Search the Community

Journal of the Endocrine Society, Volume 6, Issue 7, July 2022, bvac080, https://doi.org/10.1210/jendso/bvac080 Abstract Context Subclinical pituitary hemorrhage, necrosis, and/or cystic degeneration (SPH) presents mainly in large tumors and prolactinomas. The characteristics of patients with Cushing disease (CD) and SPH are not known. Objective To determine if SPH affects the presentation and biochemical profile of young patients with CD. Methods Pediatric and adolescent patients who were diagnosed with CD between 2005 and 2021 and available magnetic resonance imaging images were evaluated for SPH. The clinical and biochemical characteristics of patients with and without SPH were compared. Results Evidence of possible SPH was present in 12 out of 170 imaging studies (7.1%). Patients with and without SPH had similar age at diagnosis and sex distribution but differed in disease duration (median duration: 1.0 year [1.0-2.0] in the SPH group vs 2.5 years [1.5-3.0] in the non-SPH group, P = .014). When comparing their biochemical evaluation, patients with SPH had higher levels of morning adrenocorticotropin (ACTH) (60.8 pg/mL [43.5-80.3]) compared to patients without SPH (39.4 pg/mL [28.2-53.2], P = .016) and the degree of cortisol reduction after overnight high dose (8 mg or weight-based equivalent) dexamethasone was lower (–58.0% [–85.4 to –49.7]) compared to patients without SPH (85.8 [–90.5 to –76.8], P = .035). The presence of SPH did not affect the odds of remission after surgery or the risk of recurrence after initial remission. Conclusion SPH in ACTH-secreting pituitary adenomas may affect their biochemical response during endocrine evaluations. They may, for example, fail to suppress to dexamethasone which can complicate diagnosis. Thus, SPH should be mentioned on imaging and taken into consideration in the work up of pediatric patients with CD. Cushing, subclinical pituitary hemorrhage, pituitary tumor, dexamethasone, pituitary MRI Issue Section: Clinical Research Article Acute hemorrhage or necrosis of pituitary adenomas (PAs), defined as pituitary apoplexy, is a rare life-threatening condition that requires emergent neurosurgical evaluation [1]. However, subclinical hemorrhage, necrosis, intratumor cystic degeneration, and/or infarct of PAs, herein all events included in the term subclinical pituitary hemorrhage (SPH) for brevity, may occur in up to 7% to 22% of all pituitary tumors [2-9]. SPH is not associated with significant clinical symptoms and is often discovered at the time of routine diagnostic evaluation [2-9]. Previous studies suggested that SPH is more common in large tumors, prolactin-secreting or nonfunctioning PAs, while other factors, such as initiation or withdrawal of treatment with dopamine agonists, use of anticoagulants and others, have also been hypothesized to be involved in this process [5, 6]. Overall, adrenocorticotropin (ACTH)-secreting PAs represent small percentage of SPH (0%-3.2% of cases reported) [3, 5, 6, 8]. Although pituitary apoplexy is associated with pituitary hormone deficiencies, SPH has a lower if any effect on the function of the remaining pituitary gland when it occurs in nonfunctioning adenomas [3, 4]. The diagnosis of Cushing syndrome (CS) involves elaborate and time-dependent tests that are based on cortisol secretion and its regulation by ACTH [10]. Furthermore, the differential diagnosis of ACTH-dependent causes between ACTH-secreting PAs (Cushing disease, CD) and ectopic ACTH secretion is based on several dynamic tests, such as corticotropin-releasing hormone (CRH) stimulation and dexamethasone suppression [11]. The biochemical profile of corticotropinomas with SPH to both baseline and dynamic endocrine tests is not known. Materials and Methods Participants Individuals enrolled under the protocol 97-CH-0076 (ClinicalTrials.gov identifier NCT00001595) at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), from 2005 to 2020 with confirmed diagnosis of CD, were screened for eligibility in the study. Pediatric and adolescent patients (diagnosis age < 21 years) with imaging studies available before any surgical intervention were included in the analysis. Patients with previous surgery of the pituitary gland or who were evaluated during recurrence were excluded from the study since postoperative changes make imaging findings difficult to distinguish from true SPH, and biochemical presentation at recurrence often differs in severity from initial diagnosis. CS diagnosis was based on criteria defined by the Endocrine Society guidelines and adjusted for the pediatric and adolescent population as needed (abnormal measurements in at least 2 of the following criteria: elevated 24 hour urinary free cortisol [UFC], elevated midnight serum cortisol [> 4.4 mcg/dL in children or > 7.5 mcg/dL for patients age > 18 years], and/or failure to suppress cortisol to 1 mg [or weight-based equivalent dose] overnight dexamethasone suppression test [postdexamethasone cortisol > 1.8 mcg/dL]). CD diagnosis was based on postoperative histologic confirmation of ACTH-secreting PA in most cases, or remission after pituitary surgery even if histologic report failed to identify a PA in the studied material. Remission was defined as postoperative cortisol nadir of less than 2 mcg/dL and/or clinical/biochemical remission during follow-up. Informed consent was obtained from parents and assent from patients if developmentally appropriate. Study procedures were approved by the NICHD and/or central National Institutes of Health Institutional Review Board. Magnetic Resonance Imaging Scans SPH was defined as minimal or no clinical symptoms reported by the patients (apart from those commonly associated with hypercortisolemia) and magnetic resonance imaging (MRI) findings consistent with hemorrhage, intratumor infarction, and/or intratumor cyst formation (suggesting old infarcts) based on the radiologist and the principal investigator’s (C.A.S.) assessment [12, 13]. MRI scans were performed based on standard clinical protocols as previously described [14]. Briefly, MRIs at the National Institutes of Health were performed before and after intravenous administration of gadolinium contrast material, with a gradient echo sequence and thin slices (≤ 1.5 mm). MRIs were performed in either a 1.5 Tesla or 3 Tesla MR machine from various manufacturers over time. Clinical and Biochemical Data Clinical and biochemical data were extracted from electronic medical records. Tumor size was recorded as the maximum dimension retrieved from the histology report. In cases where histologic report was not available, failed to identify a PA in the studied material, or if the histology report recorded only dimensions on fragments of the tumor, the maximum dimension was retrieved from the MRI images. If the MRI was negative and the histology was negative (but the patient achieved remission after surgery), the tumor size was recorded as missing. Serum cortisol and plasma ACTH levels were calculated as the average value of the corresponding levels performed at 23:30 h and 00:00 h (reported as midnight values) and 07:30 h and 08:00 h (reported as morning values). Twenty-four–hour UFC was calculated as the average of the first 2 or 3 samples reported in the electronic medical records. Given the possible differences in the assays and reported reference range for UFC, we calculated the increase of UFC based on the upper limit of normal according to the following formula: UFC fold change = UFC/upper limit of the reference range. Serum cortisol was measured with solid-phase, competitive chemiluminescent enzyme immunoassay on a Siemens Immulite 2500 analyzer. Plasma ACTH was measured with a chemiluminescence immunoassay on a Siemens Immulite 200 XPi analyzer. UFC was measured with a chemiluminescent enzyme immunoassay until 2011 and with high-performance liquid chromatography–tandem mass spectrometry since 2011. High-dose dexamethasone suppression test was performed as previously described. Briefly, oral dexamethasone (120 mcg/kg, max 8 mg) was administered at 23:00 and cortisol was measured before (8 AM the day of administration) and after (9 AM the day after dexamethasone administration). The change of cortisol was calculated as: 100* [(postdexamethasone cortisol – predexamethasone cortisol)/predexamethasone cortisol]. Levels of cortisol lower than the lower limit of detection of the assay (< 1 mcg/dL) were substituted with the intermediate value (0.5) for all analyses. CRH stimulation test was performed as previously described. Briefly, an intravenous catheter was placed in the forearm the night before testing; the patient was fasting and lying in bed, and ovine CRH (oCRH) was administered (1 mcg/kg, max 100 mcg). Samples for cortisol and ACTH were taken at –5, 0, 15, 30, and 45 minutes after the administration of oCRH. The response to the last was expressed as the percentage change from baseline by subtracting the pretest cortisol and ACTH values from the posttest values and dividing by the former. The mean cortisol increase was estimated at 30 and 45 minutes from baseline. For ACTH the mean increase was estimated at 15 and 30 minutes after the administration of oCRH. CRH stimulation test was not performed after the discontinuation of oCRH by the company in November 2020. Statistical Analysis Categorical data are described as counts (proportions) and were compared between groups using the Fisher exact test. Fisher odds ratio (OR) was used to assess the odds of remission based on the presence of SPH and is presented as OR and 95% CI. Continuous data were checked for normality and not normally distributed data are presented as median (first quartile to third quartile) and were compared between 2 groups using Wilcoxon rank-sum test. The Cox proportional hazards test was used to assess the risk of recurrence based on the presence of SPH and is presented as hazard ratio (HR) and 95% CI. Statistical analyses were performed in R. Results Clinical Data Out of 170 patients with available MRI before first surgery, 12 patients had evidence of possible SPH (7.1%) (Table 1). Various MRI findings were noted (Fig. 1), most commonly hyperintense lesions in T1 and T2 precontrast images (Fig. 1A and 1B), while some patients had intratumor heterogeneity suggestive of cystic formation (Fig. 1C-1F). As expected, the tumor size of patients with SPH as noted in histology reports or MRI images was higher than that in patients without SPH (median size: 8.5 mm [7.0-11.25] in the SPH group vs 5.4 mm [4-8] in the non-SPH group; P < .001). Table 1. Characteristics of patients with and without subclinical pituitary hemorrhage, necrosis, and/or cystic degeneration No SPH (N = 158) SPH (N = 12) P Age at diagnosis, y 13.0 (10.6 to 15.4) 12.5 (10.6 to 15.6) .95 Sex  Female 89 (56.3%) 5 (41.7%) .49  Male 69 (43.7%) 7 (58.3%) Disease duration, y 2.50 (1.5 to 3.0) n = 138 1.00 (1.0 to 2.0) n = 10 .014 Morning cortisol, mcg/dL 16.2 (12.6 to 20.4) n = 139 18.4 (13.7 to 27.5) n = 10 .28 