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Background After adoption, children exposed to institutionalized care show significant improvement, but incomplete recovery of growth and developmental milestones. There is a paucity of data regarding risk and protective factors in children adopted from institutionalized care. This prospective study followed children recently adopted from institutionalized care to investigate the relationship between family environment, executive function, and behavioral outcomes. Methods Anthropometric measurements, physical examination, endocrine and bone age evaluations, neurocognitive testing, and behavioral questionnaires were evaluated over a 2-year period with children adopted from institutionalized care and non-adopted controls. Results Adopted children had significant deficits in growth, cognitive, and developmental measurements compared to controls that improved; however, residual deficits remained. Family cohesiveness and expressiveness were protective influences, associated with less behavioral problems, while family conflict and greater emphasis on rules were associated with greater risk for executive dysfunction. Conclusions Our data suggest that a cohesive and expressive family environment moderated the effect of pre-adoption adversity on cognitive and behavioral development in toddlers, while family conflict and greater emphasis on rules were associated with greater risk for executive dysfunction. Early assessment of child temperament and parenting context may serve to optimize the fit between parenting style, family environment, and the child’s development. Impact Children who experience institutionalized care are at increased risk for significant deficits in developmental, cognitive, and social functioning associated with a disruption in the development of the prefrontal cortex. Aspects of the family caregiving environment moderate the effect of early life social deprivation in children. Family cohesiveness and expressiveness were protective influences, while family conflict and greater emphasis on rules were associated with a greater risk for executive dysfunction problems. This study should be viewed as preliminary data to be referenced by larger studies investigating developmental and behavioral outcomes of children adopted from institutional care.

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.

Objective To investigate the effect of hypercortisolism on the developing brain we performed clinical, cognitive, and psychological evaluation of children with Cushing disease (CD) at diagnosis and 1 year after remission. Study design Prospective study of 41 children with CD. Children completed diverse sets of cognitive measures before and 1 year after remission. Neuropsychological evaluation included the Wechsler Intelligence Scale, California Verbal Learning Test, Trail Making Test, the combined subset scores of Wide Range Achievement Test and Woodcock-Johnson Psychoeducational Battery Test of Achievement, and the Behavioral Assessment System for Children. Results Comprehensive cognitive evaluations at baseline and 1 year following cure revealed significant decline mostly in nonverbal skills. Decrements occurred in most of the various indices that measure all aspects of cognitive function and younger age and early pubertal stage largely contributed to most of this decline. Results indicated that age at baseline was associated with positive regression weights for changes in scores for verbal, performance, and full intelligence quotient (IQ) scores and for subtests arithmetic, picture completion, coding, block design, scores; indicating that older age at baseline was associated with less of a deterioration in cognitive scores from pre- to posttreatment. Conclusion Our findings suggest that chronic glucocorticoid excess and accompanying secondary hormonal imbalances followed by eucortisolemia have detrimental effects on cognitive function in the developing brain; younger age and pubertal stage are risk factors for increased vulnerability, while older adolescents have cognitive vulnerabilities like that of adult patients affected with CD.

We recently reported the use of optical imaging technology to quantify facial plethora in endogenous Cushing syndrome (CS). In the present study, we studied a larger cohort of patients with Cushing disease (CD) and examined water content fraction as well as blood volume fraction as bio-optic markers for determining the efficacy of this methodology as a predictor of lasting remission after surgery for CS. We imaged 49 patients before and after transsphenoidal surgery (TSS) for Cushing disease (CD); 22 patients were also seen at 3–6 months, and 13 patients 12 months post-operatively. On all patients, we used multi-spectral imaging (MSI) to evaluate hemodynamic distributions as well as water content at a specific area of the face. We found a decrease in blood volume fraction after vs. before surgical treatment in the tested facial area in 37 of the 40 patients, as determined with biochemical markers (p

