Publications by authors named "Joseph Majzoub"

41 Publications

Severe Hypernatremia in an Adolescent With Anorexia Nervosa.

Clin Pediatr (Phila) 2021 12 27;60(14):586-590. Epub 2021 Oct 27.

Boston Children's Hospital, Boston, MA, USA.

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http://dx.doi.org/10.1177/00099228211055283DOI Listing
December 2021

A Resident-Led Virtual Journal Club to Educate Pediatric Residents About Coronavirus Disease 2019.

Acad Pediatr 2021 May-Jun;21(4):759-761. Epub 2021 Feb 17.

Department of Pediatrics, Harvard Medical School (M Rezvani, GA Smith, JA Majzoub, AD Durbin, and AS Winn), Boston, Mass; Division of General Pediatrics, Department of Pediatrics, Boston Children's Hospital (AS Winn), Boston, Mass.

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http://dx.doi.org/10.1016/j.acap.2021.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886634PMC
June 2021

The Changing Face of Adrenoleukodystrophy.

Endocr Rev 2020 08;41(4)

Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts.

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).
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http://dx.doi.org/10.1210/endrev/bnaa013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286618PMC
August 2020

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

Genet Med 2020 02 4;22(2):371-380. Epub 2019 Sep 4.

Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA, USA.

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.
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http://dx.doi.org/10.1038/s41436-019-0646-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000325PMC
February 2020

Glycogen storage disease presenting as Cushing syndrome.

JIMD Rep 2019 May 3;47(1):17-22. Epub 2019 Apr 3.

Division of Endocrinology, Department of Pediatrics Boston Children's Hospital, Harvard Medical School Boston Massachusetts.

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 , 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.
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http://dx.doi.org/10.1002/jmd2.12031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498823PMC
May 2019

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

Am J Med Genet A 2019 07 22;179(7):1299-1303. Epub 2019 Apr 22.

Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, United States.

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.
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http://dx.doi.org/10.1002/ajmg.a.61150DOI Listing
July 2019

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

Aging Cell 2019 06 1;18(3):e12944. Epub 2019 Apr 1.

Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas.

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.
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http://dx.doi.org/10.1111/acel.12944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516174PMC
June 2019

Abnormal Glycerol Metabolism in a Child with Global Developmental Delay, Adrenal Insufficiency, and Intellectual Disability.

Clin Chem 2018 12;64(12):1785-1787

Department of Laboratory Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA;

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http://dx.doi.org/10.1373/clinchem.2018.293696DOI Listing
December 2018

Behavioural dysfunctions of 10-year-old children born extremely preterm associated with corticotropin-releasing hormone expression in the placenta.

Acta Paediatr 2018 11 7;107(11):1932-1936. Epub 2018 Aug 7.

Boston University School of Medicine, Boston, MA, USA.

Aim: To evaluate the relationship between corticotropin-releasing hormone (CRH) expression in the placenta and the risk of school-related dysfunctions at the age of 10 years among children born extremely preterm (EP).

Methods: Corticotropin-releasing hormone expression was measured in the placenta of 761 EP children, who had the following assessments at the age of 10 years: Differential Ability Scales, Oral and Written Language Scales, the Wechsler Individual Achievement Test-III, NEPSY-II and the Child Symptom Inventory-4. We evaluated whether lowest and highest quartiles of CRH mRNA were associated with undesirable scores on these assessments. With 272 evaluations, we would expect 14 to be significant at p < 0.05.

Results: Only 16 associations were statistically significant. On the other hand, seven of these were social limitations among girls whose placenta CRH mRNA was in the top quartile. Adjusting for delivery indication or restricting the sample to one delivery indication group resulted in few differences.

Conclusion: Overall, placenta CRH mRNA concentrations in the top or bottom quartiles were not associated with increased risks of dysfunctions 10 years later. Girls whose placenta CRH expression was in the top quartile, however, were at increased risk of seven indicators/correlates of social limitations.
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http://dx.doi.org/10.1111/apa.14494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6179924PMC
November 2018

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

Horm Res Paediatr 2018 30;89(5):311-319. Epub 2018 May 30.

Division of Pediatric Endocrinology, Hasbro Children's Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.

