We report the case of a 62-year-old woman diagnosed in 2015 with de novo metastatic malignant insulinoma. She presented severe hypoglycemia and was initially treated with somatostatin analogs, chemotherapy (capecitabine-temozolomide), and diazoxide, but none of these controlled the symptoms. Peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-DOTATATE was initiated in 2016, resulting in marked clinical and radiological responses after four cycles. Due to recurrence, two subsequent PRRT treatments were administered in 2021 and 2024, each consisting of two cycles, leading to significant improvements in symptoms and imaging findings. To date, the patient has undergone eight PRRT cycles with sustained biochemical and morphological responses, long-term glycemic control, and excellent tolerance. This case illustrates the long-term efficacy of sequential PRRT retreatment in refractory functional pancreatic neuroendocrine tumors (pNETs).

OBJECTIVE:This analysis describes the evolution of health-related quality of life (HRQoL) over 36 weeks of metyrapone treatment in the PROMPT study, identifying patterns of early, delayed improvement, or persistence using item-level resolution. DESIGN AND METHODS:Longitudinal analysis of patient-reported outcomes from PROMPT (NCT02297945), a prospective, open-label, multicountry study of metyrapone in 49 evaluable adults with confirmed endogenous CS. HRQoL was assessed with the CushingQoL (0-100; higher = better QoL) and Tübingen CD-25 (0-100; higher = worse QoL) at weeks 4, 12, 24, and 36. Item-level analyses characterized the pattern and timing of improvement. Within-patient changes were assessed using the Wilcoxon signed-rank test. RESULTS:Both questionnaires demonstrated significant overall improvement by week 36: CushingQoL increased by 10.4 points (P < .001; 44.7% with ≥10-point improvement), and Tübingen CD-25 decreased by -7.8 points (P = .01). Early responses (by week 12) involved eating behaviour and depression symptoms. Delayed improvements (consolidating at weeks 24-36) were observed in sexual activity, environment, and social domains. Bodily restrictions (-4.3 points, P = .203) and cognition (-6.8 points, P = .143) did not show improvement over the study period. Item-level analysis identified a cluster of symptoms, predominantly psychological health anxiety and physical appearance concerns, where burden remained elevated throughout the 36 weeks despite cortisol normalization. CONCLUSIONS:Metyrapone treatment is associated with meaningful, progressive HRQoL improvements across multiple symptom domains over 36 weeks, with a pattern consistent with rapid cortisol-mediated relief (eating, mood), delayed recovery in social and sexual domains, and persistent residual burden in symptom clusters likely driven by incomplete phenotypic reversal within the study timeframe.

Introduction La néoplasie endocrinienne multiple de type 1 (NEM1) est un syndrome héréditaire rare responsable du développement de tumeurs endocrines, touchant par ordre de fréquence les parathyroïdes, le pancréas et l’hypophyse. Les tumeurs neuroendocrines (TNE) intestinales restent exceptionnelles. Nous rapportons le cas d’une patiente présentant des éléments cliniques et familiaux évocateurs d’une NEM1 atypique, sans mutation identifiée. Observation En 2020, une patiente âgée de 53 ans, est prise en charge pour une hyperparathyroïdie primaire, compliquée de lithiases urinaires et d’ostéopénie. Elle se plaint par ailleurs de diarrhées chroniques. L’anamnèse familiale révèle que ses deux parents, non apparentés, sont décédés d’une TNE de l’intestin grêle ; son père souffrait également de lithiases. Cancers digestifs et lithiases sont également rapportés du côté grand-parental. Un séquençage d’exome clinique avec analyse ciblée d’un panel de gènes liés aux TNE, notamment MEN1, est non contributif. L’IRM abdominale montre deux nodules surrénaliens d’aspect bénins. Le PET-FDG et l’IRM hypophysaire sont normaux. En 2021, un scanner abdominal réalisé pour récidive de lithiases décrit une adénomégalie para-aortique. Un Octréo-PET, réalisé quelques mois plus tard, révèle une atteinte neuroendocrine grêle multifocale avec métastases ganglionnaires. Les dosages itératifs du 5-HIAA sont normaux et la chromogranine A ne s’élève que tardivement. Un séquençage d’exome, avec analyse d’un panel plus étendu de gènes, notamment IMPK, n’a pas montré de variant pathogène. Discussion Ce cas suggère une possible forme atypique de NEM1, sans mutation identifiée des gènes connus de prédisposition aux TNE. Il soulève l’hypothèse de variants pathogènes dans un gène encore inconnu, dans un gène connu mais non détectable par les techniques actuelles, ou une contribution polygénique de variants communs. Une origine toxique environnementale ne peut être exclue, la famille élargie ayant vécu dans le même village. Ce cas souligne la complexité des prédispositions aux TNE et l’importance d’un suivi multidisciplinaire prolongé.

