Publications by authors named "Margaret F Keil"

54 Publications

Rare Germline Variants in Pediatric Patients With Cushing's Disease: What Is Their Role?

Front Endocrinol (Lausanne) 2020 3;11:433. Epub 2020 Jul 3.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, United States.

The DICER1 syndrome is a multiple neoplasia disorder caused by germline mutations in the gene. In DICER1 patients, aggressive congenital pituitary tumors lead to neonatal Cushing's disease (CD). The role of in other corticotropinomas, however, remains unknown. To perform a comprehensive screening for variants in a large cohort of CD patients, and to analyze their possible contribution to the phenotype. We included 192 CD cases: ten young-onset (age <30 years at diagnosis) patients were studied using a next generation sequencing panel, and 182 patients (170 pediatric and 12 adults) were screened via whole-exome sequencing. In seven cases, tumor samples were analyzed by Sanger sequencing. Rare germline variants were found in seven pediatric patients with no other known disease-associated germline defects or somatic second hits. By immunohistochemistry, DICER1 showed nuclear localization in 5/6 patients. Variant transmission from one of the parents was confirmed in 5/7 cases. One patient had a multinodular goiter; another had a family history of melanoma; no other patients had a history of neoplasms. Our findings suggest that gene variants may contribute to the pathogenesis of non-syndromic corticotropinomas. Clarifying whether loss-of-function is disease-causative or a mere disease-modifier in this setting, requires further studies. ClinicalTrials.gov: NCT00001595.
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http://dx.doi.org/10.3389/fendo.2020.00433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351020PMC
July 2020

Germline CDKN1B Loss-of-Function Variants Cause Pediatric Cushing's Disease With or Without an MEN4 Phenotype.

J Clin Endocrinol Metab 2020 06;105(6)

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland.

Context: Germline loss-of-function CDKN1B gene variants cause the autosomal dominant syndrome of multiple endocrine neoplasia type 4 (MEN4). Even though pituitary neuroendocrine tumors are a well-known component of the syndrome, only 2 cases of Cushing's disease (CD) have so far been described in this setting.

Aim: To screen a large cohort of CD patients for CDKN1B gene defects and to determine their functional effects.

Patients: We screened 211 CD patients (94.3% pediatric) by germline whole-exome sequencing (WES) only (n = 157), germline and tumor WES (n = 27), Sanger sequencing (n = 6), and/or germline copy number variant (CNV) analysis (n = 194). Sixty cases were previously unpublished. Variant segregation was investigated in the patients' families, and putative pathogenic variants were functionally characterized.

Results: Five variants of interest were found in 1 patient each: 1 truncating (p.Q107Rfs*12) and 4 nontruncating variants, including 3 missense changes affecting the CDKN1B protein scatter domain (p.I119T, p.E126Q, and p.D136G) and one 5' untranslated region (UTR) deletion (c.-29_-26delAGAG). No CNVs were found. All cases presented early (10.5 ± 1.3 years) and apparently sporadically. Aside from colon adenocarcinoma in 1 carrier, no additional neoplasms were detected in the probands or their families. In vitro assays demonstrated protein instability and disruption of the scatter domain of CDKN1B for all variants tested.

Conclusions: Five patients with CD and germline CDKN1B variants of uncertain significance (n = 2) or pathogenic/likely pathogenic (n = 3) were identified, accounting for 2.6% of the patients screened. Our finding that germline CDKN1B loss-of-function may present as apparently sporadic, isolated pediatric CD has important implications for clinical screening and genetic counselling.
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http://dx.doi.org/10.1210/clinem/dgaa160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190031PMC
June 2020

Germline USP8 Mutation Associated With Pediatric Cushing Disease and Other Clinical Features: A New Syndrome.

J Clin Endocrinol Metab 2019 10;104(10):4676-4682

Pediatric Endocrinology Unit, Ruth Rappaport Children's Hospital, Rambam Health Care Campus, Haifa, Israel.

Background: Somatic mutations in the ubiquitin-specific peptidase 8 (USP8) gene are common in corticotropinomas of children with Cushing disease (CD). We report a unique patient with a germline USP8 mutation who presented with CD and a constellation of other findings that constitute an intriguing genetic syndrome.

Case Description: We describe a 16-year-old female with CD, developmental delay, dysmorphic features, ichthyosiform hyperkeratosis, chronic lung disease, chronic kidney disease, hyperglycemia, dilated cardiomyopathy with congestive heart failure, and previous history of hyperinsulinism and partial GH deficiency. She was diagnosed with CD at 14 years old and underwent transsphenoidal surgery. Despite initial improvement, she developed recurrent CD.

Methods: DNA was extracted from peripheral blood and tumor DNA; whole-exome and Sanger confirmatory sequencing were performed. Immunohistochemistry was performed on the resected adenoma.

Results: A de novo germline heterozygous USP8 mutation (c.2155T>C, p.S719P) in the critical 14-3-3 binding motif hot spot locus of the gene was identified in both the peripheral blood and tumor DNA. Histopathologic evaluation of the resected tumor confirmed an ACTH-secreting adenoma.

Conclusion: Somatic USP8 mutations are common in adenomas causing CD, but to date, no germline defects have been reported. We describe a patient with a de novo germline USP8 mutation with recurrent CD and multiple other medical problems. This unique patient informs us of the multitude of signaling events that may be controlled by USP8.
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http://dx.doi.org/10.1210/jc.2019-00697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736211PMC
October 2019

Patient Support Groups are an Important Component of Your Toolbox for Patient Education.

Authors:
Margaret F Keil

J Pediatr Nurs 2019 Jan - Feb;44:137-138. Epub 2018 Nov 29.

Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. Electronic address:

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http://dx.doi.org/10.1016/j.pedn.2018.10.008DOI Listing
December 2019

Children with MEN1 gene mutations may present first (and at a young age) with Cushing disease.