Midnight cortisol, mcg/dL 14.0 (10.7 to 19.7) n = 133 16.3 (11.0 to 23.0) n = 9 .52 UFC fold change 4.89 (2.51 to 8.50) n = 131 8.81 (6.86 to 9.42) n = 9 .18 Morning ACTH, pg/mL 39.4 (28.2 to 53.2) n = 143 60.8 (43.5 to 80.3) n = 10 .016 Cortisol change during CRH stimulation test, % 68.7 (33.3 to 111) n = 128 46.0 (–7.46 to 90.7) n = 8 .22 ACTH change during CRH stimulation test, % 145 (59.6 to 260) n = 127 103 (–5.75 to 278) n = 8 .55 Cortisol change during high-dose dexamethasone suppression test, % –85.8 (–90.5 to –76.8) n = 120 –58.0 (–85.4 to –49.7) n = 9 .035 Remission  Yes 127 (80.4%) 10 (83.3%) .99  No 25 (15.8%) 2 (16.7%) Number in each cell reports the number of patients with available results. Abbreviations: ACTH, adrenocorticotropin; CRH, corticotropin-releasing hormone; SPH, subclinical pituitary hemorrhage, necrosis, and/or cystic degeneration; UFC, urinary free cortisol. Open in new tab Figure 1. Open in new tabDownload slide Imaging findings in patients with subclinical pituitary hemorrhage, necrosis, and/or cystic degeneration. A, T1, and B, T2 magnetic resonance imaging (MRI) scans of the same patient showing area of high intensity inside the tumor suggesting acute/subacute episode. C, T2, and D, T1 MRI scans of the same patient showing heterogeneity in a large tumor with high-intensity areas suggesting blood-filled cavities and/or necrosis. E, T1, and F, T2 MRI scans of the same patient showing fluid inside the tumor. Patients with and without SPH were similar in age (median age: 12.5 years [10.6-15.6] in the SPH group vs 13.0 years [10.6-15.4] in the non-SPH group; P = .95) and sex distribution (n of female = 5 (41.7%) in the SPH group vs 89 (56.3%) in the non-SPH group; P = .49). Patients with SPH had a shorter duration of disease as noted by changes in their growth chart parameters (median duration: 1.0 [1.0-2.0] year in the SPH group vs 2.5 [1.5-3.0] years in the non-SPH group; P = .014). Patients in the 2 groups did not differ on their anthropometric characteristics, including height and body mass index z scores(P > .05). They also had similar blood pressure parameters and did not differ in terms of the frequency of hypertension diagnosis. No patient was on anticoagulation treatment nor had received radiation at the time of the MRI. One patient in the SPH group had a history of lower leg deep vein thrombosis and was previously on low-heparin therapy, but he had stopped treatment at least 6 months before the MRI. Biochemical Evaluation of Hypercortisolemia Morning and midnight serum cortisol and 24-hour UFC levels were similar in both groups, but patients with SPH had higher levels of morning ACTH (60.8 pg/mL [43.5-80.3]) compared to patients without SPH (39.4 pg/mL [28.2-53.2]; P = .016). Changes in cortisol and ACTH levels during the CRH stimulation test were similar between the 2 groups, but patients with SPH who underwent the overnight high-dose dexamethasone suppression test (n = 8) had lower suppression of cortisol after dexamethasone (–58.0% [–85.4 to –49.7]) compared to patients without SPH (n = 120) (–86.0% [–90.5 to –76.7]; P = .035) (Fig. 2). When the cutoff of suppression of more than 69% was considered, patients with SPH had a lower chance of suppressing more than 69% compared to patients without SPH (OR: 0.18; 95% CI, 0.03-0.95). Figure 2. Open in new tabDownload slide Cortisol levels before and after high-dose dexamethasone suppression test in patients with and without subclinical pituitary hemorrhage, necrosis, and/or cystic degeneration (SPH). Remission After Surgical Treatment and Risk for Recurrence The chance of immediate postoperative remission after surgery was similar in patients with and without SPH. For patients with initial remission and follow-up of at least 3 months, analysis of the risk of recurrence did not show a difference in recurrence rate between the 2 groups (HR: 1.12; 95% CI, 0.13-9.4, in the SPH group compared to the non-SPH group, adjusting for the neurosurgeon). Discussion SPH is often an incidental finding in the imaging evaluation of patients with PAs. The frequency of SPH in patients with CD is low (7.1% in our study) but these patients may differ in terms of their history of shorter duration of symptoms and the biochemical evaluation. More specifically, patients with CD and SPH showed higher ACTH levels and lower suppression of cortisol to high-dose dexamethasone. This, however, did not affect their prognosis in terms of immediate postoperative remission and long-term risk of recurrence. SPH has been mainly studied in cohorts of patients with various types of PAs. From these studies important conclusions have been made suggesting that the risk of SPH is higher in patients with large nonfunctioning PAs or prolactinomas. Other risk factors for pituitary apoplexy are thought to be size of the adenoma, change in size, initiation, and withdrawal of dopamine agonists, type of dopamine agonist, use of anticoagulants, diabetes mellitus, hypertension, head trauma, radiotherapy, and preceding dynamic endocrine testing. Patients with CD often represent a small portion of these cohorts, and to our knowledge there is no study to investigate how these patients respond to stimulation/suppression tests. For that reason, we evaluated these findings in our cohort of only patients with ACTH-secreting adenomas. As most of our referrals involve pediatric patients, we limited our cohort only to patients diagnosed at younger than 21 years to have a more homogeneous group. The pathogenesis of pituitary apoplexy has been hypothesized to lie in more friable vessels in PAs, which, while the tumor increases in size, are more susceptible to rupture or cause surrounding feeding vessels to extend and bleed [7, 15]. CS, because of the coexisting hypercortisolemia, leads independently to endothelial dysfunction and coagulation defects, which are often apparent as easy bruising, thrombotic events, and other signs. However, review of the literature and the estimated frequency of SPH in our cohort suggest that patients with CD are not at increased risk for SPH, potentially related to the relatively small adenomas present in these patients [16, 17]. The main difference of patients with CD and SPH compared to those without lies in their biochemical testing, more characteristically in lower suppression to dexamethasone. The overnight high-dose dexamethasone suppression test was originally designed to differentiate various types of CS [18]. Although originally described as a highly accurate test, in clinical practice, cutoffs of 50% to 80% have shown variable sensitivity and specificity and certain centers opt not to use this test unless all other diagnostic evaluations yield confounding results [19-21]. In previous studies a threshold of suppression of more than 69% showed the highest accuracy (sensitivity: 71%, specificity: 100%), and we have incorporated this in our diagnostic algorithm (acknowledging the limitations of the test) [22, 23]. In our analysis, patients with SPH had lower suppression of cortisol under the effect of high-dose dexamethasone and a higher chance of not passing the aforementioned threshold. The mechanism for the lower suppression to dexamethasone of these tumors may be due to lower vascular circulation of dexamethasone at the level of the tumor, and/or the lower sensitivity of necrotic cells to the negative feedback by circulating glucocorticoids. A limitation of this study was that the diagnosis of SPH was based on MRI findings. However, MRI sequences and machines differed between patients and over time. Thus, although large hemorrhagic/necrotic lesions are probably accurately identified, it is possible that smaller lesions are misclassified as negative; the effect of smaller hemorrhagic areas to the biochemical testing may however be smaller as well. Further, the MRIs were not read by a central radiologist, but rather from the radiologist on call at each time point, and this could lead to discrepancies in readings. In addition, our cohort’s data may not be generalized to the pediatric or adult CD population, as often our referrals consist of patients with difficult to treat, small, or otherwise unusual tumors. In conclusion, SPH may be incidentally identified in up to 7% of patients with CD. Patients with CD and SPH may differ in terms of their response to endocrine tests, and this finding should be incorporated in their evaluation. Abbreviations ACTH adrenocorticotropin CD Cushing disease CRH corticotropin-releasing hormone CS Cushing syndrome HR hazard ratio MRI magnetic resonance imaging NICHD Eunice Kennedy Shriver National Institute of Child Health and Human Development OR odds ratio PA pituitary adenoma SPH subclinical pituitary hemorrhage UFC urinary free cortisol Financial Support This work was supported by the intramural research program of the Eunice Kennedy Shriver NICHD, NIH, Bethesda, MD 20892, USA. Disclosures Dr Stratakis holds patents on the function of the PRKAR1A, PDE11A, and GPR101 genes and related issues; his laboratory has also received research funding on the GPR101 gene, and on abnormal growth hormone secretion and its treatment by Pfizer, Inc. He is currently employed by ELPEN, SA and has been consulting for Lundbeck Pharmaceuticals and Sync, SA. The other authors have nothing to disclose. Data Availability Some or all datasets generated during and/or analyzed during the current study are not publicly available but may be available from the corresponding author on reasonable request. Published by Oxford University Press on behalf of the Endocrine Society 2022. This work is written by (a) US Government employee(s) and is in the public domain in the US. Published by Oxford University Press on behalf of the Endocrine Society 2022. Adapted From https://academic.oup.com/jes/article/6/7/bvac080/6586876?login=false

