Very early onset inflammatory bowel disease: Spectrum of clinical presentation, diagnostic tools and outcome in children.

OBJECTIVE: To explore the spectrum of presentation, underlying monogenetic defects and outcome in very early onset inflammatory bowel disease (VEO-IBD). METHOD: The prospective, observational study was conducted at the Children's Hospital, Lahore, Pakistan, from January 2017 to December 2018, and comprised children developing features of inflammatory bowel disease aged <6 years. Data included demography, clinical presentation, diagnostic tools and outcome. Data was analysed using SPSS 21. RESULTS: Of the 60 children with relevant symptoms, 26(43.3%) were diagnosed as having very early onset inflammatory bowel disease. Of them, 13(50%) had underlying monogenic defect, and 16(61.5%) had ulcerative colitis. There were 22(84.6%) males with median age of 1.5(11) months in monogenic inflammatory bowel disease versus 24(43) months for non-monogenic inflammatory bowel disease (p<0.05). In the monogenic group, isolated rectal bleeding was the major presentation 13(100%) versus non-monogenic who presented mainly with failure to thrive 13(100%). Upper and lower endoscopies with histopathology had good diagnostic yield and inflammatory infiltrates on the biopsied tissues were the major findings. Mutations detected among the subjects were XIAP, PRKDC, PIK3CD, RAG-1, LRBA, DOCK8, TTC7, MEFV and EPCAM. Mortality was significantly higher in the monogenic group 7(54%) than in the non-monogenic group 2(15%) (p<0.05). CONCLUSIONS: Very early onset inflammatory bowel disease should be suspected when conventional management fails to rectify common disease mimickers. Testing for underlying immunological defect and genetic mutation would be helpful for managing these rare disorders.

UGT1A1 gene mutations in Pakistani children suffering from inherited nonhemolytic unconjugated hyperbilirubinemias.

Two inherited unconjugated hyperbilirubinemias, Crigler-Najjar syndrome and Gilbert syndrome, arise due to deficiency of UGT1A1 enzyme activity. Crigler-Najjar syndrome type 1 (CN1) lies at the extreme severe end of the spectrum of UGT1A1 activity characterized by complete absence, followed by the less severe Crigler-Najjar syndrome type 2 (CN2). Gilbert syndrome is the mild form having only partial loss of UGT1A1 activity. The present study aimed to identify molecular genetic defects underlying unconjugated hyperbilirubinemias in children from six consanguineous Pakistani families. The patients were clinically diagnosed by exclusion of other unconjugated hyperbilirubinemias. Differential diagnosis of CN1 and CN2 was made on the basis of patient's response to phenobarbitone. The promoter region, coding exons, and adjacent splice sites of the UGT1A1 gene were PCR amplified from genomic DNA of all patients and their families, and were sequenced. DNA sequence analysis identified five different homozygous mutations: two novel missense mutations p.Y230C (proband A) and p.D36N (proband B), a 4-bp insertion c.622-625dupCAGC/p.Q208QfsX50 (probands C and E), a nonsense mutation p.R341X (proband D), and a TA insertion A(TA)7TAA in the promoter region (proband F). The present study extends the spectrum of UGT1A1 gene mutations and may be helpful in the diagnosis of Crigler-Najjar syndrome and Gilbert syndrome.

Clinical and Genetic Description of Hereditary Chronic Pancreatitis in Pakistani Children.

