Diagnosis Of Cushing's Syndrome Research Articles

Endogenous Cushing's Syndrome and Cancer Risk.

Cancer incidence in patients with endogenous Cushing's syndrome (CS) has never been established. We aimed to assess the cancer risk in patients with CS, as compared with individually matched controls. A nationwide retrospective matched-cohort study of patients with endogenous CS diagnosed between 2000-2023, using the database of Clalit Health Services in Israel. Patients with adrenal carcinoma or ectopic CS were excluded. Patients with CS were matched in a 1:5 ratio, with controls individually matched for age, sex, socioeconomic status, and body mass index. The primary outcome was defined as the first diagnosis of any malignancy following a CS diagnosis. Risk of malignancy was calculated using the Cox proportional hazards model with death as a competing event. A total of 609 patients with CS and 3018 controls were included [mean age at diagnosis, 48.0±17.2 years; 2371 (65.4%) women]. The median follow-up 14.7 years (IQR, 9.9-20.2 years).Patients with CS had an increased cancer risk, with hazard ratio (HR) of 1.78 (95% CI 1.44-2.20), compared with their matched controls. The risk of malignancy was elevated in patients with Cushing's disease (251 cases and 1246 controls; HR 1.65, 95% CI 1.15-2.36) and in patients with adrenal CS (200 cases and 991 controls; HR 2.36, 95% CI 1.70-3.29). The increased cancer risk in patients with CS persists after exclusion of thyroid malignancies. Endogenous CS is associated with increased malignancy risk. These findings underscore the need for further research to establish recommendations for cancer screening in this population.

Clinical and biochemical data for the diagnosis of endogenous hypercortisolism: the "Cushingomic" approach.

The clinical presentation of Cushing's syndrome (CS) overlaps with common conditions. Recommended screening tests are serum cortisol after 1-mg overnight dexamethasone suppression test (DST), urinary free cortisol (UFC), and late-night salivary cortisol (LNSC). We analyzed the diagnostic accuracy of screening tests in 615 patients without CS (263 suspected CS, 319 adrenal and 33 pituitary incidentaloma) and 40 with CS. Principal component analysis, K-means clustering, and neural network were used to compute an integrated analysis among tests, comorbidities, and signs/symptoms of hypercortisolism. The diagnostic accuracy of screening tests for CS was high, DST and UFC were slightly superior to LNSC. The threshold of DST should be adapted to the population considered, especially in adrenal incidentaloma with mild autonomous cortisol secretion: the cutoff to differentiate CS should be increased to 196 nmol/L. Diabetes, hypertension, and obesity were more common in patients without CS: the direction of their vectors was not aligned and their correlation with screening tests was poor. Clustering allowed us to differentiate those patients without CS in cluster one (aged osteoporotic patients with impaired screening tests), cluster two (hypertensive and metabolic phenotype), and cluster three (young subjects with a low likelihood of overt CS). A neural network model that combined screening tests and clinical presentation was able to predict the CS diagnosis in the validation cohort with 99% precision and 86% accuracy. Despite the high diagnostic accuracy of screening tests to detect CS, cortisol-related comorbidities or adrenal incidentaloma should be considered when interpreting a positive test.

Circulating miR-28-5p is overexpressed in patients with sarcopenia despite long-term remission of Cushing's syndrome: a pilot study.

Patients with Cushing's syndrome (CS) in remission show sustained fatigue, myopathy, and an increased prevalence of sarcopenia. The mechanisms that determine these persistent muscle problems are not well known. We aimed to identify circulating microRNAs (miRNAs) with differential expression that could be potential biomarkers for the diagnosis and/or prognosis in CS. Thirty-six women in sustained remission for 13 ± 7 years (mean ± SD) from CS, with a median age (IQ range) of 51 (45.2-60) years and mean ± SD BMI of 27 ± 4 Kg/m2, and 36 matched healthy controls were investigated. In 7 patients sarcopenia was present according to the European Working Group on Sarcopenia in Older People (EWGSOP) criteria. Small RNA libraries were generated and indexed using a modified Illumina TruSeq small RNA-sequencing protocol. MiRNAs were identified in plasma using bioinformatic analysis, and validation was carried out using RT-qPCR. For the validation, Taqman probes were performed on QuantStudio 5 equipment (Applied Biosystems). In a first discovery group using RNA-sequencing, plasma samples of 18 CS patients and 18 healthy subjects were investigated; circulating miR-28-5p, miR-495-3p and miR-654-5p were upregulated in CS patients as compared with controls (p<0.05). In a validation study of the 3 upregulated miRNAs in 36 patients and 26 controls, no differences were observed by RT-qPCR; however, the expression of circulating miR-28-5p was upregulated in CS patients with sarcopenia as compared with those without (AUC for fold-change in the ROC analysis, 0.798; p=0.0156). The optimized cut-off value for miR-28-5p to identify CS patients with sarcopenia was 3.80, which yielded a sensitivity of 86% and a specificity of 69%. MiR-28-5p, a muscle-specific microRNA involved in myotube proliferation and differentiation in vivo, may serve as an independent non-invasive biomarker for identifying CS patients at high-risk of sarcopenia despite biochemical remission.

