The Changing Face of Adrenoleukodystrophy.

Adrenoleukodystrophy (ALD) is a rare X-linked disorder of peroxisomal oxidation due to mutations in ABCD1. It is a progressive condition with a variable clinical spectrum that includes primary adrenal insufficiency, myelopathy, and cerebral ALD. Adrenal insufficiency affects over 80% of ALD patients. Cerebral ALD affects one-third of boys under the age of 12 and progresses to total disability and death without treatment. Hematopoietic stem cell transplantation (HSCT) remains the only disease-modifying therapy if completed in the early stages of cerebral ALD, but it does not affect the course of adrenal insufficiency. It has significant associated morbidity and mortality. A recent gene therapy clinical trial for ALD reported short-term MRI and neurological outcomes comparable to historical patients treated with HSCT without the associated adverse side effects. In addition, over a dozen states have started newborn screening (NBS) for ALD, with the number of states expecting to double in 2020. Genetic testing of NBS-positive neonates has identified novel variants of unknown significance, providing further opportunity for genetic characterization but also uncertainty in the monitoring and therapy of subclinical and/or mild adrenal insufficiency or cerebral involvement. As more individuals with ALD are identified at birth, it remains uncertain if availability of matched donors, transplant (and, potentially, gene therapy) centers, and specialists may affect the timely treatment of these individuals. As these promising gene therapy trials and NBS transform the clinical management and outcomes of ALD, there will be an increasing need for the endocrine management of presymptomatic and subclinical adrenal insufficiency. (Endocrine Reviews 41: 1 - 17, 2020).

The Genomics Research and Innovation Network: creating an interoperable, federated, genomics learning system.

PURPOSE: Clinicians and researchers must contextualize a patient's genetic variants against population-based references with detailed phenotyping. We sought to establish globally scalable technology, policy, and procedures for sharing biosamples and associated genomic and phenotypic data on broadly consented cohorts, across sites of care. METHODS: Three of the nation's leading children's hospitals launched the Genomic Research and Innovation Network (GRIN), with federated information technology infrastructure, harmonized biobanking protocols, and material transfer agreements. Pilot studies in epilepsy and short stature were completed to design and test the collaboration model. RESULTS: Harmonized, broadly consented institutional review board (IRB) protocols were approved and used for biobank enrollment, creating ever-expanding, compatible biobanks. An open source federated query infrastructure was established over genotype-phenotype databases at the three hospitals. Investigators securely access the GRIN platform for prep to research queries, receiving aggregate counts of patients with particular phenotypes or genotypes in each biobank. With proper approvals, de-identified data is exported to a shared analytic workspace. Investigators at all sites enthusiastically collaborated on the pilot studies, resulting in multiple publications. Investigators have also begun to successfully utilize the infrastructure for grant applications. CONCLUSIONS: The GRIN collaboration establishes the technology, policy, and procedures for a scalable genomic research network.

Correction: The Genomics Research and Innovation Network: creating an interoperable, federated, genomics learning system.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Glycogen storage disease presenting as Cushing syndrome.

Impaired growth is common in patients with glycogen storage disease (GSD), who also may have "cherubic" facies similar to the "moon" facies of Cushing syndrome (CS). An infant presented with moon facies, growth failure, and obesity. Laboratory evaluation of the hypothalamic-pituitary-adrenal (HPA) axis was consistent with CS. He was subsequently found to have liver disease, hypoglycemia, and a pathogenic variant in PHKA2, leading to the diagnosis of GSD type IXa. The cushingoid appearance, poor linear growth and hypercortisolemia improved after treatment to prevent recurrent hypoglycemia. We suspect this child's HPA axis activation was "appropriate" and caused by chronic hypoglycemic stress, leading to increased glucocorticoid secretion that may have contributed to his poor growth and excessive weight gain. This is in contrast to typical CS, which is due to excessive adrenocorticotropic hormone (ACTH) or cortisol secretion from neoplastic pituitary or adrenal glands, ectopic secretion of ACTH or corticotropin-releasing hormone (CRH), or exogenous administration of corticosteroid or ACTH. Pseudo-CS is a third cause of excessive glucocorticoid secretion, has no HPA axis pathology, is most often associated with underlying psychiatric disorders or obesity in children and, by itself, is thought to be benign. We speculate that some diseases, including chronic hypoglycemic disorders such as the GSDs, may have biochemical features and pathologic consequences of CS. We propose that excessive glucocorticoid secretion due to chronic stress be termed "stress-induced Cushing (SIC) syndrome" to distinguish it from the other causes of CS and pseudo-CS, and that evaluation of children with chronic hypoglycemia and poor statural growth include evaluation for CS.