OBJECTIVE:We evaluated the safety and efficacy of metyrapone treatment for Cushing's syndrome (CS). DESIGN:International, prospective, single-arm, open-label study. METHODS:Fifty adults with endogenous CS (either unsuitable for or uncontrolled after surgery) and 3 urinary free cortisol (UFC) concentrations each ≥1.5-fold the upper limit of normal (ULN) were enrolled. After 12 weeks of metyrapone titration, participants with mean 24 h UFC (mUFC) ≤ 2-fold ULN could enter a 24-week extension phase. Safety was assessed, and doses adjusted at weeks 1-5, 8, 12, and 24. Pre-defined endpoints included normalization of mUFC at weeks 12 (primary), 24, and 36, and proportion of "responders" (normalization or ≥50% decrease of baseline mUFC), time to eucortisolemia, salivary cortisol day-curve, and quality of life (QoL). RESULTS:Of the 49 evaluable participants, 47 completed the 12-week visit; 40 were evaluated at week 24 and 35 at week 36. The primary endpoint was met in 46.9% of participants (95% CI 32.5%-61.7%), with efficacy maintained at week 24 (52.5%; 95% CI 37.5%-67.1%) and week 36 (48.6%; 95% CI 33.0%-64.4%). The responder rates were 80.9%, 77.5%, and 71.4% at weeks 12, 24, and 36, respectively. Forty-seven participants (94%) developed mild-to-moderate adverse events (AEs), mostly during the first 12 weeks and most commonly nausea (38%), fatigue (26%), and headache (22%); 8 experienced severe AEs. Six participants developed reversible adrenal insufficiency during titration. Clinical features and QoL improved. CONCLUSION:Metyrapone is a safe and effective treatment for endogenous CS.

Introduction:Adrenal venous sampling (AVS) is considered the gold standard test for primary aldosteronism (PA) subtyping. Considering the limited availability of this challenging procedure, we propose a noninvasive score predicting unilateral (UPA) or bilateral (BPA) form of PA in order to reduce the need for AVS. Material and methods:The score was retrospectively developed from a cohort of 72 patients who underwent AVS (21 patients with BPA and 51 with UPA) at Cliniques Universitaires Saint Luc between 1993 and 2021. Another multicenter cohort of 130 patients who underwent AVS (67 patients with BPA and 63 with UPA) served as external validation. Results:Four predictive parameters of UPA highlighted by logistic regression analysis were integrated into the KASAI score: minimal serum potassium value, supine resting aldosteronemia, aldosteronemia at the end of the saline infusion test, and results of adrenal imaging. Depending on the results, 0, 1, or 3 points were assigned to each parameter. In both cohorts, a score greater than 9/12 identified UPA and a score less than 4/12 identified BPA with 100% specificity, while performing AVS remained indicated for scores between 4 and 9. The score may have avoided AVS in 40% of patients in the primary cohort and in 42% of patients in the validation cohort. The area under the ROC curve for discrimination of UPA from BPA was 0.81 (95% CI, 0.70-0.90) in the primary cohort and 0.86 (95% CI, 0.80-0.90) in the validation cohort. Conclusion:We propose a new biological-radiological score that could simplify the diagnostic assessment of PA.