Background: The role of the cAMP/PKA signaling in molecular pathways involved in fear memory is well established: PKA is required for fear memory formation and is a constraint for fear extinction. Previously we reported that a Prkar1a heterozygote (HZ) mouse that was developed in our lab to investigate Carney complex (CNC), the disease caused by PRKAR1A mutations, showed brain region-specific increased PKA activity that was associated with anxiety-like behavioral phenotype and threat bias (Keil, 2010, 2013). We hypothesized that Prkar1a+/- (HZ) mice would have deficits in fear extinction behavior. Brain derived neurotrophic factor (BDNF) has a critical role in formation of fear memory and its transcription is regulated by PKA/CREB. A mouse model with down regulation of PKA provides an opportunity for the first time to investigate the effect of altered PKA signaling on fear conditioning and extinction. Method: Fear conditioning, fear extinction learning, and fear extinction recall were tested in adult male HZ and wild-type (WT) mice as follows: fear conditioning training followed 24hr later by extinction training (new context), then 24hr later by extinction recall training. Percentage of time freezing was used to assess conditioned fear response. We measured BDNF gene expression in brain regions after completion of extinction recall training. Results: As expected, fear conditioning (learning) behavior was similar in HZ and WT mice. However, HZ mice showed a significant deficit in the early phase of fear extinction learning compared to WT. There was no difference in extinction recall between genotypes. Alterations in BDNF gene expression in the prefrontal cortex and amygdala was associated with deficit in fear extinction. Conclusion: Mice with a downregulation of Prkar1a gene demonstrate intact fear conditioning but impaired fear extinction learning, consistent with prior studies that report that PKA inhibition is necessary to facilitate extinction learning. Prkar1a+/- mice provide a valuable model to investigate impaired fear extinction to identify mechanisms for therapeutic targets for anxiety and trauma-related disorders.

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.

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.

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=0.0025) and a trend towards increased grooming behavior (p=0.06). 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 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 show AKAP13 involvement 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.

Background: Previously we reported impairment in quality of life (QoL) measures in children with Cushing disease (CD) by parent proxy; however, little is known about QoL measures from the affected child’s perspective. Method: Prospective study of 48 (26 females, Age:11.5±3.0 yr.) children diagnosed with CD. Prior to treatment, the Child Health Questionnaire (CHQ) was used to assess QoL by parent (proxy) and child report. Results: In children with active CD, there was a discrepancy between parent and child responses for mental health and self-esteem subscales. Child responses were significantly lower than parent responses (lower scores indicate poorer function) for mental health (56 ± 2 vs. 67 ± 2, p&lt0.001) and self-esteem (32.8 ±3 vs. 60.5 ±3, p&lt0.001). No significant differences were found between parent vs.child report for other subscale scores of the CHQ. Conclusion: This is the first study to compare child vs. parent report of health-related quality of life children with active CD. Parent reports underestimated the impact of CD on quality of life measures for mental health and self-esteem. It is important for clinicians to obtain information about health-related quality of life from the child’s perspective in order to guide management and take precautionary measures to alleviate negative outcomes.

17β-Estradiol is known to regulate energy metabolism and body weight. Ovariectomy results in body weight gain while estradiol administration results in a reversal of weight gain. Isoflavones, found in rodent chow, can mimic estrogenic effects making it crucial to understand the role of these compounds on metabolic regulation. The goal of this study is to examine the effect of dietary isoflavones on body weight regulation in the ovariectomized rat. This study will examine how dietary isoflavones can interact with estradiol treatment to affect body weight. Consistent with previous findings, animals fed an isoflavone-rich diet had decreased body weight (p

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.

Background: Previously, we reported a decline in cognitive scores of children with endogenous Cushing syndrome (CS); however, the generalizability of the findings is limited due to the small sample size. The present study investigated the relationship between change in cognitive scores prior to and one-year post transsphenoidal surgery, with age at initial presentation, duration of illness, and history of premature adrenarche (PA) as covariates. Both cortisol and adrenal androgens have key roles in the organizational and the maturational changes in brain structure and function during adolescence. Method: Prospective study of 41 children (17 females; 12 ±3 yr.) diagnosed with Cushing’s disease (CD), who completed diverse sets of cognitive measures prior to and one-year post-remission: (Wechsler Intelligence Scale for Children (WISC) or Wechsler Adult Intelligence Scale of Intelligence (WASI), Woodcock Johnson Psychoeducational Battery, California Verbal Learning, and Trail making tests. Linear regression of delta change in IQ test scores (from baseline to 1-year remission) with covariates of age, duration of illness, and history of premature adrenarche was used to analyze the data. Results: At baseline, children with CD had average to above average intelligence. Change in scores from baseline to 1-year remission was significant for performance IQ (PIQ), verbal IQ (VIQ), full IQ (FIQ), subsets: information, similarities, arithmetic, vocabulary, coding, and block design (p

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.