Clin Endocrinol (Oxf) 2018 10 20;89(4):437-443. Epub 2018 Jul 20.

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland.

Objective: Cushing disease (CD) is a rare entity caused by ACTH-secreting pituitary tumours, leading to prolonged hypercortisolism. Most cases are sporadic but can rarely occur in the context of familial predisposition, due to germline mutations in genes such as MEN1, leading to multiple endocrine neoplasia type 1, MEN1. We have reported previously that CD can be the first and only presenting manifestation of MEN1. In this report, we describe a cohort of paediatric patients who presented with CD as the first manifestation of MEN1.

Materials And Methods: A retrospective analysis of paediatric patients admitted to the National Institutes of Health (NIH) Clinical Center for evaluation of hypercortisolism, between 1997 and 2017. MEN1 was diagnosed on a clinical, familial and/or genetic basis.

Results: Of a total of 238 children with CD, six patients were subsequently diagnosed with MEN1, three males and three females with a mean age at diagnosis of CD at 13.4 ± 2.9 years. Five of the six patients had familial MEN1 and one patient was a sporadic case. Additional manifestations of MEN1 included primary hyperparathyroidism in three patients and hyperprolactinemia in two patients.

Discussion: This report describes a paediatric patient population with MEN1 in whom CD was the initial manifestation, confirming a previous observation that paediatric patients with MEN1 may present first with an ACTH-producing adenoma. Therefore, germline MEN1 mutations should be sought in paediatric CD and tested for when there is a suggestive family history and/or other manifestations.
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http://dx.doi.org/10.1111/cen.13796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341462PMC
October 2018

Cushing's Syndrome in Pediatrics: An Update.

Endocrinol Metab Clin North Am 2018 06;47(2):451-462

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1E-3330, MSC1103, Bethesda, MD 20892, USA.

Cushing syndrome (CS) is a multisystem disorder resulting from the prolonged exposure to excess glucocorticoids. In children, CS most commonly results from the exogenous administration of steroids and the typical presentation is height deceleration concomitant with weight gain. Endogenous and ectopic causes are rare. CS in children may be associated with distinct germline and somatic mutations. Clinical practice guidelines are available assist clinicians. Patients should be referred to multidisciplinary centers of excellence with experience in endocrinology and surgery. Early detection and treatment is essential to reduce associated acute and long-term morbidity and potential death.
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http://dx.doi.org/10.1016/j.ecl.2018.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962291PMC
June 2018

Mice deficient in AKAP13 (BRX) develop compulsive-like behavior and increased body weight.

Brain Res Bull 2018 06 10;140:72-79. Epub 2018 Apr 10.

Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine, Baltimore, MD, 21205, United States. Electronic address:

Objective: Hormonal contributions to the sex-dependent development of both obsessive-compulsive disorder (OCD) and obesity have been described, but the underlying mechanisms are incompletely understood. A-kinase anchoring protein 13 (AKAP13) significantly augments ligand-dependent activation of estrogen receptors alpha and beta. The hypothalamus and pituitary gland are implicated in the development and exacerbation of OCD and obesity and have strong AKAP13 expression. The AKAP13 localization pattern observed in these key brain regions together with its effects on sex steroid action suggest a potential role for AKAP13 in compulsive-like behaviors. Here we tested the role of AKAP13 in compulsive-like behavior and body weight using an Akap13 haploinsufficient murine model.

Materials And Methods: Targeted deletion of the Akap13 gene generated haploinsufficient (Akap13+/-) mice in a C57BL6/J genetic background. Established behavioral assays were conducted, video recorded, and scored blindly to assess compulsive-like behavior based on genotype and gender. Tests included: marble-burying, grooming, open- field and elevated plus-maze. Brain and body weights were also obtained. Mean levels of test outcomes were compared using multi-way ANOVA to test for genotype, sex, genotype*sex, and genotype*sex*age interaction effects with Bonferroni adjustment for multiple comparisons, to further explain any significant interactions.

Results: The marble-burying and grooming assays revealed significant sex-dependent increases in perseverative, compulsive-like behaviors in female Akap13 haploinsufficient mice compared to female wild type (WT) mice by demonstrating increased marble-burying activity (p = .0025) and a trend towards increased grooming behavior (p = .06). Male Akap13 haploinsufficient mice exhibited no behavioral changes (p > 0.05). Elevated plus-maze and open-field test results showed no overt anxiety-like behavior in Akap13 haploinsufficient mice irrespective of sex (p > 0.05, both). No differences in brain weight were found in Akap13 haploinsufficient mice compared to WT mice (p > 0.05). However, female Akap13 haploinsufficient mice weighed more than female WT mice in the 4 to <7 months age range (p = .0051). Male Akap13 haploinsufficient mice showed no differences in weight compared to male WT mice (p = >0.05) at any age range examined.

Conclusion: Akap13 haploinsufficiency led to sex-dependent, compulsive-like behavioral changes in a murine model. Interestingly, Akap13 haploinsufficiency also led to a sex-dependent increase in body weight. These results revealed a requirement for AKAP13 in murine behavior, particularly in female mice, and is the first report of AKAP13 involvement in murine behavior. Future studies may examine the involvement of AKAP13 in the pathophysiology of OCD in female humans and may contribute to a better understanding of the role of AKAP13 and sex hormones in the development and exacerbation of OCD.
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http://dx.doi.org/10.1016/j.brainresbull.2018.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6045963PMC
June 2018

Anxiety-like behavior and other consequences of early life stress in mice with increased protein kinase A activity.

Behav Brain Res 2018 08 3;348:22-30. Epub 2018 Apr 3.

Section on Endocrinology & Genetics (SEGEN) & Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA.