Subtyping of Cushing's Syndrome: A Step Ahead.

Cushing's Syndrome (CS) is a rare disease due to chronic endogenous cortisol secretion. In recent years, new developments have broadened the spectrum of differential diagnosis, traditionally categorized as adrenocorticotropic hormone (ACTH)-dependent and ACTH-independent forms. Moreover, increased awareness of the detrimental effects of cortisol on cardiometabolic health and the risk of cardiovascular events lead to increased diagnosis of mild forms, especially in the context of adrenal incidentalomas.This review provides an up-to-date narrative of the most recent literature regarding the challenges of CS diagnosis. After the description of the diagnostic tools available, the functional non-neoplastic hypercortisolism (formerly known as pseudo-Cushing state) is characterized, followed by the subtyping of the different conditions of hypercortisolism, including the differential diagnosis of ACTH-dependent forms and the management of adrenal hypercortisolism, with peculiar attention to the new genetic classification of adrenal CS, mild autonomous cortisol secretion, and bilateral adrenal adenomas.

Steroid Profiling in the Differential Diagnosis of Cushing's Syndrome and Diagnosis of MACS

Abstract Background Cushing's Syndrome (CS) is the consequence of the exposure of tissues to extremely high levels of glucocorticoids. Early diagnosis and treatment are the mainstay of optimizing patient outcomes and improving their quality of life. In the recent years steroid profiling by LC-MS sheds more light on the diagnosis of CS. Materials and methods This was a retrospective cross-sectional study. Objective To investigate serum steroid precursor differences between different etiological forms of CS and to suggest a steroid panel for the diagnosis of MACS in patients with adrenal incidentalomas. Results Our studied patients with CD had significantly lower levels of 11-deoxycorticosterone (p = 0.047) and 17 OH progesterone (p = 0.024) compared to those with adrenal forms of CS. In out cohort of patients with adrenal incidentalomas, those with MACS had significantly lower levels of androgens (DHEA, p = 0.001) and cortisone (p = 0.015) and higher levels of 11-deoxycortisol (p = 0.039) compared to the patients with non-secreting adenomas (NSA). Conclusion Introducing LC-MS based steroid profiling would be very helpful in the diagnostic process of patients with CS.

Frequency of low-dose dexamethasone suppression test (LDDST) response patterns and their correlation with clinicopathologic signs in dogs suspected of having Cushing's syndrome: A retrospective study

A retrospective cross-sectional study was conducted to assess the frequency of low-dose dexamethasone suppression test (LDDST) patterns in canine patients that had clinicopathologic signs consistent with Cushing's syndrome (CS). Medical records for patients of interest (N = 128) were reviewed between January 2014 and December 2020 to analyse and classify LDDST results based upon the following patterns: lack of suppression, partial suppression, complete suppression, escape, or inverse. Complete suppression, lack of suppression, partial suppression, escape, and inverse patterns were identified in 39.1%, 31.2%, 14.1%, 10.1% and 5.5% of cases respectively. LDDST results were also evaluated with respect to clinical signs, serum alkaline phosphatase (ALP) activity, urine specific gravity (USG) and adrenal ultrasonographic findings. There was no association between LDDST patterns and clinical signs (p = 0.11), increased ALP (p = 0.32), USG (p = 0.33) or adrenal ultrasonographic findings (p = 0.19). In all dogs that demonstrated complete suppression or an inverse pattern, CS was excluded by the attending clinician. The diagnosis of CS was also excluded without further exploration in 23.1%, 7.5% and 5.6% of dogs that demonstrated an escape pattern, lack of suppression and partial suppression pattern, respectively. These results suggest that the clinical significance of LDDST patterns, particularly escape and inverse patterns, are misunderstood by some clinicians, leading them to prematurely exclude the diagnosis of CS.

Impact of etiology, sex, diabetes mellitus and remission status on erythrocytic profile in patients with cushing's syndrome: a large population database study.

The study aimed to characterize the erythrocytic profile in patients with cushing's syndrome (CS) versus controls from the normal population according to etiology, sex, presence of diabetes mellitus (DM) and hypercortisolemia remission status. This retrospective cohort analysis compared erythrocytic parameters between patients with CS of pituitary (CD) and adrenal (aCS) etiology and age, sex, body mass index (BMI) and socioeconomic status-matched controls in a 1:5 ratio. Laboratory values at baseline were calculated as mean values during the year preceding CS diagnosis, and over one year thereafter. The cohort included 397 CS patients (68.26% female; mean age 51.11 ± 16.85years) and 1970 controls. Patients with CS had significantly higher baseline median levels of hemoglobin (Hgb) (13.70g/dL vs. 13.12g/dL [p < 0.0001]) and hematocrit (Hct) (41.64% vs. 39.80% [p < 0.0001]) compared to controls. These differences were observed for both CD and aCS and for both sexes. Patients who attained remission had Hgb and Hct levels comparable to controls (13.20g/dL and 40.08% in patients with CD and aCS vs. 13.20g/dL and 39.98% in controls). Meanwhile, those with persistent/recurrent disease maintained elevated levels. Patients with comorbid DM had similar Hgb but higher Hct (p = 0.0419), while patients without DM showed elevated erythrocytic values compared to controls (p < 0.0001). Our data illustrates that erythrocytic parameters are directly influenced by glucocorticoid excess as Hgb and Hct are higher in patients with CS, and normalize after remission. We have identified the influence of DM on erythrocytic parameters in patients with CS for the first time.

