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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.

Introduction: Intravenous etomidate infusion is effective to rapidly lower cortisol levels in severe Cushing's syndrome (CS) in the intensive care unit (ICU). Recently, etomidate treatment has also been proposed at lower doses in non-ICU wards, but it is not yet clear how this approach compares to ICU treatment. Methods: We compared data from patients with severe CS treated with high starting doses of etomidate (median: 0.30 mg/kg BW/day) in ICU or with lower starting doses (median: 0.025 mg/kg BW/day) in non-ICU medical wards. Results: Fourteen patients were included, among which ten were treated with low starting doses (LD) and four with high starting doses etomidate (HD). All patients had severe and complicated CS related to adrenal carcinoma (n = 8) or ectopic ACTH secretion (n = 6). Etomidate was effective in reducing cortisol levels below 500 nmol/L in a median of 1 day in the HD group compared to 3 days in the LD group (P = 0.013). However, all patients of the HD group had etomidate-induced cortisol insufficiency and needed frequent monitoring, while no patient from the LD group required hydrocortisone supplementation. No patient in either group died from complications of CS or etomidate treatment, but final outcome was poor as six patients in the LD group and all four patients in the HD group died from their cancer during follow-up. Conclusion: Our study suggests that, for patients with severe CS who do not require intensive organ-supporting therapy, the use of very low doses of etomidate in medical wards should be considered., SCOPUS: ar.j, info:eu-repo/semantics/published

Primary pigmented nodular adrenal disease (PPNAD) accounts for,1% of ACTH-independent Cushing syndrome. We describe the case of twin female patients with PPNAD who both had sustainable disease control after unilateral adrenalectomy, which corroborates current evidence in favor of unilateral adrenalectomy for a subset of patients with PPNAD. Patient A presented with a 10-kg weight gain over the past year and facial plethora. Diagnostic evaluation revealed abolition of normal cortisol rhythm with suppressed ACTH levels, normal adrenal CT and MRI imaging and a slightly left-predominant adrenal uptake on 131I iodomethyl norcholesterol scintigraphy coupled with single-photon emission CT/ CT. PPNAD was confirmed after genetic testing revealed a known pathogenic PRKA1A mutation (c.709 (-7-2) del6). At that time, her twin sister (patient B) was asymptomatic. Patient A underwent successful unilateral adrenalectomy and histology confirmed PPNAD. Two years after initial onset of symptoms in patient A, patient B was seen for the same subtle symptoms of progressive weight gain. Diagnostic test results were identical, revealing the same clinical features and mutational status as patient A. Patient B also underwent unilateral adrenalectomy with a favorable outcome. Follow-up 3 years after surgery for patient A and 18 months for patient B showed sustained disease control without recurrence and uncompromised quality of life, with no adrenal insufficiency having occurred. Unilateral adrenalectomy can be a successful therapeutic approach for patients with PPNAD with a mild phenotype without the risk and the inconvenience of subsequent adrenal insufficiency, which alters quality of life., SCOPUS: ar.j, info:eu-repo/semantics/published