Anxiety disorders are associated with abnormalities in fear-learning and bias to threat; early life experiences are influential to the development of an anxiety-like phenotype in adulthood. We recently reported that adult mice (Prkar1a+/-) with haploinsufficiency for the main regulatory subunit of the protein kinase A (PKA) exhibit an anxiety-like phenotype associated with increased PKA activity in the amygdala. PKA is the main effector of cyclic adenosine mono-phosphate signaling, a key pathway involved in the regulation of fear learning. Since anxiety has developmental and genetic components, we sought to examine the interaction of a genetic defect associated with anxiety phenotype and early life experiences. We investigated the effects of neonatal maternal separation or tactile stimulation on measures of behavior typical to adolescence as well as developmental changes in the behavioral phenotype between adolescent and adult wild-type (WT) and Prkar1a+/- mice. Our results showed developmental differences in assays of anxiety and novelty behavior for both genotypes. Adolescent mice showed increased exploratory and novelty seeking behavior compared to adult counterparts. However, early life experiences modulated behavior in adolescent WT differently than in adolescent Prkar1a+/- mice. Adolescent WT mice exposed to early life tactile stimulation showed attenuation of anxiety-like behavior, whereas an increase in exploratory behavior was found in Prkar1a+/- adolescent mice. The finding of behavioral differences that are apparent during adolescence in Prkar1a mice suggests that long-term exposure of the brain to increased PKA activity during critical developmental periods contributes to the anxiety-like phenotype noted in the adult animals with increased PKA activity.
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http://dx.doi.org/10.1016/j.bbr.2018.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5993604PMC
August 2018

The Key to Adrenal Insufficiency Education: Repetition, Repetition, Repetition.

Pediatr Endocrinol Rev 2017 Jun;14(Suppl 2):448-453

Organic Acid Research Section (OARS) of the Medical Genomics and Metabolic Genetics Branch (MGMGB) National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Described more than 150 years ago by Thomas Addison, adrenal gland dysfunction, while treatable, remains a clinically significant and potentially fatal disease. Vague and non-specific symptomatology can delay diagnosis of adrenal insufficiency and lead to adrenal crisis. Affected individuals may delay self-management due to knowledge deficits or lack of required therapies. Advanced practice nurses must remain vigilant for signs and symptoms of adrenal insufficiency and prevention of crisis. Education of patients and their caregivers/family members must emphasize early intervention with regards to adrenal insufficiency in order to prevent adrenal crisis. Repetition of education about sick day rules and demonstration of intramuscular injections should be incorporated as part of the routine follow-up care of all individuals to enhance their confidence and self-efficacy in self-management of adrenal insufficiency.
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http://dx.doi.org/10.17458/per.vol14.2017.kr.keyadrenalinsufficiencyDOI Listing
June 2017

Pediatric Cushing disease: disparities in disease severity and outcomes in the Hispanic and African-American populations.

Pediatr Res 2017 Aug 17;82(2):272-277. Epub 2017 May 17.

Section on Endocrinology and Genetics, Developmental Endocrinology Branch, and Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

BackgroundLittle is known about the contribution of racial and socioeconomic disparities to severity and outcomes in children with Cushing disease (CD).MethodsA total of 129 children with CD, 45 Hispanic/Latino or African-American (HI/AA) and 84 non-Hispanic White (non-HW), were included in this study. A 10-point index for rating severity (CD severity) incorporated the degree of hypercortisolemia, glucose tolerance, hypertension, anthropomorphic measurements, disease duration, and tumor characteristics. Race, ethnicity, age, gender, local obesity prevalence, estimated median income, and access to care were assessed in regression analyses of CD severity.ResultsThe mean CD severity in the HI/AA group was worse than that in the non-HW group (4.9±2.0 vs. 4.1±1.9, P=0.023); driving factors included higher cortisol levels and larger tumor size. Multiple regression models confirmed that race (P=0.027) and older age (P=0.014) were the most important predictors of worse CD severity. When followed up a median of 2.3 years after surgery, the relative risk for persistent CD combined with recurrence was 2.8 times higher in the HI/AA group compared with that in the non-HW group (95% confidence interval: 1.2-6.5).ConclusionOur data show that the driving forces for the discrepancy in severity of CD are older age and race/ethnicity. Importantly, the risk for persistent and recurrent CD was higher in minority children.
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http://dx.doi.org/10.1038/pr.2017.58DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5552413PMC
August 2017

Protein Kinase A and Anxiety-Related Behaviors: A Mini-Review.

Front Endocrinol (Lausanne) 2016 29;7:83. Epub 2016 Jun 29.

Department of Obstetrics and Gynecology, Center for Neuroscience and Regenerative Medicine, Uniformed Services University of the Health Sciences , Bethesda, MD , USA.

This review focuses on the anxiety related to cyclic AMP/protein kinase A (PKA) signaling pathway that regulates stress responses. PKA regulates an array of diverse signals that interact with various neurotransmitter systems associated with alertness, mood, and acute and social anxiety-like states. Recent mouse studies support the involvement of the PKA pathway in common neuropsychiatric disorders characterized by heightened activation of the amygdala. The amygdala is critical for adaptive responses leading to fear learning and aberrant fear memory and its heightened activation is widely thought to underpin various anxiety disorders. Stress-induced plasticity within the amygdala is involved in the transition from normal vigilance responses to emotional reactivity, fear over-generalization, and deficits in fear inhibition resulting in pathological anxiety and conditions, such as panic and depression. Human studies of PKA signaling defects also report an increased incidence of psychiatric disorders, including anxiety, depression, bipolar disorder, learning disorders, and attention deficit hyperactivity disorder. We speculate that the PKA system is uniquely suited for selective, molecularly targeted intervention that may be proven effective in anxiolytic therapy.
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http://dx.doi.org/10.3389/fendo.2016.00083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4925668PMC
July 2016

Cases of Psychiatric Morbidity in Pediatric Patients After Remission of Cushing Syndrome.

