Multi-disciplinary team approach for pediatric hemimegalencephaly: Insights from a single institutional case series.

Recent genetic studies have revealed that hemimegalencephaly (HME) is a multi-system disorder associated with germline or mosaic variants within the PI3K-mTOR-GATOR1 signaling pathways. Patients with HME typically develop drug-resistant epilepsy necessitating extensive evaluation, hemispherectomy, and long-term management. We describe the role of a multidisciplinary team (MDT) for the diagnosis and management of recent patients with HME at UCLA who underwent hemispherectomy.

The Structured Oral Examination: A Method to Improve Formative Assessment of Fellows in Pediatric Endocrinology.

Objective: A structured oral exam (SOE) can be utilized as a formative assessment to provide high-quality formative feedback to trainees, but has not been adequately studied in graduate medical education. We obtained fellow and faculty perspectives on: 1) educational effectiveness, 2) feasibility/acceptability, and 3) time/cost of a SOE for formative feedback.

Methods: Four pediatric endocrinology cases were developed and peer-reviewed to generate a SOE.

Minireview: mechanisms of growth hormone-mediated gene regulation.

GH exerts a diverse array of physiological actions that include prominent roles in growth and metabolism, with a major contribution via stimulating IGF-1 synthesis. GH achieves its effects by influencing gene expression profiles, and Igf1 is a key transcriptional target of GH signaling in liver and other tissues. This review examines the mechanisms of GH-mediated gene regulation that begin with signal transduction pathways activated downstream of the GH receptor and continue with chromatin events at target genes and additionally encompasses the topics of negative regulation and cross talk with other cellular inputs.

Towards identification of molecular mechanisms of short stature.

Growth evaluations are among the most common referrals to pediatric endocrinologists. Although a number of pathologies, both primary endocrine and non-endocrine, can present with short stature, an estimated 80% of evaluations fail to identify a clear etiology, leaving a default designation of idiopathic short stature (ISS). As a group, several features among children with ISS are suggestive of pathophysiology of the GH-IGF-1 axis, including low serum levels of IGF-1 despite normal GH secretion.

Hepatic-specific accessibility of Igf1 gene enhancers is independent of growth hormone signaling.

The diverse roles of IGF-1 in physiology include acting as the endocrine intermediate to elicit the anabolic actions of GH. The majority of serum IGF-1 is synthesized in liver, where GH stimulates Igf1 gene transcription via the transcription factor, signal transducer and activator of transcription (Stat)5b. We and others have identified multiple Stat5-binding domains at the Igf1 locus that function in gene regulation, but it remains unclear whether the roles of these domains are tissue specific.

Biochemical characterization of diverse Stat5b-binding enhancers that mediate growth hormone-activated insulin-like growth factor-I gene transcription.

Many of the biological effects of growth hormone (GH) are mediated by insulin-like growth factor I (IGF-I), a 70-amino acid secreted peptide whose gene expression is rapidly induced by GH via the Stat5b transcription factor. We previously identified multiple evolutionarily conserved GH-activated chromosomal binding domains for Stat5b within the rat Igf1 locus, and proposed that they could regulate IGF-I gene activity. Here we investigate the biochemical and functional characteristics of these putative long-range transcriptional enhancers.

Defining the epigenetic actions of growth hormone: acute chromatin changes accompany GH-activated gene transcription.

Many of the long-term physiological effects of GH require hormone-mediated changes in gene expression. The transcription factor signal transducer and activator of transcription 5b (Stat5b) plays a critical role in the actions of GH on growth and metabolism by regulating a large number of GH-dependent genes by incompletely understood mechanisms. Here we have assessed the impact of GH-initiated and Stat5b-mediated signaling on the chromatin landscape of hormone-regulated genes in the liver of pituitary-deficient young adult male rats.

Dispersed Chromosomal Stat5b-binding elements mediate growth hormone-activated insulin-like growth factor-I gene transcription.

The growth hormone (GH)-insulin-like growth factor-I (IGF-I) axis regulates somatic growth during childhood and orchestrates tissue repair throughout the life span. Recently described inactivating mutations in Stat5b in humans with impaired growth have focused attention on this transcription factor as a key agent linking GH-stimulated signals to IGF-I gene expression, and several putative Stat5b sites have been identified in the IGF-I gene. Here, we define and characterize potential GH- and Stat5b-activated chromosomal enhancers that can regulate IGF-I gene transcription.

Distinct alterations in chromatin organization of the two IGF-I promoters precede growth hormone-induced activation of IGF-I gene transcription.

Many of the physiological actions of GH are mediated by IGF-I, a secreted 70-residue peptide whose gene expression is induced by GH in the liver and other tissues via mechanisms that remain incompletely characterized but depend on the transcription factor Stat5b. Here we investigate the chromatin landscape of the IGF-I gene in the liver of pituitary-deficient young adult male rats and assess the impact of a single systemic GH injection. Despite minimal ongoing transcription in the absence of GH, both IGF-I promoters appear to reside in open chromatin environments, at least as inferred from relatively high levels of acetylation of core histones H3 and H4 when compared with adjacent intergenic DNA and from enhanced trimethylation of histone H3 at lysine 4.