Introduction: Neuroendocrine neoplasms encompass well-differentiated tumors (NETs) and poorly differentiated carcinomas (neuroendocrine carcinomas [NECs]), which are distinguished by their clinical behavior and molecular characteristics. They can cause paraneoplastic syndromes, such as ectopic adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome (CS), necessitating prompt recognition and management due to severe hypercortisolism. Case Presentation: A 66-year-old patient with a 3-year history of metastatic mixed neuroendocrine-non-neuroendocrine neoplasm with a NEC and adenocarcinoma component originating from the vulva presented to the emergency department with dyspnea and fatigue. Upon clinical examination, we found widespread hyperpigmentation, a moon-face appearance, hirsutism, buffalo hump, and muscle atrophy. Laboratory investigations revealed severe hypokalemia (2.3 mmol/L), elevated serum cortisol (1,726 nmol/L) and ACTH (194 ng/L) levels. Urinary free cortisol measurement was 21-fold the upper limit of the reference range (3,614.0 nmol/24 h), and cortisol concentration did not decrease after 1mg-dexamethasone suppression test (1,812 nmol/L for an expected value <50 nmol/L), confirming the ACTH-dependent CS. Thoracoabdominal computed tomography (CT) scan demonstrated progressive neoplastic disease in the liver, kidney, lymph nodes, peritoneum, and lungs. Brain magnetic resonance imaging indicated multifocal metastatic infiltration but no evidence of pituitary adenoma. Interestingly, despite a previously negative 68Ga-DOTATATE positron emission tomography (PET)/CT performed 1 year prior, there was moderate somatostatin receptor (SSTR) expression in lymphatic, pulmonary, peritoneal, and bone tissues, suggesting the presence of a component with redifferentiation and re-expression of the SSTR. After the workup, the patient was admitted to a supportive care facility. Hypercortisolism symptoms were effectively managed with an adrenal enzyme inhibitor (ketoconazole) in combination with somatostatin analogs. Unfortunately, the patient was too frail to benefit from peptide receptor radionuclide therapy (PRRT). Conclusion: This redifferentiation phenomenon in neuroendocrine tumors should be further investigated as patients might be, under certain conditions, eligible for PRRT. Therefore, we suggest that newly occurring paraneoplastic syndromes in patients with NEC should always be evaluated using 68Ga-DOTATATE PET/CT.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

OBJECTIVE:Hereditary pheochromocytoma (hPCC) commonly develops bilaterally, causing adrenal insufficiency when standard treatment, radical adrenalectomy (RA), is performed. Partial adrenalectomy (PA) aims to preserve adrenal function, but with higher recurrence rates. This study compares outcomes of PA versus RA in hPCC. METHODS:Patients with hPCC due to pathogenic variants in RET, VHL, NF1, MAX, and TMEM127 from 12 European centers (1974-2023) were studied retrospectively. Stratified analysis based on surgery type and initial presentation was conducted. The main outcomes included recurrence, adrenal insufficiency, metastasis, and mortality. RESULTS:The study included 256 patients (223 RA, 33 PA). Ipsilateral recurrence rates were 9/223 (4%) after RA versus 5/33 (15%) after PA (P = 0.02). Metastasis and mortality did not differ between groups. Overall, 103 patients (40%) underwent bilateral adrenalectomy either synchronously or metachronously (75 RA, 28 PA). Of these, 46% developed adrenal insufficiency after PA.In total, 191 patients presented with initial unilateral disease, of whom 50 (26%) developed metachronous contralateral disease, most commonly in RET, VHL, and MAX. In patients with metachronous bilateral disease, adrenal insufficiency developed in 3/4 (75%) when PA was performed as the first operation followed by RA, compared to 1/7 (14%) when PA was performed as the second operation after prior RA (P = 0.09). CONCLUSION:In patients with hPCC undergoing PA, local recurrence rates are higher than after RA, but metastasis and disease-specific mortality are similar. Therefore, PA seems a safe method to preserve adrenal function in patients with hPCC, in cases of both synchronous and metachronous bilateral disease, when performed as a second operation.

Biallelic loss-of-function variants in the IYD gene cause hypothyroidism resulting from iodine wasting. We describe 8 patients (from 4 families in which the parents are first cousins) who are homozygous for a variant in IYD (including a novel missense deleterious variant, c.791C>T [P264L], in 1 family). Seven patients presented between 5 and 16 years of age with a large goiter, overt hypothyroidism, and a high serum thyroglobulin. The goiter subsided with levothyroxine therapy in most. Upon stopping levothyroxine in 5 patients, goiter and hypothyroidism reappeared in 3. In these 3 patients, a rising serum thyroglobulin concentration preceded hypothyroidism and goiter and urinary iodine excretion was low. In patients who remained euthyroid, urinary iodine was normal. In conclusion, these patients bearing biallelic pathogenic variants in IYD developed a large goiter, a high serum thyroglobulin, and overt hypothyroidism when their iodine intake was low.