Pediatrics 2016 Apr 29;137(4). Epub 2016 Mar 29.

Program on Developmental Endocrinology & Genetics and Pediatric Endocrinology Inter-institute Training Program, National Institute of Child Health & Human Development, National Institutes of Health, Bethesda, Maryland;

Endogenous Cushing syndrome (CS) may have different effects in children than what has been described in adults. Previous studies of children and adolescents with CS have identified cognitive decline despite reversal of brain atrophy after remission of CS. Although the observations of parents of children and adolescents with CS support personality changes, significant psychopathology has not been described in the literature. We report 9 children who underwent successful surgery (transsphenoidal surgery [TSS] or resection of bronchial carcinoid) for treatment of CS and subsequently developed significant affective pathology. Affective symptoms included anger-rage outbursts, suicidal ideation, irritability, anxiety, and depression. One child, who committed suicide 60 months after TSS, had recently discontinued antidepressant medication. She had a history of anxiety during active CS and was treated with an anxiolytic. The 7 patients with onset of symptoms within 7 months of TSS were on glucocorticoid replacement, and 1-year follow-up evaluation showed recovery of hypothalamic-pituitary-adrenal axis and biochemical evidence of remission. The 2 patients who presented with onset of symptoms at 48 months or later underwent endocrine evaluation that showed biochemical evidence of remission and normal anterior pituitary hormone levels. This is the first report of affective symptoms and behavioral dysregulation, including suicidal ideation, in a subgroup of children and adolescents after remission of CS. Health care providers caring for children with CS who have been cured should continue to screen for mental illness, monitor for changes in behavior, and refer as appropriate to mental health professionals.
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http://dx.doi.org/10.1542/peds.2015-2234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811308PMC
April 2016

Studies of mice with cyclic AMP-dependent protein kinase (PKA) defects reveal the critical role of PKA's catalytic subunits in anxiety.

Behav Brain Res 2016 07 16;307:1-10. Epub 2016 Mar 16.

Section on Endocrinology and Genetics, Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, United States.

Cyclic adenosine mono-phosphate-dependent protein kinase (PKA) is critically involved in the regulation of behavioral responses. Previous studies showed that PKA's main regulatory subunit, R1α, is involved in anxiety-like behaviors. The purpose of this study was to determine how the catalytic subunit, Cα, might affect R1α's function and determine its effects on anxiety-related behaviors. The marble bury (MB) and elevated plus maze (EPM) tests were used to assess anxiety-like behavior and the hotplate test to assess nociception in wild type (WT) mouse, a Prkar1a heterozygote (Prkar1a(+/-)) mouse with haploinsufficiency for the regulatory subunit (R1α), a Prkaca heterozygote (Prkaca(+/-)) mouse with haploinsufficiency for the catalytic subunit (Cα), and a double heterozygote mouse (Prkar1a(+/-)/Prkaca(+/-)) with haploinsufficiency for both R1α and Cα. We then examined specific brain nuclei involved in anxiety. Results of MB test showed a genotype effect, with increased anxiety-like behavior in Prkar1a(+/-) and Prkar1a(+/-)/Prkaca(+/-) compared to WT mice. In the EPM, Prkar1a(+/-) spent significantly less time in the open arms, while Prkaca(+/-) and Prkar1a(+/-)/Prkaca(+/-) mice displayed less exploratory behavior compared to WT mice. The loss of one Prkar1a allele was associated with a significant increase in PKA activity in the basolateral (BLA) and central (CeA) amygdala and ventromedial hypothalamus (VMH) in both Prkar1a(+/-) and Prkar1a(+/-)/Prkaca(+/-) mice. Alterations of PKA activity induced by haploinsufficiency of its main regulatory or most important catalytic subunits result in anxiety-like behaviors. The BLA, CeA, and VMH are implicated in mediating these PKA effects in brain.
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http://dx.doi.org/10.1016/j.bbr.2016.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4853257PMC
July 2016

The Role of Protein Kinase A in Anxiety Behaviors.

Neuroendocrinology 2016 4;103(6):625-39. Epub 2016 Mar 4.

Section on Endocrinology and Genetics, Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Md., USA.

This review focuses on the genetic and other evidence supporting the notion that the cyclic AMP (cAMP) signaling pathway and its mediator, the protein kinase A (PKA) enzyme, which respond to environmental stressors and regulate stress responses, are central to the pathogenesis of disorders related to anxiety. We describe the PKA pathway and review in vitro animal studies (mouse) and other evidence that support the importance of PKA in regulating behaviors that lead to anxiety. Since cAMP signaling and PKA have been pharmacologically exploited since the 1940s (even before the identification of cAMP as a second messenger with PKA as its mediator) for a number of disorders from asthma to cardiovascular diseases, there is ample opportunity to develop therapies using this new knowledge about cAMP, PKA, and anxiety disorders.
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http://dx.doi.org/10.1159/000444880DOI Listing
May 2017

Kidney Stones as an Underrecognized Clinical Sign in Pediatric Cushing Disease.

J Pediatr 2016 Mar 15;170:273-7.e1. Epub 2015 Dec 15.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD.

Objective: To investigate the prevalence of kidney stones in a population of children with Cushing disease (CD) and to compare it with the prevalence of kidney stones in healthy children.

Study Design: Clinical and biochemical data from 139 pediatric patients with CD (68 females, 71 males) were analyzed retrospectively. Computed tomography scans were reviewed for kidney stones.

Results: Among 139 patients, 27 with CD (19.4%) had either radiographic evidence and/or a history of kidney stones. Those with kidney stones had higher urine free cortisol (P = .008) and transsphenoidal surgery at an older age (P = .007). The average urinary calcium/creatinine ratio was elevated in patients with CD (0.22 ± 0.11). The prevalence of kidney stones was higher in children with CD than in normal children (19.42% vs 1.0%; P < .001).