Objectives: Chronic hypercortisolemia suppresses AVP secretion. Copeptin makes up the C-terminal portion of the AVP precursor pre-pro-AVP, is released in stoichiometric amounts with AVP, and is a stable surrogate marker of AVP.A post-operative increase in plasma copeptin was hypothesized to be a marker of remission of Cushing Disease (CD). Methods: Plasma copeptin was obtained in patients with CD before and daily in the first week after transsphenoidal surgery (TSS), measured using the Brahm Kryptor Compact PLUS sandwich immunofluorescent assay. Urine output, serum sodium, urine specific gravity, and urine/serum osmolality were used to determine development of central diabetes insipidus (DI) and/or syndrome of inappropriate anti-diuretic hormone secretion (SIADH). Change in copeptin reflects pre-TSS to peak post-TSS copeptin levels. Statistical analyses were completed using non-parametric tests. Results are presented as median (inter-quartile range). Results: Forty-four patients (64% female, 7-55 years old) were included. After TSS, 8 (18%) developed DI, 13 (30%) developed SIADH, 4 (9%) developed both DI and SIADH, and 19 (43%) developed neither. Thirty-three patients had a follow-up at 3-6 months. Overall, there was no difference in peak post-TSS copeptin for patients in remission versus those not in remission [6.1 pmol/L (4.3-12.1) vs. 7.3 pmol/L (5.4-8.4), p=0.88]. There was, also, no difference in the copeptin change for those in remission versus not in remission [2.3 pmol/L (-0.5-8.2) vs. 0.1 pmol/L (-0.1-2.2), p=0.46]. When we excluded patients who developed a water balance disorder postoperatively, there was a difference in peak post-TSS copeptin for those in remission [10.2 pmol/L (6.9-21.0)] vs. those not in remission [5.4 pmol/L (4.6-7.3), p=0.032], but not in the change in copeptin for those in remission vs. not in remission [5.1 pmol/L (0.3-19.5) vs. 1.1 pmol/L (-0.1-2.2), p=0.39]. Conclusions: Post-TSS plasma copeptin may be a useful early marker to predict remission of CD after TSS. However, the utility of this test may be limited to those who do not develop water balance disorders post-operatively. Additional studies with larger sample sizes are needed to confirm these findings and to determine a post-operative plasma copeptin cutoff level that may predict remission of CD.

We recently reported the use of optical imaging technology to quantify facial plethora in endogenous Cushing syndrome (CS). In the present study, we studied a larger cohort of patients with Cushing disease (CD) and examined water content fraction as well as blood volume fraction as bio-optic markers for determining the efficacy of this methodology as a predictor of lasting remission after surgery for CS. We imaged 49 patients before and after transsphenoidal surgery (TSS) for Cushing disease (CD); 22 patients were also seen at 3–6 months, and 13 patients 12 months post-operatively. On all patients, we used multi-spectral imaging (MSI) to evaluate hemodynamic distributions as well as water content at a specific area of the face. We found a decrease in blood volume fraction after vs. before surgical treatment in the tested facial area in 37 of the 40 patients, as determined with biochemical markers (p < 0.001). All patients that were followed up for up to 12 months showed the same decrease from preoperative values and they remained in remission from CD. We conclude that MSI can be used for the evaluation of remission from CD, at least in the immediate post-operative period and up to one year after surgery. The use of this technology can supplement biochemical and other testing for the evaluation of the various treatment modalities available for patients with CD.

This chapter introduces evidence-based practice and research, explaining the nurse’s role in accessing and appraising evidence for endocrinology nursing practice. The contribution of different types of research studies to the evidence base is discussed. The chapter considers how best evidence can be implemented in practice, with reference to quality improvement methods. Nurses are in a good position to identify gaps in the available evidence and identify new research questions. Clinical academic roles provide the opportunity for nurses to take forward their research ideas and combine clinical nursing with research. Clinical research is essential for finding new treatments and improving patient care and so clinical research nurses make a vital contribution, focusing on the care of research participants within clinical research studies. All research must be conducted in accordance with international standards for research ethics and local processes for ethical scrutiny. This chapter’s sections on evidence-based practice, clinical academic roles and clinical research nursing all include application to endocrinology nursing.

Cushing’s syndrome is a rare disorder characterized by prolonged exposure to excessive concentrations of glucocorticoids. Endogenous Cushing’s syndrome, which will be the focus of this chapter, is usually divided into adrenocorticotropic hormone (ACTH)-dependent and ACTH-independent causes. ACTH-dependent Cushing’s syndrome accounts for approximately 80–85% of all cases and is primarily due to excess ACTH production from a pituitary adenoma. This is also called Cushing’s disease. In Cushing’s disease, pituitary adrenocorticotropic hormone (ACTH) oversecretion (from corticotrophs) prompts bilateral adrenocortical hyperplasia, excess production of cortisol, adrenal androgens, and 11-deoxycorticosterone which together cause the clinical and biological features of this disease. The most common clinical features of Cushing’s syndrome include central obesity, diabetes, hypertension, moon facies, facial plethora, proximal muscle weakness, and reddish purple striae and in children, impaired growth with concomitant weight gain.

