Accuracy of the 10 µg desmopressin test for differential diagnosis of Cushing syndrome: a systematic review and meta-analysis.

We evaluated the accuracy of the 10 µg desmopressin test in differentiating Cushing disease (CD) from non-neoplastic hypercortisolism (NNH) and ectopic ACTH syndrome (EAS). A systematic review of studies on diagnostic test accuracy in patients with CD, NNH, or EAS subjected to the desmopressin test obtained from LILACS, PubMed, EMBASE, and CENTRAL databases was performed. Two reviewers independently selected the studies, assessed the risk of bias, and extracted the data. Hierarchical and bivariate models on Stata software were used for meta-analytical summaries. The certainty of evidence was measured using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation Working Group) approach. In total, 14 studies were included: 3 studies on differentiated CD versus NNH and 11 studies on differentiated CD versus EAS. Considering ΔACTH in 8 studies involving 429 patients, the pooled sensitivity for distinguishing CD from EAS was 0.85 (95% confidence interval [CI]: 0.80-0.89, I2 = 17.6%) and specificity was 0.64 (95% CI: 0.49-0.76, I2 = 9.46%). Regarding Δcortisol in 6 studies involving 233 participants, the sensitivity for distinguishing CD from EAS was 0.81 (95% CI: 0.74-0.87, I2 = 7.98%) and specificity was 0.80 (95% CI: 0.61-0.91, I2 = 12.89%). The sensitivity and specificity of the combination of ΔACTH > 35% and Δcortisol > 20% in 5 studies involving 511 participants were 0.88 (95% CI: 0.79-0.93, I2 = 35%) and 0.74 (95% CI: 0.55-0.87, I2 = 27%), respectively. The pooled sensitivity for distinguishing CD from NNH in 3 studies involving 170 participants was 0.88 (95% CI: 0.79-0.93) and the specificity was 0.94 (95% CI: 0.86-0.97). Based on the desmopressin test for differentiating CD from EAS, considering ΔACTH, Δcortisol, or both percent increments, 15%, 19%, or 20% of patients with CD, respectively, would be incorrectly classified as having EAS. For CD versus NNH, 11% of patients with CD would be falsely diagnosed as having NNH, whereas 7% of patients with NNH would be falsely diagnosed as having CD. However, in all hierarchical plots, the prediction intervals were considerably wider than the confidence intervals. This indicates low confidence in the estimated accuracy, and the true accuracy is likely to be different. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=85634, identifier CRD42018085634; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=68317, identifier CRD42017068317.

Clinical Spectrum of USP8 Pathogenic Variants in Cushing's Disease.

Cushing's disease (CD) is a life-threatening condition with a challenging diagnostic process and scarce treatment options. CD is caused by usually benign adrenocorticotrophic hormone (ACTH)-secreting pituitary neuroendocrine tumors (PitNETs), known as corticotropinomas. These tumors are predominantly of sporadic origin, and usually derive from the monoclonal expansion of a mutated cell. Somatic activating variants located within a hotspot of the USP8 gene are present in 11-62% of corticotropinomas, making USP8 the most frequent genetic driver of corticotroph neoplasia. In contrast, other somatic defects such as those affecting the glucocorticoid receptor gene (NR3C1), the BRAF oncogene, the deubiquitinase-encoding gene USP48, and TP53 are infrequent. Moreover, patients with familial tumor syndromes, such as multiple endocrine neoplasia, familial isolated pituitary adenoma, and DICER1 rarely develop corticotropinomas. One of the main molecular alterations in USP8-driven tumors is an overactivation of the epidermal growth factor receptor (EGFR) signaling pathway, which induces ACTH production. Hotspot USP8 variants lead to persistent EGFR overexpression, thereby perpetuating the hyper-synthesis of ACTH. More importantly, they condition a characteristic transcriptomic signature that might be useful for the clinical prognosis of patients with CD. Nevertheless, the clinical phenotype associated with USP8 variants is less well defined. Hereby we discuss the current knowledge on the molecular pathogenesis and clinical picture associated with USP8 hotspot variants. We focus on the potential significance of the USP8 mutational status for the design of tailored clinical strategies in CD.