Gene regulation by growth hormone.

Since the somatomedin hypothesis of growth hormone (GH) action was first formulated more than 50 years ago, the key roles of both GH and insulin-like growth factor-I (IGF-I) in human growth have been extended to include important effects on tissue maintenance and repair. More recent observations have revealed that this pathway has a negative side, as it has been implicated as a potential contributor to the development of several human cancers and has been linked to diminished lifespan in experimental animals. This brief review focuses on fundamental aspects of gene regulation by GH, as long-term hormonal effects all require changes in gene expression.

Signal transducer and activator of transcription (Stat) 5b-mediated inhibition of insulin-like growth factor binding protein-1 gene transcription: a mechanism for repression of gene expression by growth hormone.

GH plays a central role in controlling somatic growth, tissue regeneration, and intermediary metabolism in most vertebrate species through mechanisms dependent on the regulation of gene expression. Recent studies using transcript profiling have identified large cohorts of genes whose expression is induced by GH. Other results have demonstrated that signal transducer and activator of transcription (Stat) 5b, a latent transcription factor activated by the GH receptor-associated protein kinase, Jak2, is a key agent in the GH-stimulated gene activation that leads to somatic growth.

Childhood obesity and the metabolic syndrome.

The current epidemic of obesity reflects environmental changes that have an impact on a genetically susceptible population. The scope of obesity and its associated comorbidities warrants its position among the most crucial global public health problems faced today. Society has gained better appreciation for the significance of this problem yet still has much to learn regarding how best to address the obesity crisis.

In vivo transcript profiling and phylogenetic analysis identifies suppressor of cytokine signaling 2 as a direct signal transducer and activator of transcription 5b target in liver.

The GH-activated signal transducer and activator of transcription 5b (STAT5b) is an essential regulator of somatic growth. The transcriptional response to STAT5b in liver is poorly understood. We have combined microarray-based expression profiling and phylogenetic analysis of gene regulatory regions to study the interplay between STAT5b and GH in the regulation of hepatic gene expression.

Characterization of distinct Stat5b binding sites that mediate growth hormone-stimulated IGF-I gene transcription.

A key agent in the anabolic actions of growth hormone (GH) is insulin-like growth factor-I (IGF-I), a 70-amino acid secreted protein with direct effects on somatic growth and tissue maintenance and repair. GH rapidly and potently stimulates IGF-I gene transcription by mechanisms independent of new protein synthesis, and recent studies have linked the transcription factor Stat5b to a regulatory network connecting the activated GH receptor on the cell membrane to the IGF-I gene in the nucleus. Here we analyze two distinct conserved GH response elements in the rat IGF-I locus that contain paired Stat5b sites.

Aberrant folding of a mutant Stat5b causes growth hormone insensitivity and proteasomal dysfunction.

A predicted alanine to proline substitution in Stat5b that results in profound short stature, growth hormone insensitivity, and immunodeficiency represents the first natural mutation of this transcription factor in a human. To understand the mechanisms responsible for these pathophysiological abnormalities, we have studied the biochemical and biophysical properties of the mutant Stat5b molecule. In a cellular reconstitution model growth hormone robustly stimulated tyrosine phosphorylation and transcriptional activity of wild-type Stat5b while Stat5bA630P was minimally modified and did not promote reporter gene expression.

Molecular physiology, pathology, and regulation of the growth hormone/insulin-like growth factor-I system.

Since the somatomedin hypothesis of growth hormone (GH) action was first formulated nearly 50 years ago, the key roles of both GH and insulin-like growth factor (IGF)-I in human growth have been confirmed and extended to include local effects on tissue maintenance and repair. More recent insights have revealed a dark side to the GH/IGF-I signaling system. Both proteins have been implicated as potential contributing factors in selected human cancers, and normal activity through this signaling pathway has been linked to diminished lifespan in experimental animals.

Mechanisms of growth hormone (GH) action. Identification of conserved Stat5 binding sites that mediate GH-induced insulin-like growth factor-I gene activation.

Many of the actions of growth hormone (GH) on somatic growth and tissue maintenance are mediated by insulin-like growth factor-I (IGF-I), a secreted protein whose gene expression is rapidly and potently induced by GH by unknown mechanisms. Recent studies implicating Stat5a and Stat5b in the growth response to GH in mice and observations linking Stat5b to control of IGF-I gene transcription in rats have prompted the current investigations into the molecular determinants of a putative regulatory network extending from GH through Stat5b to IGF-I. Here we characterize as critical components of this hormone-activated transcriptional pathway two adjacent Stat5 binding sites in the second intron of the rat IGF-I gene located within a conserved region previously found to undergo acute and reversible changes in chromatin structure after in vivo GH treatment.