Context Genomic losses/gains are associated with cancer progression and prognosis. In pituitary adenomas, analyses of copy number variations (CNVs) have shown that a subset of adenomas have higher genomic variability. However, whether CNVs are associated with tumor aggressiveness and prognosis has not been determined. Objective We hypothesized that somatic CNVs of pituitary tumors may play a role in the progression and aggressiveness of pituitary corticotropinomas in children and adolescents. Samples and design Paired germline and tumor DNA samples from 27 pediatric patients with Cushing disease (CD), were subjected to whole exome sequencing. Somatic CNVs were identified using the ExomeDepth tool. Clinical, histological, and biochemical data from the patients were collected and correlated with the results of the CNV analysis. Results Chromosomal instability, involving 23% to 59% of the tumor genome, was noted in 5 of the 27 samples (18.5%). The patients with tumors showing chromosomal instability had similar clinical and biochemical characteristics to the remaining patients, except for tumor size, which was larger (median size 18 mm vs 5.5 mm, P = 0.005). Tumors with chromosomal instability were also associated with a higher rate of invasion of the cavernous sinus (P = 0.029). There was insufficient information on persistence or recurrence of CD to determine whether the risk was higher in those with chromosomal instability. Conclusions A subgroup of corticotropinomas demonstrates chromosomal instability that is associated with markers of aggressiveness of these adenomas. It appears that more genomic gains/losses in a few, rare corticotropinomas may predict poorer prognosis for pediatric patients with CD.

Cushing syndrome (CS) is a multisystem disorder that results from the prolonged exposure to excess glucocorticoids. It is characterized by growth deceleration, weight gain, truncal obesity, facial plethora, and hypertension. In children, CS most commonly results from the exogenous administration of steroids. Endogenous causes of CS are rare, and include ACTH overproduction from a pituitary adenoma, or adrenal hypersecretion of cortisol secondary to an adenoma, carcinoma, or hyperplasia; ectopic causes are rare. Clinical practice guidelines, including diagnostic algorithms are available to assist clinicians; patients should be referred to multidisciplinary centers of excellence with experience in endocrinology and surgery. CS in children may be associated with distinct germline and somatic mutations. Early detection and treatment is essential to reduce associated acute and long-term morbidity and potential death.

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.

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.

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.).

ObjectiveTo assess skeletal maturity by measuring bone age (BA) in children with Cushing syndrome (CS) before and 1-year after transsphenoidal surgery or adrenalectomy, and to correlate BA with hormone levels and other measurements.Study designThis case series conducted at the National Institutes of Health Clinical Center included 93 children with Cushing disease (CD) (43 females; mean age, 12.3 ± 2.9 years) and 31 children with adrenocorticotropic hormone-independent CS (AICS) (22 females, mean age 10.3 ± 4.5 years). BA was obtained before surgery and at follow-up. Outcome measures were comparison of BA in CD vs AICS and analysis of the effects of hypercortisolism, insulin excess, body mass index, and androgen excess on BA.ResultsTwenty-six of the 124 children (21.0%) had advanced BA, compared with the expected general population prevalence of 2.5% (P < .0001). Only 4 of 124 (3.2%) had delayed BA. The majority of children (76%) had normal BA. The average BA z-score was similar in the children with CD and those with AICS (0.6 ± 1.4 vs 0.5 ± 1.8; P=.8865). Body mass index SDS and normalized values of dehydroepiandrosterone, dehydroepiandrosterone sulfate, androsteonedione, estradiol, and testosterone were all significantly higher in the children with advanced BA vs those with normal or delayed BA. Fifty-nine children who remained in remission from CD had follow-up BA 1.2 ± 0.3 years after transsphenoidal surgery, demonstrating decreased BA z-score (1.0 ± 1.6 vs 0.3 ± 1.4; P < .0001).ConclusionContrary to common belief, endogenous CS in children appears to be associated with normal or even advanced skeletal maturation. When present, BA advancement in CS is related to obesity, insulin resistance, and elevated adrenal androgen levels and aromatization. This finding may have significant implications for treatment decisions and final height predictions in these children.

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.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.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.

