Untargeted Maternal Plasma Metabolomics in Hirschsprung Disease: A Pilot Study.

Background and Aims: Hirschsprung disease (HSCR) is a congenital disorder of unknown etiology affecting the enteric nervous system (ENS). Since the early gestational development of the ENS is dependent on the prenatal maternal metabolic environment, the objective of this pilot study was to explore the role of specific maternal plasma metabolites in the etiology of HSCR. Methods: In this cross-sectional study, postnatal (as a surrogate for prenatal) plasma samples were obtained from mothers of children diagnosed with HSCR (n = 7) and age-matched mothers of normal children (n = 6). The plasma metabolome was analyzed by ultra-high-pressure liquid chromatography and mass spectrometry. Metabolites were identified by mzCloud using Compound Discoverer software. Using an untargeted metabolomics workflow, metabolites with case versus control group differences were identified. Results: A total of 268 unique plasma metabolites were identified and annotated in maternal plasma. Of these, 57 were significantly different between case and control groups (P < 0.05, t-test). Using a false discovery rate corrected cutoff of 10% to adjust for multiple comparisons, 19 metabolites were significantly different in HSCR cases, including carnitines, medium-chain fatty acids, and glutamic acid. Pathways affected were for amino acid and lipid metabolism. Conclusion: Disordered prenatal metabolic pathways may be involved in the etiopathogenesis of HSCR in the developing fetus. This is the first study to assess maternal plasma metabolomics in HSCR.

Maternal Vitamin A Status as a Risk Factor of Hirschsprung Disease in the Child.

INTRODUCTION: The gene-environment interaction of the REarranged during Transfection ( RET ) gene with vitamin A in the etiopathogenesis of Hirschsprung disease (HSCR) has been suggested in rodents. The aim of this study was to evaluate vitamin A status in mothers of children with HSCR and to assess its association with pathogenic variants of the RET gene in affected children. METHODS: This was a case-control study of stable isotope-based vitamin A measurement stores of mothers of children diagnosed with HSCR (within 8 months from birth, n = 7) and age-matched mothers of normal children (n = 6). Next-generation sequencing of RET exons, along with their upstream promoter region, was performed in the 7 HSCR proband-parent triads to evaluate pathogenic variants. RESULTS: Maternal vitamin A stores in the HSCR group was almost 50% that of those in controls, tending toward significance (0.50 ± 0.17 vs 0.89 ± 0.51 µmol/g respectively, P = 0.079). Two novel pathogenic de novo mutations were identified in 2 cases, and a rare single-nucleotide deletion was detected in the 3.5-kb RET upstream region, in a heterozygous state, in all 7 proband-parent triads. Low-penetrance RET haplotypes associated with HSCR were detected in 5 cases. DISCUSSION: Mothers with children with HSCR had lower vitamin A liver stores than mothers with normal children, and the children who were affected had HSCR despite having no established pathogenic RET variants. Lower maternal vitamin A status may increase the penetrance of genetic mutations in RET , and vitamin-A mediated gene-environment interactions may underpin some of the etiology of HSCR.

Antenatal urolithiasis: A case report.

Introduction: Although pediatric urolithiasis is an established entity, its antenatal diagnosis is rare. We hereby report a case detected at 20 weeks gestation and discuss the etiopathogenesis, predisposition, and surveillance following intervention. Case report: A 2-year-old girl with left renal pelvic calculus detected antenatally at 20 weeks was evaluated. Left hydronephrosis, obstructive pelvic calculus with a decrease in differential renal function on ethylene dicysteine (EC) renogram was confirmed. The metabolic workup was normal. Following stone extraction by left pyelolithotomy, a left ureteropelvic junction obstruction secondary to a mucosal valve was apparent which was excised and left pyeloplasty was done. Stone analysis revealed 100% cystine. Differential renal function and drainage improved post-surgery. The child, however, did not have a follow-up in the interim and presented with a recurrent stone one and a half years later. Conclusion: Knowledge of antenatal urolithiasis ensures continued follow-up, evaluation for metabolic disorders, and associated structural defects, especially with increasing stone size and increasing hydronephrosis. This helps in timely intervention and continued surveillance.

Pelviureteric Junction Obstruction Due to Vascular Anomalies in Children - Simple Surgical Options.