Venous thromboembolism in Cushing syndrome: results from an EuRRECa and Endo-ERN survey.

Patients with Cushing syndrome (CS) are at increased risk of venous thromboembolism (VTE). The aim was to evaluate the current management of new cases of CS with a focus on VTE and thromboprophylaxis. A survey was conducted within those that report in the electronic reporting tool (e-REC) of the European Registries for Rare Endocrine Conditions (EuRRECa) and the involved main thematic groups (MTG's) of the European Reference Networks for Rare Endocrine Disorders (Endo-ERN) on new patients with CS from January 2021 to July 2022. Of 222 patients (mean age 44 years, 165 females), 141 patients had Cushing disease (64%), 69 adrenal CS (31%), and 12 patients with ectopic CS (5.4%). The mean follow-up period post-CS diagnosis was 15 months (range 3-30). Cortisol-lowering medications were initiated in 38% of patients. One hundred fifty-four patients (69%) received thromboprophylaxis (including patients on chronic anticoagulant treatment), of which low-molecular-weight heparins were used in 96% of cases. VTE was reported in six patients (2.7%), of which one was fatal: two long before CS diagnosis, two between diagnosis and surgery, and two postoperatively. Three patients were using thromboprophylaxis at time of the VTE diagnosis. The incidence rate of VTE in patients after Cushing syndrome diagnosis in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. Thirty percent of patients with CS did not receive preoperative thromboprophylaxis during their active disease stage, and half of the VTE cases even occurred during this stage despite thromboprophylaxis. Prospective trials to establish the optimal thromboprophylaxis strategy in CS patients are highly needed. The incidence rate of venous thromboembolism in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. Notably, this survey showed that there is great heterogeneity regarding time of initiation and duration of thromboprophylaxis in expert centers throughout Europe.

Development of diagnostic algorithm for Cushing's syndrome: a tertiary centre experience.

No consensus exists as the gold standard for Cushing's Syndrome (CS) screening. This study aimed to evaluate the diagnostic accuracy and utility of late-night salivary cortisol (LNSC) and cortisone (LNSE), overnight dexamethasone suppression test (ODST), and urinary free cortisol (UFC) in developing a screening algorithm for CS. A retrospective, single-centre analysis on 93 adult patients referred to the Oxford Centre for Diabetes, Endocrinology, and Metabolism for CS evaluation (2017-2022). Data were analysed using binomial logistic regression and area under the receiver-operating curve (AUROC). Fifty-three patients were diagnosed with CS. LNSC (sensitivity 87.5%, specificity 64.9%, AUC 0.76), LNSE (sensitivity 72.4%, specificity 85.7%, AUC 0.79), and ODST (sensitivity 94.7%, specificity 52.1%; AUC 0.74) demonstrated comparable effectiveness for CS diagnosis. Their combined application increased diagnostic accuracy (AUC 0.91). UFC was not statistically significant. Pre-test clinical symptom inclusion improved screening test performance (AUC LNSC: 0.83; LNSE: 0.84; ODST: 0.82). For CD diagnosis, LNSE + LNSC (AUC 0.95) outperformed ODST. Combining these with ACTH levels < 12.6pmol/L perfectly distinguished MACS (AUC 1.00). ODST (AUC 0.76) exhibited superior performance (sensitivity 100.0%, specificity 52.2%) in MACS detection. LNSC, LNSE, and ODST are robust tools for CS screening, with their combined use offering the highest diagnostic precision. LNSE, especially when used with LNSC, is highly effective for CD diagnosis, exceeding ODST accuracy. ODST is preferable for MACS identification. Integrating ACTH levels markedly improves differentiation between CD and MACS. Conversely, UFC shows limited diagnostic utility.

Machine Learning May Be An Alternative To BIPSS In The Differential Diagnosis Of ACTH-Dependent Cushing's Syndrome.

This study aimed to develop machine learning (ML) algorithms for the differential diagnosis of adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (CS) based on biochemical and radiological features. Logistic regression algorithms were used for ML, and the area under the receiver operating characteristics curve (AUROC) was used to measure performance. We used Shapley Contributed Comments (SHAP) values, which help explain the results of the ML models to identify the meaning of each feature and facilitate interpretation. A total of 106 patients, 80 with Cushing's disease (CD) and 26 with ectopic ACTH syndrome (EAS), were enrolled in the study. The ML task was created to classify patients with ACTH-dependent CS into CD and EAS. The average AUROC value obtained in the cross-validation of the logistic regression model created for the classification task was 0.850. The diagnostic accuracy of the algorithm was 86%. The SHAP values indicated that the most important determinants for the model were the 2-day 2-mg dexamethasone suppression test, the > 50% suppression in the 8-mg high-dose dexamethasone test, late-night salivary cortisol, and the diameter of the pituitary adenoma. We have also made our algorithm available to all clinicians via a user-friendly interface. ML algorithms have the potential to serve as an alternative decision support tool to invasive procedures in the differential diagnosis of ACTH-dependent CS.