BACKGROUND/AIMS: The purpose of this study was to identify the spectrum and frequency of pathogenic variants as well as the clinical and genetic insight of hereditary chronic pancreatitis in Pakistani children. MATERIALS AND METHODS: The deoxyribonucleic acid of affected probands of 44 unrelated Pakistani families, having hereditary chronic pancreatitis-affected children, were subjected to massive parallel sequencing for candidate reported genes (SPINK1, PRSS1, CFTR, CPA1, CTRC, CBS, AGL, PHKB, and LPL). Data were analyzed using different bioinformatics tools for the variants and in-silico analysis. All the identified variants were validated by direct sequencing of the targeted exons in the probands and their parents. RESULTS: There were 50 patients included in this study with confirmed hereditary chronic pancreatitis. Nine known mutations in SPINK1, PRSS1, CFTR, CTRC, CBS, and AGL genes, and 10 novel variants in LPL, CFTR, CTR, and PHKB genes were identified. The identified variants were found in heterozygous, compound heterozygous, and trans-heterozygous forms, with rare allele frequency in the normal population. The novel variants were [c.378C>T(p.Lys126Asn) and c.719G>A(p.Arg240Gln) in CTRC, c.586-3C>A and c.763A>G(p.Arg255Gly) in CPA1, c.1160_1161insT(p.Lys387Asnfs*26), c.784C>T(p.Gln262*), c.1139+1G>A, c.175G>A(p.Gly59Arg) in LPL, c.388C>G(p.leu130val) in CFTR, and c.2327G>A(p.Arg776His in PHKB)]. The phenotypic characteristics were variable and correlated with the relevant variant. CONCLUSIONS: The genetic composition plays a significant role in the predisposition of hereditary chronic pancreatitis. The clinical presentation varies with the genetic determinant involved. This information would help in building up a diagnostic algorithm for our population that can be used for genetic screening services in affected cohorts.

Spectrum of Clinical Presentation of Celiac Disease in Pediatric Population.

Background Classic form of celiac disease (CCD) presents with diarrhea and is traditionally taught as malabsorption syndrome. This form of CD is diagnosed with ease but non-classical form presenting without diarrhea is often missed and heavily underdiagnosed. Objective To determine the clinical spectrum of patients with CD. Methods This study was conducted in the Department of Gastroenterology & Hepatology at the Children's Hospital, Lahore. Confirmed CD children according to NASPGHAN (North American Society of Pediatric Gastroenterology, Hepatology & Nutrition) criteria were enrolled in this study from June to September, 2020. Initial positivity followed by small bowel biopsy with Modified Marsh 2 and above is considered consistent with the diagnosis of CD. Results A total of 90 patients were selected according to NASPGHAN criteria, 77 (85.6%) patients had CCD whereas 13 (14.4%) patients had non-classical CD (NCCD). The mean ± SD age at diagnosis of CCD was 2.6 ± 2.3 years whereas mean ± SD in NCCD was 9 ± 1.8 years. Females clearly predominate in our cohort in general. Chronic diarrhea followed by failure to thrive (85%) were the most common symptoms in CCD whereas short stature (69%) was the most frequent feature in NCCD. Among CD patients, tissue transglutaminase-​immunoglobulin A (TTG-IgA) titre was significantly high (>10 times) in 80% of CD patients and the rest had positivity but not up to 10 times. There was no significant difference in titre of anti-TTG between CCD and NCCD. Conclusion Classical CD is still the most common in developing countries like Pakistan. High index of suspicion of CD should be maintained for patients who present with short stature, recurrent abdominal pain and refractory anemia.

Could It Be Schistosomiasis?

Schistosomiasis may cause diverse symptoms and it is usually not considered as a cause of disease especially in patients with normal immune system. We are reporting an eleven-year-old child who was initially diagnosed as a case of lymphoma but later on proved to be a case of acute schistosomiasis.

Vitamin D Intoxication In 7-Month-Old Infant With Recommended Daily Intake Of Vitamin D.

Over the past decade there is increased use of vitamin D supplementation because of its benefits on bone health. It is a fat-soluble vitamin and cannot be excreted from the body. There is need for monitoring 25-hydroxyvitamin D levels in infants and children who receive long-term vitamin D supplementation at or above the upper level intake that is currently recommended. Vitamin D intoxication can present from mild ignorable to severe life-threatening symptoms. We present a 7- month-old infant with vitamin D intoxication at recommended daily doses of vitamin D.