Paediatric Gastrointestinal, Hepatic and Pancreatic Inflammatory Myofibroblastic Tumours, A Single Centre Experience.

ABSTRACT: Inflammatory myofibroblastic tumours (IMTs) are rare soft tissue tumours. Reports of gastrointestinal tract, liver and pancreas tumours are limited. The objective of this study is to identify presenting features, contributing prognostic / etiological factors and any variability in outcomes in the context of different historical treatments. We retrospectively reviewed the records of seven children treated at our hospital between 2006 and 2019 and assessed the demographic, presentation, treatment, immunohistochemistry, and outcomes of their tumours. Age range at presentation was 4 months-15 years with a male predominance. Presentations were typically due to local mass effect or incidental discovery. Systemic symptoms were rare. Outcomes were good with six out of seven stable or in remission irrespective of treatment. Surgical resection where possible is the treatment of choice. Medical therapy had good outcomes with chemotherapy acting as first line treatment when required. The only negative prognostic factor identified was local spread at the time of presentation.

Paternal mosaicism for a novel PBX1 mutation associated with recurrent perinatal death: Phenotypic expansion of the PBX1-related syndrome.

Autosomal dominant (de novo) mutations in PBX1 are known to cause congenital abnormalities of the kidney and urinary tract (CAKUT), with or without extra-renal abnormalities. Using trio exome sequencing, we identified a PBX1 p.(Arg107Trp) mutation in a deceased one-day-old neonate presenting with CAKUT, asplenia, and severe bilateral diaphragmatic thinning and eventration. Further investigation by droplet digital PCR revealed that the mutation had occurred post-zygotically in the father, with different variant allele frequencies of the mosaic PBX1 mutation in blood (10%) and sperm (20%). Interestingly, the father had subclinical hydronephrosis in childhood. With an expected recurrence risk of one in five, chorionic villus sampling and prenatal diagnosis for the PBX1 mutation identified recurrence in a subsequent pregnancy. The family opted to continue the pregnancy and the second affected sibling was stillborn at 35 weeks, presenting with similar severe bilateral diaphragmatic eventration, microsplenia, and complete sex reversal (46, XY female). This study highlights the importance of follow-up studies for presumed de novo and low-level mosaic variants and broadens the phenotypic spectrum of developmental abnormalities caused by PBX1 mutations.

Genomic autopsy to identify underlying causes of pregnancy loss and perinatal death.

Pregnancy loss and perinatal death are devastating events for families. We assessed 'genomic autopsy' as an adjunct to standard autopsy for 200 families who had experienced fetal or newborn death, providing a definitive or candidate genetic diagnosis in 105 families. Our cohort provides evidence of severe atypical in utero presentations of known genetic disorders and identifies novel phenotypes and disease genes. Inheritance of 42% of definitive diagnoses were either autosomal recessive (30.8%), X-linked recessive (3.8%) or autosomal dominant (excluding de novos, 7.7%), with risk of recurrence in future pregnancies. We report that at least ten families (5%) used their diagnosis for preimplantation (5) or prenatal diagnosis (5) of 12 pregnancies. We emphasize the clinical importance of genomic investigations of pregnancy loss and perinatal death, with short turnaround times for diagnostic reporting and followed by systematic research follow-up investigations. This approach has the potential to enable accurate counseling for future pregnancies.

Compound heterozygous variants in LAMC3 in association with posterior periventricular nodular heterotopia.

BACKGROUND: Periventricular nodular heterotopia (PNH) is a malformation of cortical development characterized by nodules of abnormally migrated neurons. The cause of posteriorly placed PNH is not well characterised and we present a case that provides insights into the cause of posterior PNH. CASE PRESENTATION: We report a fetus with extensive posterior PNH in association with biallelic variants in LAMC3. LAMC3 mutations have previously been shown to cause polymicrogyria and pachygyria in the occipital cortex, but not PNH. The occipital location of PNH in our case and the proposed function of LAMC3 in cortical development suggest that the identified LAMC3 variants may be causal of PNH in this fetus. CONCLUSION: We hypothesise that this finding extends the cortical phenotype associated with LAMC3 and provides valuable insight into genetic cause of posterior PNH.

Zinc homeostasis and gut function in children with celiac disease.

BACKGROUND: Celiac disease (CD) is an immunologic enteropathy triggered by the intake of gluten. It is thought that the enteropathy impairs gut function and absorption. OBJECTIVE: We assessed the zinc-absorption capacity and small-bowel integrity in children with CD. DESIGN: Children in whom a diagnosis of CD was considered clinically and either confirmed (n = 16; Marsh score ≥3) or not (n = 22; Marsh score of 0) with a small-bowel biopsy (SBB) were recruited. The fractional absorption of zinc (FAZ) was determined by the administration of an oral (67)Zn dose (2.5 mg) and an intravenous (70)Zn dose (0.2 mg) 2 h before and during the SBB, respectively. Spot urine samples were collected, and zinc isotopic ratios were determined by ion-coupled plasma mass spectrometry. Gut health was assessed by the ingestion of (13)C-sucrose (20 g) after an overnight fast, and breath samples were collected and analyzed by isotope ratio mass spectrometry. RESULTS: There was no difference in FAZ between children with a Marsh score ≥3 (mean ± SEM: 0.68 ± 0.05) and children with a Marsh score of 0 (0.74 ± 0.05). The exchangeable zinc pool (EZP) was significantly (P < 0.05) lower in children with a Marsh score ≥3 (2.6 ± 0.8 mg/kg) than in children with a Marsh score of 0 (3.8 ± 1.4 mg/kg). Gut function in children with a Marsh score ≥3 (4.5 ± 0.7% cumulative dose recovered at 90 min) was lower than the lower cutoff of a normal gut-function breath test (5.06% cumulative dose recovered at 90 min) but not significantly different from that in children with a Marsh score of 0 (4.9 ± 0.4%). There was a significant (P < 0.01) correlation between zinc absorption and gut function in children with CD. CONCLUSIONS: Zinc absorption did not appear below usual amounts in subjects with CD. Children with CD have impaired gut function that may affect their zinc nutritional status as shown by a smaller EZP. However, the EZP decrease in children with CD was not compared with that in healthy control subjects, and its biological meaning is uncertain.