Cushing's Syndrome in Pregnancy Secondary to Adrenocortical Adenoma: A Case Series and Review.

To present a case series of Cushing's syndrome (CS) during pregnancy caused by adrenocortical adenomas, highlighting clinical features, hormonal assessments and outcomes. We describe five pregnant women with CS, detailing clinical presentations and laboratory findings. Common clinical features included a full moon face, buffalo back and severe hypertension. Elevated blood cortisol levels with circadian rhythm disruption and suppressed adrenocorticotrophic hormone (ACTH) levels were observed. Imaging revealed unilateral adrenal tumours. Two cases underwent laparoscopic adrenalectomies during the second trimester, while three had postpartum surgery. All required hormone replacement therapy, with postoperative pathological confirmation of adrenocortical adenomas. Diagnosis of CS during pregnancy is challenging due to overlapping features with normal pregnancy: elevated blood cortisol levels and abnormal diurnal rhythm of blood cortisol, suppressed aid diagnosis. Treatment should be individualised due to a lack of explicit optimum therapeutic approaches. Laparoscopic adrenalectomy may be an optimal choice, along with multidisciplinary management including hormone replacement therapy.

Validation of a LC-MS/MS method for establishing reference intervals and assessing diagnostic performance of urinary free cortisol and cortisone

Background24-h urinary free cortisol (UFF) is recommended for screening of Cushing's syndrome (CS), a rare disease characterized by apparent cortisol and cortisone excess. We aimed to validate a simple LC-MS/MS method for accurate measurement of UFF and urinary free cortisone (UFE), establishment of reference ranges, and evaluation of performance for CS diagnosis. MethodsUrine samples were processed using solid-phase extraction cartridges, followed by elution with methanol and acetonitrile. Analysis was performed via tandem mass spectrometry, utilizing multiple reaction monitoring and electrospray ionization source in positive ion mode. ResultsThe assay displayed excellent linearity (r > 0.99) in the range of 0.05–100 ng/mL for cortisol and 0.25–500 ng/mL for cortisone, with lower limits of quantification (LLOQ) at 0.05 ng/mL for cortisol and 0.25 ng/mL for cortisone. The obtained results for intra-day and inter-day imprecision for both analytes were within the acceptable range of less than 10 %. The trueness values for both compounds were also within the acceptable limit of 15 %. No significant matrix effects or carry over observed in our method. The reference intervals of UFF, UFE and UFF:UFE ratio were 7.01–45.66 µg/24-h, 27.97–139.21 µg/24-h and 0.17–0.56, respectively. UFF > 56.75 µg/24-h showed 100 % specificity and 100 % sensitivity for CS diagnosis, which was superior to UFF:UFE ratio. ConclusionsWe developed and validated a sensitive LC-MS/MS method to detect UFF and UFE. Our data indicate that UFF measured by the current LC-MS/MS assay exhibited high diagnostic performance for CS.

Diverse presentations of Cushing's syndrome during pregnancy - A case series.

Cushing's syndrome (CS) encompasses various causes of hypercortisolism including adrenocorticotropic hormone (ACTH) secreting pituitary adenoma with or without bilateral adrenal hyperplasia, an adrenal adenoma or carcinoma, ectopic ACTH or corticotrophin-releasing hormone (CRH) secretion by a neoplasm or exogenous corticosteroid therapy. The diagnosis of CS in pregnancy presents a challenge due to overlapping clinical features of pregnancy (weight gain, striae, acne). If untreated, CS in pregnancy is associated with increased risk of maternal and fetal complications. With fewer than 250 cases currently published, we aim to review the clinical presentations, diagnostic methods, management, and outcomes of patients with CS in pregnancy to help optimise our clinical practice. This is a single-centre, retrospective review of woman with documented hypercortisolism receiving antenatal care at a tertiary maternity hospital in Perth between 2006 to 2022. Data were collated from electronic and chart reviews. OMNI calculator was used for birthweight calculations. Local ethics and patient consent were obtained. Five women and seven pregnancies were identified. Four women had a pituitary source of ACTH-dependent CS as confirmed by brain magnetic resonance imaging. One woman had an ectopic source of ACTH. Two women were diagnosed during pregnancy. All pregnancies occurring prior to treatment of the Cushing's disease were complicated by secondary hypertension and diabetes. CS represents a rare and difficult to diagnose condition in pregnancy. When untreated, maternal and fetal outcomes are compromised. Close monitoring of the associated complications with involvement of a multidisciplinary team are recommended.

