MPV17 mutation-related mitochondrial DNA depletion syndrome: A case series in infants.

MPV17 is a mitochondrial inner membrane protein, involved in transporting deoxynucleotides into the mitochondria. Pathogenic MPV17 mutations can cause mitochondrial deoxyribonucleic acid (DNA) depletion syndrome, which has a varied presentation with neurological, muscular and hepatic involvement. Presentation as liver failure is relatively uncommon. Here, we report four infants from four separate families with pathogenic, homozygous MPV17 mutations. All had predominant hepatic involvement with cholestasis, lactic acidosis and hypoketotic hypoglycemia. Three of them had presented with liver failure. Interestingly, one of them showed fluctuating liver functions, which worsened with infection and improved after aggressive treatment with antibiotics and supplements. Two of the four cases died in infancy, while the other two improved on conservative management with medium-chain triglyceride-based diet, vitamin supplements, co-enzyme Q and carnitine. The two surviving children are alive at 12 and 25 months of age with native liver with normal to mildly deranged liver function and no neurological dysfunction. Next-generation sequencing confirmed the diagnosis in all of our cases. One of the detected mutations, c.55delC (p.Gln19ArgfsTer3) is a novel pathogenic frameshift mutation, while another mutation c.388G>C (p.Ala130Pro), which was previously reported in Single Nucleotide Polymorphism Database in heterozygous form, is being predicted as likely pathogenic in our case series. We, therefore, propose mutation testing for MPV17 gene during evaluation of indeterminate infantile liver failure, especially those with hypoglycemia and raised plasma lactate.

Efficacy and Predictors of Pain Response to Combined Antioxidants in Children with Chronic Pancreatitis.

BACKGROUND: Pain is a major problem in 90% of patients with chronic pancreatitis (CP). Studies evaluating response to antioxidants (AO) are conflicting and no pediatric studies are available. AIMS: To evaluate markers of oxidative stress (OS), and efficacy and predictors of response to AO in improving pain in children with CP. METHODS: Antioxidants were given to CP children for 6 months. Subjects were assessed at baseline and post-therapy for pain and markers of OS [serum thiobarbituric acid reactive substances (TBARS), superoxide dismutase (S-SOD)] and antioxidant levels [vitamin C, selenium, total antioxidant capacity-ferric reducing ability of plasma (FRAP)]. Matched healthy controls were assessed for OS and antioxidant levels. Good response was defined as ≥ 50% reduction in number of painful days/month. RESULTS: 48 CP children (25 boys, age 13 years) and 14 controls were enrolled. 38/48 cases completed 6 months of therapy. CP cases had higher OS [TBARS (7.8 vs 5.2 nmol/mL; p < 0.001)] and lower antioxidant levels [FRAP (231 vs. 381.3 µmol/L; p = 0.003), vitamin C (0.646 vs. 0.780 mg/dL; p < 0.001)] than controls. Significant reduction in TBARS and S-SOD and increase in FRAP, vitamin C, and selenium occurred after 6 months. 10.5% cases had minor side effects. 26(68%) cases had a good response, with 9(24%) becoming pain-free. Subjects with severe ductal changes had lower median BMI (- 0.73 vs 0.10; p = 0.04) and responded less often than those with mild changes (17/29 vs 9/9; p = 0.036). CONCLUSION: CP children have higher OS than healthy controls. Antioxidant therapy is safe. Pain response is seen in 68% cases, less often in patients with severe ductal changes.

Effect of chelation therapy in pediatric Wilson's disease: Liver and endoscopic outcome.