Aims: Pelviureteric junction obstruction (PUJO) due to aberrant lower polar artery is conventionally managed with pyeloplasty. We present our experience of managing PUJO due to "vascular" anomalies-aberrant lower polar artery and vascular adhesions with simpler surgical options. Subjects and Methods: This is a protocol based, retrospective study of PUJO. Preoperative investigations included ultrasonography (USG) and diuretic renogram. An intraoperative methylene blue test (MBT) assessed transit across the Pelviureteric junction (PUJ) after release of vascular compression. Surgical management included adhesiolysis for vascular adhesions and pyelopyelostomy anterior to the aberrant polar artery. Postoperative studies were repeated after 3 and 6 months. Results: Fourteen of 144 PUJO (9.7%) were "vascular" obstructions. Those with vascular adhesions (six) were largely infants with antenatal hydronephrosis. Children with aberrant lower polar artery (eight) were older, had fleeting symptoms, minimally increased pelvic diameter and subtle impairment on diuretic renogram. Majority were term males with urinary tract infection. The MBT showed normal transit across the PUJ in all. Postoperatively, there was progressive improvement on USG and diuretic renogram after 3 and 6 months. None had any complication or redosurgeries. At a mean follow-up of 41.2 months, all are asymptomatic. Conclusions: PUJO due to extrinsic vascular anomalies is rare. Intraoperative evaluation with the MBT ruled out associated intrinsic pathology. We describe two simple surgical alternatives preserving the normal PUJ - adhesiolysis for vascular adhesions and pyelopyelostomy for aberrant lower polar artery. The preliminary outcomes are comparable to conventional pyeloplasty.

Effects of oxybutynin in children with posterior urethral valves post fulguration: Report in a select cohort of children.

OBJECTIVES: Posterior urethral valves (PUV) is the commonest obstructive uropathy with varied consequences. Though valve fulguration is the treatment of choice, appropriate bladder management modifies outcome and includes rational use of anticholinergics. Here, we aim to evaluate the effects of oxybutynin on the bladder and urinary tract morphology and function. Concurrently, we document adverse effects encountered, patient compliance, and medication adherence. METHODS: A retrospective study of children below 5 years of age (2012-2017) post fulguration and on oxybutynin for at least 6 months. Patient demographics, clinical features, renal ultrasound, micturating cystourethrogram, dimercaptosuccinic acid scan, adverse effects, and pill count for medication adherence were collated. RESULTS: 48 children below the age of 5 years were included, and 12 were excluded either due to the presence of concomitant problems or were not on oxybutynin. Of the 36, four were lost to follow-up and one had died due to an unrelated condition. Thus, a total of 31 children were analyzed. At follow-up, 28/31 patients were asymptomatic, two had daytime incontinence, and one had recurrent urinary tract infection. All patients except one have preserved renal function tests. On ultrasonography, hydroureteronephrosis worsened in only 1/25 children and two showed significant post void residues. The resolution of vesicoureteral reflux was noted in almost 50%. 4/31 renal units had progressive scars. Only two parents defaulted medication. Urodynamic study done in half of these children showed stable bladder pressures except in two. CONCLUSION: Oxybutynin therapy following adequate valve fulguration aids upper tracts preservation by stabilizing deranged bladder dynamics. The medication is well tolerated with minimal or no side effects.

Multiple Atypical Esophageal Foreign Bodies in an Infant.

Foreign body ingestion is a common accidental emergency in children. We report an unusual case of multiple blunt and sharp esophageal foreign bodies in a female infant probably associated with homicidal intent and its management.

Infantile pulmonary tuberculosis: the great mimic.

PURPOSE: Infantile tuberculosis is common in developing countries and rarely presents as space occupying thoracic lesions mimicking congenital malformations. This case series reviews four such infants with varied presentations and their outcome. METHODS: Four cases of infantile pulmonary/mediastinal tuberculosis that presented like congenital thoracic lesions are described. Details of demography, symptomatology, contact history, immunization status, provisional diagnosis, tuberculin testing, imaging, histopathology, final diagnosis, management and outcome were retrospectively collated and analyzed. RESULTS: They were 4-6-month males, term-born and immunized. They presented with pneumonia/hyperactive airway disease since 2-12 weeks. One had a suspect and another a close tuberculous contact. The provisional diagnosis after imaging were infected congenital lung cyst, posterior mediastinal cyst and bronchopulmonary malformation. Two were tuberculin positive; none had gastric acid-fast bacilli. One underwent a pulmonary lobectomy for necrotic lung cyst; the second had a biopsy and drainage of a posterior mediastinal cyst that contained caseating material and was densely adherent to the esophagus. Surgical biopsy showed necrotizing granulomatous inflammation in both; one with acid-fast bacilli. Both succumbed to postoperative complications. The other two with tuberculous contacts who were managed with early antituberculous therapy, responded well and recovered uneventfully. CONCLUSIONS: Infantile pulmonary/mediastinal tuberculosis may mimic congenital thoracic malformations. A review of contact history, investigations and imaging help to establish the tuberculous etiology, avoids surgical misadventures and prompts early antituberculous therapy to achieve a favorable outcome.