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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.

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

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.

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.

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.

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.

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 2–3years. 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.

Pituitary tumors are rare in childhood and adolescence, with a reported prevalence of up to 1 per million children. Only 2-6% of surgically treated pituitary tumors occur in children, with some variation attributed to a lack of consensus for a pediatric age range and whether age at surgery or age at onset of symptoms was used. Although pituitary tumors in children are almost never malignant and hormonal secretion is rare, these tumors may result in significant morbidity. Pituitary adenomas produce a variety of hormonal conditions such as hyperprolactinemia, acromegaly or gigantism, or Cushing disease. Sporadic lesions comprise the majority of pituitary tumors in children and there is sparse information about genetic causes. However, in children more frequently than in adults, pituitary tumors may be a manifestation of genetic conditions such as Carney complex, McCune-Albright syndrome, multiple endocrine neoplasia type 1 (MEN 1), and familial isolated pituitary adenoma (FIPA). 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. Molecular understanding of pituitary adenoma formation is essential for the development of medical therapies and the treatment of post-operative recurrences. In general, mutations in genes involved in genetic syndromes associated with pituitary tumors are not a common finding in sporadic lesions. In contrast MEN1 and AIP mutations may be more frequent among specific subgroups of patients, such as in children and young adults with growth hormone-producing adenomas. In this presentation, we review the most recent data on clinical diagnosis and outcomes, as well as in the molecular pathogenesis of pituitary adenomas and discuss some of the most recent findings from our laboratory. Guidelines for genetic screening and clinical counseling of patients with pituitary tumors are provided.

Steroid hormones modulate memory in animals and human adults. Little is known on the developmental effect of these hormones on the neural networks underlying memory. Using Congenital Adrenal Hyperplasia (CAH) as a naturalistic model of early steroid abnormalities, this study examines the consequences of CAH on memory and its neural correlates for emotionally arousing and neutral material in children. Seventeen patients with CAH and 17 age- and sex-matched healthy children (ages 12 to 14 years) completed the study. Subjects were presented positive, negative and neutral pictures. Memory recall occurred about 30 minutes after viewing the pictures. Children with CAH showed memory deficits for negative pictures compared to healthy children (p < 0.01). There were no group differences on memory performance for either positive or neutral pictures (p’s >0.1). In patients, 24h urinary-free cortisol levels (reflecting glucocorticoid replacement therapy) and testosterone levels were not associated with memory performance. These findings suggest that early steroid imbalances affect memory for negative material in children with CAH. Such memory impairments may result from abnormal brain organization and function following hormonal dysfunction during critical periods of development.