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 3β-hydroxysteroid dehydrogenase type 2 (3βHSD2)-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 3βHSD2 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 3βHSD2 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.
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http://dx.doi.org/10.1159/000488777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6031466PMC
October 2018

Racial differences in neonatal hypoglycemia among very early preterm births.

J Perinatol 2018 03 5;38(3):258-263. Epub 2017 Dec 5.

Division of Endocrinology, Boston Children's Hospital, Boston, MA, USA.

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.
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http://dx.doi.org/10.1038/s41372-017-0003-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906150PMC
March 2018

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

Nat Rev Endocrinol 2015 Nov 13;11(11):672-80. Epub 2015 Oct 13.

Institut Gustave Roussy and University Paris-Sud, 114 Rue Edouard Vaillant, 94800 Villejuif, France.

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.
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http://dx.doi.org/10.1038/nrendo.2015.164DOI Listing
November 2015

Brain disorders associated with corticotropin-releasing hormone expression in the placenta among children born before the 28th week of gestation.

Acta Paediatr 2016 Jan 13;105(1):e7-11. Epub 2015 Nov 13.

Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.

Aim: To evaluate the relationship between placenta corticotropin-releasing hormone (CRH) expression and brain structure and function abnormalities in extremely preterm newborns.

Methods: In a sample of 1243 infants born before the 28th week of gestation, we evaluated the relationship between CRH expression in the placenta and the risk of brain ultrasound scan abnormalities identified while these infants were in the intensive care nursery, low scores on the Bayley Scales of Infant Development-II of 900 of these children at age two years and head circumference measurements then more than one and two standard deviations below the mean.

Results: Infants who had a low placenta CRH messenger ribonucleic acid (mRNA) concentration were at increased risk of ventriculomegaly on an ultrasound scan. An elevated placenta CRH mRNA concentration was associated with increased risk of an inability to walk at age two years, and a Bayley Motor Scale 3 standard deviations below the mean.

Conclusion: Placenta CRH mRNA concentration appears to convey information about the risk of brain damage in the infant born at an extremely low gestational age.
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http://dx.doi.org/10.1111/apa.13174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701600PMC
January 2016

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

J Pharmacol Exp Ther 2015 Jan 29;352(1):67-76. Epub 2014 Oct 29.

Division of Basic Medical Sciences (J.L.T., V.L.M.) and Department of Ob-Gyn (J.L.T.), Mercer University School of Medicine, Macon, Georgia; Department of Biochemistry, Mercer University School of Medicine, Savannah, Georgia (M.R., G.A.D., H.S.B.); Memorial University Medical Center, Anderson Cancer Institute, Savannah, Georgia (H.S.B.); and Division of Endocrinology, Boston Children's Hospital, and Harvard Medical School, Boston, Massachusetts (J.A.M.).

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 3β-hydroxysteroid dehydrogenase type 2 (3βHSD2). In this study, the inhibition of purified human 3βHSD2 by the adrenal steroids, androstenedione, cortisone, and cortisol, was investigated and related to changes in secondary enzyme structure. Solubilized, purified 3βHSD2 was inhibited competitively by androstenedione with high affinity, by cortisone at lower affinity, and by cortisol only at very high, nonphysiologic levels. When purified 3βHSD2 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 3βHSD2 secondary structure was significantly altered by the binding of cortisol, but not by androstenedione and cortisone. Our import studies show that 3βHSD2 binds in the intermitochondrial space as a membrane-associated protein. Androstenedione inhibits purified 3βHSD2 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.
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http://dx.doi.org/10.1124/jpet.114.219550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4279106PMC
January 2015

An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge.

Genome Biol 2014 Mar 25;15(3):R53. Epub 2014 Mar 25.

Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance.

Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization.

Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.
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http://dx.doi.org/10.1186/gb-2014-15-3-r53DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073084PMC
March 2014

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

Dev Cell 2013 Sep 12;26(6):666-673. Epub 2013 Sep 12.

Division of Endocrinology, Boston Children's Hospital, Boston, MA 02115 USA.

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.
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http://dx.doi.org/10.1016/j.devcel.2013.07.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791142PMC
September 2013

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

Science 2013 Jul;341(6143):275-8

Division of Endocrinology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.