Hyperadrenocorticism of calorie restriction contributes to its anti-inflammatory action in mice.

Calorie restriction (CR), which lengthens lifespan in many species, is associated with moderate hyperadrenocorticism and attenuated inflammation. Given the anti-inflammatory action of glucocorticoids, we tested the hypothesis that the hyperadrenocorticism of CR contributes to its attenuated inflammatory response. We used a corticotropin-releasing-hormone knockout (CRHKO) mouse, which is glucocorticoid insufficient. There were four controls groups: CRHKO mice and wild-type (WT) littermates fed either ad libitum (AL) or CR (60% of AL food intake), and three experimental groups: (a) AL-fed CRHKO mice given corticosterone (CORT) in their drinking water titrated to match the integrated 24-hr plasma CORT levels of AL-fed WT mice, (b) CR-fed CRHKO mice given CORT to match the 24-hr CORT levels of AL-fed WT mice, and (c) CR-fed CHRKO mice given CORT to match the 24-hr CORT levels of CR-fed WT mice. Inflammation was measured volumetrically as footpad edema induced by carrageenan injection. As previously observed, CR attenuated footpad edema in WT mice. This attenuation was significantly blocked in CORT-deficient CR-fed CRHKO mice. Replacement of CORT in CR-fed CRHKO mice to the elevated levels observed in CR-fed WT mice, but not to the levels observed in AL-fed WT mice, restored the anti-inflammatory effect of CR. These results indicate that the hyperadrenocorticism of CR contributes to the anti-inflammatory action of CR, which may in turn contribute to its life-extending actions.

A novel missense mutation in TFAP2B associated with Char syndrome and central diabetes insipidus.

Char syndrome is characterized by persistent patent ductus arteriosus (PDA) associated with hand-skeletal abnormalities and distinctive facial dysmorphism. Pathogenic variants in the transcription factor gene TFAP2B have been shown to cause Char syndrome; however, there is significant phenotypic variability linked to variant location. Here, we report a pediatric patient with a novel de novo variant in the fifth exon of TFAP2B, c.917C > T (p.Thr306Met), who presented with PDA, patent foramen ovale, postaxial polydactyly of the left fifth toe and clinodactyly of the left fourth toe, sensorineural hearing loss, scoliosis, dental anomalies, and central diabetes insipidus (CDI). CDI, scoliosis, and hearing loss have not previously been reported in a patient with Char syndrome, and while the association may be coincidental, this report expands the genotypes and potentially phenotypes associated with this syndrome.

A New Model for Adrenarche: Inhibition of 3ß-Hydroxysteroid Dehydrogenase Type 2 by Intra-Adrenal Cortisol.