Enhancing Cushing's disease diagnosis: exploring the impact of desmopressin on ACTH gradient during BIPSS.

Introduction: The differential diagnosis between Cushing's disease (CD) and ectopic ACTH syndrome (EAS) is complex, and bilateral inferior petrosal sinus sampling (BIPSS) is considered the gold-standard test. However, BIPSS with corticotropin-releasing hormone (CRH) stimulation is rarely available. Objective: This retrospective cohort study aimed to assess the accuracy of the inferior petrosal sinus to peripheral ACTH gradient (IPS:P) before and after desmopressin stimulation for the differential diagnosis of ACTH-dependent Cushing's syndrome (CS), applying different cutoff values. Methods: A total of 50 patients (48 with CD and 2 with EAS) who underwent BIPSS were included in this study. The sensitivity and specificity of IPS:P in BIPSS before and after desmopressin stimulation were evaluated. Various cutoff values for IPS:P were examined to determine their diagnostic accuracy. Results: Using the traditional IPS:P cutoff, the sensitivity was 85.1% before stimulation, 89.6% after stimulation, and a combined sensitivity of 91.7%. Applying cutoff values of IPS:P >1.4 before and >2.8 after stimulation, the sensitivity was 87.2% and 89.6%, respectively, with a combined sensitivity of 91.7%. Receiver operating characteristic (ROC) curve analysis determined optimal cutoff values of 1.2 before stimulation and 1.57 after stimulation, resulting in a sensitivity of 93.6% and 93.8%, respectively, with a combined sensitivity of 97.9%. Specificity remained at 100% throughout all analyses. Among the 43 patients who responded positively to stimulation, 42 (97.7%) did so within the first three minutes, and all 43 (100%) did so within the first five minutes. None of the assessed clinical variables predicted the ACTH response to stimulation in BIPSS with statistical significance. Discussion: ACTH stimulation with desmopressin during BIPSS improves the accuracy of IPS:P, making it a valuable tool for investigating ACTH-dependent Cushing's syndrome. Considering the low risk of complications, we recommend the use of desmopressin stimulation during BIPSS for the differential diagnosis of ACTH-dependent CS.

Determinants of Clinical Behavior and Prognosis in Cushing's Disease: A Quest for Useful Biomarkers.

Abstract: Cushing's disease (CD) is the most common cause of endogenous hypercortisolemia. The clinical management of this condition is complex and entails multiple therapeutic strategies, treatment of chronic comorbidities, and lifelong surveillance for recurrences and complications. The identification of robust, practical, and reliable markers of disease behavior and prognosis could potentially allow for a tailored and cost-efficient management of each patient, as well as for a reduction of the medical procedure-associated stress. For this purpose, multiple clinical, biochemical, imaging, histopathological, molecular, and genetic features have been evaluated over the years. Only a handful of them, however, have been sufficiently validated for their application in the routine care of patients with CD. This review summarizes the current status of the established and potential biomarkers of CD, bases for their use, proposed and/or established utility, as well as advantages and barriers for their implementation in the clinic. (Rev Invest Clin. 2022;74(5):244-57).

Diagnostic Power of Bilateral Inferior Petrosal Sinus Sampling with Desmopressin in Paediatric Cushing's Disease

Objective: The aim of this study was to evaluate the diagnostic accuracy of bilateral inferior petrosal sinus sampling (BIPSS) with desmopressin for pediatric Cushing's disease (CD). Methods: We reviewed studies performed in children that evaluated the accuracy of BIPSS with desmopressin. Results: All included studies were case series of children with adrenocorticotropin hormone (ACTH)-dependent Cushing's syndrome. The overall accuracy of BIPSS before stimulation was 84.1% (37/44), and after stimulation it was 92.3% (36/39). The overall lateralizing accuracy of BIPSS was 50.0%. Conclusion: Considering that available evidence is limited, it appears that BIPSS with desmopressin stimulation is accurate for the diagnosis of pediatric CD, but its lateralizing accuracy is probably not suitable for pediatric clinical practice.