A 60-year-old men was admitted mid-January for acute left abdominal pain. He had no medical history and didn’t smoke or take any medication. Abdominal CT-scan showed a voluminous (61 × 57 × 47 mm), heterogeneous, hemorrhagic mass in left adrenal gland with a high spontaneous density (45UH). Pheochromocytoma diagnosis was first suspected although 24-hours urine fractionated metanephrines and catecholamines measurements were only slightly increased (NA:1.1xULN and NMN:1.2xULN). Hormonal evaluation did not demonstrate excessive cortisol or sexual steroids secretion. 18F-FDG PET-CT imaging revealed intense FDG-uptake in the left adrenal gland as well as in the right adrenal gland and in the heart. With this new information, the differential diagnosis includes carcinoid cardiac tumor, malignant cardiac myxoma, sarcoma and metastases. All others tumor markers were negative (5HIAA, NSE, CA 19-9, CA 125, CEA, PSA, β-hCG). For Valentine's Day, cardiac MRI confirmed a pathological thickening of right inter-atrioventricular groove with marked late enhancement at this level, corresponding to pathological areas in isotopic imaging. Next day, patient presented acute right flank pain similar to the one he had on left side one month earlier. New abdominal CT-scan showed a large hemorrhage in right adrenal gland that was not present on 18F-FDG PET-CT performed 3 days before. Latest Ga-DOTATATE-PET imaging didn’t show anywhere STT-receptors presence. Morning cortisol level (411 nmol/L) remained non-suggestive of adrenal insufficiency. This case was discussed by web-conference with the French experts of the national COMETE multidisciplinary committee: it was decided to obtain histology from left adrenal tumor by percutaneous biopsy rather than by unilateral adrenalectomy because the radicality of surgery might change depending on histological diagnosis. So far, diagnosis has not yet been established. This case underlines importance of discussing complex situations with experts as allowed by COMETE or ENDO-ERN networks.

Introduction Le ganglioneurome (GN) est une tumeur neuroblastique differenciee, rare, issue du systeme nerveux sympathique peripherique. Il se developpe aux depens de la glande surrenale dans 20 a 25 % des cas. L’objectif de cette etude est de caracteriser les GN surrenaliens et d’etudier le risque de recidive apres chirurgie. Materiel/patients et methodes Etude retrospective multicentrique des cas de GN surrenaliens dans 20 centres francais appartenant au reseau COMETE et un centre belge. Resultats Parmi les 106 cas recenses, 60,4 % sont des femmes (N = 64/106), l’âge median au diagnostic est de 29 ans avec 25 cas pediatriques. 60,4 % (N = 64/106) des GN sont des incidentalomes. Les tumeurs ne secretent pas dans 90 % des cas (N = 90/100), le bilan hormonal preoperatoire est douteux pour 10 % des patients (N = 10/100). Au niveau radiologique, ce sont des tumeurs de grande taille (mediane a 50 mm) avec une densite spontanee > 10 UH dans 98 % des cas (N = 54/55) et des calcifications dans 65,3 % des cas (N = 32/49). Un hypermetabolisme en scintigraphie 123I-MIBG et en TEP 18FDG est retrouve dans respectivement 25,8 % (N = 8/31) et 41,3 % (N = 19/46) des tumeurs. 104 patients ont ete operes. Parmi les 42 patients ayant eu un suivi d’imagerie de plus de 3 mois (suivi moyen de 29,6 mois ; mediane 18 mois [4–156]), aucune recidive radiologique n’est retrouvee. Discussion Les GN surrenaliens sont des tumeurs de grande taille, classiquement non secretantes, ne possedant pas les caracteristiques radiologiques de benignite. Cependant, aucune recidive n’a ete identifiee dans notre cohorte. La revue des donnees de la litterature conforte l’absence de recidive post-operatoire.

Introduction L’etomidate est un hypnotique et anticortisolique puissant par inhibition de la 11-beta-hydroxylase. Son administration intraveineuse continue aux soins intensifs est efficace dans le syndrome de Cushing severe (SCS). Recemment, ce traitement a ete propose a plus faibles doses dans des unites non-intensives. Methodes Nous avons compare l’evolution de patients avec SCS traite par etomidate a dose de depart haute aux soins intensifs (mediane : 0,30 mg/kg/j) ou basse en unite non-intensive (mediane : 0,025 mg/kg/j). Resultats 14 patients ont ete etudies : 10 avec dose initiale basse (LD) et 4 avec dose initiale plus elevee (HD). Le SCS etait toujours secondaire a un cancer, soit carcinome surrenalien (n = 8), ou tumeur neuroendocrine avec secretion ectopique d’ACTH (n = 6). L’etomidate a permis de reduire la cortisolemie sous la valeur cible de 500 nmol/l chez tous les patients, mais plus rapidement dans le groupe HD (mediane : 1 jour) que dans le groupe LD (mediane : 3 jours, p = 0,013). Cependant, tous les patients du groupe HD ont developpe une hypocortisolemie alors qu’aucun patient dans le groupe LD n’a eu besoin d’hydrocortisone. Aucun des 14 patients n’est decede de complications de son SCS ou du traitement. Leur pronostic fut cependant sombre : 6/10 patients dans le groupe LD et 4 patients/4 dans le groupe HD sont decedes de leur cancer apres un delai moyen de 5,7 mois. Conclusion Nous suggerons que certains patients avec SCS et qui ne requierent pas de therapie intensive peuvent etre traites par de faibles d’etomidate en unite non-intensive.