We propose that the normal adrenarche-related rise in dehydroepiandrosterone (DHEA) secretion is ultimately caused by the rise in cortisol production occurring during childhood and adolescent growth, by the following mechanisms. (1) The onset of childhood growth leads to a slight fall in serum cortisol concentration due to growth-induced dilution and a decrease in the negative feedback of cortisol upon ACTH secretion. (2) In response, ACTH rises and stimulates increased cortisol synthesis and secretion in the growing body to restore the serum cortisol concentration to normal. (3) The cortisol concentration produced within and taken up by adrenocortical steroidogenic cells may rise during this time. (4) Cortisol competitively inhibits 3ß-hydroxysteroid dehydrogenase type 2 (3ßHSD2)-mediated conversion of 17αOH-pregnenolone to cortisol, causing a further fall in serum cortisol, a further decrease in the negative feedback of cortisol upon ACTH, a further rise in ACTH, and further stimulation of adrenal steroidogenesis. (5) The cortisol-mediated inhibition of 3ßHSD2 also blocks the conversion of DHEA to androstenedione, causing a rise in adrenal DHEA and DHEA sulfate relative to androstenedione secretion. Thus, the combination of normal body growth plus inhibition of 3ßHSD2 by intra-adrenal cortisol may cause normal adrenarche. Childhood obesity may hasten this process by causing a pathologic increase in body size that triggers these same processes at an earlier age, resulting in the premature onset of adrenarche.

Racial differences in neonatal hypoglycemia among very early preterm births.

OBJECTIVE: To determine whether the prevalence of neonatal hypoglycemia differs by race/ethnicity. STUDY DESIGN: A retrospective cohort study using prospectively collected data from 515 neonates born very preterm (<32 weeks) to normoglycemic women and admitted to the neonatal intensive care unit (NICU) at a major tertiary hospital in Boston, MA, between 2008 and 2012. RESULTS: A total of 61%, 12%, 7%, 7%, and 13% were White, Black, Hispanic, Asian, and Other, respectively. Among the 66% spontaneous preterm births, 63% of the black neonates experienced hypoglycemia (blood glucose level < 40 mg/dL), while only 22-30% of the other racial/ethnic neonates did so (Black vs. White RR 2.15; 95% CI: 1.54-3.00). After adjusting for maternal education, maternal age, multiple gestations, delivery type, gestational age, birth weight, and neonates' sex, this association remained significant (adjusted Black vs. White RR: 1.61, 95% CI: 1.13-2.29). An increased risk of infant hypoglycemia was not seen in infants of other racial/ethnic groups, nor in any racial/ethnic group with a medically indicated preterm birth. CONCLUSIONS: Black neonates delivered for spontaneous (but not medical) indications at <32 weeks had a higher risk of hypoglycemia, which could provide critical information about mechanisms of preterm birth and adverse postnatal outcomes in this high-risk group.

Endocrinology research-reflecting on the past decade and looking to the next.

The inaugural issue of this journal, published in November 2005, included articles on thyroid cancer, type 2 diabetes mellitus, the metabolic syndrome, pituitary adenomas and obesity. 10 years later, we are still publishing articles on these topics (and many others). Although a great deal of progress has been made in our understanding of the pathogenesis, diagnosis and treatment of diseases of the endocrine system over the past 10 years, many challenges still remain. For this Viewpoint, we have asked five of our Advisory Board Members to comment on the progress and challenges from the past 10 years. They were also asked to offer their thoughts on where money should be spent going forward, and their predictions for what advances might be achieved in the next 10 years.

Regulation of human 3ß-hydroxysteroid dehydrogenase type 2 by adrenal corticosteroids and product-feedback by androstenedione in human adrenarche.

In human adrenarche during childhood, the secretion of dehydroepiandrosterone (DHEA) from the adrenal gland increases due to its increased synthesis and/or decreased metabolism. DHEA is synthesized by 17α-hydroxylase/17,20-lyase, and is metabolized by 3ß-hydroxysteroid dehydrogenase type 2 (3ßHSD2). In this study, the inhibition of purified human 3ßHSD2 by the adrenal steroids, androstenedione, cortisone, and cortisol, was investigated and related to changes in secondary enzyme structure. Solubilized, purified 3ßHSD2 was inhibited competitively by androstenedione with high affinity, by cortisone at lower affinity, and by cortisol only at very high, nonphysiologic levels. When purified 3ßHSD2 was bound to lipid vesicles, the competitive Ki values for androstenedione and cortisone were slightly decreased, and the Ki value of cortisol was decreased 2.5-fold, although still at a nonphysiologic level. The circular dichroism spectrum that measured 3ßHSD2 secondary structure was significantly altered by the binding of cortisol, but not by androstenedione and cortisone. Our import studies show that 3ßHSD2 binds in the intermitochondrial space as a membrane-associated protein. Androstenedione inhibits purified 3ßHSD2 at physiologic levels, but similar actions for cortisol and cortisone are not supported. In summary, our results have clarified the mechanisms for limiting the metabolism of DHEA during human adrenarche.