Phytoestrogens are plant derived, non-steroidal compounds naturally found in rodent chows that potentially have endocrine-disrupting effects. Isoflavones, the most common phytoestrogens, have a similar structure and molecular weight to 17β-estradiol (E2) and have the ability to bind and activate both isoforms of the estrogen receptor (ER). Most isoflavones have a higher affinity for ERβ, which is involved in sexually dimorphic behavioral regulation. The goal of this study was to examine the interaction of isoflavones and E2 presence in the OVX rat on anxiety- and depressive- like behavior and the related BDNF pathophysiology. E2 administration resulted in anxiogenic behaviors when isoflavones were present in the diet (p < 0.05), but anxiolytic behaviors when isoflavones were not present (p < 0.05). E2 resulted in antidepressive-like behaviors in animals fed an isoflavone-rich diet (p < 0.05), with no effect when isoflavones were removed. Increased hippocampal BDNF expression was observed in animals fed an isoflavone-rich diet after E2 administration (p < 0.05). BDNF expression in the amygdala and hypothalamus was increased after E2 treatment in animals fed an isoflavone-rich diet. Overall, these results demonstrate that the presence of dietary isoflavones can differentially regulate the effect of E2 replacement on behavior and BDNF expression.

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.

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.

Summary 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. Clinical Trial numbers: NCT00001595, NCT00001452, NCT00005927.

Recovery of the hypothalamic-pituitary-adrenal axis (HPAA) after transsphenoidal surgery (TSS) for Cushing's disease (CD) in children has not been adequately studied.Our objective was to assess time to recovery of the HPAA after TSS in children with CD.This was a case series at the National Institutes of Health Clinical Center.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.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.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.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.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.

Limited data exist regarding the association between binge eating and quality of life (QOL) in obese adolescent girls and boys. We, therefore, studied binge eating and QOL in 158 obese (BMI ≥ 95th percentile) adolescents (14.5 ± 1.4 years, 68.0% female, 59% African-American) prior to weight-loss treatment. Youth completed an interview to assess binge eating and a questionnaire measure of QOL. Controlling for body composition, binge eating youth (n = 35), overall, reported poorer QOL in domains of health, mobility, and self-esteem compared to those without binge eating ( ps < 0.05). Also, girls, overall, reported poorer QOL than boys in activities of daily-living, mobility, self-esteem, and social/interpersonal functioning (ps < 0.05). Girls with binge eating reported the greatest impairments in activities of daily living, mobility, self-esteem, social/interpersonal functioning, and work/school QOL (ps < 0.05). Among treatment-seeking obese adolescents, binge eating appears to be a marker of QOL impairment, especially among girls. Prospective and treatment designs are needed to explore the directional relationship between binge eating and QOL and their impact on weight outcomes.

Author(s): Blain, Hailey; Sinaii, Ninet; Zeltser, Deena; Lyssikatos, Charalampos; Belyavskaya, Elena; Keil, Margaret; Bluemke, David A; Stratakis, Constantine; Bandettini, Wiphada Patricia; Lodish, Maya | Abstract: ObjectiveTo investigate early signs of cardiovascular arterial remodelling in paediatric patients with Cushing syndrome (CS) in comparison with normative values from healthy children.Study designThe metrics used to assess cardiac health were from thoracic aorta and carotid MRI. Scans were performed on 18 children with CS (mean: 12.5 ± 3.1 years, range: 6.0-16.8 years, 10 female). Pulse wave velocity (PWV), aortic distensibility (AD) and carotid intima-media thickness (cIMT), well-validated measurements of cardiac compromise, were measured from the images and compared to normative age-matched values where available.ResultsPatients with CS had significantly higher PWV compared to age-adjusted normal median control values (4.0 ± 0.7 m/s vs. 3.4 ± 0.2 m/s, respectively, P = 0.0115). PWV was positively correlated with midnight plasma cortisol (r = 0.56, P = 0.02). Internal and common cIMT were negatively correlated with ascending AD (r = -0.75, P = 0.0022, r = -0.69, P = 0.0068, respectively).ConclusionPulse wave velocity data indicate that paediatric patients with CS have early evidence of cardiovascular remodelling. The results suggest the opportunity for monitoring as these changes begin in childhood.