Authors Nisticò D , Bossini B, Benvenuto S, Pellegrin MC, Tornese G Received 29 October 2021 Accepted for publication 28 December 2021 Published 11 January 2022 Volume 2022:18 Pages 47—60 DOI https://doi.org/10.2147/TCRM.S294065 Checked for plagiarism Yes Review by Single anonymous peer review Peer reviewer comments 2 Editor who approved publication: Professor Garry Walsh Download Article [PDF] Daniela Nisticò,1 Benedetta Bossini,1 Simone Benvenuto,1 Maria Chiara Pellegrin,1 Gianluca Tornese2 1University of Trieste, Trieste, Italy; 2Department of Pediatrics, Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy Correspondence: Gianluca Tornese Department of Pediatrics, Institute for Maternal and Child Health IRCCS Burlo Garofolo, Via dell’Istria 65/1, Trieste, 34137, Italy Tel +39 040 3785470 Email gianluca.tornese@burlo.trieste.it Abstract: Adrenal insufficiency is an insidious diagnosis that can be initially misdiagnosed as other life-threatening endocrine conditions, as well as sepsis, metabolic disorders, or cardiovascular disease. In newborns, cortisol deficiency causes delayed bile acid synthesis and transport maturation, determining prolonged cholestatic jaundice. Subclinical adrenal insufficiency is a particular challenge for a pediatric endocrinologist, representing the preclinical stage of acute adrenal insufficiency. Although often included in the extensive work-up of an unwell child, a single cortisol value is usually difficult to interpret; therefore, in most cases, a dynamic test is required for diagnosis to assess the hypothalamic-pituitary-adrenal axis. Stimulation tests using corticotropin analogs are recommended as first-line for diagnosis. All patients with adrenal insufficiency need long-term glucocorticoid replacement therapy, and oral hydrocortisone is the first-choice replacement treatment in pediatric. However, children that experience low cortisol concentrations and symptoms of cortisol insufficiency can take advantage using a modified release hydrocortisone formulation. The acute adrenal crisis is a life-threatening condition in all ages, treatment is effective if administered promptly, and it must not be delayed for any reason. Keywords: adrenal gland, primary adrenal insufficiency, central adrenal insufficiency, Addison disease, children, adrenal crisis, hydrocortisone Introduction Primary adrenal insufficiency (PAI) is a condition resulting from impaired steroid synthesis, adrenal destruction, or abnormal gland development affecting the adrenal cortex.1 Acquired primary adrenal insufficiency is termed Addison disease. Central adrenal insufficiency (CAI) is caused by an impaired production or release of adrenocorticotropic hormone (ACTH). It can originate either from a pituitary disease (secondary adrenal insufficiency) or arise from an impaired release of corticotropin-releasing hormone (CRH) from the hypothalamus (tertiary adrenal insufficiency). An underlying genetic cause should be investigated in every case of adrenal insufficiency (AI) presenting in the neonatal period or first few months of life, although AI is relatively rare at this age (1:5.000–10.000).2 Physiology of the Adrenal Gland The adrenal cortex consists of three zones: the zona glomerulosa, the zona fasciculata, and the zona reticularis, responsible for aldosterone, cortisol, and androgens synthesis, respectively.3 Aldosterone production is under the control of the renin-angiotensin system, while cortisol is regulated by the hypothalamic-pituitary-adrenal axis (HPA).4 This explains why patients affected by CAI only manifest glucocorticoid deficiency while mineralocorticoid function is spared. CRH is secreted from the hypothalamic paraventricular nucleus into the hypophyseal-portal venous system in response to light, stress, and other inputs. It binds to a specific cell-surface receptor, the melanocortin 2 receptor, stimulating the release of preformed ACTH and the de novo transcription of the precursor molecule pro-opiomelanocortin (POMC). ACTH is derived from the cleavage of POMC by proprotein convertase-1.5–9 ACTH binds to steroidogenic cells of both the zona fasciculata and reticularis, activating adrenal steroidogenesis. It also has a trophic effect on adrenal tissue; therefore, ACTH deficiency determines adrenocortical atrophy and decreases the capacity to secrete glucocorticoids. Circulating cortisol is 75% bound to corticosteroid-binding protein, 15% to albumin, and 10% free. The endogenous production rate is estimated between 6 and 10 mg/m2/day, even though it depends on age, gender, and pubertal development. Glucocorticoids have multiple effects: they regulate immune, circulatory, and renal function, influence growth, development, energy and bone metabolism, and central nervous system activity. Several studies reported higher cortisol plasma concentrations in girls than in boys and younger children.3,4,8 Cortisol secretion follows a circadian and ultradian rhythm according to varying amplitudes of ACTH pulses. Pulses of ACTH and cortisol occur every 30–120 minutes, are highest at about the time of waking, and decline throughout the day, reaching a nadir overnight.3,8,9 This pattern can change in the presence of serious illness, major surgery, and sleep deprivation. During stressful situations, glucocorticoid secretion can increase up to 10-fold to enhance survival through increased cardiac contractility and cardiac output, sensitivity to catecholamines, work capacity of the skeletal muscles, and availability of energy stores.3 The interaction between the hypothalamus and the two endocrine glands is essential to maintain plasma cortisol homeostasis (Figure 1). Cortisol exerts double-negative feedback on the HPA axis. It acts on the hypothalamus and the corticotrophin cells of the anterior pituitary, reducing CRH and ACTH synthesis and release.6 ACTH inhibits its secretion through a feedback effect mediated at the level of the hypothalamus.3 Increased androgen production occurs in the case of cortisol biosynthesis enzymatic deficits. Figure 1 The hypothalamic–pituitary–adrenal axis. Primary Adrenal Insufficiency PAI affects 10–15 per 100,000 individuals and recognizes different classes of genetic causes (Table 1). Congenital adrenal hyperplasia (CAH) is the main cause of PAI in the neonatal period, being included among the disorders of steroidogenesis secondary to deficits in enzymes. It has an autosomal recessive transmission.1,10,11 The estimated incidence ranges between 1:10,000 and 1:20,000 births. CAH phenotype depends on disease-causing mutations and residual enzyme activity. 21-hydroxylase deficiency (21OHD) accounts for more than 90% of cases, 21-hydroxylase converts cortisol and aldosterone precursors, respectively 17-hydroxyprogesterone (17-OHP) to 11-deoxycortisol and progesterone to deoxycortisone. Less frequent forms of CAH include 11 β -hydroxylase deficiency (11BOHD, 8% of cases), 17α-hydroxylase/17–20 lyase deficiency (17OHD), 3β-hydroxysteroid dehydrogenase deficiency (3BHDS), P450 oxidoreductase deficiency (PORD).12 Steroidogenesis may also be impaired by steroidogenic acute regulatory (StAR) protein deficiency, which is involved in cholesterol transport into mitochondria, or P450 cytochrome side-chain cleavage (P450scc) deficiency, that converts cholesterol into pregnenolone.12,13 Of these conditions, 21OHD and 11BOHD only affect adrenal steroidogenesis, whereas the other deficits also impact gonadal steroid production. In classic CAH, enzyme activity can be absent (salt-wasting form) or low (1–2% enzyme activity, simple virilizing form). The salt-wasting form is the most severe and affects 75% of patients with classic 21OHD.1,10,12,14 Non-classic CAH (NCCAH) is more prevalent than the classic form, in which there is 20–50% of residual enzymatic activity. Two-thirds of NCCAH individuals are compound heterozygotes with different CYP21A2 mutations in two different alleles (classic severe mutation plus mild mutation in two different alleles or homozygous with two mild mutations). Notably, 70% of NCCAH patients carry the point mutation Val281Leu. Table 1 Causes of Primary Adrenal Insufficiency (PAI) Central Adrenal Insufficiency CAI incidence is estimated between 150 and 280 per million, and it should be suspected when mineralocorticoid function is preserved. When, rarely, isolated is due to iatrogenic HPA suppression secondary to prolonged glucocorticoid therapy or the removal of an ACTH- or cortisol-producing tumor (Cushing syndrome).15 Defects in POMC,16 characterized by red or auburn-haired children, pale skin (due to melanocyte stimulating hormone [MSH] - deficiency) and hyperphagia later in life, and in transcription factor TPIT,17 which regulates POMC synthesis in corticotrope cells, are the two leading genetic causes of isolated ACTH deficiency (Table 2). Mainly, it occurs as part of complex syndromes in which a combined multiple pituitary hormone deficiency (CMPD) is associated with craniofacial and midline defects, such as Prader-Willi syndrome, CHARGE syndrome, Pallister-Hall syndrome (anatomical pituitary abnormalities), white vanishing matter disease (progressive leukoencephalopathy).5 Individuals with an isolated pituitary deficiency, usually a growth hormone deficiency (GHD), may develop multiple pituitary hormone deficiencies over the years. Therefore, excluding a latent CAI at GHD onset and periodically monitoring of HPA axis is of utmost importance. Notably, cortisol reduction secondary to an increased basal metabolism when starting GHD or thyroxin substitutive therapy may unleash a misdiagnosed CAI. CMPD can be caused by several defective genes, such as GLI1, LHX3, LHX4, SOX2, SOX3, HESX1: in such cases, hypoglycemia or small penis with undescended testes may respectively suggest concomitant GH and gonadotropins deficits.18 Table 2 Causes of Central Adrenal Insufficiency (CAI) Clinical Manifestations of Adrenal Insufficiency AI is an insidious diagnosis presenting non-specific symptoms and may be mistaken with other life-threatening endocrine conditions (septic shock unresponsive to inotropes or recurrent sepsis, acute surgical abdomen).1,19 Children can be initially misdiagnosed as having sepsis, metabolic disorders, or cardiovascular disease, highlighting the need to consider adrenal dysfunction as a differential diagnosis for an unwell or deteriorating infant. With age-related items, clinical features depend on the type of AI (primary or central) and could manifest in an acute or chronic setting (Table 3). Table 3 Features of Isolated Adrenal Insufficiency in Pediatric Age Clinical signs of PAI are based on the deficiency of both gluco- and mineralocorticoids. Signs due to glucocorticoid deficiency are weakness, anorexia, and weight loss. Hypoglycemia with normal or low insulin levels is frequent and often severe in the pediatric population. Mineralocorticoid deficiency contributes to hyponatremia, hyperkalemia, acidosis, tachycardia, hypotension, and salt craving. The lack of glucocorticoid-negative feedback is responsible for the elevated ACTH levels. The high levels of ACTH and other POMC peptides, including the various forms of MSH, cause melanin hypersecretion, stimulating mucosal and cutaneous hyperpigmentation. Searching for an increased pigmentation may represent an essential diagnostic tool since all the other symptoms of PAI are non-specific. However, hyperpigmentation is variable, dependent on ethnic origin, and more prominent in skin exposed to sun and in extension surface of knees, elbows, and knuckles.15 In autoimmune PAI, vitiligo may be associated with hyperpigmentation. In the classic CAH simple virilizing form, salt wasting is absent due to the presence of aldosterone production. In males, diagnosis typically occurs between 3 and 4 years of age with pubarche, accelerated growth velocity, and advanced bone age at presentation.1,10,12,14 NCCAH may occur in late childhood with signs of hyperandrogenism (premature pubarche, acne, adult apocrine odor, advanced bone age) or be asymptomatic. In adolescents and adult women, conditions of androgen excess (acne, oligomenorrhea, hirsutism) may underlie an NCCAH.20,21 The clinical presentation of CAI may be more complex when