P-03 A report of recurring pregnancy-induced Cushing's Syndrome

Abstract Introduction The incidence of pregnancy-induced Cushing's syndrome (CS) is very low. However, the diagnosis of CS in pregnant patients is very difficult because of an overlapping signs and symptoms. Clinical Case A 20-year-old woman with polycystic ovarian syndrome (PCOS) was successfully treated with clomiphene for infertility and pregnant in September of 2016 for the first time. She experienced out of proportion abdominal obesity, excessive striosis, exacerbation of hirsutism and myasthenia during the first trimester of her pregnancy. Initial diagnosis of ovarian hyperstimulation syndrome (OHSS) was made and due to concomitant intrauterine growth retardation (IUGR), the pregnancy was electively terminated at the 8th week. All associated symptoms spontaneously regressed within 2-3 months after the abortion. The second pregnancy was induced with a pulse treatment of letrozole 5 mg, followed by 3 every other day injections of 100 units recombinant follicle-stimulating hormone. Within the first 4 weeks into the second pregnancy, the patient developed recurrence of OHSS symptoms. In addition to the prior symptoms and progressive proximal myasthenia, the patient developed hypertension, round moon-like face, back hump, and suprasternal fat pad consistent with the typical features of CS. In week 14 of pregnancy, the patient complained from acute-onset bilateral blindness and hypertension (blood pressure of 180/120 mmHg), which soon progressed into loss of consciousness and grand-mal seizure. She was admitted to the intensive care unit (ICU). Admission laboratory testing included those to assess the function of the pituitary-adrenal axis (HPA) due to the presence of symptoms related to CS. Based on available clinical information a diagnosis of hemolysis, elevated liver enzymes, and a low platelet count (HELLP) syndrome was made and emergency termination of pregnancy was carried out at the gestational age of 14 weeks. The patient`s clinical signs such as hypertension and acute blindness were totally subsided soon after the therapeutic abortion. Diagnosis of ACTH independent CS was made based on elevated 8 a.m. serum cortisol level unresponsive to low-dose dexamethasone (45-41 µg/ dL). Conclusion Diagnosis of CS in pregnancy is challenging as the physiological changes during pregnancy may mimic those of CS. Long-term treatment of gestational CS has not been as successful. However, in the case of adrenal hyperplasia, bilateral adrenalectomy offers a certain cure. Our patient had a therapeutic abortion due to severe maternal complications and development of CS during the early gestational age. The patient was reeducated on the subject of contraception and the possibility of adrenalectomy for future pregnancies. Due to the temporal relation between the occurrence of CS after each pregnancy the diagnosis of gestational hypercortisolism was made, and for further pregnancies bilateral adrenalectomy was recommended.

P-62 Silent Corticotroph Adenoma or Cyclic Cushing's Syndrome?

Abstract Introduction Silent corticotroph adenomas (pituitary neuroendocrine tumours (PitNET)) are a rare subset of nonfunctioning adenomas. The higher aggressiveness in terms of invasion and recurrence make these tumors dangerous and close follow-up in experienced centers is recommended. Clinical Case A 21-year-old obeseo (Body Mass Index:31.71) male patient unable to lose weight and complaining of headaches was referred to the Department of Neurosurgery for a pituitary macroadenoma. He had previously used liraglutide treatment Many purple striae were also seen on the body of the patient, who stated that his wounds did not heal easily. Visual acuity and visual field were normal. There was no neurodeficiency. Endocrinological evaluation revealed that the tumor was nonfunctioning (Table 1). Magnetic resonance imaging of the pituitary gland showed a mass lesion in the right side of the pituitary gland extending to the suprasellar and parasellar area (Knosp grade II) (Fig.1). The tumor with soft consistency was totally removed by endoscopic binostril transsphenoidal approach. The postoperative cortisol was 11.53 µg/dl (6.02-18.4) and free T4 was 1.32 ng/dL (0.93-1.7). The patient had a transient diabetes insipidus in the postoperative course, and he was discharged on the 4th day after surgery. Pathological examination revealed a pituitary adenoma immunostaining diffusely with ACTH, other hormones were unexpressed. Ki-67 was %2. Histological invasion of the dura was noted. Although the patient was clinically overweight and had purple striae suggestive of Cushing's syndrome (CS), his cortisol and ACTH levels were normal and suppressible with 1 mg dexamethasone suppression test. However, his tumour tissue showed diffuse ACTH expression, which led to the diagnosis of a silent ACTH adenoma. Since the clinical findings were not completely silent, could we assume that he suffered from cyclic CS? Cyclic (intermittent or periodic) CS is a condition characterised by alternating periods of transiently elevated cortisol levels followed by normal to reduced levels. The diagnosis of cyclic CS requires the presence of at least three confirmed episodes of elevated cortisol levels interspersed with two periods of normal cortisol levels. As we know, the cortisol secretion cycle is unpredictable and laboratory tests during the normal cortisol secretion period of the cyclic CS often show negative results as in our patient. Conclusion Postoperative follow-up of a silent corticotroph PitNET and cyclic CS patient, both of whom require close and life-long monitoring.Figure 1.Magnetic resonance imaging of the pituitary gland; coronal sections T1- weighted (a), T2-weighted (b), sagittal (c), and coronal (d) sections with T1 contrast enhancement. The mass lesion on the right side of the pituitary gland extending superiorly to the right internal carotid artery contains a hemorrhagic fluid component with heterogeneous contrast enhancement, is 16*12*9 mm in size, and corresponds to a hemorrhagic pituitary macroadenoma. Table 1.Hormonal values at presentationACTH, adrenocorticotropic hormone; DST, dexamethasone suppression test; fT4, free thyroxine; IGF-1, insulin-like growth factor 1; PRL, prolactin; TSH, thyroid-stimulating hormone.