Background Smith-Lemli-Opitz Syndrome (SLOS) is an autosomal recessive inborn error of cholesterol synthesis caused by mutation of the 7-dehydrocholesterol reductase (DHCR7) gene. This results in abnormal sterol levels, increased 7-dehydrocholesterol and typically decreased cholesterol. Although SLOS has a characteristic physical phenotype, with the most common finding being 2-3 toe syndactyly, there are also multiple behavioral abnormalities. These include cognitive deficits, anxiety, hyper-activity, sleep cycle disturbance, language impairment and autism spectrum behaviors. Methods There are currently two main mouse models of SLOS; a homozygous null, Dhcr7Δ3-5/Δ3-5, and a model combining the null mutation and the common p.T93M missense mutation, Dhcr7Δ3-5/T93M. Unlike the null model, the hypomorphic Dhcr7T93M/Δ3-5 mice can live to adulthood and are therefore suitable for behavioral studies. Anxiety can be measured via multiple commonly used protocols; elevated plus maze (EPM), open field test and assessing burrowing and nesting behavior. Results Although there was variation in all genders and genotypes, overall the Dhcr7T93M/Δ3-5 mice were marginally more likely to have increased burrowing compared to controls. However, this was only significant at 4 months in the overnight study. In contrast, the Nestlet test and EPM are both suggestive of decreased anxiety in the Dhcr7T93M/Δ3-5 mice. Additional histological analysis showed that Dhcr7T93M/Δ3-5 mice tended to have a smaller hippocampus and anterior commissure than age and gender matched controls. Discussion The increased burrowing could be showing the increased anxiety phenotype or hyperactivity, which is also noted in the increased gait speed of the Dhcr7T93M/Δ3-5 mice in the open field test. However, the results of the Nestlet test and EPM are opposite to what is typically observed in patients, therefore these findings are either the result of a secondary defect or suggest that the Dhcr7T93M/Δ3-5 model does not replicate the behavioral traits of patients. The hippocampus is the part of the brain responsible for learning, memory and spatial awareness. As such, the changes seen in the hippocampus could explain the decreased shredding observed in the Nestlet test and the potential delayed learning of the Dhcr7T93M/Δ3-5 mice, observed by the normalization of the behaviors in the EPM and open field tasks. These results are suggestive of subtle structural defects and justify further analysis, particularly using mice with an isogenic background where the differences may be more distinct. As SLOS does not have an optimal treatment pathway, if the results suggested by these tests are accurate, it could help aid the development of therapeutic interventions.

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

Objectives To define the incidence and risk factors of postoperative sodium alterations in pediatric patients undergoing transsphenoidal surgery (TSS) for adrenocorticotropic hormone and growth hormone secreting pituitary adenomas. Study design We retrospectively reviewed 160 patients ≤18 years of age who had TSS for pituitary adenomas at our institution from 1999 to 2017. Variables included daily serum sodium through postoperative day 10, urine specific gravity, and medications administered. We examined associations between sex, repeat surgery, manipulation of the posterior pituitary (PP), tumor invasion into the PP, tumor type and size, cerebrospinal fluid (CSF) leak, lumbar drain insertion, body mass index, puberty, and development of diabetes insipidus (DI) or syndrome of inappropriate antidiuretic hormone secretion (SIADH). Results Mean age was 12.9 ± 3.4 years (female = 81). Patients had adrenocorticotropic hormone (150/160) and growth hormone (10/160) producing adenomas. Forty-two (26%) patients developed DI. Among the 37 of 160 who required desmopressin acutely, 13 of 37 required it long term. Risk of long-term need for desmopressin was significantly higher in patients who had CSF leak 9 of 48 (P = .003), lumbar drain 6 of 30 (P = .019), manipulation 11 of 50 (P Conclusions Among 160 children who underwent TSS for pituitary adenomas, the incidence of DI and SIADH after TSS was 26% and 14%, respectively. Combined risk factors for DI and/or SIADH include female sex, manipulation of and/or tumor invasion into the PP, and CSF leak or lumbar drain. Trial registration ClinicalTrials.gov : NCT00001595 and NCT00060541 .