BACKGROUND: As there is paucity of exclusive literature on pediatric hepatic Wilson's disease (WD), this study was undertaken to evaluate the efficacy of chelation on hepatocellular function and portal hypertension in WD. METHODS: Wilson's disease patients with ≥9 months of follow-up were evaluated for response to chelation therapy in the following categories: (a) complete remission, (b) partial remission (c) progression of disease; (d) drug toxicity. Pediatric end-stage liver disease (PELD), Nazar and New Wilson Index scores were compared. Hemodynamically stable patients underwent esophagogastroduodenoscopy (baseline and surveillance) and received prophylaxis (primary or secondary). Endoscopic outcome was assessed at follow-up. RESULTS: Of the 111 WD children (aged 9 [3-15] years; PELD score 16 [-11 to 60]), 65 with follow-up of 3.6 (0.8-12) years on chelation (83% D-penicillamine monotherapy, 17% D-penicillamine and zinc) were analyzed. 81% had severe disease at presentation. Favorable outcome (complete and or partial remission), progression of disease and drug toxicity were seen in 71%, 29% and 10.8%, respectively. Two-thirds had esophageal varices which did not show progression. Large esophageal varices (16%) were effectively downgraded in 3 (2-6) therapeutic endoscopic sessions. Nazar score and PELD score at baseline were independent predictors of outcome with favorable correlation with each other (r = .864, P < .001). PELD cutoff 9.45 (AUC: 71%, sensitivity: 87%, specificity: 50%; P = .009) and Nazar score cut off 3.5 (AUC: 68%, sensitivity: 83%, specificity: 50%; P = .02) were associated with poor prognosis. CONCLUSIONS: Despite severe liver disease, the majority of hepatic WD can be managed on D-penicillamine monotherapy. PELD score and Nazar score effectively determine the outcome.

Chronic vomiting in children: A prospective study reveals rumination syndrome is an important etiology that is underdiagnosed and untreated.

BACKGROUND: The diagnosis of rumination syndrome is frequently overlooked, and under-recognized; children are subjected to unnecessary testing and inappropriate treatment for a condition which can be diagnosed clinically and managed easily. In the first ever systematic exploration of this condition from India, we present a prospective study on children with chronic vomiting in which rumination emerged as the predominant cause. METHODS: This was a prospective study in which all consecutive children (5-18 years) presenting with chronic or recurrent vomiting of at least 2-month duration were enrolled. Clinical history was assessed by a physician-administered questionnaire. All subjects underwent standard testing followed by additional investigations as required. The ROME III criteria were used. RESULTS: Fifty children (28 boys, age 12.2 + 3 years) were enrolled. Diagnosis was rumination syndrome 30, cyclical vomiting 8, functional vomiting 6, intestinal tuberculosis 4, intestinal malrotation 1, and superior mesenteric artery syndrome 1. Children with rumination syndrome had a relapsing and remitting (12, 40%) or a chronically symptomatic course (18, 60%). These children received incorrect diagnoses (26, 87%) or no diagnosis (3, 10%) and extensive investigation before referral. Before referral, children with rumination syndrome were treated with a median of four drugs (range 1 to 9); two underwent surgery (appendectomy) for their symptoms while one child was subjected to electroconvulsive therapy. Overall, resolution after treatment was seen in 26 (87%) with a relapse in 8 (27%) children. CONCLUSION: The diagnosis of rumination syndrome is delayed and these children are often inappropriately treated. Therapy in the form of diaphragmatic breathing has a good success rate.

Solitary Rectal Ulcer Syndrome in Children: A Report of 140 Cases.

OBJECTIVES: Solitary rectal ulcer syndrome (SRUS) is said to be rare in children (largest series so far; 55 in children, 116 in adults). We analyzed our experience to look at its clinical presentations, endoscopic appearance, and treatment outcome in a large cohort of children. METHODS: Clinical and endoscopic data were collected between 2000 and 2018. Children (18 years or younger) diagnosed to have SRUS on colonoscopy and confirmed by histopathology were included. All children with SRUS were treated with behavioral modification, bulk laxative. Most with ulcer received steroid enema and some sulfasalazine or sucralfate enema. RESULTS: The median age of 140 children was 12 (interquartile range [IQR]: 10-14) years, 79% were boys. The median symptom duration was 21 (IQR: 9-36) months. Rectal bleeding was the presenting feature in 131 (93.6%); constipation in 38 (27%); and small, frequent stools in 79 (56%). Most children had features of dyssynergic defecation such as prolonged sitting in the toilet (131, 93.6%), excessive straining (138, 98.6%), a feeling of incomplete evacuation (130, 92.8%), and rectal digitation (71, 50.7%). Rectal prolapse was noted in 24 (17%) cases. Colonoscopy documented rectal ulcer in 101 (72%) [Single: 84]. Over a median follow-up of 6 (IQR: 4-18) months, 27 patients were lost to follow-up and of the remaining 113 cases, 71 (62.8%) showed clinical improvement (healing of ulcer documented in 36/82, 44%). CONCLUSIONS: The majority of cases of SRUS presented in second decade with rectal bleeding and features of dyssynergic defecation. Ulcer was noted in three fourths of cases. The outcome of medical treatment with behavioral modification and local therapy was modest.