ObjectivePrimary adrenal insufficiency (PAI) is a rare disease with an increasing prevalence, which may be complicated by life-threatening adrenal crisis (AC). Good quality epidemiological data remain scarce. We performed a Belgian survey to describe the aetiology, clinical characteristics, treatment regimens, comorbidities and frequency of AC in PAI. MethodsA nationwide multicentre study involving 10 major university hospitals in Belgium collected data from adult patients with known PAI. ResultsTwo hundred patients were included in this survey. The median age at diagnosis was 38 years (IQR 25-48) with a higher female prevalence (F/M sex ratio = 1.53). The median disease duration was 13 years (IQR 7-25). Autoimmune disease was the most common aetiology (62.5%) followed by bilateral adrenalectomy (23.5%) and genetic variations (8.5%). The majority (96%) of patients were treated with hydrocortisone at a mean daily dose of 24.5 & PLUSMN; 7.0 mg, whereas 87.5% of patients also received fludrocortisone. About one-third of patients experienced one or more AC over the follow-up period, giving an incidence of 3.2 crises per 100 patient-years. There was no association between the incidence of AC and the maintenance dose of hydrocortisone. As high as 27.5% of patients were hypertensive, 17.5% had diabetes and 17.5% had a diagnosis of osteoporosis. ConclusionThis study provides the first information on the management of PAI in large clinical centres in Belgium, showing an increased frequency of postsurgical PAI, a nearly normal prevalence of several comorbidities and an overall good quality of care with a low incidence of adrenal crises, compared with data from other registries.

Abstract Disclosure: K. De Sousa: None. V. Pautasso: None. C. Duparc: None. S. Renouf: None. B. Ragazzon: None. F. Violon: None. L. Bouys: None. F. Bonnet-Serrano: None. M. Sibony: None. N. Driessens: None. S. Espiard: None. G. Raverot: None. J.Y. Bertherat: None. E. Louiset: None. H. Lefebvre: None. Context: Bilateral macronodular adrenocortical disease (BMAD) is a rare cause of primary Cushing syndrome, occurring mostly in women. ARMC5 and KDM1A mutations are responsible for distinct forms of BMAD. In particular, KDM1A mutations are associated with food-dependent Cushing syndrome. In addition, BMAD tissues can express illegitimate receptors, including LH receptor, that lead to aberrant control of cortisol secretion by various factors. Moreover, steroidogenic cells are able to abnormally produce bioactive factors, such as ACTH and the Leydig cell hormone INSL3. Since LH receptor, ACTH and INSL3 are known to be produced in gonads, we speculated on a gonadal-like differentiation of adrenocortical cells in BMAD tissues. Aim: The aim of our study was to investigate the presence of different gonadal markers in a series of BMAD tissues, and to search for secretion of adrenal and gonadal hormones by BMAD cells. Methodology: Gene expression of gonadal markers were evaluated by RNAseq. Immunohistochemical studies were performed on 41 BMAD and 9 normal adrenal samples to examine the presence of hormones (ACTH, INSL3, anti-Mullerian hormone [AMH]), the estrogen synthetizing enzyme aromatase, and transcription factors (GATA4, SOX9, FOXL2, MAGEA4) known to be expressed in testis or ovary. Perifusion experiments, coupled to immunoassays or liquid chromatography/mass spectrometry, were conducted to quantify hormone secretion by 2 adrenal explants. Results: BMAD tissues were collected from patients (60% women) without or with ARMC5 (32%) or KDM1A (13%) mutations. ARMC5-mutated tissues overexpressed FOXL2 and CYP19A1 (encoding aromatase) in comparison with other BMAD samples. In normal adrenals, cortisol-producing cells, located in the zona fasciculata, were immunonegative for INSL3, AMH, aromatase, GATA4 and SOX9, whereas FOXL2 and MAGEA4 immunostainings were detected in the cortex. In BMAH tissues, the presence of positive cells for ACTH (100% of BMAD), INSL3 (90%), AMH (50%), aromatase (77%), SOX9 (92%), GATA4 (97%), FOXL2 (100%) and MAGEA4 (100%) were observed in most of the samples regardless of the gender or mutational status. FOXL2 and MAGEA4 immunostainings were detected throughout BMAD tissues. Distribution of other gonadal markers was heterogenous in tissue sections with clusters of cells positive for ACTH, aromatase and GATA4 or ACTH and SOX9. Functional studies revealed pulsatile secretion of different glucocorticoids and INSL3 by BMAD explants. ACTH and hCG stimulated steroid production but were without effect on INSL3 release. Conclusion: These data show that steroidogenic cells in BMAD tissues exhibit a gonadal-type phenotype and abnormally secrete INSL3. They suggest that BMAD may result from a genetically driven defect occurring during early embryogenesis and affecting differentiation and development of adrenal tissues. Presentation: Friday, June 16, 2023