Doença de cushing e hipertensão arterial: relato de caso / Cushing disease and hypertension: a case report

Caso clínico de VNS, 23 anos, sexo feminino, branca, solteira, estudante, natural e procedente de São Paulo- SP com queixa de "pressão alta" há 4 anos. A paciente foi encaminhada para consulta ambulatorial após ter sido atendida em pronto-socorro (PS) com cefaleia, tonturas e pressão arterial (PA) 210x110 mm Hg e medicada com losartana 50 mg a cada 12 horas e hidroclorotiazida 25 mg ao dia. Na avaliação ambulatorial relatava episódios prévios de cefaleia holocraniana de forte intensidade, latejante, de início gradual há 4 anos com piora há 2 anos, que a levava ao pronto-socorro (PS) com muita frequência. Além disso, referia aumento de peso e fraqueza generalizada. Ao exame físico apresentava-se com níveis elevados da PA 160x100 mm Hg em uso das medicações prescritas no PS, obesidade grau III (IMC 41), adiposidade localizada (giba), acantose nigricans e estrias violáceas abdominais. Foi diagnosticada a doença de Cushing associada à hipertensão arterial não controlada, realizados ajustes dos agentes anti-hipertensivos (associado anlodipino 5 mg a cada 12 horas) e solicitados exames laboratoriais. A monitorização ambulatorial da PA (MAPA) de 24 horas caracterizou a hipertensão resistente, as dosagens de cortisol (cortisol salivar = 8h:172; após 23h:280, supressão com dexametasona =<2,5) e a ressonância nuclear magnética evidenciou um macroadenoma da hipófise confirmando o diagnóstico da doença de Cushing com base nos achados do exame físico, laboratorial e de imagem. A paciente foi tratada clinicamente com cetoconazol via oral sem sucesso e após isso submetida a ressecção transesfenoidal do macroadenoma de hipófise. Após o tratamento cirúrgico, houve perda de peso e resolução da hipertensão confirmada pelas medidas ambulatoriais de consultório e pela MAPA.

Clinical case of VNS, 23 years old, female, white, single, student, born and living in São Paulo-SP, complaining of "high blood pressure" 4 years ago. The patient was referred to an outpatient clinic after being seen in the emergency room (ER) with headache, dizziness and blood pressure (BP) 210x110 mm Hg and medicated with losartan 50 mg every 12 hours and hydrochlorothiazide 25 mg daily. In the outpatient evaluation, she reported previous episodes of severe, throbbing holocranial headache, which started gradually over 4 years and worsened over 2 years ago, which took her to the ER very often. In addition, she reported weight gain and generalized weakness. On physical examination, he presented with high BP levels 160x100 mm Hg using the medications prescribed in ER, obesity grade III (BMI 41), localized adiposity (gib), acanthosis nigricans and abdominal violet streaks. Cushing's syndrome was diagnosed associated with uncontrolled arterial hypertension, adjustments were made to antihypertensive agents (associated with amlodipine 5 mg every 12 hours) and laboratory tests were requested. 24-hour ambulatory BP monitoring (ABPM) characterized resistant hypertension, cortisol levels (salivary cortisol = 8:00 am: 172; after 11:00 pm: 280, dexamethasone suppression = <2.5) and magnetic resonance imaging revealed a macroadenoma of the pituitary gland confirming the diagnosis of Cushing's disease based on the findings of the physical, laboratory and imaging exam. The patient was clinically treated with oral ketoconazole and underwent transphenoid resection of the pituitary macroadenoma. After the surgery the patient was no longer hipertensive, without use of antihypertensive medications, outpatient office measurements were normal, as were measurements outside the office by ABPM

Diabetes, Active Disease, and Afternoon Serum Cortisol Levels Predict Cushing's Disease Mortality: A Cohort Study.