Conclusion: Our results illustrate that kidney stones are an underestimated complication of pediatric CD, especially when compared with the prevalence of nephrolithiasis in the general pediatric population. Long-term consequences for kidney function are not known and need to be studied.
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http://dx.doi.org/10.1016/j.jpeds.2015.11.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4769940PMC
March 2016

Long-Term Outcome of Bilateral Laparoscopic Adrenalectomy Measured by Disease-Specific Questionnaire in a Unique Group of Patients with Cushing's Syndrome.

Ann Surg Oncol 2015 Dec 13;22 Suppl 3:S699-706. Epub 2015 May 13.

Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Background: Laparoscopic bilateral adrenalectomy (LBA) is recommended for patients with bilateral adrenal disease and occult or unresectable ectopic Cushing's syndrome (CS). There are limited data on long-term outcomes after LBA, partly due to the lack of disease-specific tools for the measurement of impact on patients' health and quality of life.

Methods: We used a disease-specific questionnaire covering all major clinicopathologic characteristics of CS. We compared the outcome from LBA to a control group of 60 patients who had thyroidectomy (matched for age, gender, and time of surgery, 2:1 control-to-CS).

Results: Twenty-eight patients (20 women and 8 men) underwent LBA for CS. Of them, 24 patients (86 %) provided responses to our questionnaire. Ninety-two percent of patients' responses indicated a significant improvement of general Cushing's physical features with complete resolution reported in 59 % of responses. Significant improvement of associated biochemical abnormalities and comorbidities was reported in 83 % of patients' responses including complete reversal in 58 %. Significant improvement in emotional-behavioral symptoms was reported in 84 % of patients' responses with complete recovery in 53 %. All patients expressed satisfaction with LBA and significant improvement in their general health and self-reported quality of life. All of the improvements after LBA were statistically significant compared with the control group.

Conclusions: Our disease-specific questionnaire enables a clearer understanding of the association between the clinical, metabolic, and emotional-behavioral features of CS, its treatment with LBA, and long-term impact on patient-reported quality of life. This disease-specific questionnaire may be useful for future studies in patients with CS.
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http://dx.doi.org/10.1245/s10434-015-4605-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379917PMC
December 2015

Cushing syndrome: establishing a timely diagnosis.

J Pediatr Nurs 2015 May-Jun;30(3):528-30. Epub 2015 Feb 24.

Clinical Center Nursing Department, National Institutes of Health, Bethesda, MD; Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD. Electronic address:

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http://dx.doi.org/10.1016/j.pedn.2015.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420658PMC
March 2017

Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation.

N Engl J Med 2014 Dec 3;371(25):2363-74. Epub 2014 Dec 3.

The authors' affiliations are listed in the Appendix.

Background: Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood.

Methods: We performed clinical and genetic studies of samples obtained from 43 patients with gigantism and then sequenced an implicated gene in samples from 248 patients with acromegaly.

Results: We observed microduplication on chromosome Xq26.3 in samples from 13 patients with gigantism; of these samples, 4 were obtained from members of two unrelated kindreds, and 9 were from patients with sporadic cases. All the patients had disease onset during early childhood. Of the patients with gigantism who did not carry an Xq26.3 microduplication, none presented before the age of 5 years. Genomic characterization of the Xq26.3 region suggests that the microduplications are generated during chromosome replication and that they contain four protein-coding genes. Only one of these genes, GPR101, which encodes a G-protein-coupled receptor, was overexpressed in patients' pituitary lesions. We identified a recurrent GPR101 mutation (p.E308D) in 11 of 248 patients with acromegaly, with the mutation found mostly in tumors. When the mutation was transfected into rat GH3 cells, it led to increased release of growth hormone and proliferation of growth hormone-producing cells.

Conclusions: We describe a pediatric disorder (which we have termed X-linked acrogigantism [X-LAG]) that is caused by an Xq26.3 genomic duplication and is characterized by early-onset gigantism resulting from an excess of growth hormone. Duplication of GPR101 probably causes X-LAG. We also found a recurrent mutation in GPR101 in some adults with acromegaly. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.).
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http://dx.doi.org/10.1056/NEJMoa1408028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4291174PMC
December 2014

A gender-dependent analysis of Cushing's disease in childhood: pre- and postoperative follow-up.

Clin Endocrinol (Oxf) 2015 Jul 2;83(1):72-7. Epub 2015 Feb 2.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

Objective: To analyse gender differences in the clinical presentation and recovery of paediatric patients with Cushing's disease (CD) after transsphenoidal surgery (TSS). Indeed, gender differences between paediatric patients with CD during presentation, after TSS and postoperative recovery have not been adequately studied.

Design: Data were obtained and retrospectively analysed from clinical reports and biochemical tests at the time of presentation, 5-9 days after TSS and at the 6 and 12 months postoperative follow-up visits to determine hypothalamic-pituitary-adrenal axis (HPAA) recovery.

Patients: Data from 102 paediatric patients (48 females, 54 males, mean age 12.9 ± 3.0) with CD who underwent TSS at the National Institute of Health (NIH) Clinical Center between 1997 and 2011.

Results: There was equal distribution of paediatric CD between males and females (53% vs 47%; n = 102, P = 0.484). Males were more likely than females to present with higher mean BMI Z-scores (2.2 ± 0.7 vs 1.9 ± 0.6, P = 0.0079), lower mean height Z-scores (-1.2 ± 1.3 vs -0.7 ± 1.1, P = 0.0467) and higher median plasma ACTH (12.2 vs 8.5 pmol/l; P = 0.0495). Females did not present more frequently with any single sign or symptom. No significant differences were found between males and females for CD cure rates 5-9 days after TSS (87.0% males vs 87.5% females, P = 1.0), long-term cure rates (86.5% vs 93.7%; n = 69; P = 0.4374) and HPAA recovery time (11.2 ± 2.5 vs 11.7 ± 2.5 months; n = 47; P = 0.1992).