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.
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http://dx.doi.org/10.1126/science.1233000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3788688PMC
July 2013

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

Int J Biochem Cell Biol 2012 Jun 3;44(6):905-13. Epub 2012 Mar 3.

Division of Critical Care Medicine, Department of Anesthesiology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.

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.
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http://dx.doi.org/10.1016/j.biocel.2012.02.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4710484PMC
June 2012

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

Am J Obstet Gynecol 2012 Mar 16;206(3):236.e1-8. Epub 2011 Dec 16.

Division of Endocrinology, Department of Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.

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.
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http://dx.doi.org/10.1016/j.ajog.2011.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3696892PMC
March 2012

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

J Clin Endocrinol Metab 2011 Jan 13;96(1):E31-9. Epub 2010 Oct 13.

Division of Endocrinology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA.

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 3βHSD2 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 3βHSD2 activity.

Conclusions: Cortisol inhibits 3βHSD2 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 3βHSD2. We hypothesize that a rise in intraadrenal cortisol during childhood growth may lead to inhibition of 3βHSD2 activity and contribute to the initiation of adrenarche.
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http://dx.doi.org/10.1210/jc.2010-0692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3038480PMC
January 2011

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

Int J Pediatr Endocrinol 2010 14;2010. Epub 2010 Sep 14.

Division of Endocrinology, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA.

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.
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http://dx.doi.org/10.1155/2010/347636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2943098PMC
July 2011

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

Mol Cell Endocrinol 2010 Oct 7;328(1-2):34-9. Epub 2010 Jul 7.

Division of Critical Care Medicine, Department of Anesthesiology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, United States.

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.
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http://dx.doi.org/10.1016/j.mce.2010.06.019DOI Listing
October 2010

Monitoring of therapy in congenital adrenal hyperplasia.

Clin Chem 2010 Aug 17;56(8):1245-51. Epub 2010 Jun 17.

Division of Endocrinology, Children's Hospital Boston, Boston, MA, USA.

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.
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http://dx.doi.org/10.1373/clinchem.2010.146035DOI Listing
August 2010

Permanent Neonatal Diabetes in a Patient with a KCNJ11/Q52R Mutation Accompanied by Intermittent Hypoglycemia and Liver Failure.

Int J Pediatr Endocrinol 2009 8;2009:453240. Epub 2009 Oct 8.

Division of Endocrinology, Department of Medicine, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA.

The most common monogenic cause of neonatal diabetes is mutation in KCNJ11, which encodes a potassium channel in pancreatic beta cells. Some mutations in this gene, including Q52R, have been described in association with neurological deficits, but never with hepatic involvement. We report the second case of neonatal diabetes in a patient with a KCNJ11/Q52R mutation. This patient's clinical course did not include obvious neurological deficits despite the presence of prematurity, but did include transient hyperbilirubinemia, and recurrent hypoglycemia. The phenotypic spectrum of KCNJ11 mutations is variable and is likely influenced by additional genetic and environmental factors.
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http://dx.doi.org/10.1155/2009/453240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2774578PMC
July 2011

Glucocorticoid treatment--effect on adrenal medullary catecholamine production.

Shock 2010 Feb;33(2):213-7

Division of Critical Care Medicine, Department of Anesthesiology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA.

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.
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http://dx.doi.org/10.1097/SHK.0b013e3181af0633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4713031PMC
February 2010

Mass spectrometry in the clinical laboratory: how have we done, and where do we need to be?

Clin Chem 2009 Jun 24;55(6):1236-9. Epub 2009 Apr 24.

Department of Pathology, University of Michigan Health Sciences Center, Ann Arbor, MI, USA.

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http://dx.doi.org/10.1373/clinchem.2009.127522DOI Listing
June 2009

Maternal levels of corticotropin-releasing hormone during pregnancy in relation to adiponectin and leptin in early childhood.

J Clin Endocrinol Metab 2009 Apr 3;94(4):1409-15. Epub 2009 Feb 3.

Medisinsk Teknisk Forskningssenter, 7489 Trondheim, Norway.