CONTEXT: Cushing's disease (CD) is a life-threating disease, with increased mortality in comparison with the general population. OBJECTIVE: This study aimed to evaluate standardized mortality ratios (SMRs) in CD patients. We also analyzed independent risk factors related to increased mortality. DESIGN: We conducted a longitudinal cohort study in a 3rd level specialty center, from 1979 to 2018, in patients with CD. RESULTS: From 1375 cases with a pathology diagnosis of pituitary adenoma, 191 cases had the confirmed diagnosis of CD (14%). A total of 172 patients completed follow-up, with a mean age at diagnosis of 33 ±â€…11 years, female predominance (n = 154, 89.5%), majority of them with microadenoma (n = 136, 79%), and a median follow-up of 7.5 years (2.4-15). Eighteen patients (10.5%) died, 8 of them (44%) were with active CD, 8 (44%) were under remission, and 2 (11%) were under disease control. Estimated all-cause SMR = 3.1, 95% confidence interval (CI) 1.9-4.8, P < 0.001. Cardiovascular disease was the main cause of death (SMR = 4.2, 1.5-9.3, P = 0.01). Multivariate Cox regression models adjusted for potential cofounders showed that diabetes (HR = 5.2, IC 95% 1.8-15.4, P = 0.002), high cortisol levels after 1600 hours at diagnosis (3.4, 2.3-7.0, P = 0.02), and active CD (7.5, 3.8-17.3, P = 0.003) significantly increased the risk of mortality. CONCLUSIONS: Main cause of CD mortality was cardiovascular disease. Main risk factors for mortality were uncontrolled diabetes, persistently high cortisol levels after 1600 hours at diagnosis, and active disease at last follow-up.

High accuracy of bilateral and simultaneous petrosal sinus sampling with desmopressin for the differential diagnosis of pediatric ACTH-dependent Cushing's syndrome.

PURPOSE: To analyze the bilateral and simultaneous petrosal sinus sampling (BIPSS) in a subgroup of children and adolescents with ACTH-dependent Cushing's syndrome (ADCS) METHODS: Retrospective study in a tertiary reference center. From 1993 and 2017, 19 children and adolescents (PED) were submitted to the BIPSS, median age of 14 years (range 9-19 years), 53% were males, 18 had Cushing's disease (CD) and one had ectopic ACTH syndrome (EAS). All procedures were performed with 10 µg of intravenous desmopressin. RESULTS: The catheter positioning was successful in all cases. The central ACTH gradient was met in 17/19 cases. At baseline, central gradient occurred in 16/19 (84%) with gradient values of 7.2 ± 6.0. After stimulation, there was an increase in the center-periphery gradient values (33.6 ± 44.3). In one case, central gradient was defined only after stimulation. Two cases presented without a central gradient; one case of CD with a false-negative and one EAS case. Lateralization occurred in all cases with a central gradient. Confirmation of the tumor location presumed by the procedure with the surgical description occurred in 60% of the cases. The BIPSS in this PED subgroup of ADCS presented a sensitivity of 94.4% and specificity of 100%. There were no complications of the procedure. CONCLUSION: In a series of children and adolescents with ADCS, BIPSS was safe and highly accurate in defining the central to peripheral ACTH gradient using desmopressin as secretagogue. Nevertheless, there was a limited value of the ACTH-gradient between the petrosal sinuses for the tumor location.

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

OBJECTIVE: To investigate the prevalence of kidney stones in a population of children with Cushing disease (CD) and to compare it with the prevalence of kidney stones in healthy children. STUDY DESIGN: Clinical and biochemical data from 139 pediatric patients with CD (68 females, 71 males) were analyzed retrospectively. Computed tomography scans were reviewed for kidney stones. RESULTS: Among 139 patients, 27 with CD (19.4%) had either radiographic evidence and/or a history of kidney stones. Those with kidney stones had higher urine free cortisol (P = .008) and transsphenoidal surgery at an older age (P = .007). The average urinary calcium/creatinine ratio was elevated in patients with CD (0.22 ± 0.11). The prevalence of kidney stones was higher in children with CD than in normal children (19.42% vs 1.0%; P < .001). CONCLUSION: Our results illustrate that kidney stones are an underestimated complication of pediatric CD, especially when compared with the prevalence of nephrolithiasis in the general pediatric population. Long-term consequences for kidney function are not known and need to be studied.

Evaluation of the DDAVP test in the diagnosis of Cushing's Disease.

