction(LVNC),and four(50%)had hypertrophic cardiomyopathy(HCMP).Except four patients identified prenatally,the remaining patients presented at a median age of 85.5 days.WES identified genetic variants in a total of seven(87.5%)patients and mtDNA sequencing in the other case.TPM1 and MYH7 variants were identified in the two patients with DCMP;MYH11 and MYLK2 variants in the two patients with LVNC;HRAS,BRAF,and MYH7 variants in three patients with HCMP;and MT-ND1 variant in one patient with HCMP having high blood lactic acid levels.Among the eight variants,four were classified as pathogenic or likely-pathogenic according to the American College of Medical Genetics(ACMG)guidelines,and the remaining were identified as variants of unknown significance(VUSs).Three pathogenic mutations were de novo,whereas four(likely-pathogenic or VUSs)were inherited from a respective parent,excluding one variant where parental testing was unavailable,questioning whether these inherited variants are disease-causing.Three patients died before 3 months of age.Conclusion:Genomic studies,such as WES with additional mtDNA sequencing,can identify a genetic variant in high proportions of patients with infantile-onset cardiomyopathy.The clinical implication of the parentally inherited variant needs to be assessed in a larger patient and family cohort with a longitudinal follow-up.

Atypical infantile-onset Pompe disease with good prognosis from China's Mainland:A case report

BACKGROUND Pompe disease has a broad disease spectrum,including infantile-onset Pompe disease(IOPD)and late-onset Pompe disease(LOPD)forms.It is a type of glycogen storage disorder belonging to autosomal recessive genetic disease,for an estimated incidence of 1/40000 among the neonatal population.In severe cases,the natural course is characterized by death due to cardiopulmonary failure in the first year after birth.However,the clinical outcomes have improved since the emergence of enzyme replacement therapy(ERT)was widely used.CASE SUMMARY The reported female case in China was an atypical IOPD,which demonstrates an unusual presentation of glycogen accumulation syndrome typeⅡwithout obvious skeletal muscle involvement,and reviewed physical examination,biochemical examinations,chest radiograph,and acidα-glucosidase(GAA)mutation analysis.After 4-mo specific ERT,the case received 12-mo follow-up.Moreover,the patient has obtained a very good prognosis under ERT.CONCLUSION For the atypical IOPD patients,early diagnosis and treatment may contribute to good prognosis.