Background: Metyrapone is a steroidogenesis inhibitor approved in Europe for the treatment of endogenous Cushing’s syndrome (CS) based on observational retrospective studies published over more than 50 years. We present data from the first prospective study designed to confirm metyrapone efficacy and good tolerance in patients with CS. Methods: This single arm, open-label, multicenter, international trial enrolled 50 patients with CS who had three baseline 24 hours urine free cortisol (UFC) values at least 50% above the upper limit of normal (ULN=165 nmol/24h). Metyrapone was titrated over 12 weeks (W12) to achieve normal urine (mean of 3 values, mUFC) and serum cortisol levels. Patients whose mUFC did not exceed 2-fold the ULN could enter a 6-month extension period. The primary efficacy endpoint was the proportion of patients with mUFC ≤ ULN at W12 assessed in a central laboratory using LC-MS/MS. The most important secondary endpoint was mUFC decrease of ≥ 50% at W12. Results: At baseline: mean age was 47 years, median mUFC (range) was 570 (291 - 8476) nmol/24h (3.5 x ULN). Hypercortisolism was in 96% of patients either moderate (mUFC ≥ 2xULN; < 5x ULN) in 63% or severe (≥5 x ULN) in 33%. Hypertension (69%) and diabetes mellitus (47%) were the most common comorbidities. At W12: 47% (23/ 49) met primary endpoint. Another 40% (19 / 49) had mUFC ≤ 2xULN. Median percentage decrease in mUFC from baseline to W12 was -74%. Secondary endpoint was met by 80% of patients who had a mUFC decrease of 50%. Final median metyrapone dose was 1500 (250; 5500) mg/day. Physical signs and symptoms were normalized or improved in 66% of patients. Circulating cholesterol, HbA1C and fasting glucose and insulin improved with median decrease of 12%, 3%, 5% and 9% respectively and median systolic and diastolic blood pressure also decreased by 4 and 5mmHg respectively. Among patients with antihypertensive treatments, 10 (31%) had a decrease in number of drugs and 5 (16%) had an increase in number of drugs during the study. Median ACTH increased by 11 % from baseline. Twenty six (52%) patients experienced mild to moderate study drug related adverse events (AEs). One patient discontinued before W12 because of an unrelated SAE on day 2 (pneumonia with septic shock). The most common AEs were nausea (24%), decreased appetite (18%), fatigue (14%), headache (10%), peripheral edema (6.0%), hypokalemia (6.0%) and hypertension (6.0%). Reversible adrenal insufficiency occurred in 6 (12%) patients. Few patients 14% (7/50) experienced at least one AE that led to a dose interruption or dose adjustment. Cushing Quality of Life Questionnaire increased of 10 points from baseline which is close to minimal clinically important difference = 10.1. Conclusions: This prospective study in patients with CS confirms that metyrapone effectively lowers UFC levels with a tolerability profile similar to the previously reported safety profile and improves QoL, at Week 12.