Infant with hepatomegaly and hypoglycemia: A setting for fatty acid oxidation defects.

Fatty acid oxidation defects (FAOD) are one of the commonest metabolic liver diseases (MLDs) that can have varied presentations in different age groups. An infant presented with short history of jaundice and irritability, examination showed soft hepatomegaly. Investigations revealed non-ketotic hypoglycemia suggesting FAOD which was later confirmed as carnitine uptake defect with gas chromatography and mass spectrometry and mutation analysis. Patient improved with acute management of metabolic crisis, carnitine supplementation and corn starch therapy with reversal of encephalopathy, reduction in hepatomegaly, maintenance of euglycemia and improvement in liver function tests and creatine phosphokinase on follow up. Non-ketotic hypoglycemia is a characteristic finding in FAODs. Early diagnosis and appropriate management can result in excellent outcomes in patients with FAODs.

Approach to Constipation in Children.

PURPOSE: There is a scarcity of literature, and prevalent misconceptions about constipation in India. METHODS: A literature search in PubMed was conducted with regard to epidemiology, clinical features, and management of constipation. Special emphasis was paid to functional constipation and refractory constipation. English language studies available full text over the last 25 years were considered and relevant information was extracted. CONCLUSIONS: Estimated prevalence of constipation is 3% among toddlers and pre-school children worldwide and 95%, of them are considered functional. A careful history and thorough physical examination is all that is required to diagnose functional constipation. Management includes disimpaction followed by maintenance therapy with oral laxative, dietary modification and toilet training. A close and regular follow-up is necessary for successful treatment. In most of the cases laxative needs to be continued for several months and sometimes years. Early withdrawal of laxative is the commonest cause of recurrence. Refractory constipation is less common in primary care set up. Radiological colon transit study is useful in picking up Slow transit constipation. Antegrade continence enema plays an important role in the management of slow transit constipation.

Refeeding syndrome in children in developing countries who have celiac disease.

OBJECTIVES: The clinical presentations of celiac crisis and refeeding syndrome in celiac disease are almost similar, but information about refeeding syndrome is scarce. We are reporting for the first time 5 cases of refeeding syndrome in children with celiac disease that could have otherwise been labeled as celiac crisis. METHODS: From January to December 2010, a chart review of hospital records of all celiac disease cases was performed, and refeeding syndrome was ascribed in those celiac patients who deteriorated clinically after initiation of a gluten-free diet and had biochemical parameters suggestive of refeeding syndrome such as hypophosphatemia, hypokalemia, hypocalcemia, and hypoalbuminemia. RESULTS: Of the total 35 celiac disease patients, 5 (median age 6.5 [range 2.2-10] years, 3 boys) were identified as having refeeding syndrome. All 5 children were severely malnourished (body mass index <14 kg/m) and all of them had anemia, hypophosphatemia, hypokalemia, hypoalbuminemia, and hypocalcemia, meaning that they had the perfect setting for developing refeeding syndrome. At the same time, their clinical features fulfilled the criteria for celiac crisis except that their symptoms have worsened after the introduction of a gluten-free diet. Nevertheless, instead of using steroids, they were managed as refeeding syndrome in terms of correction of electrolytes and gradual feeding, and that led to a successful outcome in all of them. CONCLUSIONS: Severely malnourished patients with celiac disease are at risk of developing potentially life-threatening refeeding syndrome, which may mimic celiac crisis, especially in developing countries. Early recognition and appropriate treatment are the keys to a successful outcome.