OBJECTIVE: To analyse the performance of the desmopressin (DDAVP) test in the diagnosis of Cushing's disease (CD). METHODS: This was a prospective cohort study of 124 patients with suspected hypercortisolism who were recruited from an outpatient endocrinology clinic and investigated for Cushing's syndrome (CS). The ACTH and cortisol responses to the DDAVP test were assessed to determine patient diagnosis and test the procedure's diagnostic accuracy. RESULTS: A total of 68 patients had CD, while 56 had suspected CS. According to ROC analysis, an ACTH peak of 71·8 pg/ml (15·8 pmol/l) following DDAVP administration was able to diagnose CD with a specificity of 94·6% and a sensitivity of 90·8%, a negative predictive value (NPV) of 89·9% and a positive predictive value (PPV) of 95·3%. An absolute ACTH increment ≥37 pg/ml (8·1 pmol/l) over baseline had a sensitivity of 88·0%, specificity of 96·4%, NPV of 87·0% and PPV of 95·3% in diagnosing CD. Only 2 of 56 cases without CD had an absolute ACTH increment ≥37 pg/ml (8·1 pmol/l) over baseline. The DDAVP test was superior to other clinical instruments in diagnosing CS. CONCLUSIONS: The DDAVP test could be a useful additional tool to diagnose CD in patients with suspected CS.

Hipercortisolismo subclínico / Subclinical hypercortisolism

El hipercortisolismo subclínico se define como una alteración del eje hipotálamo hipófisis adrenal en ausencia de los síntomas y signos clásicos del exceso de cortisol. Es una enfermedad endocrina que se presenta hasta en 20 por ciento de los pacientes a los cuales se les diagnostica un tumor adrenal. Las investigaciones realizadas, sugieren la hipótesis que puede estar asociado a complicaciones crónicas como la hipertensión arterial, la diabetes mellitus, el sobrepeso/obesidad y la osteoporosis. El diagnóstico y tratamiento del hipercortisolismo subclínico se han convertido actualmente en un tema de creciente interés y debate, pero aún no existe consenso. Se necesitan estudios prospectivos y aleatorizados para confirmar la hipótesis propuesta, establecer la mejor forma de realizar el diagnóstico y de seleccionar los pacientes que se beneficien con el tratamiento quirúrgico(AU)

Subclinical hypercortisolism is an alteration of the hypothalamus-hypophysis-adrenal axis in absence of classical symptoms and signs of excessive cortisol. It is an endocrine disease that affects up to 20 percent of patients diagnosed with an adrenal tumor. The research studies indicate the hypothesis that this entity could be associated to chronic complications such as blood hypertension, diabetes mellitus, overweight/obesity and osteoporosis. The diagnosis and treatment of subclinical hypercortisolism has turned into a topic of growing interest and discussion nowadays, but the consensus is still pending. It is then necessary to perform prospective and randomized studies in order to confirm the suggested hypothesis, to determine the best way of making a diagnosis and to select the patients who are going to really benefit from a surgical treatment(AU)

Síndrome de Cushing ACTH Dependiente, secreción ectópica: desarrollo de un caso / ACTH Dependent Cushing Syndrome due to ectopic secretion: report of a case

Se presenta el caso de un paciente varón de 32 años, derivado a nuestro servicio para evaluación de cuadro de 8 meses de evolución caracterizado por edema y rubicundez facial, obesidad central, edema en miembros inferiores e hipertensión arterial, compatible con síndrome de Cushing clínico. Aportaba estudios previos con cortisol séríco 29,8 y 33 Ag/dl (determinaciones realizadas con un mes de diferencia), ACTH 72,8 pg/ml, cortisol salival 2,1 Ag/dl, cortisol libre urinario (CLU) 993,4 Ag/24 hs. Los estudios imagenológicos (ecografía doppler renal, TAC de abdomen y pelvis c/contraste oral y e.v., TAC de cráneo s/contraste y RMI de cráneo c/contraste e.v.) no aportaron datos relevantes. Se confirmó bioquímicamente el síndrome de Cushing dependiente de ACTH: cortisol sérico (8 hs) 34,8 Ag/dl, ACTH (8 hs) 72 pg/ml, cortisol libre urinario 828 Ag/24 hs. El test de Nugent no mostró freno. El test de Liddle (8 mg oral dexametasona 23 hs) produjo un descenso del cortisol plasmático de solo 21%. La función tiroidea, las gonadotrofinas y la prolactina séricas eran normales. La radiografía de tórax mostró mediastino ensanchado e imagen nodular parahiliar basal derecha; esto se confirmó por TAC. La formación nodular medía 20 x 13mm, era de bordes lisos y aspecto inespecífico. Se exploró quirúrgicamente esta lesión, con diagnóstico intraoperatorio de población linfoide de pequeño tamaño. Se realizó nodulectomía por toracotomía con la sospecha de lesión linfoproliferativa. El diagnóstico anatomopatológico definitivo: tumor neuroendócrino bien diferenciado ... (AU)