We studied the mechanism that may explain the relative resistance of thyrocytes to H2O2 compared to other cell types. Ability to degrade H2O2, glutathione peroxidase (GPx) activity, heme oxygenase-1 (HO-1) expression, cell survival and capacity to repair DNA damage after H2O2 exposure or irradiation were measured in human thyrocytes in primary culture and compared to the values obtained in human T-cells and different cell lines. Compared to other cell types, thyrocytes presented a low mortality rate after H2O2 exposure, rapidly degraded extracellular H2O2 and presented a high basal seleno-dependent GPx activity. Only in thyrocytes, H2O2 up-regulated GPx activity and expression of HO-1 mRNA. These effects were not reproduced by irradiation. DNA damage caused by H2O2 was more slowly repaired than that caused by irradiation and not repaired at all in T-cells. Our study demonstrates that the thyrocyte has specific protective mechanisms against H2O2 and its mutagenic effects., SCOPUS: ar.j, info:eu-repo/semantics/published

La confirmation du diagnostic de syndrome de Cushing chez un patient presentant une clinique evocatrice necessite des tests complementaires. La mesure du cortisol salivaire de minuit, du cortisol libre urinaire de 24 heures (CLU) et le test de freinage minute par 1 mg de Dexamethasone (DXM) representent les tests de depistage classiquement utilises en premiere ligne. Chez les femmes utilisant des oestro-progestatifs, le freinage minute est souvent amoindri pouvant engendrer des faux positifs (FP = cortisolemie matinale post-DXM > 50 nmol/L). Le but de notre etude est de comparer le freinage minute et le test de Liddle (DXM 0,5 mg/6 h pendant 48 h) dans un echantillon de 30 volontaires saines utilisant une contraception oestro-progestative. Nous avons egalement mesure le cortisol salivaire a minuit et 8 h apres chacun des 2 tests. Nous avons egalement mesure le CLU au 2e jour du test de Liddle. Nos resultats preliminaires montrent un taux de FP de 62 % (7/18) au freinage minute contre seulement 15 % (2/13) au test de Liddle. Le CLU au second jour du test Liddle elimine les derniers FP (0/12). Le pourcentage de diminution de la cortisolemie est de 95 % pour les 2 tests chez les vrais negatifs tandis que chez les FP, il est de 90 % apres freinage minute et de 95 % apres Liddle. Le cortisol salivaire de minuit est toujours dans les normes, y compris chez les FP aux 2 tests de freinage. En conclusion, nos resultats preliminaires suggerent que, si un test de suppression est souhaite, le test de Liddle pourrait etre une meilleure option que le test minute chez la femme utilisant des oestro-progestatifs et ne souhaitant pas les arreter. Chez ces patientes, le dosage du cortisol salivaire de minuit reste une excellente alternative de meme que le CLU au second jour du test Liddle.

Observation Une patiente de 32 ans a beneficie d’une mise au point pour amaigrissement. L’examen physique etait normal en dehors d’un IMC a 13 kg/m2. Le CT-scanner abdominal a permis de decouvrir une masse surrenalienne gauche de 41 × 36 × 44 mm, heterogene, d’une densite a blanc de 25 UH et contenant des calcifications. Le bilan hormonal n’etait pas en faveur d’une tumeur secretant de l’aldosterone, du cortisol ou des androgenes. Deux recoltes urinaires de 24 h sur milieu acidifie ont retrouve une elevation des catecholamines et normetanephrines (de 1,7 a 3,5 fois la limite superieure de la normale). Une TEP au 18F-FDG a montre uniquement une avidite de la masse pour le traceur. Une chirurgie laparoscopique a permis l’exerese d’une surrenale contenant une lesion solide de 45 × 35 × 50 mm au centre kystico-hemorragique constituee de cellules epithelioides de grande taille, au cytoplasme eosinophile. Le Ki67 etait inferieur a 2 % mais la tumeur presentait plusieurs criteres de malignite : anisonucleose, mitoses atypiques, effraction capsulaire. Sur base de differents immunomarquages (positifs pour les anti-Synaptophysine, anti-Vimentine, anti-MelanA, anti-Inhibin-a et anti-NSE et negatifs pour les anti-Chromogranine et anti-S100) le diagnostic de carcinome oncocytaire a ete retenu. Discussion Habituellement considerees comme benignes, les tumeurs oncocytaires de la surrenales sont des tumeurs tres rares mais a potentiel malin pour lesquelles il n’y a pas de recommandations therapeutiques precises. Ce cas illustre l’importance de la caracterisation anatomoclinique de ces tumeurs (notamment par l’etablissement du score de Lin–Weiss–Bisceglia) afin de definir des facteurs predictifs d’evolution et/ou de recidive qui orienteront le traitement et le suivi.

