Enhancer redundancy provides phenotypic robustness in mammalian development.

Distant-acting tissue-specific enhancers, which regulate gene expression, vastly outnumber protein-coding genes in mammalian genomes, but the functional importance of this regulatory complexity remains unclear. Here we show that the pervasive presence of multiple enhancers with similar activities near the same gene confers phenotypic robustness to loss-of-function mutations in individual enhancers. We used genome editing to create 23 mouse deletion lines and inter-crosses, including both single and combinatorial enhancer deletions at seven distinct loci required for limb development. Unexpectedly, none of the ten deletions of individual enhancers caused noticeable changes in limb morphology. By contrast, the removal of pairs of limb enhancers near the same gene resulted in discernible phenotypes, indicating that enhancers function redundantly in establishing normal morphology. In a genetic background sensitized by reduced baseline expression of the target gene, even single enhancer deletions caused limb abnormalities, suggesting that functional redundancy is conferred by additive effects of enhancers on gene expression levels. A genome-wide analysis integrating epigenomic and transcriptomic data from 29 developmental mouse tissues revealed that mammalian genes are very commonly associated with multiple enhancers that have similar spatiotemporal activity. Systematic exploration of three representative developmental structures (limb, brain and heart) uncovered more than one thousand cases in which five or more enhancers with redundant activity patterns were found near the same gene. Together, our data indicate that enhancer redundancy is a remarkably widespread feature of mammalian genomes that provides an effective regulatory buffer to prevent deleterious phenotypic consequences upon the loss of individual enhancers.

Infant in extremis: respiratory failure secondary to lower airway infantile hemangioma.

BACKGROUND: Infantile hemangiomas (IHs) are vascular tumors that commonly affect infants and usually regress spontaneously or can be easily treated as an outpatient with topical beta-blockers. However, IHs that present in the airway may cause life-threatening symptoms due to airway obstruction or risk of bleeding. Here we present the first documented case of an infant with rapid deterioration and acute respiratory failure secondary to a lower airway hemangioma. CASE PRESENTATION: This 3-month-old male initially presented in respiratory distress with symptoms consistent with a viral respiratory infection, however showed no clinical improvement with standard therapies. An urgent CT scan revealed a mass occluding the right mainstem bronchus. Upon transfer to a tertiary care facility, he developed acute respiratory failure requiring emergent intubation and single lung ventilation. The availability of multiple subspecialists allowed for stabilization of a critically ill child, expedited diagnosis, and ultimately initiation of life-saving treatment with beta blockers. After 17 total hospital days, he was extubated successfully and discharged home in good condition. CONCLUSIONS: While IH is a rare cause of infantile respiratory distress, we present multiple pearls for the general pediatrician for management of IHs of the airway.

Multisystem Inflammatory Syndrome in Children.

Multisystem inflammatory disease in children (MIS-C) is a condition typically seen 3 to 6 weeks after acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Believed to be a postinfection hyperinflammatory response, the clinical manifestation of this viral sequelae can vary significantly in severity and symptomatic presentation. Clinical prodrome includes persistent fever and dysfunction of at least two organ systems. Often developing after asymptomatic or mildly symptomatic coronavirus disease 2019 (COVID-19) infection, MIS-C is a diagnosis of exclusion that requires evaluation for other infectious or noninfectious etiology for symptoms. Vital sign instability, including fever, tachycardia, and hypotension; laboratory studies demonstrating elevated inflammatory markers and elevated cardiac markers; and positive SARS-CoV-2 polymerase chain reaction, SARS-CoV-2 antibodies, or exposure to someone with confirmed COVID-19 infection 4 to 6 weeks before clinical presentation are used to diagnose this condition. Skin and mucosal involvement, gastrointestinal symptoms, and neurologic manifestations are also commonly seen. An echocardiogram is indicated to evaluate for cardiac dysfunction, including but not limited to coronary artery enlargement, left ventricular dysfunction, arrythmias, or atrioventricular block. [Pediatr Ann. 2023;52(3):e114-e121.].

Unique hepatic manifestations of COVID-19-induced immune dysregulation in children.

The two cases we present are the first to demonstrate novel manifestations of COVID-19 related interaction between the liver and the immune system in pediatric patients. Written informed consent was obtained from the parent/guardian to publish this report in accordance with the journal's patient consent policy.

Genome-wide fetalization of enhancer architecture in heart disease.

Heart disease is associated with re-expression of key transcription factors normally active only during prenatal development of the heart. However, the impact of this reactivation on the regulatory landscape in heart disease is unclear. Here, we use RNA-seq and ChIP-seq targeting a histone modification associated with active transcriptional enhancers to generate genome-wide enhancer maps from left ventricle tissue from up to 26 healthy controls, 18 individuals with idiopathic dilated cardiomyopathy (DCM), and five fetal hearts. Healthy individuals have a highly reproducible epigenomic landscape, consisting of more than 33,000 predicted heart enhancers. In contrast, we observe reproducible disease-associated changes in activity at 6,850 predicted heart enhancers. Combined analysis of adult and fetal samples reveals that the heart disease epigenome and transcriptome both acquire fetal-like characteristics, with 3,400 individual enhancers sharing fetal regulatory properties. We also provide a comprehensive data resource (http://heart.lbl.gov) for the mechanistic exploration of DCM etiology.

The effect of low magnitude mechanical stimulation (LMMS) on bone density in patients with Rett syndrome: a pilot and feasibility study.

PURPOSE: Low magnitude mechanical stimulation (LMMS) has been used successfully to promote bone formation in certain patient populations. This study evaluated the feasibility and effectiveness of LMMS on improving bone mineral density (BMD) in patients with Rett syndrome. METHODS: A 12-month crossover pilot study design of 6 months of intervention with LMMS and 6 months without was studied in 14 subjects divided in two subgroups. BMD was assessed using Dual Energy X-ray Absorptiometry (DXA). The levels of 25-hydroxy vitamin D (25OHD), Parathyroid Hormone (PTH), Insulin-Like Growth Factor 1 (IGF-1), and circulating markers of bone resorption (NTx) were analyzed in blood samples. Health questionnaires and diet logs were obtained at 0, 6, and 12 months. RESULTS: Of the 11 subjects who completed the protocol, 9 had an adherence of > 65% and showed an increase in spine BMD Z-scores from the intervention (Z: -2.51) compared to non-intervention period (Z: -2.27) of 0.23 SD (p=0.048). Following intervention, favorable trends were also observed for IGF-1 (p=0.06) and right distal femur BMD Z-scores (p=0.07). CONCLUSIONS: These preliminary results are promising for a larger, placebo-controlled randomized study of subjects with Rett syndrome.