Paediatric Cushing syndrome: a prospective, multisite, observational cohort study

Paediatric endogenous Cushing syndrome is a rare condition with variable signs and symptoms of presentation. We studied a large cohort of paediatric patients with endogenous Cushing syndrome with the aim of describing anthropometric, clinical, and biochemical characteristics as well as associated complications and outcomes to aid diagnosis, treatment, and management. In this prospective, multisite cohort study, we studied children and adolescents (≤18 years at time of presentation) with a diagnosis of Cushing syndrome. Patients had either received their initial diagnosis and evaluation at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Bethesda, MD, USA) or been referred from other centres in the USA or outside the USA. We collected participants' clinical, biochemical, and imaging findings and recorded their post-operative course until their latest appointment. Of 342 paediatric patients with a diagnosis of Cushing syndrome, 193 (56%) were female and 149 (44%) male. 261 (76%) patients had corticotroph pituitary neuroendocrine tumours (Cushing disease), 74 (22%) had adrenal-associated Cushing syndrome, and seven (2%) had ectopic Cushing syndrome. Patients were diagnosed at a median of 2 years (IQR 1·0-3·0) after the first concerning sign or symptom, and patients with adrenal-associated Cushing syndrome were the youngest at diagnosis (median 10·4 years [IQR 7·4-13·6] vs 13·0 years [10·5-15·3] for Cushing disease vs 13·4 years [11·0-13·7] for ectopic Cushing syndrome; p<0·0001). Body-mass index z-scores did not differ between the diagnostic groups (1·90 [1·19-2·34] for adrenal-associated Cushing syndrome vs 2·18 [1·60-2·56] for Cushing disease vs 2·22 [1·42-2·35] for ectopic Cushing syndrome; p=0·26). Baseline biochemical screening for cortisol and adrenocorticotropin at diagnosis showed overlapping results between subtypes, and especially between Cushing disease and ectopic Cushing syndrome. However, patients with ectopic Cushing syndrome had higher urinary free cortisol (fold change in median cortisol concentration from upper limit of normal: 15·5 [IQR 12·7-18·0]) than patients with adrenal-associated Cushing syndrome (1·5 [0·6-5·7]) or Cushing disease (3·9 [2·3-6·9]; p<0·0001). Common complications of endogenous Cushing syndrome were hypertension (147 [52%] of 281 patients), hyperglycaemia (78 [30%] of 260 patients), elevated alanine transaminase (145 [64%] of 227 patients), and dyslipidaemia (105 [48%] of 219 patients). Long-term recurrence was noted in at least 16 (8%) of 195 patients with Cushing disease. This extensive description of a unique cohort of paediatric patients with Cushing syndrome has the potential to inform diagnostic workup, preventative actions, and follow-up of children with this rare endocrine condition. Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health.

THU012 Incidental Pituitary Adenoma In A Patient With Ectopic ACTH Secreting Cushing Syndrome - A Diagnostic Conundrum

Abstract Disclosure: M.S. Nali: None. R.R. Yatavelli: None. Background: Cushing’s syndrome (CS) is a rare condition with an estimated incidence of 2-3 cases/million. Endogenous CS can be divided into ACTH -dependent (80%) and ACTH Independent (20%) with Ectopic Cushing’s syndrome (ECS) accounting for 10-20% of all cases of ACTH-dependent CS. Herein we present a case with indolent onset ACTH-dependent CS who on initial work-up showed a pituitary microadenoma raising the suspicion for Cushing disease, but the source of excess ACTH was found to be from a pulmonary neuroendocrine tumor. Clinical Case: A 44-yr-old female with history of type 1 DM, Obesity, BMI 43.60, Sleep apnea was evaluated elsewhere for suspected Cushing’s due to increased insulin requirements and progressive weight gain. Outside labs showed cortisol of 4.5 ug/dl on 1 mg DST &amp; 8 mg DST cortisol was 3 ug/dl. MRI of the pituitary showed a 3.5x 2.8x 1.8 mm microadenoma &amp; she was initially presumed to have Cushing’s disease secondary to pituitary microadenoma. The patient was seen by neurosurgery who referred to endocrine for localization of cortisol excess by IPSS. Clinically she had moon facies, hirsutism, dorsocervical fat pad, violaceous striae on abdomen. On further laboratory evaluation her ACTH: 88 (0-46) and random cortisol 14 ug/dl with normal rest of pituitary hormones. Her 24-hour urine free Cortisol was 45ug/d (3.5 - 45) and late-night salivary cortisol: 74 &amp;&amp;lt;50 (Ref. range &amp;lt;100 ng/dl) on couple of nights, respectively. Due to non-suppressed cortisol on high dose DST, a CT chest was obtained which showed a 2cms non calcified nodule in the left lower lobe of lung. Transbronchial biopsy was performed, cytopathology showed well differentiated neuroendocrine tumor, likely carcinoid and stained strongly positive for ACTH confirming ectopic ACTH producing tumor. Gallium-68 Dotatate Scan showed abnormal increased uptake in the known left lung nodule. The patient was recommended for surgical removal of neuroendocrine tumor, but she could not tolerate anesthesia and had to undergo stereotactic body radiation therapy (SBRT) for the lung lesion. Repeat ACTH levels 2 months post SBRT showed the ACTH levels were elevated and lesion was still persistent on imaging, however on discussion with rad oncology, the neuroendocrine tumors tend to take longer to show response on imaging and plan is to repeat imaging and biochemical work up in couple of months. Conclusion: The diagnosis of CS and recognizing the source of hormonal excess poses significant challenges Pituitary adenomas are incidentally discovered in up to 10% of the normal population &amp; IPSS is advised for patients with ACTH-dependent Cushing's syndrome and an adenoma smaller than 6 mm, however in patients with equivocal findings, it is important to look for other sources of ACTH prior to any invasive procedure. The source of ectopic ACTH secretion should be established after diagnosis because the excision of an ACTH-producing tumor can be curative. Presentation: Thursday, June 15, 2023