La survenue d’une polyglobulie comme manifestation d’un carcinome surrenalien n’est pas habituelle. Nous presentons l’histoire d’une octogenaire aux principaux antecedents de carcinome mammaire et d’hypertension arterielle qui avait subi une surrenalectomie droite par cœlioscopie pour une masse de grande taille (7 × 5 cm), de densite a blanc elevee (> 30 UH), non secretante. L’examen anatomapathologique avait conclu a un adenome cortico-surrenalien sans signes de malignite : score de Weiss de 2 et Ki67 Deux ans apres, elle developpe une polyglobulie [Hb : 17,9 g/dL (n = 11,8–15,5) ; hematocrite : 53,5 % (n = 35,3–46,1)] sans atteinte des autres lignees hematopoietiques. Le taux d’EPO etait normal et aucune mutation JAK2 n’a ete mise en evidence. Quelques mois plus tard, elle est referee en endocrinologie car elle se plaignait d’une pilosite inhabituelle aux bras et au visage avec prise de poids. L’examen clinique objectivait aussi des signes d’hypercorticisme : comblement graisseux des creux sus-claviculaires, legere bosse de bison, fragilite cutaneo-vasculaire et amyotrophie proximale. Le bilan hormonal confirmera la presence d’une hyperandrogenie severe [testosterone totale : 28,3 nmol/L (n = 0,50–1,67) ; DHEAs > 27,00 μmol/L (n = 0,33–4,18) ; androstenedione : 18,0 ng/mL (n = 0,1–3,0)] et d’une autonomie de secretion du cortisol (absence de freination du cortisol plasmatique par le test minute a la dexamethasone et cortisol libre urinaire a 3 fois les valeurs superieures des normes). L’imagerie abdominopelvienne montrera une recidive tumorale dans la loge de surrenalectomie droite avec carcinomatose peritoneale confirmant le diagnostic de carcinome surrenalien co-secretant cortisol et androgenes avec polyglobulie secondaire. Ce cas illustre bien la necessite d’une prise en charge pluridisciplinaire des tumeurs rares comme les corticosurrenalomes.

Aberrant expression of serotonin receptors in an aldosterone- and cortisol-producing adenoma Introduction Aberrant expression of serotonin receptors has been described to be involved in the pathophysiology of both aldosterone-producing and cortisol-producing adrenal adenomas. Case report A 46-year-old woman was referred for evaluation of severe hypertension associated with hypokalaemia. Primary aldosteronism with concurrent subclinical Cushing’s syndrome was diagnosed. A CT-scan identified a lesion of 4 cm in the right adrenal gland and a second lesion of 1 cm in the left adrenal gland, both displaying benign imaging phenotype. Following dexamethasone suppression, we explored the potential aberrant expression of serotonin receptors in the adrenal cortex by intravenous administration of metoclopramide, a serotonin type 4 receptor (5-HT4-R) agonist. This led to abnormal cortisol increase and physiological response of aldosterone in peripheral blood. Adrenal venous sampling was then performed in basal conditions and after metoclopramide stimulation. An increase in cortisol level was observed in the left adrenal vein after stimulation. 131I-19-Iodocholesterol scintigraphy showed intense radiotracer uptake in the right adrenal mass and weak uptake in the contralateral mass. Right laparoscopic adrenalectomy was performed. Histological examination revealed an adrenocortical adenoma. In vitro, cultured adrenocortical cells derived from the tumoural tissue exhibited aldosterone and cortisol co-secretion. Administration of 5-HT or metoclopramide to the cells induced a dose-dependent increase in cortisol production. These effects were inhibited by concomitant administration of the 5-HT4-R antagonist GR113808. Incubation of tumour tissue fragments with 5-HT induced a significant increase in aldosterone production which was abrogated in the presence of GR113808. These data were suggestive of aberrant expression of 5HT4-R in the tumoural tissue. Conclusion We report a rare case of an aldosterone- and cortisol-co-producing adenoma in a patient with severe hypertension and bilateral adrenal masses exhibiting an abnormal plasma cortisol response to metoclopramide. In vitro studies revealed enhanced sensitivity of the tumour tissue to 5-HT indicative of illicit expression of 5-HT4 receptors.