Conclusions: Paediatric CD is found to have equal distribution between males and females, but male patients present with elevated BMI and potentially shorter height and higher plasma ACTH. There is no significant difference in the cure rate or HPAA recovery time after TSS between males and females.
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http://dx.doi.org/10.1111/cen.12644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342464PMC
July 2015

Death in pediatric Cushing syndrome is uncommon but still occurs.

Eur J Pediatr 2015 Apr 23;174(4):501-7. Epub 2014 Sep 23.

Section on Endocrinology and Genetics and Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, MD, 20892, USA,

Unlabelled: Cushing syndrome (CS) in children is rare. Delayed diagnosis and treatment of CS may be associated with increased morbidity and, unfortunately, mortality. We performed a retrospective review of all patients with CS under the age of 18 years referred to the National Institutes of Health (NIH) from 1998 to 2013 in order to describe deceased patients among cases of pediatric CS referred to the National Institutes of Health (NIH). The deaths of four children (three females and one male), aged 7.5-15.5 years (mean age 11.2 years) with length of disease 2-4 years, were recorded among 160 (2.5 %) children seen at or referred to the NIH over the last 15 years. All died at different institutions, prior to coming to the NIH (two) or after leaving NIH (two). Presenting symptoms included increasing weight and decreasing height gain, facial plethora, dorsocervical fat pad (webbed neck), striae, headache, vision disturbances, and depression and other mood or behavior changes; there were no differences between how these patients presented and the others in our cohort. The causes of CS in the deceased patients were also not different, in fact, they spanned the entire spectrum of CS: pituitary disease (one), ectopic corticotropin production (one), and primary adrenal hyperplasia (one). In one patient, the cause of CS could not be verified. Three died of sepsis and one due to residual disease and complications of the primary tumor.

Conclusions: Despite the advances in early diagnosis and treatment of pediatric CS, a 2.5 % mortality rate was identified in a large cohort of patients with this condition referred to an experienced, tertiary care referral center (although these deaths occurred elsewhere). Pediatricians need to recognize the possibility of death, primarily due to sepsis, in a patient with pediatric CS and treat accordingly.
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http://dx.doi.org/10.1007/s00431-014-2427-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4370787PMC
April 2015

Deletions of the PRKAR1A locus at 17q24.2-q24.3 in Carney complex: genotype-phenotype correlations and implications for genetic testing.

J Clin Endocrinol Metab 2014 Jan 20;99(1):E183-8. Epub 2013 Dec 20.

Section on Endocrinology and Genetics (P.S., E.L., F.R.F., I.L., E.G., M.F.K., C.L., C.A.S.), Program on Developmental Endocrinology and Genetics and Pediatric Endocrinology Inter-institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Department of Biochemistry and Molecular Medicine (A.H.), The George Washington University, Washington, D.C. 20037; Department of Molecular Medicine (A.V., A.F., O.Z.), University of Pavia, Pavia 27100, Italy; Division of Genetics and Endocrinology (A.D., I.A.H.), Boston Children's Hospital, Boston, Massachusetts; Regional Medical Genetics Center (P.J.M.), Queens University Belfast, Belfast BT9 7AB, United Kingdom; and Quest Diagnostics Nichols Institute (E.D.S., M.A.S., J.C.K., Z.D., P.M.), Chantilly, Virginia 20151.

Background: Carney complex (CNC) is a multiple neoplasia syndrome caused by PRKAR1A-inactivating mutations. One-third of the patients, however, have no detectable PRKAR1A coding sequence defects. Small deletions of the gene were previously reported in few patients, but large deletions of the chromosomal PRKAR1A locus have not been studied systematically in a large cohort of patients with CNC.

Setting: A tertiary care referral center was the setting for analysis of an international cohort of patients with CNC.

Methods: Methods included genome-wide array analysis followed by fluorescent in situ hybridization, mRNA, and other studies as well as a retrospective analysis of clinical information and phenotype-genotype correlation.

Results: We detected 17q24.2-q24.3 deletions of varying size that included the PRKAR1A gene in 11 CNC patients (of 51 tested). Quantitative PCR showed that these patients had significantly lower PRKAR1A mRNA levels. Phenotype varied but was generally severe and included manifestations that are not commonly associated with CNC, presumably due to haploinsufficiency of other genes in addition to PRKAR1A.

Conclusions: A significant number (21.6%) of patients with CNC that are negative in currently available testing may have PRKAR1A haploinsufficiency due to genomic defects that are not detected by Sanger sequencing. Array-based studies are necessary for diagnostic confirmation of these defects and should be done in patients with unusual and severe phenotypes who are PRKAR1A mutation-negative.
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http://dx.doi.org/10.1210/jc.2013-3159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3879675PMC
January 2014

Quality of life and other outcomes in children treated for Cushing syndrome.

Authors:
Margaret F Keil

J Clin Endocrinol Metab 2013 Jul 2;98(7):2667-78. Epub 2013 May 2.

Section on Endocrinology Genetics, Program on Developmental Endocrinology Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.

Context: Cushing syndrome (CS) in children is associated with residual impairment in measures of health-related quality of life, even after successful resolution of hypercortisolemia, highlighting the need for early identification of morbidities and improvements in long-term management of these patients.

Evidence Acquisition And Synthesis: A PubMed, Scopus, and Web of Science search of articles from 1900 onward identified available studies related to quality of life and complications of pediatric CS as well as important historical articles. This review summarizes studies through November 2012 and highlights recent developments.