The case of a male patient aged 32, referred to our service for evaluation of 8-month history of facial redness and edema,central obesity, lower limb edema and arterial hypertension consistent with clinical Cushing syndrome is presented. He hadprevious studies showing serum cortisol 29.8 and 33 mg/dl (determinations performed one month apart), ACTH 72.8 pg/ml, salivary cortisol 2.1 Ag/dl, urinary free cortisol (UFC) 993.4 Ag/24 h. Imaging studies (renal ultrasound doppler, CTof the abdomen and pelvis with oral and iv contrast, skull CT without contrast and skull RMI with iv contrast) did notprovide relevant data. Serum cortisol (8 hours) 34.8 Ag/dl, ACTH (8 h) 72 pg/ml, urinary free cortisol 828 Ag/24 h: anACTH-dependent CushingÆs syndrome was biochemically confirmed. NugentÆs test was negative. Overnight LiddleÆs test (8mg oral dexamethasone 23 h) resulted in a modest decrease (21%) in plasma cortisol. Thyroid function, serum gonadotropinsand prolactin were normal. The chest radiograph showed widened mediastinum and a right basal parahilar nodularimage; this was confirmed by CT. The nodule measured 20 x 13 mm, it had smooth edges and nonspecific appearance. Thislesion was explored surgically, with intraoperative diagnosis of small lymphoid population. Lumpectomy was performed bythoracotomy The final pathological diagnosis was well-differentiated neuroendocrine tumo...(AU)

Hipercortisolismo subclínico / Subclinical hypercortisolism

El hipercortisolismo subclínico se define como una alteración del eje hipotálamo hipófisis adrenal en ausencia de los síntomas y signos clásicos del exceso de cortisol. Es una enfermedad endocrina que se presenta hasta en 20 por ciento de los pacientes a los cuales se les diagnostica un tumor adrenal. Las investigaciones realizadas, sugieren la hipótesis que puede estar asociado a complicaciones crónicas como la hipertensión arterial, la diabetes mellitus, el sobrepeso/obesidad y la osteoporosis. El diagnóstico y tratamiento del hipercortisolismo subclínico se han convertido actualmente en un tema de creciente interés y debate, pero aún no existe consenso. Se necesitan estudios prospectivos y aleatorizados para confirmar la hipótesis propuesta, establecer la mejor forma de realizar el diagnóstico y de seleccionar los pacientes que se beneficien con el tratamiento quirúrgico(AU)

Subclinical hypercortisolism is an alteration of the hypothalamus-hypophysis-adrenal axis in absence of classical symptoms and signs of excessive cortisol. It is an endocrine disease that affects up to 20 percent of patients diagnosed with an adrenal tumor. The research studies indicate the hypothesis that this entity could be associated to chronic complications such as blood hypertension, diabetes mellitus, overweight/obesity and osteoporosis. The diagnosis and treatment of subclinical hypercortisolism has turned into a topic of growing interest and discussion nowadays, but the consensus is still pending. It is then necessary to perform prospective and randomized studies in order to confirm the suggested hypothesis, to determine the best way of making a diagnosis and to select the patients who are going to really benefit from a surgical treatment(AU)

Evaluation of Cushing's disease remission after transsphenoidal surgery based on early serum cortisol dynamics.