Autoimmune polyendocrinopathy type 1 (APS1), or APECED syndrome, is a rare genetic disease. Auto-immune hypoparathyroidism is usually the first clinical manifestation and the most prevalent disease. Treatment will depend on the affected organ and could be challenging throughout life, especially because of development of combination of different auto-immune disorders. A 22-year-old woman was diagnosed for hypoparathyroidism at the age of 4 after seizure caused by hypocalcemia. At 14-year-old, she developed an ovarian failure. At that time, APS1 was confirmed by molecular analysis showing a mutated AIRE gene. Serum calcium was stable over time under oral calcium (1.5 g/day) and calcitriol (0.75 μg/day). Despite persistent adherence to the treatment, she was admitted for severe acute hypocalcemia (corrected serum calcium: 1.3 mmol/L). In addition to hypocalcemia related-tetany, she complained of abdominal pain and diarrhea. Biology revealed inflammatory syndrome. Repeated microbiological samples remained negative. Acute treatment was initiated with intravenous administration of calcium gluconate. Persisting hypocalcemia required increased oral doses of calcium (4 g/day) and calcitriol (2 μg/day). 1,25-dihydroxy-vitamin D raised slightly despite the doubling of calcitriol dose (from 28.5 to 50.5 pg/mL [N: 22–111]). Therefore, malabsorption syndrome was suspected and finally confirmed by the presence of a steatorrhea with a steatocrit value of 82%. High dose of calcium and calcitriol use is limited by the risk of hypercalcemia and by side effects as nephrolithiasis. This case illustrates the necessity to test new therapies like subcutaneous recombinant PTH that could be a good alternative for patients with hypoparathyroidism associated with malabsorption.

Adrenocortical carcinoma is a rare malignancy of poor prognosis with frequent excessive secretion of cortisol or androgens or both. The treatment could be challenging, especially in advanced or metastatic cases. We present the case of a 26-year-old woman with a multiple metastatic adrenocortical carcinoma. A few months prior to diagnosis, she developed clinical signs of virilization and a Cushing's syndrome. Mitotane and ketoconazole combination therapy was initiated after histopathological confirmation. A surgical resection of the left adrenal gland was performed. The tumor was classified pT2Nx (score Weiss 9, Ki67 10%). Cisplatin-Etoposide chemotherapy was started 20 days postoperatively. In the presence of persistent severe and life-threatening hypercortisolism (Urinary free cortisol [UFC] > 20-fold the upper limit of the normal range [ULN]), adding metyrapone was indicated but this drug is not available in Belgium. An alternative urgent treatment with etomidate (0.3 mg/kg/hour) by continuous intravenous infusion was administrated for 24 hours. The inhibition of the adrenal cortisol production was rapid prompting a need for a substitution by hydrocortisone (8 hours after treatment initiation). UFC decreased to less than 5-fold the ULN. One month later, the medical evaluation shows normalized UFC and regression of metastasis after 2 cycles of chemotherapy. Etomidate, mostly known as anesthetic, is a strong enzymatic inhibitor of the 11β-hydroxylase implicated in the last step of the adrenal cortisol steroidogenesis. There are only limited data on its use in severe hypercortisolism. This case illustrates its utility and efficacy in acute phase of hypercortisolism while waiting for action of other adrenal-directed therapies.