Adrenocortical zonation results from lineage conversion of differentiated zona glomerulosa cells.

Lineage conversion of differentiated cells in response to hormonal feedback has yet to be described. To investigate this, we studied the adrenal cortex, which is composed of functionally distinct concentric layers that develop postnatally, the outer zona glomerulosa (zG) and the inner zona fasciculata (zF). These layers have separate functions, are continuously renewed in response to physiological demands, and are regulated by discrete hormonal feedback loops. Their cellular origin, lineage relationship, and renewal mechanism, however, remain poorly understood. Cell-fate mapping and gene-deletion studies using zG-specific Cre expression demonstrate that differentiated zG cells undergo lineage conversion into zF cells. In addition, zG maintenance is dependent on the master transcriptional regulator Steroidogenic Factor 1 (SF-1), and zG-specific Sf-1 deletion prevents lineage conversion. These findings demonstrate that adrenocortical zonation and regeneration result from lineage conversion and may provide a paradigm for homeostatic cellular renewal in other tissues.

Loss of function of the melanocortin 2 receptor accessory protein 2 is associated with mammalian obesity.

Melanocortin receptor accessory proteins (MRAPs) modulate signaling of melanocortin receptors in vitro. To investigate the physiological role of brain-expressed melanocortin 2 receptor accessory protein 2 (MRAP2), we characterized mice with whole-body and brain-specific targeted deletion of Mrap2, both of which develop severe obesity at a young age. Mrap2 interacts directly with melanocortin 4 receptor (Mc4r), a protein previously implicated in mammalian obesity, and it enhances Mc4r-mediated generation of the second messenger cyclic adenosine monophosphate, suggesting that alterations in Mc4r signaling may be one mechanism underlying the association between Mrap2 disruption and obesity. In a study of humans with severe, early-onset obesity, we found four rare, potentially pathogenic genetic variants in MRAP2, suggesting that the gene may also contribute to body weight regulation in humans.

Epinephrine deficiency results in intact glucose counter-regulation, severe hepatic steatosis and possible defective autophagy in fasting mice.

Epinephrine is one of the major hormones involved in glucose counter-regulation and gluconeogenesis. However, little is known about its importance in energy homeostasis during fasting. Our objective is to study the specific role of epinephrine in glucose and lipid metabolism during starvation. In our experiment, we subject regular mice and epinephrine-deficient mice to a 48-h fast then we evaluate the different metabolic responses to fasting. Our results show that epinephrine is not required for glucose counter-regulation: epinephrine-deficient mice maintain their blood glucose at normal fasting levels via glycogenolysis and gluconeogenesis, with normal fasting-induced changes in the peroxisomal activators: peroxisome proliferator activated receptor γ coactivator α (PGC-1α), fibroblast growth factor 21 (FGF-21), peroxisome proliferator activated receptor α (PPAR-α), and sterol regulatory element binding protein (SREBP-1c). However, fasted epinephrine-deficient mice develop severe ketosis and hepatic steatosis, with evidence for inhibition of hepatic autophagy, a process that normally provides essential energy via degradation of hepatic triglycerides during starvation. We conclude that, during fasting, epinephrine is not required for glucose homeostasis, lipolysis or ketogenesis. Epinephrine may have an essential role in lipid handling, possibly via an autophagy-dependent mechanism.

Fetal-placental inflammation, but not adrenal activation, is associated with extreme preterm delivery.