OBJECTIVE: To evaluate the ability of post-transsphenoidal pituitary surgery (TSS) serum cortisol levels (s-cortisol) to predict surgical remission and recurrence of Cushing's disease (CD). DESIGN: One hundred and three patients with CD from a tertiary referral centre were prospectively analysed over 6·0 ± 4·8 years of follow-up. Twenty patients received perioperative glucocorticoids as routine care and had s-cortisol measured 10-12 days after TSS (Protocol I). Eighty-six patients (91 surgeries) had s-cortisol measured at 6, 12, 18, 24, 48 h, and 10-12 days after TSS, and received glucocorticoids only in case of adrenal insufficiency (Protocol II). MAIN OUTCOMES: Remission [clinical signs and symptoms of adrenal insufficiency (or hypocortisolism) plus cortisol <3 µg/dl on the 1-mg overnight test (OT) and/or normal free urinary cortisol] during follow-up. Recurrence was defined as loss of remission criteria at least 1 year after TSS. RESULTS: The remission rate after first TSS was 80%; 8% had recurrence. An s-cortisol nadir ≤3·5 µg/dl within 48 h after TSS had sensitivity of 73%, specificity and positive predictive value (PPV) of 100% and negative predictive value (NPV) of 60% and an s-cortisol nadir ≤5·7 µg/dl within 10-12 days of TSS had specificity and PPV of 100% and sensitivity of 91% NPV of 78% for CD remission. CONCLUSION: At hospital discharge, the s-cortisol nadir within 48 h after TSS was already able to predict surgical remission for some patients, and the s-cortisol nadir within 10-12 days of TSS was able to predict cohort-wide surgical remission.

Influence of the fibroblast growth factor receptor 4 expression and the G388R functional polymorphism on Cushing's disease outcome.

CONTEXT: Abnormal FGFR4 expression has been detected in pituitary tumors, especially in larger and invasive adenomas. In addition, the FGFR4 functional polymorphism G388R has been associated with poor outcome in several human malignancies. Then, we hypothesized that FGFR4 expression and genotype could be markers of adverse outcome of Cushing's disease after transsphenoidal surgery. OBJECTIVES: The objective was to investigate whether there is an association between the postoperative outcome of Cushing's disease (remission/recurrence) and the FGFR4 G388R genotype or the FGFR4 expression in corticotrophinomas. DESIGN AND PATIENTS: Clinical, hormonal, and pathological data of 76 patients who underwent the first transsphenoidal surgery were retrospectively reviewed. All patients were genotyped for G388R polymorphism. FGFR4 expression was assessed by real-time PCR in 18 corticotrophinomas. MAIN OUTCOME MEASURES: The outcome measures included the FGFR4 G388R genotype and FGFR4 expression in postoperative remission and recurrence of Cushing's disease. RESULTS: Homozygosis for FGFR4 glycine (Gly(388)) allele was associated with reduced disease-free survival, in the univariate analysis (hazard ratio of 6.91; 95% confidence interval of 1.14-11.26; P = 0.028). Male gender (P = 0.036), lack of pathology confirmation (P = 0.009), and cortisol levels more than 2 µg/dl in the early postoperative period (P < 0.001) were also significant predictors of Cushing's disease recurrence in the univariate analysis. FGFR4 overexpression was found in 44% of the corticotrophinomas, and it was associated with lower postoperative remission rate (P = 0.009). CONCLUSIONS: Our data suggest that homozygosis for FGFR4 Gly(388) allele and FGFR4 overexpression are associated with higher frequency of postoperative recurrence and persistence of Cushing's disease, respectively.

Role for postoperative cortisol response to desmopressin in predicting the risk for recurrent Cushing's disease.