Context: Some studies suggest the presence of metabolic syndrome before adulthood may identify those at high risk for later cardiovascular morbidity, but there are few data examining the reliability of pediatric metabolic syndrome. Objective: To examine the short- and long-term stability of pediatric metabolic syndrome. Design: Metabolic syndrome was defined as having at least three of the following: waist circumference, blood pressure, and fasting serum triglycerides in the 90th or higher percentile for age/sex; high-density lipoprotein-cholesterol 10th or lower percentile for age/sex; and fasting serum glucose of at least 100 mg/dl. Short-term metabolic syndrome stability (repeated measurements within 60 d) was assessed in obese youth ages 6–17 yr. Long-term metabolic syndrome stability (repeated measurements more than 1.5 yr apart) was studied in 146 obese and nonobese children age 6–12 yr at baseline. Patients and Setting: Convenience samples of obese and nonobese youth ages 6–17 yr participating in research studies were collected at a clinical research hospital. Results: Short-term metabolic syndrome stability (repeat measurements performed 19.7 ± 13.1 d apart) was assessed in 220 children. The diagnosis of metabolic syndrome was unstable in 31.6% of cases. At their short-term follow-up visit, incidence of metabolic syndrome among participants who did not have metabolic syndrome at baseline was 24%. In the long term (repeat measurements performed 5.6 ± 1.9 yr apart), the diagnosis of metabolic syndrome was unstable in 45.5% of cases. Conclusions: Cutoff-point-based definitions for pediatric metabolic syndrome have substantial instability in the short and long term. The value of making a cutoff-point-based diagnosis of metabolic syndrome during childhood or adolescence remains in question.

Pituitary tumors are rare in childhood and adolescence, with a reported prevalence of up to one per 1 million children. Only 2-6% of surgically treated pituitary tumors occur in children. Although pituitary tumors in children are almost never malignant and hormonal secretion is rare, these tumors may result in significant morbidity. Tumors within the pituitary fossa are mainly of two types: craniopharyngiomas and adenomas. Craniopharyngiomas cause symptoms by compressing normal pituitary, causing hormonal deficiencies and producing mass effects on surrounding tissues and the brain; adenomas produce a variety of hormonal conditions such as hyperprolactinemia, Cushing disease and acromegaly or gigantism. Little is known about the genetic causes of sporadic lesions, which comprise the majority of pituitary tumors, but in children, more frequently than in adults, pituitary tumors may be a manifestation of genetic conditions such as multiple endocrine neoplasia type 1, Carney complex, familial isolated pituitary adenoma and McCune-Albright syndrome. The study of pituitary tumorigenesis in the context of these genetic syndromes has advanced our knowledge of the molecular basis of pituitary tumors and may lead to new therapeutic developments.

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 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.

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.

Facial plethora is a clinical sign described since ancient times for a variety of diseases. In the 19th century, it was linked to increased blood volume or flow, but this has never been proven. Facial plethora is also one of the earliest described clinical features of Cushing's syndrome (CS).This study aimed to quantify facial plethora changes in CS as an early assessment of cure after surgery using noninvasive near-infrared multispectral imaging (MSI).The longitudinal cohort study was initiated in August 2012 and completed in August 2014.Clinical research hospital, National Institutes of Health.Thirty-four of the 38 patients who received surgical treatment for CS under protocol 97CH0076 during this period were included.MSI was performed on the right cheek of patients before surgery and 4.9 ± 3.1 days afterward.Average blood volume fraction as measured by MSI and serum cortisol.All but four of the 28 patients (86%) who were assessed as cured by postoperative plasma cortisol measurements of3 μg/dL showed a decrease in blood volume fraction (17.7 ± 0.03 vs 15.8 ± 0.03%; P = .0019), whereas an increase was seen in patients with persistent CS (18.5 ± 0.03 vs 21.4 ± 0.04%; P = .0017). Change in blood volume fraction before and after surgery was correlated with postoperative cortisol (rs = 0.58; P = .0003).Clinical data obtained from 34 patients indicate that a decrease in facial plethora after surgery, as evidenced by a decrease in blood volume fraction, is correlated with CS outcome. This novel technology for the first time identified a physiological mechanism associated with an ancient clinical sign. Furthermore, as a proof of principle, MSI is a promising early marker of cure in patients with CS that complements biochemical and clinical data.

OBJECTIVE. Limited data suggest that psychological factors, including binge eating, dieting, and depressive symptoms, may predispose children to excessive weight gain. We investigated the relationship between baseline psychological measures and changes in body fat (measured with dual-energy x-ray absorptiometry) over time among children thought to be at high risk for adult obesity. METHODS. A cohort study of a convenience sample of children (age: 6–12 years) recruited from Washington, DC, and its suburbs was performed. Subjects were selected to be at increased risk for adult obesity, either because they were overweight when first examined or because their parents were overweight. Children completed questionnaires at baseline that assessed dieting, binge eating, disordered eating attitudes, and depressive symptoms; they underwent measurements of body fat mass at baseline and annually for an average of 4.2 years (SD: 1.8 years). RESULTS. Five hundred sixty-eight measurements were obtained between July 1996 and December 2004, for 146 children. Both binge eating and dieting predicted increases in body fat. Neither depressive symptoms nor disturbed eating attitudes served as significant predictors. Children who reported binge eating gained, on average, 15% more fat mass, compared with children who did not report binge eating. CONCLUSIONS. Children’s reports of binge eating and dieting were salient predictors of gains in fat mass during middle childhood among children at high risk for adult obesity. Interventions targeting disordered eating behaviors may be useful in preventing excessive fat gain in this high-risk group.