THU531 A Case Of Cushing Syndrome Due To Ectopic ACTH Secreting Lung Neuroendocrine Tumor Treated With Cryoablation

Abstract Disclosure: S. Paknikar: None. J. McHugh: None. K. Rachmasari: None. I. Bancos: None. Introduction: Ectopic secretion of adrenocorticotropic hormone (ACTH) is a rare and severe form of Cushing Syndrome (CS) that requires an urgent specialized approach for diagnosis and management. Clinical Case: A 50-year-old woman was referred to endocrinology due to concern for CS. Over the previous year she had developed progressive weakness, edema, weight gain with abdominal fat redistribution, hypertension, and multiple compression fractures. On exam, she had a profound proximal myopathy, reported 10/10 pain along the spine, and was hypertensive (170/105 mm Hg) with normal other vitals. The patient's sodium was 141mmol/L [reference range 135-145 mmol/ L], potassium 4.1 mmol/L [3.6-5.2 mmol/L] while on spironolactone, and creatinine was 0.57 mg/dL [0.59-1.04 mg/dL]. Due to the severity of her symptoms, she was admitted to the hospital. Hormonal work up was consistent with an ACTH dependent CS: ACTH was 121pg/mL [7.2-63 pg/mL] and 24-hour urine cortisol was 645 mcg/24 hr [3.5-45 mcg/24 hr]. Workup for ACTH secreting tumor included a pituitary MRI which showed a 3 mm area of delayed enhancement in the pituitary gland, felt to be artifactual. A chest computed tomography (CT) showed a 1.3 cm low-density nodule in the right upper lobe concerning for a neuroendocrine tumor. A Gallium-68 DOTATATE Positron emission tomography/CT scan was performed and demonstrated that the nodule was highly DOTATATE avid (Krenning score of 3, scale of 0-4). These findings supported a diagnosis of ectopic CS caused by an ACTH secreting lung neuroendocrine tumor. Management of ectopic CS was twofold: addressing the underlying ACTH secreting lesion and urgent treatment of hypercortisolism and its consequences. In this case, this was achieved with CT-guided cryoablation of the right upper lobe nodule. The ACTH levels were monitored postoperatively, and when decreased (9.3pg/mL [ 7.2-63 pg/mL], glucocorticoid replacement therapy was initiated. As a result of prolonged hypercortisolism, the patient experienced multiple compression fractures and debility. Physical therapy was recommended for recovery from the compression fractures as well as proximal myopathy. Enoxaparin was initiated due to risk of venous thromboembolism from CS. From an osteoporosis standpoint, she was continued on calcium and vitamin-D supplementation and treated with weekly alendronate. Her hypertension improved allowing medication reduction. Postoperatively, she received education on adrenal insufficiency and biochemical monitoring for adrenal insufficiency recovery was implemented. Conclusion: Ectopic ACTH secreting tumors represent a rare cause of CS and effective management requires consideration of medical comorbidities to determine the approach: surgical, cryoablative, or medical therapy alone, mitigation of Cushing syndrome sequelae, and prompt recognition and treatment of glucocorticoid withdrawal. Presentation: Thursday, June 15, 2023

FRI204 A Rare Case Of Cushing Syndrome In Pregnancy: Diagnosis And Therapeutic Challenges