OBJECTIVE: Spontaneous labor at term involves the activation of placental corticotropin-releasing hormone and the fetal adrenal axis, but the basis for extreme preterm labor is unknown. Our objective was to determine whether placental corticotropin-releasing hormone is activated in extreme preterm labor. STUDY DESIGN: One thousand five hundred six mothers delivering at less than 28 weeks' gestation were enrolled. Each mother/infant pair was assigned to the category that described the primary reason for hospitalization. Observers who had no knowledge of patient categorization assessed placenta microbiology, histology, and corticotropin-releasing hormone expression. These were correlated with the primary reason for hospitalization. RESULTS: Among infants delivered at less than 28 weeks' gestation, spontaneous (vs induced) delivery was associated with less placental corticotropin-releasing hormone expression and more frequent signs of placental inflammation and infection. CONCLUSION: Inflammation and infection, rather than premature activation of the fetal adrenal axis, should be the major focus of research to prevent extremely preterm human birth.

Cortisol stimulates secretion of dehydroepiandrosterone in human adrenocortical cells through inhibition of 3betaHSD2.

CONTEXT: Initiating factors leading to production of adrenal androgens are poorly defined. Cortisol is present in high concentrations within the adrenal gland, and its production rises with growth during childhood. OBJECTIVE: Our aim was to characterize the effect of cortisol and other glucocorticoids on androgen secretion from a human adrenocortical cell line and from nonadrenal cells transfected with CYP17A1 or HSD3B2. DESIGN/SETTING: This study was performed in cultured cells, at an academic medical center. METHODS: The effects of cortisol upon steroid production in human adrenal NCI-H295R cells were measured by immunoassay, tandem mass spectrometry, and thin-layer chromatography. The effects of cortisol upon the activities of 17, 20 lyase and 3ßHSD2 were measured in NCI-H295R cells and in transfected COS-7 cells. RESULTS: Cortisol markedly and rapidly stimulated dehydroepiandrosterone (DHEA) in a dose-dependent manner at cortisol concentrations ≥50 µM. Cortisone and 11-deoxycortisol were also potent stimulators of DHEA secretion, whereas prednisolone and dexamethasone were not. Treatment with cortisol did not affect expression of CYP17A1 or HSD3B2 mRNAs. Stimulation of DHEA secretion by cortisol was associated with competitive inhibition of 3ßHSD2 activity. CONCLUSIONS: Cortisol inhibits 3ßHSD2 activity in adrenal cells and in COS-7 cells transfected with HSD3B2. Thus, it is possible that intraadrenal cortisol may participate in the regulation of adrenal DHEA secretion through inhibition of 3ßHSD2. We hypothesize that a rise in intraadrenal cortisol during childhood growth may lead to inhibition of 3ßHSD2 activity and contribute to the initiation of adrenarche.

Nocturnal Dexamethasone versus Hydrocortisone for the Treatment of Children with Congenital Adrenal Hyperplasia.

Classic congenital adrenal hyperplasia affects approximately 1 in 15,000 children. Current treatment strategies using multiple daily doses of hydrocortisone lead to suboptimal outcomes. We tested the hypothesis that nocturnal administration of dexamethasone will suppress the hypothalamic-pituitary-adrenal axis more effectively than standard hydrocortisone treatment by blocking the inherent diurnal secretion of ACTH. We performed a pilot study of five prepubertal patients comparing CAH control during two 24-hour hospitalizations, one on hydrocortisone and the other on dexamethasone. The patterns of adrenal suppression differed markedly between hydrocortisone and nocturnal dexamethasone, with significant suppression of the morning rise in ACTH, 17-hydroxyprogesterone, and androstenedione while on dexamethasone. On hydrocortisone therapy, there is a marked variation in ACTH and adrenal hormones depending on time of day and timing of hydrocortisone administration. Longer-term studies are needed to investigate the lowest effective dose and potential toxicity of nocturnal dexamethasone to determine its utility as a therapy for CAH.

Effect of epinephrine deficiency on cold tolerance and on brown adipose tissue.