To assess the impact of obesity on quality of life (QOL) in black and white adolescents.One hundred ten overweight (body mass index [BMI], 41.7 +/- 8.9 kg/m2) and 34 nonoverweight adolescents (BMI, 20.6 +/- 2.9 kg/m2) and their parents completed measures of QOL.Overweight was associated with poorer adolescent-reported QOL and parent reports of their children's QOL. Examining groups by weight status and race, overweight whites reported the greatest impairment on Social/Interpersonal, Self-Esteem, and Physical Appearance QOL (all P.01), whereas parents of overweight blacks reported the poorest General Health Perceptions scores regarding their children. Interactions between BMI z-score and race were detected for Social/Interpersonal, Self-esteem, Daily Living, Self-Efficacy, Self-regard, and Physical Appearance QOL (all P.05): Higher BMI in whites was associated with greater impairments in QOL than in blacks. Parents reported similar relations for their children.According to adolescent and parent reports, overweight is associated with poorer QOL in adolescence, regardless of race; however, compared with overweight white adolescents, blacks report less impairment in QOL. Future research is required to determine whether differences in QOL are predictive of treatment success.

Background: Little is known about how simpler and more available methods to measure change in body fatness compare with criterion methods such as dual-energy X-ray absorptiometry (DXA) in children. Objective: Our objective was to determine the ability of airdisplacement plethysmography (ADP) and formulas based on triceps skinfold thickness (TSF) and bioelectrical impedance analysis (BIA) to estimate changes in body fat over time in children. Design: Eighty-six nonoverweight and overweight boys (n 34) and girls (n 52) with an average age of 11.0 2.4 y underwent ADP, TSF measurement, BIA, and DXA to estimate body fatness at baseline and 1 0.3 y later. Recent equations were used to estimate percentage body fat by TSF measurement (Dezenberg equation) and by BIA (Suprasongsin and Lewy equations). Percentage body fat estimates by ADP, TSF measurement, and BIA were compared with those by DXA. Results: All methods were highly correlated with DXA (P 0.001). No mean bias for estimates of percentage body fat change was found for ADP (Siri equation) compared with DXA for all subjects examined together, and agreement between body fat estimation by ADP and DXA did not vary with race or sex. Magnitude bias was present for ADP relative to DXA (P 0.01). Estimates of change in percentage body fat were systematically overestimated by BIA equations (1.37 6.98%; P 0.001). TSF accounted for only 13% of the variance in percentage body fat change. Conclusion: Compared with DXA, there appears to be no noninvasive and simple method to measure changes in children’s percentage body fat accurately and precisely, but ADP performed better than did TSF or BIA. ADP could prove useful for measuring changes in adiposity in children. Am J Clin Nutr 2004;80:64 –9.

SummaryObjective 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.

The Pediatric Endocrinology Nursing Society (PENS) is committed to the development and advancement of nurses in the art and science of pediatric endocrinology nursing and to improve the care of all children with endocrine disorders through the education of the pediatric healthcare community. To aid in achieving that goal, the purpose of A 12-year-old Hispanic female presents to the local emergency room with seizures and severe hypertension. Over the past year, she gained 15 kilograms, with no changes in her appetite or level of physical activity, yet she stopped growing in height. Her BMI increased from 21.9 to 29 kg/m2. She was recently diagnosed with type 2 diabetes mellitus and was treated with metformin and diet modification. Her mother noticed that she was more impatient and irritable in the last 4–5 months. Significant findings on her physical exam included severe acne (face, chest, and back); acanthosis nigricans; hirsutism; wide purple striae on legs, abdomen, trunk; facial plethora; fat pads in supraclavicular, temporal, and dorsocervical areas; scattered petechiae on arms and shins; proximal muscle weakness; tinea versicolor; candida albicans; Tanner V pubic hair and Tanner II breast development. Her blood pressure remained N 90% for age–height, even with treatment with three antihypertensive medications. Alarmed by the severity of her hypertension along with concomitant development of rapid onset weight gain, diabetes, and numerous physical changes in a young girl, the emergency room doctor suspected Cushing syndrome and referred the child to a pediatric endocrinologist. Following is a brief overview of Cushing syndrome and the integral role of the pediatric nurse in the care of these children.