caused by an underlying central nervous system disease or by CMPD. In the case of a pituitary or hypothalamic tumor, patients may present headache, vomiting, visual disturbances, short stature, delayed or precocious puberty. In the case of CMPD, manifestations vary considerably and depend on the number and severity of the associated hormonal deficiencies. In CAI, aldosterone production is spared, which means that serum electrolytes are usually normal. However, cortisol contributes to regulating free water excretion, so patients with CAI are at risk for dilutional hyponatremia, with normal serum potassium levels. Since adrenal androgen secretion is under the control of ACTH, girls with ACTH deficiency may present light pubic hair. Patients with partial and isolated ACTH defects can be “asymptomatic”, and adrenal crisis appears during stress or in case of major illness (high fever, surgery). The acute adrenal crisis is a life-threatening condition in all ages. Patients present with profound malaise, fatigue, nausea, vomiting, abdominal or flank pain, muscle pain or cramps, and dehydration, which lead to hypotension, shock, and metabolic acidosis. Hyponatremia and hyperkalemia are less common in CAI than in PAI, but possible in acute AI. Severe hypoglycemia causes weakness, pallor, sweatiness, and impaired cognitive function, including confusion, loss of consciousness, and coma. Immediate treatment is required (see below). Children and adolescents affected by autoimmune primary adrenal insufficiency develop a chronic AI, with an insidious onset and slow progress to an acute adrenal crisis over months or even years. Initial symptoms are decreased appetite, anorexia, nausea, abdominal pain, unintentional weight loss, lethargy, headache, weakness, and fatigue, with prominent pain in the joints and muscles. Due to salt loss through the urine and the subsequent reduction in blood volume, blood pressure decreases, and orthostatic hypotension develops together with salt craving. An increased risk of infection in AI patients is reported only in those exposed to glucocorticoids. However, in APECED (Autoimmune Polyendocrinopathy-Candidiasis- Ectodermal-Dystrophy) patients, there is an increased risk of candidiasis and splenic atrophy increases the likelihood for severe infections. In neonates, AI classically presents with failure to thrive and hypoglycemia, commonly severe and associated with seizures. The condition can be life-threatening and, if misdiagnosed, may result in coma and unexplained neonatal death. In newborns, cortisol deficiency causes delayed bile acid synthesis and transport maturation, determining prolonged cholestatic jaundice with persistently raised serum liver enzymes. The cholestasis can be resolved within ten weeks of correct treatment. StAR deficiency and P450scc cause salt-losing AI with female external genitalia in genetically male neonates.22 In the classic CAH salt-wasting form, the mineralocorticoid deficiency presents with the adrenal crisis at 10–20 days of life. Females show atypical genitalia with signs of virilization (clitoral enlargement, labial fusion, urogenital sinus), whereas males have normal-appearing genitalia, except for subtle signs as scrotal hyperpigmentation and enlarged phallus.1,10,12,14 Neonates with CMPD may display non-specific symptoms including hypoglycemia, lethargy, apnea, poor feeding, jaundice, seizures, hyponatremia without hyperkalemia, temperature and hemodynamic instability, recurrent sepsis, and poor weight gain. A male with hypogonadism may have undescended testes and micropenis. Infants with optic nerve hypoplasia or agenesis of the corpus callosum may present with nystagmus. Furthermore, infants with midline defects may have various neuro-psychological problems or sensorineural deafness. Genetic Disorders and Other Conditions at Increased Risk for Adrenal Insufficiency Among the cholesterol biosynthesis disorder, there is the Smith-Lemli-Opitz syndrome,23 where microcephaly, micrognathia, low-set posteriorly rotated ears, syndactyly of the second and third toes, and atypical genital may, although rarely, combine with AI; this autosomal recessive disorder is due to defective 7-dehydrocholesterol reductase so that elevated 7-dehydrocholesterol is diagnostic. In lysosomal acid lipase A deficiency,24 AI is due to calcification of the adrenal gland as a result of the accumulation of esterified lipids; in infantile form, that is Wolman disease, hepatosplenomegaly with hepatic fibrosis and malabsorption lead to death in the first year of life, if not treated with enzyme replacement therapy such as sebelipase alfa.25 Adrenal development may be impaired in X-linked congenital adrenal hypoplasia (AHC),13,26 a disorder caused by defective nuclear receptor DAX-1, presenting with salt-losing AI in infancy in approximately half of the cases, but also later in childhood or adolescence with two other key features such as hypogonadotropic hypogonadism and impaired spermatogenesis. Two syndromes combine adrenal hypoplasia with intrauterine growth restriction (IUGR): in IMAGe syndrome,27 caused by CDKN1C gain-of-function mutations, IUGR and AI present with metaphyseal dysplasia and genitourinary anomalies; MIRAGE syndrome28 is instead characterized by myelodysplasia, infections, genital abnormalities, and enteropathy, as a result of gain-of-function mutations in SAMD9, with elevated mortality rates. In some other conditions, AI is due to ACTH resistance. Familial Glucocorticoid Deficiency type 1 (FGD1)13,29 and type 2 (FGD2)30 derive from defective ACTH receptor (MC2R) or its accessory protein MRAP, and both present with early glucocorticoid insufficiency (hypoglycemia, prolonged jaundice) and pronounced hyperpigmentation; there is usually an excellent response to cortisol replacement therapy, even though ACTH levels remain elevated. In Allgrove or Triple-A Syndrome,13,31 defective Aladin protein (an acronym for alacrimia-achalasia-adrenal insufficiency) leads to primary ACTH-resistant adrenal insufficiency with achalasia and absent lacrimation, often combined with neurological dysfunction, either peripheral, central, or autonomic. It is an autosome recessive condition, phenotypically characterized by microcephaly, short stature, and skin hyperpigmentation.32,33 Among metabolic disorders associated with AI, Sphingosine-1-Phosphate Lyase (SGPL1) Deficiency34 is a sphingolipidosis with various features such as steroid-resistant nephrotic syndrome, primary hypothyroidism, undescended testes, neurological impairment, lymphopenia, ichthyosis; interestingly, in cases where nephrotic syndrome develops before AI, the latter may be masked by glucocorticoid treatment. Adrenoleukodystrophy (ALD)35–37 is an X-linked recessive proximal disorder of beta-oxidation due to defective ABCD1, where the accumulation of very-long-chain fatty acids (VLCFA) affects in almost all cases adrenal gland among other tissues. Most patients present with progressive neurological impairment, but in some, AI is the only (approximately 10%) or first manifestation, so that every unexplained AI in boys should receive plasma VLCFA evaluation to diagnose ALD and reduce cerebral involvement through a low VLCFAs diet (Lorenzo’s oil) and allogeneic bone marrow transplantation. Early disease-modifying therapies have been developed. Gene therapy adds new functional copies of the ABCD1 gene in hematopoietic stem cells through a lentiviral vector reinfusing the modified cells in the patient’s bloodstream. Recent trials show encouraging results.38 In Zellweger syndrome, caused by mutations in peroxin genes (PEX), peroxisomes are absent, and disease presentation occurs in the neonatal period, with low survival rates after the first year of life. Finally, mitochondrial disorders have been described to occasionally develop AI: Pearson syndrome (sideroblastic anemia, pancreatic dysfunction), MELAS syndrome (encephalopathy with stroke-like episodes), and Kearns-Sayre syndrome (external ophthalmoplegia, heart block, retinal pigmentary changes) belong to this class.39 Autoimmune pathogenesis (Addison disease) accounts for approximately 15% of cases of primary AI in children, in contrast with adolescents and adults where it is the most common mechanism; half of these children present other glands involvement as well. Two syndromes recognize specific combinations: in Autoimmune Polyglandular Syndrome Type 1 (APS1, or APECED)40 defective autoimmune regulator AIRE causes AI, hypoparathyroidism, hypogonadism, malabsorption, chronic mucocutaneous candidiasis; APS2 usually present later in life (third-fourth decades) with AI, thyroiditis, and type 1 diabetes mellitus (T1DM). Antibodies against 21-hydroxylase enzyme are the hallmark of APS. Apart from a genetic disorder, a strong link between autoimmune conditions and autoimmune primary AI has been established, with more than 50% of patients with the latter also having one or more other autoimmune endocrine disorders; on the other hand, only a few patients with T1DM or autoimmune thyroiditis or Graves’ disease develop AI. As an example, in a study of 629 patients with T1DM, only 11 (1.7%) presented 21-hydroxylase autoantibodies, with three of them having AI.41 Nevertheless, these patients are to be considered at increased risk for a condition that is potentially fatal yet easy to diagnose and treat; that is why it is reasonable to screen for autoimmune AI at least patients with T1DM, significantly if associated with DQ8 HLA combined with DRB*0404 HLA alleles, who have been observed to develop AI in 80% of cases if also 21-hydroxylase autoantibodies positive.42 Regarding immunological disruption, the link with celiac disease is instead well established: celiac patients have an 11-fold increased risk for AI, while in a study, 6 of 76 patients with AI had celiac disease, so that mutual evaluation should be granted in these patients.43,44 Subclinical Adrenal Insufficiency Subclinical AI is a particularly insidious challenge for a pediatric endocrinologist. It represents the preclinical stage of Addison disease when 21-hydroxylase autoantibodies are already detectable but still absent from evident symptoms. 