Catecholamines are involved in thermogenesis. We investigated the specific role of epinephrine in regulation of temperature homeostasis in mice. We subjected adult wildtype (WT) and phenylethanolamine N-methyl transferase knock out mice (Pnmt(-/-)) lacking epinephrine to cold for 24h. Body temperature and thyroid hormone levels were not different between WT and Pnmt(-/-) mice. Although temperature was normal in Pnmt(-/-) mice, the brown fat response to cold was abnormal with no increase in Ucp-1 or Pgc-1alpha mRNA levels (but with an exaggerated cold-induced lipid loss from the tissue). Our results show that epinephrine may have a role in brown fat mitochondrial uncoupling through regulation of Ucp-1 and Pgc-1alpha, although this is not required to maintain a normal temperature during acute cold exposure. We conclude that epinephrine may have an important role in induction of Ucp-1 and Pgc-1alpha gene expression during cold stress.

Monitoring of therapy in congenital adrenal hyperplasia.

BACKGROUND: Congenital adrenal hyperplasia is a group of disorders caused by defects in the adrenal steroidogenic pathways. In its most common form, 21-hydroxylase deficiency, patients develop varying degrees of glucocorticoid and mineralocorticoid deficiency as well as androgen excess. Therapy is guided by monitoring clinical parameters as well as adrenal hormone and metabolite concentrations. CONTENT: We review the evidence for clinical and biochemical parameters used in monitoring therapy for congenital adrenal hyperplasia. We discuss the utility of 24-h urine collections for pregnanetriol and 17-ketosteroids as well as serum measurements of 17-hydroxyprogesterone, androstenedione, and testosterone. In addition, we examine the added value of daily hormonal profiles obtained from salivary or blood-spot samples and discuss the limitations of the various assays. SUMMARY: Clinical parameters such as growth velocity and bone age remain the gold standard for monitoring the adequacy of therapy in congenital adrenal hyperplasia. The use of 24-h urine collections for pregnanetriol and 17-ketosteroid may offer an integrated view of adrenal hormone production but target concentrations must be better defined. Random serum hormone measurements are of little value and fluctuate with time of day and timing relative to glucocorticoid administration. Assays of daily hormonal profiles from saliva or blood spots offer a more detailed assessment of therapeutic control, although salivary assays have variable quality.

Glucocorticoid treatment--effect on adrenal medullary catecholamine production.

Glucocorticoid and epinephrine are important stress hormones secreted from the adrenal gland during critical illness. Adrenal glucocorticoid stimulates phenylethanolamine N-methyltransferase (PNMT) to convert norepinephrine to epinephrine in the adrenal medulla. Glucocorticoid is sometimes used in catecholamine-resistant septic shock in critically ill patients. By suppressing adrenal glucocorticoid production, glucocorticoid therapy might also reduce the secretion of epinephrine during stress. To investigate this, we used a mouse model subjected to glucocorticoid therapy under basal conditions (experiment 1) and during stress (experiment 2). In experiment 1, pellets containing 0% to 8% dexamethasone were implanted subcutaneously in mice for 4 weeks. In experiment 2, animals received 14 days of intraperitoneal injections of normal saline, low- or high-dose dexamethasone, followed by 2 h of restraint. We found that in experiment 1, adrenal corticosterone did not differ with dexamethasone treatment. Phenylethanolamine N-methyltransferase messenger RNA levels and adrenal catecholamines were highest in the 8% dexamethasone group. Compared with experiment 1, restrained control mice in experiment 2 had high adrenal corticosterone, which decreased with dexamethasone. Phenylethanolamine N-methyltransferase messenger RNA content doubled with restraint but decreased with dexamethasone treatment. As in experiment 1, adrenal catecholamine content increased significantly with dexamethasone treatment. We conclude that without stress, when adrenocorticotropic hormone is low, high doses of exogenous dexamethasone stimulate PNMT and catecholamine synthesis, likely independently of adrenal corticosterone concentration. After stress, adrenocorticotropic hormone levels are elevated, and exogenous dexamethasone suppresses endogenous corticosterone and PNMT production. Nonetheless, catecholamines increase, possibly due to direct neural stimulation, which may override the hormonal regulation of epinephrine synthesis during stress.