Conclusions: A review of the literature identifies significant morbidities associated with CS of pediatric onset, which must not be treated in isolation. CS affects children and adolescents in many ways that are different than adults. Post-treatment challenges for the child or adolescent treated for CS include: optimize growth and pubertal development, normalize body composition, and promote psychological health and cognitive maturation. All these factors impact health-related quality of life, which is an important outcome measure to assess the burden of disease as well as the effect of treatment. Future research efforts are needed to improve management of the physical, psychological, and emotional aspects of this disease in order to diminish the residual impairments experienced by the pediatric CS patient population.
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http://dx.doi.org/10.1210/jc.2013-1123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3701267PMC
July 2013

Salivary cortisol: a tool for biobehavioral research in children.

Authors:
Margaret F Keil

J Pediatr Nurs 2012 Jun 8;27(3):287-9. Epub 2012 Mar 8.

Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development,The National Institutes of Health, Bethesda, MD, USA.

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http://dx.doi.org/10.1016/j.pedn.2012.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3335961PMC
June 2012

Recovery of the hypothalamic-pituitary-adrenal axis in children and adolescents after surgical cure of Cushing's disease.

J Clin Endocrinol Metab 2012 May 7;97(5):1483-91. Epub 2012 Mar 7.

Section on Endocrinology and Genetics Program on Developmental Endocrinology and Genetics, National Institutes of Health, Bethesda, Maryland 20892, USA.

Context: Recovery of the hypothalamic-pituitary-adrenal axis (HPAA) after transsphenoidal surgery (TSS) for Cushing's disease (CD) in children has not been adequately studied.

Objective: Our objective was to assess time to recovery of the HPAA after TSS in children with CD.

Design And Setting: This was a case series at the National Institutes of Health Clinical Center.

Patients: Fifty-seven patients with CD (6-18 yr, mean 13.0 ± 3.1 yr) given a standard regimen of glucocorticoid tapering after TSS were studied out of a total of 73 recruited.

Interventions: ACTH (250 μg) stimulation tests were administered at approximately 6-month intervals for up to 36 months. Age, sex, pubertal status, body mass index, length of disease, midnight cortisol, and urinary free cortisol at diagnosis were analyzed for effects on recovery.

Main Outcome Measure: The main outcome measure was complete recovery of the HPAA as defined by a cortisol level of at least 18 μg/dl in response to 250 μg ACTH.

Results: Full recovery was reached by 43 (75.4%) of 57 patients, with 29 of the 43 (67.4%) and 41 of the 43 (95.3%) recovering by 12 and 18 months, respectively. The overall mean time to recovery was 12.6 ± 3.3 months. Kaplan-Meier survivor function estimated a 50% chance of recovering by 12 months after TSS and 75% chance of recovering within 14 months. By receiver operating characteristic curve assessment, the cutoff of at least 10-11 μg/dl of cortisol as the peak of ACTH stimulation testing at 6 months after TSS yielded the highest sensitivity (70-80%) and specificity (64-73%) to predict full recovery of the HPAA at 12 months. Two of the four patients that recovered fully within 6 months had recurrent CD.

Conclusions: Although this is not a randomized study, we present our standardized tapering regimen for glucocorticoid replacement after TSS that led to recovery of the HPAA in most patients within the first postoperative year. Multiple factors may affect this process, but an early recovery may indicate disease recurrence.
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http://dx.doi.org/10.1210/jc.2011-2325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3339895PMC
May 2012

Anthropometric measures and fasting insulin levels in children before and after cure of Cushing syndrome.

Clin Nutr 2012 Jun 7;31(3):359-63. Epub 2011 Dec 7.

Section on Endocrinology Genetics, Program on Developmental Endocrinology Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.

Background & Aims: Children with Cushing syndrome present with growth delay and excess adiposity that tends to be generalized rather than centripetal. There are no prospective studies of this phenotype as it evolves before and after treatment in children. The aims of this study were to evaluate children prior to and one-year after surgical cure compared to controls and to determine fasting insulin levels and their possible association with waist circumference and waist-height ratio, pre- and post-cure of Cushing syndrome.

Methods: 30 children with Cushing syndrome were evaluated prior to and one-year post-treatment and compared to 14 age and body mass index-matched controls.

Results: Only triceps skin fold z- score showed a significant difference between patients with active Cushing syndrome and controls. A positive correlation between fasting insulin levels and waist circumference z- score was found for children with Cushing syndrome; this association persisted one-year following cure.

Conclusions: Unlike adults affected with Cushing syndrome, upper arm muscle area of children with Cushing syndrome did not differ from obese children without Cushing syndrome. The persistence of a positive correlation between waist circumference and fasting insulin despite remission of Cushing syndrome suggests that children with a history of Cushing syndrome may have an increased risk for adverse long-term effects of increased abdominal fat mass.
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http://dx.doi.org/10.1016/j.clnu.2011.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319516PMC
June 2012

Anxiety phenotype in mice that overexpress protein kinase A.

Psychoneuroendocrinology 2012 Jun 22;37(6):836-43. Epub 2011 Oct 22.

Section on Endocrinology and Genetics, Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD 20892, USA.