21-hydroxylase autoantibodies positivity carries a greater risk to develop overt AI in children than in adults: in a study, estimated risk was 100% in children versus 32% in adults on a medium six-year period of follow-up.45 As the adrenal crisis is a potentially lethal condition, it is essential to recognize and adequately manage subclinical AI. Although asymptomatic by definition, subclinical AI may present with non-specific symptoms such as fatigue, lethargy, gastrointestinal symptoms (nausea, vomiting, diarrhea, constipation), hypotension; physical or psychosocial stresses may sometimes exacerbate these symptoms. When symptoms lack, subclinical AI may be identified thanks to the co-occurrence with other autoimmune endocrinopathies.46 21-hydroxylase autoantibodies titer is considered a marker of autoimmune activity and correlates with disease progression.47 Other reported risk factors for the disease evolution include young age, male sex, hypoparathyroidism or candidiasis coexistence, increased renin activity, or an altered synacthen test with normal baseline cortisol and ACTH.45 ACTH elevation has been reported as the best predictor of progression to the clinical stage in 2 years (94% sensitivity and 78% specificity).48 Management of patients with subclinical AI should include serum cortisol, ACTH, renin measurement, and a synacthen test. If normal, cortisol and ACTH should be repeated in 12–18 months, while synacthen test every two years. After synacthen test results are subnormal, cortisol and ACTH should be assessed every 6–9 months if ACTH remains in range or every six months if ACTH becomes elevated.49 In the latter case, therapy with hydrocortisone should be started.19 This strategy will prevent acute crises and possibly improve the quality of life in patients reporting non-specific symptoms. Diagnosis Laboratory evaluation of a stable patient with suspected AI should start with combined early morning (between 6 and 8 AM) serum cortisol and ACTH measurements (Figure 2). Figure 2 Diagnostic algorithm for adrenal insufficiency. Although often included in the extensive work-up of an unwell child, a single cortisol value is usually challenging to interpret: circadian cortisol rhythm is highly variable and morning peak is unpredictable; morning cortisol levels in children with diagnosed AI may range up to 706 nmol/L (97th percentile); several factors, such as exogenous estrogens, may alter total serum cortisol values by influencing the free cortisol to cortisol binding globulin or albumin-bound cortisol ratio.7 Significant variability is also observed depending on the specific type of cortisol assay; therefore, it is recommended to check the reference ranges with the laboratory. Mass spectrometry analysis and the new platform methods (Roche Diagnostics Elecsys Cortisol II)50 have more specificity because it detects lower cortisol concentrations than standard immunoassays.15 Low serum cortisol with normal or low ACTH levels is compatible with CAI. In such cases, morning serum cortisol levels below 3 µg/dL (83 nmol/L) best predict AI, while greater than 13 µg/dL (365 nmol/L) values tend to exclude it.51 This is why in most cases, a dynamic test is required for diagnosis and has been introduced to assess the hypothalamic-pituitary-adrenal (HPA) axis in case of intermediate values.5 The insulin tolerance test (ITT) is considered the gold standard for CAI diagnosis as hypoglycemia results in an excellent HPA axis activation; moreover, it allows simultaneous growth hormone evaluation in patients with suspected CPHD. Serum cortisol is measured at baseline and 15, 30, 45, 60, 90, and 120 minutes after intravenous administration of 0.1 UI/Kg regular insulin; the test is valid if serum glucose is reduced by 50% or below 2.2 mmol/L (40 mg/dL).52 CAI is diagnosed for a <20 µg/dL (550 nmol/L) cortisol value at its peak.15 Hypoglycemic seizures and hypokalemia (due to glucose infusion) are the main risks of this test so that it is contraindicated in case of a history of seizures or cardiovascular disease. Glucagon stimulation test (GST, 30 µg/Kg up to 1 mg i.m. glucagon with cortisol measurements every 30 min for 180 min) allows both CAI and growth hormone deficiency evaluation as well but is characterized by frequent gastrointestinal side effects and poor specificity.8 Metyrapone is an 11-hydroxylase inhibitor, thereby decreasing cortisol synthesis and removing its negative feedback on ACTH release. Overnight metyrapone test is based on oral administration of 30 mg/Kg metyrapone at midnight, and 11-deoxycortisol measurement on the following morning: in case of CAI, its level will not reach 7 µg/dL (200 nmol/L). This test may, however, induce an adrenal crisis so that it is rarely performed. Given their safety profile and accuracy, corticotropin analogs such as tetracosactrin (Synacthen®) or cosyntropin (Cortrosyn®) are recommended as first-line stimulation tests. Nevertheless, false-negative results are probable in the case of recent or moderate ACTH deficiency, which would not have induced adrenal atrophy. The standard dose short synacthen test (SDSST) is based on a 250 µg Synacthen vial administration with serum cortisol measurement at baseline and 30 and 60 minutes after. CAI is diagnosed if peak cortisol level is <16 µg/dL (440 nmol/L), or excluded if >39 µg/dL (1076 nmol/L). However, the cut-offs for both the new platform immunoassay and mass spectrometry serum cortisol assays are 13.5 to 14.9 mcg/dL (373 to 412 nmol/L).53 The 250 µg Synacthen dose is considered a supraphysiological stimulus since it is 500 times greater than the minimum ACTH dose reported to induce a maximal cortisol response (500 ng/1.73 m2). The low dose short synacthen test (LDSST) has been introduced as a more sensitive first-line test in children greater than two years.54 The recommended dose is 1 µg55, which is contained in 1 mL of the solution obtained by diluting a 250 µg vial into 250 mL saline. Serum cortisol level is then measured at baseline and after 30 minutes, resulting in diagnose of CAI if <16 µg/dL (440 nmol/L), otherwise ruling it out if >22 µg/dL (660 nmol/L). Using these thresholds, LDSST is more precise than SDSST in children, with an area under the ROC curve of 0.99 (95% CI 0.98–1.00).56 LDSST has not been validated in acutely ill patients, pituitary acute disorders or surgery or radiation therapy, and impaired sleep-wake cycle. Patients with an indeterminate LDSST result should be furtherly studied with ITT or metyrapone test. Finally, the CRH test is based on 1 µg/Kg human CRH (Ferring®) administration and may differentiate secondary from tertiary AI, but its thresholds are still not precisely defined.57 Once CAI is diagnosed, other pituitary hormones should be assessed (prolactin, IGF1, LH, FSH, fT4, TSH), and an MRI of the pituitary region should be performed to exclude neoplastic or infiltrative processes. Primary adrenal insufficiency (PAI) should be suspected in case of low serum cortisol with elevated ACTH levels. When hypocortisolemia has been confirmed, ACTH levels >66 pmol/L or greater than twice the upper limit best predict PAI. Nevertheless, a confirmatory dynamic test is always recommended for diagnosis.19 Given the comparable accuracy between standard and low dose SST reported in these patients, SDSST is recommended as the most feasible test.58 Moreover, suspected PAI cases should receive plasma renin activity or direct renin and aldosterone assessment to evaluate mineralocorticoid deficiency. Etiologic work-up of confirmed PAI should start from 21-hydroxylase antibodies assessment: if positive, differential diagnosis will include Addison disease and APS1 or APS2. Adrenal autoantibody negative patients should instead be screened for CAH by measuring 17-hydroxyprogesterone, ALD (if young male) by assessing VLCFA, and tuberculosis if endemic; adrenal glands imaging will complete the work-up in order to exclude infection, hemorrhage, or tumor.6 While universal newborn screening is already implemented for CAH in many countries, allowing a timely replacement therapy, basal salivary cortisol, and salivary cortisone measurements could improve CAI screening in the future: this technique is simple, cost-effective, and independent of binding proteins.15 Treatment All patients with adrenal insufficiency need long-term glucocorticoid replacement therapy. Individuals with PAI also require mineralocorticoids replacement, together with salt intake as required (Table 4). Otherwise, guidelines do not recommend androgen replacement.5,9,19 Table 4 Management of Adrenal Insufficiency (AI) Oral hydrocortisone is the first-choice replacement treatment in children due to its short half-life, rapid peak in plasma concentration, lower potency, and fewer adverse effects than prednisolone and dexamethasone.5,8 Based on endogenous production, dosing replacement regimens vary from 7.5 to 15 mg/m2/day, divided into two, three, or four doses.19 The first and largest dose should be taken at awakening, the next in the early afternoon to avoid sleep disturbances. Small and frequent dosing mimic the physiological rhythm of cortisol secretion, but high peak cortisol levels after drug assumption and prolonged periods of hypocortisolemia between doses are described.8,9 Some children experience low cortisol concentrations and symptoms of cortisol insufficiency (eg, fatigue, nausea, headache) despite modifications in dosing. This cohort of patients can take advantage of using a modified-release hydrocortisone formulation, such as Chronocort® and Plenadren®. Plenadren®, approved for adults, consists of a coating of hydrocortisone released rapidly, followed by a slow release of hydrocortisone from the tablet center. It is available as 5 and 20 mg tablets. Park et al demonstrate smoother cortisol profiles and normal growth and weight gain patterns using Plenadren® in children.59 In a few cases, the continuous subcutaneous infusion of hydrocortisone using insulin pump technology proved to be a feasible, well-tolerated and safe option for selected patients with poor response to conventional therapy.19 Monitoring glucocorticoid therapy is based on growth, weight gain, and well-being. Cortisol measurements are usually not useful, apart from cases when a discrepancy between daily doses and patient symptoms exists.15 The concomitant use of hydrocortisone and CYP3A4 inducers, such as Rifampicin, Phenytoin, Carbamazepine, requires an increased dose of glucocorticoids. Conversely, the inhibition of CYP3A4 impairs hydrocortisone metabolism.5 Mineralocorticoid replacement is unnecessary if the patient has a normal renin-angiotensin-aldosterone axis and, hence, normal aldosterone secretion, as well as in CAI. By contrast, patients with PAI and confirmed aldosterone deficiency need fludrocortisone at the dosage of 0.1–0.2 mg/day when given together with hydrocortisone, which has some mineralocorticoid activity. When using other synthetic glucocorticoids for replacement, higher fludrocortisone doses may be needed. Infants younger than one year should also be supplemented with sodium chloride due to their relatively low dietary sodium intake and relative renal resistance to mineralocorticoids. The dose is approximately 1 gram (17 mEq) daily.19 Surgery and anesthesia increase the glucocorticoid requirement during the pre-, intra-, and post-operative periods (Table 4). All children with AI should receive an intravenous dose of hydrocortisone at induction (2 mg/kg for minor or major surgery under general anesthesia). For minor procedures or sedation, the child should receive a double morning dose of hydrocortisone orally.60 Adrenal crisis is a life-threatening condition, treatment is effective if administered promptly, and it must not be delayed for any reason. Hydrocortisone should be administered as soon as possible with an intravenous bolus