Abstract Disclosure: Z. Cardona: None. E.D. Szmuilowicz: None. Introduction: Cushing’s syndrome (CS) rarely occurs during pregnancy, and diagnosis of Cushing’s syndrome in pregnancy is challenging due to physiologic changes during gestation. CS is associated with severe maternal and fetal complications. Clinical Case: A 36-year-old woman presented at 21 weeks gestational age with a known adrenal nodule admitted for evaluation of HTN, bilateral lower extremity edema, transaminitis, hyperglycemia, and acute hypoxemic respiratory failure. Reported proximal muscle weakness, facial swelling, anxiety, depression, perspiration, and headaches associated with HTN. Physical exam notable for mild supraclavicular fat deposition, chest and neck plethora, hypertrichosis, and bruising. CT abdomen pelvis revealed a 2.3-cm left adrenal nodule measuring 30 Hounsfield units. Biochemical evaluation included a plasma renin activity of 0.719 ng/mL/h [ref range: 0.167-5.380 ng/mL/h], aldosterone &amp;lt;1.0 ng/dL [ref range: 0.167-5.380 ng/dL], potassium 2.6 mEq/dL, free plasma metanephrines (MN) &amp;lt; 25 pg/mL [ref range: &amp;lt; or = 57 pg/mL], free normetanephrines (NMN) &amp;lt; 25 pg/mL [ref range: &amp;lt; or = 148 pg/mL, total free MN and NMN &amp;lt; 25 [ref range: &amp;lt; or = 205 pg/mL]. 24-hour urine free cortisol (UFC) was markedly elevated at 1854.1 mcg/24h [ref range: 3.1-50.0 mcg/24h], repeat 2186.2 mcg/24h, ACTH: 1.5 pg/mL [ref range: 7.2-63.6 pg/mL], confirming a diagnosis of ACTH-independent CS. Her case was complicated due to the adrenal nodule location. Patients with left adrenal nodules are at risk of developing inferior vena cava (IVC) syndrome during left adrenalectomies, especially in the third trimester, due to compression exerted by the uterus while lying on the right side during the procedure. She underwent an uncomplicated laparoscopic left adrenalectomy. Was started on hydrocortisone (HC) following surgery. There was concern for transient neonatal adrenal insufficiency at delivery. Measuring adrenal insufficiency in utero is challenging; however, estriol could serve as a surrogate marker of fetal adrenal function. Her estriol was normal, possibly indicating intact fetal adrenal activity. She had an uncomplicated vaginal delivery with no signs of adrenal insufficiency in her baby. Interestingly, she had a severely low alkaline phosphatase (ALP) which completely normalized soon after adrenalectomy. Clinical Lesson: This case depicts the challenges in managing CS in pregnancy and its repercussions regarding maternal, fetal, and delivery outcomes. Additionally, it highlights the importance of implementing a multidisciplinary approach, including obstetricians, endocrinologists, endocrine surgeons, and pediatricians, to ensure the optimization of therapeutic strategies. Presentation: Friday, June 16, 2023

THU014 Post-surgical Remission After Resection Of Solitary Mediastinal Lymph Node In A Metastatic Occult Ectopic ACTH Syndrome Patient

Abstract Disclosure: I.P. de Magalhães: None. C.P. Oliveira: None. L.P. Lins: None. N.X. Andrade: None. M.S. Lima: None. S.A. Siqueira: None. J.S. Fonini: None. E.C. Assis Filho: None. A.W. Mariani: None. M.C. Machado: None. BACKGROUND: The prevalence of occult cases has been increasing in the most recent series of Ectopic ACTH syndrome (EAS) maybe due to the small size of pulmonary neuroendocrine tumors. We present an atypical and very rare case of EAS with initial presentation of a single metastatic mediastinal lymph node that evolved with remission after your resection with no defined primary tumor. CASE REPORT: A 15-year-old female patient presented a clinical feature of Cushing’s syndrome (CS) with a 1-year evolution. Hormonal evaluation confirmed ACTH-dependent CS: urinary free cortisol of 819 µg/24h (3-43), late night salivary cortisol of 409 ng/dL (&amp;lt;274) and ACTH of 105 pg/mL (&amp;lt;63.3). Noninvasive methods for differential diagnosis of ACTH-dependent CS did not clarify the etiology (conflicting results): pituitary MRI negative, suppression of 59.6% of cortisol after high dose dexamethasone suppression test, positive response of ACTH and cortisol at desmopressin test, suppression of 81% of ACTH at acute octreotide SC test, negative serum tumor markers (gastrin, calcitonin, CEA, CA125, alpha-fetoprotein, CA19.9 and bhCG), negative cervical and pelvic ultrasound, negative computed tomography of thorax and negative abdominal MRI. Bilateral and simultaneous petrosal inferior sinus sampling with desmopressin confirmed EAS due to negative central to peripheral ACTH gradient, even after normalized PRL/ACTH gradients. Finally, PET/CT with Ga68-DOTATATE revealed a single infracarinal nodule of 1.5x0.6 cm with high capture of radioligand, SUVmax of 23.2, suggestive of affected mediastinal lymph node. The patient was submitted to thoracic surgery and the infracarinal lymph node was dissected and removed. Anatomopathological and immunohistochemical analyses disclosed a lymph node metastatic of a well-differentiated grade neuroendocrine tumor ACTH positive, Ki-67 2%. After surgery, the patient exhibited CS improvement and impressive drop of hormones at 5th postsurgical day (serum cortisol &amp;lt;1.0 µg/dL and ACTH of 2.2 pg/mL) confirming remission of CS. CONCLUSION: To our knowledge, approximately 36 cases of EAS due to neuroendocrine tumor of unknown primary origin were reported. However, previous cases commonly exhibited no remission after only removal of metastasis. Our case presented initial remission even with no primary tumor identified (occult primary tumor non-functioning?). Follow up with clinical, hormonal and imaging methods are necessary due to recurrence risk. Presentation: Thursday, June 15, 2023