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

La métyrapone est un inhibiteur de la stéroïdogenèse approuvé en Europe pour le traitement du syndrome de Cushing endogène, sur la base d’études rétrospectives. Nous présentons les résultats de la première étude prospective sponsorisée par HRA Pharma RD. L’étude comporte un seul bras de patients traités pendant 12 semaines (S12), période de titration suivie d’une extension de 24 semaines. Les 50 patients recrutés devaient avoir trois cortisoluries de 24 h (CLU) augmentées chacune d’au moins 50 % par rapports aux valeurs normales (VN = 165 nmol/24 h) avant traitement. Les patients gardant un CLU moyen (CLUm) inférieur à 2xVN à S12 pouvaient participer à l’extension jusqu’à S36. La médiane du CLUm était 3,5xVN avant traitement. L’hypercortisolisme était modéré (> 2xVN et ≤ 5xVN) chez 63 % des patients et sévère (≥ 5xVN) chez 33 %. On a observé une normalisation du CLUm (49 % des patients) ou une amélioration cliniquement significative (40 % des patients) à S12 où la médiane du CLUm était de 1,03xVN. Cette efficacité s’est maintenue à S36 où la médiane du CLUm était de 1,04xVN (CLUm normalisé chez 49 % et cliniquement significativement amélioré chez 31 %). La dose quotidienne médiane de métyrapone était de 1500 mg à S12 et S36. Les effets indésirables (EI), étaient majoritairement légers à modérés. Les EI ≥ 15 % étaient des signes d’hypocortisolisme : nausées (38 %), fatigue (26 %), anorexie (18 %), céphalées (22 %) et vertiges (16 %). Six patients ont présenté une insuffisance surrénalienne. Quatre ont interrompu l’étude pour autres EI. La métyrapone est efficace et bien tolérée dans le traitement du syndrome de Cushing.

OBJECTIVE:Adrenal ganglioneuromas are rare, differentiated, neuroblastic tumors that originate from the peripheral sympathetic nervous system. Because of their rarity, information is limited, derived from small cases series. Our objective was to characterize this tumor and provide help for its management. METHODS:A retrospective multicenter analysis of adrenal ganglioneuromas from 20 French centers belonging to the COMETE network and one Belgian center. RESULTS:Among the 104 cases identified, 59.6% were women (n = 62/104), median age at diagnosis was 29 years, with 24 pediatric cases. 60.6% (n = 63/104) were incidentalomas. Ganglioneuromas were non-secreting tumors in 90.8% of cases (n = 89/98), whereas the preoperative hormonal evaluation was indeterminate for 9.2% of patients (n = 9/98). CT imaging, performed on 96 patients, revealed large tumors (median diameter of 50 mm) with a non-contrast density > 10 Hounsfield units in 98.1% (n = 52/53) and calcifications in 64.6% of cases (n = 31/48). Increased uptake on 123I-MIBG scintigraphy and 18F-FDG-PET/CT was observed in 26.7% (n = 8/30) and 42.2% (n = 19/45) of the tumors, respectively. All 104 patients underwent surgery. No recurrence was observed among the 42 patients who had an imaging follow-up (mean 29.6 months, median 18 months (4-156)). CONCLUSION:Adrenal ganglioneuromas are large tumors, mostly nonfunctioning, without benign imaging features. Although the duration of follow-up was limited in our series, no recurrence was identified. A review of the literature confirms the absence of postoperative recurrence. Based on all available data, in the absence of special circumstances (genetic form, uncertain histological diagnosis), long-term follow-up is not necessary after complete surgery for patients with an adrenal ganglioneuroma.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)