of 4 mg/kg followed by a continuous infusion of 2 mg/kg/day until stabilization. In the alternative, it can be administered as a bolus every four hours intravenous or intramuscular. In difficult peripheral venous access, the intramuscular route must be used as the first choice. In order to counteract hypotension, a bolus of normal saline 0.9% should be given at a dose of 20 mL/kg; it can repeat up to a total of 60 mL/kg within one hour for shock. If there is hypoglycemia, 10% dextrose at a 5 mL/kg dose should be administered.5,19,61,62 Patients with AI require additional doses of glucocorticoids in case of physiologic stress such as illness or surgical procedures to avoid an adrenal crisis. Home management of illness with a fever (> 38°C), vomiting or diarrhea, is based on the increase from two to three times the usual dose orally. If the child is unable to tolerate oral therapy, intramuscular injection of hydrocortisone should be administered (Table 4). Education for caregivers and patients (if adolescent) is crucial to prevent adrenal crisis. They should recognize signs and symptoms of adrenal crisis and should receive a steroid emergency card with the sick day rules. Prescribing doctors should provide for additional oral glucocorticoids and adequate training in hydrocortisone emergency self-injection. Abbreviations AI, adrenal insufficiency; PAI, primary adrenal insufficiency; CAI, central adrenal insufficiency; HPA, hypothalamic-pituitary-adrenal axis; CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone; POMC, pro-opiomelanocortin; CAH, congenital adrenal hyperplasia; STAR, steroidogenic acute regulatory; 21OHD, 21-hydroxylase deficiency; 11BOHD, 11-B-hydroxylase deficiency; P450scc, P450 cytochrome side-chain cleavage deficiency; 17-OHP, 17-hydroxyprogesterone; NCCAH, non-classic congenital adrenal hyperplasia; ALD, adrenoleukodystrophy; VLCFA, very long-chain fatty acids; CMPD, combined multiple pituitary hormone deficiency; GHD, growth hormone deficiency; MSH, melanocyte stimulating hormone; IUGR, intrauterine growth restriction; APS1, autoimmune polyglandular syndrome type 1; SDSST, standard dose short synacthen test; LDSST, low dose short synacthen test. Take Home Messages In neonates and infants CAH is the commonest cause of PAI, causing almost 71.8% of cases. Adrenoleukodystrophy should be considered in any male with hypoadrenalism. Unexplained hyponatremia, hyperpigmentation and the loss of pubic and axillary hair should raise the suspicion of AI. Adrenal insufficiency can present with non-specific clinical features; therefore a single cortisol measurement should be included in the biochemical work-up of an unwell child. Patients and parents should be well-trained in adrenal crisis recognition and management. Disclosure The authors report no conflicts of interest in this work. References 1. Charmandari E, Nicolaides N, Chrousos G. Adrenal insufficiency. Lancet. 2021;383(9935):2152–2167. doi:10.1016/S0140-6736(13)61684-0 2. White PC. Adrenocortical insufficiency. In: Nelson Textbook of Pediatrics. Elsevier. 2019:11575–11617. 3. White PC. Physiology of the adrenal gland. Nelson Textbook of Pediatrics. Elsevier. 2019. 4. Butler G, Kirk J. Adrenal gland disorders. In: Paediatric Endocrinology and Diabetes. Oxford University Press. 2020:274–288. 5. Patti G, Guzzeti C, Di Iorgi N, Loche S. Central adrenal insufficiency in children and adolescents. Best Pract Res Clin Endocrinol Metab. 2018;32(4):425–444. doi:10.1016/j.beem.2018.03.012 6. Martin-grace J, Dineen R, Sherlock M, Thompson CJ. Adrenal insufficiency: physiology, clinical presentation and diagnostic challenges. Clin Chim Acta. 2020;505:78–91. doi:10.1016/j.cca.2020.01.029 7. Shaunak M, Blair JC, Davies JH. How to interpret a single cortisol measurement. Arch Dis Child Educ Pract. 2020;105:347–351. doi:10.1136/archdischild-2019-318431 8. Park J, Didi M, Blair J. The diagnosis and treatment of adrenal insuf fi ciency during childhood and adolescence. Arch Dis Child. 2016;101:860–865. doi:10.1136/archdischild-2015-308799 9. Husebye ES, Pearce SH, Krone NP, Kämpe O. Adrenal insufficiency. Lancet. 2021;397:613–629. doi:10.1016/S0140-6736(21)00136-7 10. Speiser P, Azziz R, Baskin L, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(9):4133–4160. doi:10.1210/jc.2009-2631 11. Buonocore F, McGlacken-Byrne S, Del Valle I, Achermann J. Current insights into adrenal insufficiency in the newborn and young infant. Front Pediatr. 2020;8:619041. doi:10.3389/fped.2020.619041 12. Bacila I, Elder C, Krone N. Update on adrenal steroid hormone biosynthesis and clinical implications. Arch Dis Child. 2019;104(12):1223–1228. doi:10.1136/archdischild-2017-313873 13. Buonocore F, Maharaj A, Qamar Y, et al. Genetic analysis of pediatric primary adrenal insufficiency of unknown etiology: 25 years’ experience in the UK. J Endocr Soc. 2021;5(8):1–15. doi:10.1210/jendso/bvab086 14. Balsamo A, Baronio F, Ortolano R, et al. Congenital adrenal hyperplasias presenting in the newborn and young infant. Front Pediatr. 2020;8:593315. doi:10.3389/fped.2020.593315 15. Hahner S, Ross RJ, Arlt W, et al. Adrenal insufficiency. Nat Rev Dis Prim. 2021;7(1):1–24. doi:10.1038/s41572-021-00252-7 16. Krude H, Biebermann H, Luck W, et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet. 1998;19:155–157. doi:10.1038/509 17. Vallette-Kasic S, Brue T, Pulichino A-M, et al. Congenital isolated adrenocorticotropin deficiency: an underestimated cause of neonatal death, explained by TPIT gene mutations. J Clin Endocrinol Metab. 2005;90:1323–1331. doi:10.1210/jc.2004-1300 18. Alatzoglou K, Dattani M. Genetic forms of hypopituitarism and their manifestation in the neonatal period. Early Hum Dev. 2009;85:705–712. doi:10.1016/j.earlhumdev.2009.08.057 19. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2016;101:364–389. doi:10.1210/jc.2015-1710 20. Kurtoğlu S, Hatipoğlu N. Non-classical congenital adrenal hyperplasia in childhood. J Clin Res Pediatr Endocrinol. 2017;9(1):1–7. doi:10.4274/jcrpe.3378 21. Livadas S, Bothou C. Management of the female with non-classical congenital adrenal hyperplasia (NCCAH): a patient-oriented approach. Front Endocrinol. 2019;10:366. doi:10.3389/fendo.2019.00366 22. Miller W. Disorders in the initial steps of steroid hormone synthesis. J Steroid Biochem Mol Biol. 2017;165:18–37. doi:10.1016/j.jsbmb.2016.03.009 23. Nowaczyk M, Irons M. Smith–Lemli–Opitz syndrome: phenotype, natural history, and epidemiology. Am J Med Genet Part C Semin Med Genet. 2012;160:250–262. doi:10.1002/ajmg.c.31343 24. Anderson R, Byrum R, Coates P, Sando G. Mutations at the lysosomal acid cholesteryl ester hydrolase gene locus in Wolman disease. Proc Natl Acad Sci USA. 1994;91:2718. doi:10.1073/pnas.91.7.2718 25. Jones S, Rojas-Caro S, Quinn A. Survival in infants treated with sebelipase Alfa for lysosomal acid lipase deficiency: an open-label, multicenter, dose-escalation study. Orphanet J Rare Dis. 2017;12:25. doi:10.1186/s13023-017-0587-3 26. Muscatelli F, Strom T, Walker A, et al. Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Nature. 1994;372:672–676. doi:10.1038/372672a0 27. Vilain E, Merrer M, Lecointre C, et al. IMAGe, a new clinical association of Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, and Genital anomalies. J Clin Endocrinol Metab. 1999;84(12):4335–4340. doi:10.1210/jcem.84.12.6186 28. Narumi S, Amano N, Ishii T, et al. SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7. Nat Genet. 2016;48:792–797. doi:10.1038/ng.3569 29. Maharaj A, Maudhoo A, Chan L, et al. Isolated glucocorticoid deficiency: genetic causes and animal models. J Steroid Biochem Mol Biol. 2019;189:73–80. doi:10.1016/j.jsbmb.2019.02.012 30. Metherell L, Chapple J, Cooray S, et al. Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2. Nat Genet. 2005;37:166–170. doi:10.1038/ng1501 31. Prpic I, Huebner A, Persic M, et al. Triple A syndrome: genotype-phenotype assessment. Clin Genet. 2003;63:415. doi:10.1034/j.1399-0004.2003.00070.x 32. Kurnaz E, Duminuco P, Aycan Z, et al. Clinical and genetic characterisation of a series of patients with triple A syndrome. Eur J Pediatr. 2018;177(3):363–369. doi:10.1007/s00431-017-3068-8 33. Brett E, Auchus R. Genetic forms of adrenal insufficiency. Endocr Pract. 2015;21(4):395–399. doi:10.4158/EP14503.RA 34. Prasad R, Hadjidemetriou I, Maharaj A, et al. Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome. J Clin Invest. 2017;127:942–953. doi:10.1172/JCI90171 35. Moser H, Moser A, Smith K, et al. Adrenoleukodystrophy: phenotypic variability and implications for therapy. J Inherit Metab Dis. 1992;15:645. doi:10.1007/BF01799621 36. Bradbury A, Ream M. Recent advancements in the diagnosis and treatment of leukodystrophies. Semin Pediatr Neurol. 2021;37:100876. doi:10.1016/j.spen.2021.100876 37. Engelen M, Kemp S. X-linked adrenoleukodystrophy: pathogenesis and treatment. Curr Neurol Neurosci Rep. 2014;14(10):486. doi:10.1007/s11910-014-0486-0 38. Federico A, de Visser M. New disease modifying therapies for two genetic childhood-onset neurometabolic disorders (metachromatic leucodystrophy and adrenoleucodystrophy). Neurol Sci. 2021;42(7):2603–2606. doi:10.1007/s10072-021-05412-x 39. Artuch R, Pavía C, Playán A, et al. Multiple endocrine involvement in two pediatric patients with Kearns-Sayre syndrome. Horm Res. 1998;50:99. doi:10.1159/000023243 40. Peterson P, Pitkänen J, Sillanpää N, et al. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED): a model disease to study molecular aspects of endocrine autoimmunity. Clin Exp Immunol. 2004;135:348. doi:10.1111/j.1365-2249.2004.02384.x 41. Brewer K, Parziale VS, Eisenbarth GS, et al. Screening patients with insulin-dependent diabetes mellitus for adrenal insufficiency. New Engl J Med. 1997;337:202. doi:10.1056/NEJM199707173370314 42. Yu L, Brewer K, Gates S, et al. DRB1*04 and DQ alleles: expression of 21-hydroxylase autoantibodies and risk of progression to Addison’s disease. J Clin Endocrinol Metab. 1999;84:328. doi:10.1210/jcem.84.1.5414 43. Myhre A, Aarsetøy H, Undlien D, et al. High frequency of coeliac disease among patients with autoimmune adrenocortical failure. Scand J Gastroenterol. 2003;38:511. doi:10.1080/00365520310002544 44. Elfström P, Montgomery S, Kämpe O, et al. Risk of primary adrenal insufficiency in patients with celiac disease. J Clin Endocrinol Metab. 2007;92:3595. doi:10.1210/jc.2007-0960 45. Coco G, Dal Pra C, Presotto F, et al. Estimated risk for developing autoimmune Addison’s disease in patients with adrenal cortex autoantibodies. J Clin Endocrinol Metab. 2006;91(5):1637–1645. doi:10.1210/jc.2005-0860 46. Yamamoto YT. Latent adrenal insufficiency: concept, clues to detection, and diagnosis. Endocr Pract. 2018;24(8):746–755. doi:10.4158/EP-2018-0114 47. Laureti S, De Bellis A, Muccitelli V, et al. Levels of adrenocortical autoantibodies correlate with the degree of adrenal dysfunction in subjects with preclinical Addison’s disease. J Clin Endocrinol Metab. 