Background: Fetal glucocorticoid exposure is associated with later development of features of the metabolic syndrome such as central obesity and insulin resistance. Fat tissue, especially visceral fat, produces adiponectin, which is inversely associated with insulin resistance in older children and adults. Adipocytes also produce leptin, directly related to measures of adiposity. It is unknown how the secretion of these hormones in early childhood is related to pregnancy levels of CRH, a proxy of fetal glucocorticoid exposure.

Aim: Our aim was to study the relationship of maternal midpregnancy CRH levels with offspring levels of adiponectin and leptin in early childhood.

Methods: The study population consisted of 349 mother-children pairs from Project Viva, a prospective prebirth cohort study from eastern Massachusetts. We created a general linear model with log CRH levels in midpregnancy maternal blood as the predictor and adiponectin and leptin measured in the 3-yr-old offspring as outcomes, adjusting for covariates.

Results: The means (sd) of log CRH, adiponectin, and leptin were 4.97 (0.65) log pg/ml, 22.4 (5.8) microg/ml, and 1.9 (1.8) ng/ml. For each unit increment in log CRH, mean value of offspring adiponectin was 1.10 microg/ml (95% confidence interval = 0.06-2.14) higher. We found no association with leptin (-0.08 ng/ml; 95% confidence interval = -0.40-0.24).

Conclusions: Higher maternal blood levels of CRH were associated with higher levels of adiponectin but unchanged levels of leptin at age 3 yr. The increased adiponectin levels might represent secretion from organs other than fat or reflect a compensatory mechanism to increase insulin sensitivity.
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http://dx.doi.org/10.1210/jc.2008-1424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2682476PMC
April 2009

Long-term effects of dietary glycemic index on adiposity, energy metabolism, and physical activity in mice.

Am J Physiol Endocrinol Metab 2008 Nov 9;295(5):E1126-31. Epub 2008 Sep 9.

Department of Medicine, Children's Hospital Boston, Boston, Massachusetts 02115, USA.

A high-glycemic index (GI) diet has been shown to increase adiposity in rodents; however, the long-term metabolic effects of a low- and high-GI diet have not been examined. In this study, a total of 48 male 129SvPas mice were fed diets high in either rapidly absorbed carbohydrate (RAC; high GI) or slowly absorbed carbohydrate (SAC; low GI) for up to 40 wk. Diets were controlled for macronutrient and micronutrient content, differing only in starch type. Body composition and insulin sensitivity were measured longitudinally by DEXA scan and oral glucose tolerance test, respectively. Food intake, respiratory quotient, physical activity, and energy expenditure were assessed using metabolic cages. Despite having similar mean body weights, mice fed the RAC diet had 40% greater body fat by the end of the study and a mean 2.2-fold greater insulin resistance compared with mice fed the SAC diet. Respiratory quotient was higher in the RAC group, indicating comparatively less fat oxidation. Although no differences in energy expenditure were observed throughout the study, total physical activity was 45% higher for the SAC-fed mice after 38 wk of feeding. We conclude that, in this animal model, 1) the effect of GI on body composition is mediated by changes in substrate oxidation, not energy intake; 2) a high-GI diet causes insulin resistance; and 3) dietary composition can affect physical activity level.
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http://dx.doi.org/10.1152/ajpendo.90487.2008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2584816PMC
November 2008

Genetic diagnosis of primary immune deficiencies.

Immunol Allergy Clin North Am 2008 May;28(2):387-412, x

Correlagen Diagnostics, Inc., 307 Waverley Oaks Road, Suite 101, Waltham, MA 02452, USA.

Gene testing in primary immune deficiencies (PIDs) once was limited to expert academic laboratories, but now is easily available to physicians with a broad range of clinical expertise. Such testing can establish or confirm a suspected diagnosis and also may predict future disease risk in advance of clinical signs and symptoms, inform reproductive decision making, and guide clinicians in selecting the most appropriate therapeutic options. This article, based on the authors' experience and a review of the published literature, discusses some of the advances and challenges currently encountered in the clinical molecular genetic diagnosis of PIDs.
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http://dx.doi.org/10.1016/j.iac.2008.01.004DOI Listing
May 2008
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