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In industrialised areas of Europe, North America, Australia and New Zealand, vitamin B12 deficiency during infancy is thought to be uncommon and the majority of reported cases are in exclusively breastfed infants of mothers consuming vegetarian or vegan diets. We describe a breastfed infant whose mother eats a very diverse diet who developed growth failure, refusal to wean from the breast or eat solid foods and irritability as a result of profound vitamin B12 deficiency caused by unrecognised maternal vitamin B12 deficiency likely secondary to asymptomatic atrophic gastritis and pernicious anaemia. Recent literature suggests vitamin B12 deficiency in breastfed infants is much more common than previously recognised and this case emphasises the importance of considering the possibility of vitamin B12 deficiency in any breastfed infant with poor growth, neurologic symptoms or signs, developmental delay and/or feeding difficulties, particularly difficulty with introduction of complementary foods or weaning from the breast.

Sodium is an essential nutrient and inadequate sodium intake and/or excessive sodium losses can result in suboptimal growth. Infants with ileostomies are at significant risk of developing growth failure as a result of excessive sodium loss in their ileostomy effluent. Chronic sodium depletion can also limit the kidney’s ability to excrete hydrogen and potassium ions, mimicking electrolyte abnormalities found in type 4 renal tubular acidosis. This report describes an infant with an ileostomy with severe growth failure, hyperkalaemia and metabolic acidosis—all of which promptly resolved with sodium supplementation.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Here, using whole-genome, exome and transcriptome sequencing of 2,754 childhood patients with ALL, we find that, despite a generally low mutation burden, ALL cases harbor a median of four putative somatic driver alterations per sample, with 376 putative driver genes identified varying in prevalence across ALL subtypes. Most samples harbor at least one rare gene alteration, including 70 putative cancer driver genes associated with ubiquitination, SUMOylation, noncoding transcripts and other functions. In hyperdiploid B-ALL, chromosomal gains are acquired early and synchronously before ultraviolet-induced mutation. By contrast, ultraviolet-induced mutations precede chromosomal gains in B-ALL cases with intrachromosomal amplification of chromosome 21. We also demonstrate the prognostic significance of genetic alterations within subtypes. Intriguingly, DUX4 - and KMT2A -rearranged subtypes separate into CEBPA/FLT3 - or NFATC4 -expressing subgroups with potential clinical implications. Together, these results deepen understanding of the ALL genomic landscape and associated outcomes. A genomic and transcriptomic analysis of 2,754 childhood acute lymphoblastic leukemias identifies 376 putative driver genes, and associations between disease subtypes and prognosis.

Chromosomal rearrangements are initiating events in acute lymphoblastic leukaemia (ALL). Here using RNA sequencing of 560 ALL cases, we identify rearrangements between MEF2D (myocyte enhancer factor 2D) and five genes ( BCL9 , CSF1R , DAZAP1 , HNRNPUL1 and SS18 ) in 22 B progenitor ALL (B-ALL) cases with a distinct gene expression profile, the most common of which is MEF2D-BCL9 . Examination of an extended cohort of 1,164 B-ALL cases identified 30 cases with MEF2D rearrangements, which include an additional fusion partner, FOXJ2 ; thus, MEF2D- rearranged cases comprise 5.3% of cases lacking recurring alterations. MEF2D- rearranged ALL is characterized by a distinct immunophenotype, DNA copy number alterations at the rearrangement sites, older diagnosis age and poor outcome. The rearrangements result in enhanced MEF2D transcriptional activity, lymphoid transformation, activation of HDAC9 expression and sensitive to histone deacetylase inhibitor treatment. Thus, MEF2D- rearranged ALL represents a distinct form of high-risk leukaemia, for which new therapeutic approaches should be considered. Acute lymphoblastic leukaemia is characterized by chromosomal rearrangements. Here, the authors carry out RNA-sequencing on a large cohort of patients and identify recurrent rearrangements of MEF2D , which lead to increased transcriptional activity of the gene, and cellular transformation in vitro .

Recent genomic studies have identified chromosomal rearrangements defining new subtypes of B-progenitor acute lymphoblastic leukemia (B-ALL), however many cases lack a known initiating genetic alteration. Using integrated genomic analysis of 1,988 childhood and adult cases, we describe a revised taxonomy of B-ALL incorporating 23 subtypes defined by chromosomal rearrangements, sequence mutations or heterogeneous genomic alterations, many of which show marked variation in prevalence according to age. Two subtypes have frequent alterations of the B lymphoid transcription-factor gene PAX5 . One, PAX5alt (7.4%), has diverse PAX5 alterations (rearrangements, intragenic amplifications or mutations); a second subtype is defined by PAX5 p.Pro80Arg and biallelic PAX5 alterations. We show that p.Pro80Arg impairs B lymphoid development and promotes the development of B-ALL with biallelic Pax5 alteration in vivo. These results demonstrate the utility of transcriptome sequencing to classify B-ALL and reinforce the central role of PAX5 as a checkpoint in B lymphoid maturation and leukemogenesis. Analysis of 1,988 cases of B-cell acute lymphoblastic leukemia characterizes 23 subtypes defined by genomic features and shows that two of the subtypes have frequent PAX5 alterations.