1998;83:3507–3511. doi:10.1210/jcem.83.10.5149 48. Baker P, Nanduri P, Gottlieb P, et al. Predicting the onset of Addison’s disease: ACTH, renin, cortisol and 21-hydroxylase autoantibodies. Clin Endocrinol. 2012;76:617–624. doi:10.1111/j.1365-2265.2011.04276.x 49. Thuillier P, Kerlan V. Subclinical adrenal diseases: silent pheochromocytoma and subclinical Addison’s disease. Ann Endocrinol. 2012;73(Suppl 1):S45–S54. doi:10.1016/S0003-4266(12)70014-8 50. Raverot V, Richet C, Morel Y, Raverot G, Borson-Chazot F. Establishment of revised diagnostic cut-offs for adrenal laboratory investigation using the new Roche Diagnostics Elecsys® Cortisol II assay. Ann Endocrinol. 2016;77(5):620–622. doi:10.1016/j.ando.2016.05.002 51. Grossman A. The diagnosis and management of central hypoadrenalism. J Clin Endocrinol Metab. 2010;95:4855e63. doi:10.1210/jc.2010-0982 52. Petersenn S, Quabbe HJ, Schöfl C, et al. The rational use of pituitary stimulation tests. Dtsch Arztebl Int. 2010;107(25):437–443. doi:10.3238/arztebl.2010.0437 53. Kline GA, Buse J, Krause RD. Clinical implications for biochemical diagnostic thresholds of adrenal sufficiency using a highly specific cortisol immunoassay. Clin Biochem. 2017;50(9):475–480. doi:10.1016/j.clinbiochem.2017.02.008 54. Agwu JC, Spoudeas H, Hindmarsh PC, Pringle PJ, Brook CGD. Tests of adrenal insufficiency. Arch Dis Child. 1999;80(4):330–333. doi:10.1136/adc.80.4.330 55. Maghnie M, Uga E, Temporini F, et al. Evaluation of adrenal function in patients with growth hormone deficiency and hypothalamic-pituitary disorders: comparison between insulin-induced hypoglycemia, low-dose ACTH, standard ACTH and CRH stimulation tests. Eur J Endocrinol. 2005;152:735–741. doi:10.1530/eje.1.01911 56. Kazlauskaite R, Maghnie M. Pitfalls in the diagnosis of central adrenal insufficiency in children. Endocr Dev. 2010;17:96e107. 57. Chanson P, Guignat L, Goichot B, et al. Group 2: adrenal insufficiency: screening methods and confirmation of diagnosis. Ann Endocrinol. 2017;78:495e511. doi:10.1016/j.ando.2017.10.005 58. Ospina N, Al Nofal A, Bancos I, et al. ACTH stimulation tests for the diagnosis of adrenal insufficiency: systematic review and meta-analysis. J Clin Endocrinol Metab. 2016;101(2):427–434. doi:10.1210/jc.2015-1700 59. Park J, Das U, Didi M, et al. The challenges of cortisol replacement therapy in childhood: observations from a case series of children treated with modified-release hydrocortisone. Pediatr Drugs. 2018;20(6):567–573. doi:10.1007/s40272-018-0306-0 60. Woodcock T, Barker P, Daniel S, et al. Guidelines for the management of glucocorticoids during the peri-operative period for patients with adrenal insuf fi ciency Guidelines from the Association of Anaesthetists, the Royal College of Physicians and the Society for Endocrinology UK. Anaesthesia. 2020;75:654–663. doi:10.1111/anae.14963 61. Rushworth R, Torpy DJ, Falhammar H. Adrenal crisis. N Engl J Med. 2019;381(9):852–861. doi:10.1056/NEJMra1807486 62. Miller BS, Spencer SP, Geffner ME, et al. Emergency management of adrenal insufficiency in children: advocating for treatment options in outpatient and field settings. J Investig Med. 2020;68:16–25. doi:10.1136/jim-2019-000999 This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms. Download Article [PDF] From https://www.dovepress.com/pediatric-adrenal-insufficiency-challenges-and-solutions-peer-reviewed-fulltext-article-TCRM

Adrenal insufficiency increases the risk for severe outcomes, including death, 23-fold for children who contract COVID-19, according to a data analysis presented at the ENDO annual meeting. “Adrenal insufficiency in pediatrics does increase risk of complications with COVID-19 infections,” Manish Gope Raisingani, MD, assistant professor in the department of pediatrics in the division of pediatric endocrinology at Arkansas Children's Hospital, University of Arkansas for Medical Sciences, told Healio. “The relative risk of complications is over 20 for sepsis, intubation and mortality, which is very significant.” Source: Adobe Stock Using the TriNetX tool and information on COVID-19 from 54 health care organizations, Raisingani and colleagues analyzed data from children (aged 0-18 years) with COVID-19; 846 had adrenal insufficiency and 252,211 did not. The mortality rate among children with adrenal insufficiency was 2.25% compared with 0.097% for those without, for a relative risk for death of 23.2 (P < .0001) for children with adrenal insufficiency and COVID-19. RRs for these children were 21.68 for endotracheal intubation and 25.45 for sepsis. “Children with adrenal insufficiency should be very careful during the pandemic,” Raisingani said. “They should take their steroid medication properly. They should also be appropriately trained on stress steroids for infection, other significant events.” From https://www.healio.com/news/endocrinology/20210321/severe-covid19-risks-greatly-increased-for-children-with-adrenal-insufficiency

Removal of pituitary adenomas by inserting surgical instruments through the nose (transsphenoidal resection) remains the best treatment option for pediatric patients, despite its inherent technical difficulties, a new study shows. The study, “Transsphenoidal surgery for pituitary adenomas in pediatric patients: a multicentric retrospective study,” was published in the journal Child’s Nervous System. Pituitary adenomas are rare, benign tumors that slowly grow in the pituitary gland. The incidence of such tumors in the pediatric population is reported to be between 1% and 10% of all childhood brain tumors and between 3% and 6% of all surgically treated adenomas. Characteristics of patients that develop these pituitary adenomas vary significantly in different studies with regards to their age, gender, size of adenoma, hormonal activity, and recurrence rates. As the pituitary gland is responsible for hormonal balance, alterations in hormone function due to a pituitary adenoma can significantly affect the quality of life of a child. In most cases, pituitary adenomas can be removed surgically. A common removal method is with a transsphenoidal resection, the goal of which is to completely remove the growing mass and cause the least harm to the surrounding structures. In this study, the researchers report the surgical treatment of pediatric pituitary adenomas at three institutions. They collected data from 27 children who were operated for pituitary adenoma using one of two types of transsphenoidal surgeries — endoscopic endonasal transsphenoidal surgery (EETS) and transsphenoidal microsurgery (TMS) — at the University Cerrahpasa Medical Faculty in Istanbul, Turkey, at San Matteo Hospital in Pavia, and at the University of Insubria-Varese in Varese, Italy. The study included 11 males (40.7%) and 16 females (59.3%), with a mean age of 15.3 (ranging between 4 and 18). Medical records indicated that 32 surgical procedures were performed in the 27 patients, as six children required a second operation. Among the patients, 13 had Cushing’s disease, while the rest had growth-hormone-secreting adenomas, prolactinomas, or non-functional adenomas. The researchers found that most patients underwent remission following their surgery. Among the 27 patients, 22 patients (81.4%) underwent remission while five patients (18.5%) did not. Four patients underwent remission after a second operation. Based on these findings, the team believes that the transsphenoidal surgical approach adequately removes pituitary tumors and restores normal hormonal balance in the majority of pediatric patients with pituitary adenomas. “Satisfactory results are reported with both EETS and TMS in the literature,” they wrote. “Despite the technical difficulties in pediatric age, transsphenoidal resection of adenoma is still the mainstay treatment that provides cure in pediatric patients.” From https://cushingsdiseasenews.com/2019/05/30/transsphenoidal-surgery-effective-remove-pituitaty-adenomas-children-study/

Childs Nerv Syst. 2018 Nov 28. doi: 10.1007/s00381-018-4013-5. [Epub ahead of print] Gazioglu N1, Canaz H2, Camlar M3, Tanrıöver N4, Kocer N5, Islak C5, Evliyaoglu O6, Ercan O6. Author information Abstract AIM: Pituitary adenomas are rare in childhood in contrast with adults. Adrenocorticotropic hormone (ACTH)-secreting adenomas account for Cushing's disease (CD) which is the most common form of ACTH-dependent Cushing's syndrome (CS). Treatment strategies are generally based on data of adult CD patients, although some difficulties and differences exist in pediatric patients. The aim of this study is to share our experience of 10 children and adolescents with CD. PATIENTS AND METHOD: Medical records, images, and operative notes of 10 consecutive children and adolescents who underwent transsphenoidal surgery for CD between 1999 and 2014 in Cerrahpasa Faculty of Medicine were retrospectively reviewed. Mean age at operation was 14.8 ± 4.2 years (range 5-18). The mean length of symptoms was 24.2 months. The mean follow-up period was 11 years (range 4 to 19 years). RESULTS: Mean preoperative cortisol level was 23.435 μg/dl (range 8.81-59.8 μg/dl). Mean preoperative ACTH level was 57.358 μg/dl (range 28.9-139.9 μg/dl). MR images localized microadenoma in three patients (30%), macroadenoma in four patients (40%) in our series. Transsphenoidal microsurgery and endoscopic transsphenoidal surgery were performed in 8 and 2 patients respectively. Remission was provided in 8 patients (80%). Five patients (50%) met remission criteria after initial operations. Three patients (30%) underwent additional operations to meet remission criteria. CONCLUSION: Transsphenoidal surgery remains the mainstay therapy for CD in pediatric patients as well as adults. It is an effective treatment option with low rate of complications. Both endoscopic and microscopic approaches provide safe access to sella and satisfactory surgical results. KEYWORDS: Cushing’s disease; Endoscopic pituitary surgery; Pediatric; Transsphenoidal microsurgery PMID: 30488233 DOI: 10.1007/s00381-018-4013-5 Full Text

