Chromosome 20p11.2 deletions cause congenital hyperinsulinism via the loss of FOXA2 or its regulatory elements.

Persistent congenital hyperinsulinism (HI) is a rare genetically heterogeneous condition characterised by dysregulated insulin secretion leading to life-threatening hypoglycaemia. For up to 50% of affected individuals screening of the known HI genes does not identify a disease-causing variant. Large deletions have previously been used to identify novel regulatory regions causing HI. Here, we used genome sequencing to search for novel large (>1 Mb) deletions in 180 probands with HI of unknown cause and replicated our findings in a large cohort of 883 genetically unsolved individuals with HI using off-target copy number variant calling from targeted gene panels. We identified overlapping heterozygous deletions in five individuals (range 3-8 Mb) spanning chromosome 20p11.2. The pancreatic beta-cell transcription factor gene, FOXA2, a known cause of HI was deleted in two of the five individuals. In the remaining three, we found a minimal deleted region of 2.4 Mb adjacent to FOXA2 that encompasses multiple non-coding regulatory elements that are in conformational contact with FOXA2. Our data suggests that the deletions in these three children may cause disease through the dysregulation of FOXA2 expression. These findings provide new insights into the regulation of FOXA2 in the beta-cell and confirm an aetiological role for chromosome 20p11.2 deletions in syndromic HI.

Periportal necrosis and successful liver transplantation following Lamotrigine drug-induced liver injury in a child.

Lamotrigine is one of the most prescribed antiepileptics in children and a well-known cause of drug-induced liver injury (DILI). The typical presentation usually includes a drug rash with eosinophilia and systemic symptoms (DRESS syndrome). Cases are typically mild and self-limiting, requiring supportive care only. We report a severe Lamotrigine-induced DILI with a non-typical presentation with hyperammonaemia and rapid clinical deterioration. We present a literature review exploring contributing factors, transplant considerations and liver histology. Histology showed periportal necrosis, which is recognised as a pattern of DILI but has not been previously described with Lamotrigine. Our patient proceeded to transplant and is the first reported liver transplant for Lamotrigine DILI in a child. A directed and rapid diagnostic approach is crucial to avoid delays and rule out multisystemic metabolic and genetic conditions that preclude liver transplantation.

Has the incidence of empyema in Scottish children continued to increase beyond 2005?

BACKGROUND: The incidence of empyema increased dramatically in children during the 1990s and early 2000s. We investigated the relationship between changes in the incidence of childhood empyema in Scotland following the 2006 introduction of routine heptavalent conjugate pneumococcal vaccination (PCv-7) and the 2010 introduction of the 13-valent (PCV-13) vaccine. METHODS: This was a whole-population study of Scottish hospital admissions between 1981 and 2013 using ICD (International Classification of Diseases)-9 and ICD-10 diagnostic codes for empyema. The number of admissions for pneumonia and croup was also captured to give insight into secular trends in admissions with other related and unrelated respiratory presentations. RESULTS: There were 217 admissions with empyema between 1981 and 2005 (mean incidence 9 cases/million/year) and 323 between 2006 and 2013 (mean incidence 47 cases/million/year), p<0.001. The introduction of conjugate vaccines in 2006 was associated with an overall increase in admissions for empyema of 2.0 (95% CI 1.4 to 2.8) per 100 000 children, however, the incidence rate ratio for empyema admission between 2010 and 2013 was lower relative to 2006-2009 (0.78 (95% CI 0.63 to 0.98)). Secular changes in pneumonia, but not croup, were comparable with those for empyema. CONCLUSIONS: The incidence of empyema in Scottish children initially rose in children aged 1 to 9 years after the introduction of routine conjugate pneumococcal vaccination, however, empyema incidence has fallen since 2010 when the PCV-13 was introduced.