UNLABELLED: In the early postoperative period of Cushing's disease patients, desmopressin may stimulate ACTH secretion in the remnant corticotrophic tumour, but not in nontumour suppressed cells. OBJECTIVE: The aim of this study is to evaluate the serum cortisol responses to desmopressin after pituitary surgery, establishing an optimal cut-off for absolute increment (Delta) of serum cortisol (F) suitable to predict recurrence risk. DESIGN: Retrospective case record study. PATIENTS: Fifty-seven Cushing's disease patients submitted to pituitary surgery and desmopressin stimulation in the early postoperative with a long-term follow-up (20-161 months) were studied. METHODS AND MEASUREMENTS: Serum cortisol levels after desmopressin test (10 microg i.v.) 15-30 days after adenomectomy were used to determine DeltaF (absolute increment of F: F peak - F baseline). Sensitivity and specificity of DeltaF were calculated and a ROC curve was performed to establish an optimal cut-off for DeltaF to predict recurrence risk. RESULTS: Fifteen patients had immediate postoperative failure (basal F > 165 nmol/l; 6 microg/dl) and one patient was lost during the follow-up. Forty-one patients achieved initial remission and were followed-up. Five of 11 patients who recurred had DeltaF > 193 nmol/l (7 microg/dl), but none of 30 patients who remained in prolonged remission showed DeltaF > 193 nmol/l after postoperative desmopressin stimulation. CONCLUSIONS: Persistence of cortisol response (DeltaF > 193 nmol/l) to desmopressin in the early postoperative period can help to identify Cushing's disease patients with initial remission who present risk for later recurrence.

The role of non-invasive dynamic tests in the diagnosis of Cushing's syndrome.

OBJECTIVE: To evaluate the role of non-invasive dynamic tests in the diagnosis and differential diagnosis of Cushing's syndrome (CS). METHODS: We studied laboratory features of 74 patients with endogenous CS, subdivided as follows: 46 (62.1%) with Cushing's disease (CD), 21 (28.3%) with an adrenal tumor, and 7 (9.5%) with ectopic ACTH syndrome (EAS). RESULTS: In 100% of cases of CS we found serum cortisol levels greater than 1.8 microg/dl after low-dose dexamethasone suppression tests (LDDST), as well as elevation of midnight serum or salivary cortisol. However, urinary free cortisol was normal in 11.5% of patients. ACTH levels were suppressed in patients with adrenal tumors, normal or high in CD and invariably increased in EAS. After the 8-mg overnight dexamethasone suppression test (HDDST), serum cortisol suppression >50% was observed in 79.5% of cases of CD and in 28.6% of subjects with EAS, whereas cortisol suppression >80% was only found in CD. After stimulation with CRH or desmopressin an ACTH rise > or =35% occurred in 86.5% of individuals with CD and 14.3% of those with EAS, whereas an ACTH rise > or =50 achieved 100% specificity. Moreover, the combination of serum cortisol suppression >50% after HDDST and an ACTH increase > or =35% after the administration of CRH or desmopressin only occurred in CD. CONCLUSION: Our findings demonstrate that LDDST had 100% sensitivity for the diagnosis of CS and that HDDST and stimulation tests with CRH or desmopressin may be very useful for confirmation of CS etiology when analyzed together or when more stringent cut-offs are used.

Pediatric Cushing's syndrome: clinical features, diagnosis, and treatment: [review]

Cushing's syndrome (CS) results from prolonged exposure to supraphysiological levels of circulating glucocorticoids, endogenously or exogenously derived. Although rare in childhood, CS remains a difficult condition to diagnose and treat. A multidisciplinary approach and close collaboration with adult colleagues is adopted at most large centres that manage pediatric CS patients. Although pediatric protocols are derived from adult data, significant differences exist between adult and childhood CS. Furthermore, long term outcome parameters including final height, bone mineral density, reproductive function, body composition and psychological health pose challenges for pediatric care. This article will aim to provide an overall view of pediatric CS highlighting some of the differences between adult and pediatric CS.

A síndrome de Cushing (SC) resulta da exposição prolongada a níveis suprafisiológicos de glicocorticóides circulantes, tanto endógenos como de seus derivados exógenos. Embora rara na infância, a SC permanece uma condição difícil de ser diagnosticada e tratada. Uma avaliação multidisciplinar e a colaboração próxima com colegas da área não-pediátrica são adotadas na maioria dos grandes centros que cuidam de pacientes pediátricos com SC. Embora os protocolos pediátricos sejam derivados de dados em adultos, existem diferenças significativas entre a SC no adulto e na infância. Além disso, parâmetros evolutivos finais, incluindo altura final, densidade mineral óssea, função reprodutiva, composição corporal e saúde psicológica trazem desafios no cuidado pediátrico. Este artigo procura oferecer uma visão geral da SC pediátrica, focalizando algumas das diferenças entre a SC adulta e a pediátrica.