Minimally invasive diagnostic methods and transnasal surgery may lead to remission in nearly all children with Cushing’s disease, while avoiding more aggressive approaches such as radiation or removal of the adrenal glands, a study shows. The study, “A personal series of 100 children operated for Cushing’s disease (CD): optimizing minimally invasive diagnosis and transnasal surgery to achieve nearly 100% remission including reoperations,” was published in the Journal of Pediatric Endocrinology and Metabolism. Normally, the pituitary produces adrenocorticotropic hormone (ACTH), which stimulates the adrenal glands to produce cortisol. When a patient has a pituitary tumor, that indirectly leads to high levels of cortisol, leading to development of Cushing’s disease (CD). In transnasal surgery (TNS), a surgeon goes through the nose using an endoscope to remove a pituitary tumor. The approach is the first-choice treatment for children with Cushing’s disease due to ACTH-secreting adenomas — or tumors — in the pituitary gland. Micro-adenomas, defined as less than 4 mm, are more common in children and need surgical expertise for removal. It is necessary to determine the exact location of the tumor before conducting the surgery. Additionally, many surgeons perform radiotherapy or bilateral adrenalectomy (removal of both adrenal glands) after the surgery. However, these options are not ideal as they can be detrimental to children who need to re-establish normal growth and development patterns. Dieter K. Lüdecke, a surgeon from Germany’s University of Hamburg, has been able to achieve nearly 100% remission while minimizing the need for pituitary radiation or bilateral adrenalectomy. In this study, researchers looked at how these high remission rates can be achieved while minimizing radiotherapy or bilateral adrenalectomy. Researchers analyzed 100 patients with pediatric CD who had been referred to Lüdecke for surgery from 1980-2009. Data was published in two separate series — series 1, which covers patients from 1980-1995, and series 2, which covers 1996-2009. All the surgeries employed direct TNS. Diagnostic methods for CD have improved significantly over the past 30 years. Advanced endocrine diagnostic investigations, such as testing for levels of salivary cortisol in the late evening and cortisol-releasing hormone tests, have made a diagnosis of CD less invasive. This is particularly important for excluding children with obesity alone from children with obesity and CD. Methods to determine the precise location of micro-adenomas have also improved. The initial methodology to localize tumors was known as inferior petrosal sinus sampling (IPSS), an invasive procedure in which ACTH levels are sampled from the veins that drain the pituitary gland. In series 1, IPSS was performed in 24% of patients, among which 46% were found to have the wrong tumor location. Therefore, IPSS was deemed invasive, risky, and unreliable for this purpose. All adenomas were removed with extensive pituitary exploration. Two patients in series 1 underwent early repeat surgery; all were successful. Lüdecke introduced intraoperative cavernous sinus sampling (CSS), an improved way to predict location of adenomas. This was found to be very helpful in highly select cases and could also be done preoperatively for very small adenomas. In series 2, CSS was used in only 15% of patients thanks to improved MRI and endocrinology tests. All patients who underwent CSS had correct localization of their tumors, indicating its superiority over IPSS. In series 2, three patients underwent repeat TNS, which was successful. In these recurrences, TNS minimized the need for irradiation. The side effects of TNS were minimal. Recurrence rate in series 1 was 16% and 11% in series 2. While Lüdecke’s patients achieved a remission rate of 98%, other studies show cure rates of 45-69%. Only 4% of patients in these two series received radiation therapy. “Minimally invasive unilateral, microsurgical TNS is important functionally for both the nose and pituitary,” the researchers concluded. “Including early re-operations, a 98% remission rate could be achieved and the high risk of pituitary function loss with radiotherapy could be avoided.” From https://cushingsdiseasenews.com/2018/09/04/minimally-invasive-methods-yield-high-remission-in-cushings-disease-children/

Children with Cushing’s syndrome are at risk of developing new autoimmune and related disorders after being cured of the disease, a new study shows. The study, “Incidence of Autoimmune and Related Disorders After Resolution of Endogenous Cushing Syndrome in Children,” was published in Hormone and Metabolic Research. Patients with Cushing’s syndrome have excess levels of the hormone cortisol, a corticosteroid that inhibits the effects of the immune system. As a result, these patients are protected from autoimmune and related diseases. But it is not known if the risk rises after their disease is resolved. To address this, researchers at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) examined 127 children with Cushing’s syndrome at the National Institutes of Health from 1997 until 2017. Among the participants, 77.5 percent had a pituitary tumor causing the disease, 21.7 percent had ACTH-independent disease, and one patient had ectopic Cushing’s syndrome. All patients underwent surgery to treat their symptoms. After a mean follow-up of 31.2 months, 7.8 percent of patients developed a new autoimmune or related disorder. Researchers found no significant differences in age at diagnosis, gender, cortisol levels, and urinary-free cortisol at diagnosis, when comparing those who developed autoimmune disorders with those who didn’t. However, those who developed an immune disorder had a significantly shorter symptom duration of Cushing’s syndrome. This suggests that increased cortisol levels, even for a short period of time, may contribute to more reactivity of the immune system after treatment. The new disorder was diagnosed, on average, 9.8 months after Cushing’s treatment. The disorders reported were celiac disease, psoriasis, Hashimoto thyroiditis, Graves disease, optic nerve inflammation, skin hypopigmentation/vitiligo, allergic rhinitis/asthma, and nerve cell damage of unknown origin responsive to glucocorticoids. “Although the size of our cohort did not allow for comparison of the frequency with the general population, it seems that there was a higher frequency of optic neuritis than expected,” the researchers stated. It is still unclear why autoimmune disorders tend to develop after Cushing’s resolution, but the researchers hypothesized it could be a consequence of the impact of glucocorticoids on the immune system. Overall, the study shows that children with Cushing’s syndrome are at risk for autoimmune and related disorders after their condition is managed. “The presentation of new autoimmune diseases or recurrence of previously known autoimmune conditions should be considered when concerning symptoms arise,” the researchers stated. Additional studies are warranted to further explore this link and improve care of this specific population. From https://cushingsdiseasenews.com/2018/03/06/after-cushings-cured-autoimmune-disease-risk-looms-study/

ORLANDO – Cushing’s disease may begin to exert its harmful cardiovascular effects quite early, a small pediatric study has found. Children as young as 6 years old with the disorder already may show signs of cardiovascular remodeling, with stiffer aortas and higher aortic pulse-wave velocity than do age-matched controls, Hailey Blain and Maya Lodish, MD, said at the annual meeting of the Endocrine Society. “The study, which included 10 patients, is small, but we continue to add new patients,” said Dr. Lodish, director of the pediatric endocrinology fellowship program at the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Ten more children are being added to the cohort now, and she and Ms. Blain, a former research fellow at NIH, intend to grow the group and follow patients longitudinally. Cushing’s disease has long been linked with increased cardiovascular risk in adults, but the study by Dr. Lodish and Ms. Blain is one of the first to examine the link in children. Their findings suggest that early cardiovascular risk factor management should be a routine part of these patients’ care, Dr. Lodish said in an interview. “It’s very important to make sure that there is recognition of the cardiovascular risk factors that go along with this disease. Elevated levels of cholesterol, hypertension, and other risk factors that are in these individuals should be ameliorated as soon as possible from an early age and, most importantly, physicians should be diagnosing and treating children early, once they are identified as having Cushing’s disease. And, given that we are not sure whether these changes are reversible, we need to make sure these children are followed very closely.” Indeed, Dr. Lodish has reason to believe that the changes may be long lasting or even permanent. “We are looking at these children longitudinally and have 3-year data on some patients already. We want to see if they return to normal pulse wave velocity after surgical cure, or whether this is permanent remodeling. There is an implication already that it may be in a subset of individuals,” she said, citing her own 2009 study on hypertension in pediatric Cushing’s patients. “We looked at blood pressure at presentation, after surgical cure, and 1 year later. A significant portion of the kids still had hypertension at 1 year. This leads us to wonder if they will continue to be at risk for cardiovascular morbidity as adults.” Ms. Blaine, an undergraduate at Bowdoin College, Brunswick, Maine, worked on the study during a summer internship with Dr. Lodish and presented its results in a poster forum during meeting. She examined two indicators of cardiovascular remodeling – aortic pulse wave velocity and aortic distensibility – in 10 patients who were a mean of 13 years old. All of the children came to NIH for diagnosis and treatment of Cushing’s; as part of that, all underwent a cardiac MRI. The patients had a mean 2.5-year history of Cushing’s disease Their mean midnight cortisol level was 18.8 mcg/dL and mean plasma adrenocorticotropic hormone level, 77.3 pg/mL. Five patients were taking antihypertensive medications. Low- and high-density lipoprotein levels were acceptable in all patients. The cardiovascular measures were compared to an age-matched historical control group. In this comparison, patients had significantly higher pulse wave velocity compared with controls (mean 4 vs. 3.4 m/s). Pulse wave velocity positively correlated with both midnight plasma cortisol and 24-hour urinary free cortisol collections. In the three patients with long-term follow-up after surgical cure of Cushing’s, the pulse wave velocity did not improve, either at 6 months or 1 year after surgery. This finding echoes those of Dr. Lodish’s 2009 paper, suggesting that once cardiovascular remodeling sets in, the changes may be long lasting. “The link between Cushing’s and cardiovascular remodeling is related to the other things that go along with the disease,” Dr. Lodish said. “The hypertension, the adiposity, and the high cholesterol all may contribute to arterial rigidity. It’s also thought to be due to an increase in connective tissue. The bioelastic function of the aorta may be affected by having Cushing’s.” That connection also suggests that certain antihypertensives may be more beneficial to patients with Cushing’s disease, she added. “It might have an implication in what blood pressure drug you use. Angiotensin-converting enzyme inhibitors increase vascular distensibility and inhibit collagen formation and fibrosis. It is a pilot study and needs longitudinal follow up and additional patient accrual, however, finding signs of cardiovascular remodeling in young children with Cushing’s is intriguing and deserves further study.” Neither Ms. Blain nor Dr. Lodish had any financial disclosures. msullivan@frontlinemedcom.com