The role of cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) signaling in the molecular pathways involved in fear and memory is well established. Prior studies in our lab reported that transgenic mice with an inactivating mutation in Prkar1a gene (codes for the 1-alpha regulatory subunit (R1α) of PKA) exhibited behavioral abnormalities including anxiety and depression. In the present study, we examined the role of altered PKA signaling on anxiety-like behaviors in Prkar1a(+/-) mice compared to wild-type (WT) littermates. The elevated plus maze (EPM) and marble bury (MB) tests were used to assess anxiety-like behavior. The hotplate test was performed to evaluate analgesia. We further examined the impact of the Prkar1a inactivating mutation on PKA activity in specific nuclei of the brain associated with anxiety-like behavior. Results for the MB test showed a genotype effect, with increased anxiety-like behavior in Prkar1a(+/-) mice, compared to WT littermates (p<0.05). MANOVA analysis showed a significant genotype difference in anxiety-like behavior in the EPM between WT and Prkar1a(+/-) mice on combined dependent variables (open arm time and open to total time ratio; p<0.05). Results of hotplate testing showed no genotype effect however; the expected sex difference was noted. Analysis of PKA activity showed the loss of one Prkar1a allele led to an increase in basal and cAMP-stimulated kinase activity in both the basolateral and central amygdala. These results suggest that the alteration in PKA signaling in Prkar1a(+/-) mice is not a ubiquitous effect; and supports the importance of cAMP/PKA pathway in neurobiological processes involved in anxiety and fear sensitization.
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http://dx.doi.org/10.1016/j.psyneuen.2011.09.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3320692PMC
June 2012

Cushing's syndrome secondary to isolated micronodular adrenocortical disease (iMAD) associated with rapid onset weight gain and negative abdominal MRI findings in a 3 year old male.

J Pediatr Endocrinol Metab 2010 Jun;23(6):613-20

Endocrinology, Seattle Children's Hospital, Seattle, WA, USA.

Cushing's syndrome (CS) is uncommon in childhood. CS may be either dependent or independent of adrenocorticotrophic hormone (ACTH). ACTH independent micronodular adrenocortical (MAD) disease may present in the second to third decade of life or between ages 2-3 years. It may occur in isolation, or as a part of the Carney complex and it represents an elusive entity to diagnose. We present a 3 year 7 month old boy with isolated MAD (iMAD). Abdominal CT revealed prominent mildly lobulated anteromedial margin of adrenals with nodular appearance. Cardiac echo, thyroid and testicular ultrasounds performed as a work up for Carney complex were normal. Bilateral adrenalectomy confirmed MAD as the cause of CS.We present the history and identification of a unique case of iMAD.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3094852PMC
http://dx.doi.org/10.1515/jpem.2010.101DOI Listing
June 2010

Effects of Cushing disease on bone mineral density in a pediatric population.

J Pediatr 2010 Jun 10;156(6):1001-1005. Epub 2010 Mar 10.

Section on Endocrinology Genetics, Program on Developmental Endocrinology Genetics, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health, Bethesda, MD; Pediatric Endocrinology Inter-Institute Training Program, National Institutes of Health, Bethesda, MD.

Objective: To evaluate bone mineral density (BMD) in children with Cushing disease before and after transphenoidal surgery (TSS).

Study Design: Hologic dual-energy x-ray absorptiometry (DXA) scans of 35 children with Cushing disease were analyzed retrospectively. Sixteen of the 35 patients had follow-up DXA scans performed 13 to 18 months after TSS. BMD and bone mineral apparent density (BMAD) for lumbar spine (LS) L1 to L4 and femoral neck (FN) were calculated.

Results: Preoperatively, 38% and 23% of patients had osteopenia of the LS and FN, respectively. Both BMD and BMAD Z-scores of the LS were worse than those for the FN (-1.60 +/- 1.37 versus -1.04 +/- 1.19, P = .003), and (-1.90 +/- 1.49 versus -0.06 +/- 1.90, P < .001); postoperative improvement in BMD and BMAD were more pronounced in LS than in the FN (0.84 +/- 0.88 versus 0.15 +/- 0.62, P<.001; and 0.73 +/- 1.13 versus -0.26 +/- 1.21, P = .015). Pubertal stage, cortisol levels, and length of disease had no effect on BMD.

Conclusions: In children with Cushing disease, vertebral BMD was more severely affected than femoral BMD and this effect was independent of degree or duration of hypercortisolism. BMD for the LS improved significantly after TSS; osteopenia in this group may be reversible.
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http://dx.doi.org/10.1016/j.jpeds.2009.12.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2875346PMC
June 2010

Hypoglycemia during acute illness in children with classic congenital adrenal hyperplasia.

J Pediatr Nurs 2010 Feb 4;25(1):18-24. Epub 2008 Nov 4.

Reproductive Medicine and Biology Branch, National Institutes of Health, Bethesda, MD, USA.

Congenital adrenal hyperplasia (CAH) describes a group of genetic, autosomal recessive conditions, where there is a block in cortisol biosynthesis. Approximately 95 percent of cases are due to 21-hydroxylase deficiency, which is discussed in this article. Patients with the severe or classic form of CAH have epinephrine deficiency in addition to cortisol deficiency. Both epinephrine and cortisol are important counterregulatory hormones and help prevent hypoglycemia during physical stress. This is the first prospective study to evaluate the incidence of hypoglycemia during acute illness in children with classic CAH. Our objective was to examine blood glucose levels and symptoms of these children during the physical stressor of a typical acute illness managed at home. Twenty patients, ages 3 to 10 years with classic CAH participated. Parents were instructed regarding management of illnesses, home blood glucose monitoring and questionnaire completion. Over 29 months, 20 patients completed questionnaires and 6 patients performed home blood glucose monitoring. A blood glucose of <60 mg/dL was documented in 3 out of 8 monitored acute illness episodes, and in 2 out of 6 of monitored children. The acute illness episodes with documented blood glucose <60 mg/dL were not associated with vomiting. Our data suggest that children with classic CAH may experience lowering of blood glucose during illnesses, and patient education regarding the management of common childhood illness should include glucose supplementation.
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http://dx.doi.org/10.1016/j.pedn.2008.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2819226PMC
February 2010

Advances in the Diagnosis, Treatment, and Molecular Genetics of Pituitary Adenomas in Childhood.

US Endocrinol 2009 Feb;4(2):81-85

Office of the Chief, Program on Developmental Endocrinology and Genetics (PDEGEN).

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2779046PMC
http://dx.doi.org/10.17925/ee.2008.04.02.81DOI Listing
February 2009