Introduction L’acrodysostose correspond a un syndrome de dysplasie squelettique rare caracterise par une tres petite taille finale, des malformations osseuses des mains et des pieds (brachydactylie severe), une dysostose faciale avec hypoplasie nasale et un retard mental de severite variable. Cette pathologie, autrefois apparentee a la pseudo-hypoparathyroidie type 1a (PHP1a), peut etre associee a des resistances aux hormones se liant aux recepteurs couples aux proteines G impliquees dans la voie de l’AMP cyclique. Plusieurs mutations de differents genes dependants de cette voie (GNAS, PRKAR1A, PDE4D) donnant un phenotype similaire, une nouvelle classification basee sur les caracteres genotypiques a recemment ete proposee. Observations Notre patiente est suivie depuis l’âge de 3,5 ans pour un retard statural associe a une surcharge ponderale dans un contexte de dysmorphie. Elle est nee a terme avec un poids de 2,2 kg (−3,7 DS) pour une taille de 42 cm (−5 DS). Le bilan hormonal evoquait une pseudo-hypoparathyroidie type1 (PHP1) avec resistance a la PTH et a la TSH. Les caracteristiques dysmorphiques (brachymetacarpie, anomalies des 3 e et 5 e metatarsiens avec raccourcissement des 3 derniers orteils) etaient suggestives d’une acrodysostose, confirmee par la presence d’une mutation (Q372X) du gene codant la PRKAR1A. Cette pathologie correspond a une iPPSD4 selon la nouvelle classification de l’EuroPHP. La patiente a beneficie d’un traitement par calcitriol et L-thyroxine avec incompliance therapeutique majeure. Elle est actuellement âgee de 25 ans, pese 90 kg pour une taille de 136 cm (−5 DS). Le dernier dosage de TSH etait a 100 mU/L (N 0,4–4,0). Discussion La chronicite des traitements, la dysmorphie, l’obesite et les complications metaboliques font de l’acrodysostose une pathologie lourde sur le plan physique et psychologique surtout a la transition et compliquent l’insertion psychosociale. De plus, l’incompliance therapeutique est un facteur limitant frequent dans la prise en charge de ces patients, deja difficilement autonomes.

Context: Radiation is an established cause of thyroid cancer, and growing evidence supports a role for hydrogen peroxide (H2O2) in spontaneous thyroid carcinogenesis. Little is known about the molecular programs activated by these agents in thyrocytes. Objective: The purpose of this study was to compare the responses of thyrocytes and T cells to H2O2 and radiation. Methods: We profiled the DNA damage and cell death induced by γ-radiation (0.1–5 Gy) and H2O2 (0.0025–0.3 mM) in primary human thyrocytes and T cells. We next prepared thyroid and T-cell primary cultures from 8 donors operated for noncancerous thyroid pathological conditions and profiled their genome-wide transcriptional response 4 hours after (1) exposure to 1-Gy radiation, (2) treatment with H2O2 and (3) no treatment. Two H2O2 concentrations were investigated, calibrated in each cell type to elicit levels of single- and double-strand breaks equivalent to 1-Gy γ-radiation. Results: Although thyrocytes and T cells had comparable radiation responses, 3- to 10-fold more H2O2 was needed to induce detectable DNA damage in thyrocytes. At H2O2 and radiation doses inducing double-strand breaks, cell death occurred after 24 hours in T cells but not in thyrocytes. The transcriptional responses of thyrocytes and T cells to radiation were similar, involving DNA repair and cell death genes. In addition to this transcriptional program, H2O2 also up-regulated antioxidant genes in thyrocytes, including glutathione peroxidases and heme oxygenase at the double-strand breaks–inducing concentration. In contrast, a transcriptional storm involving thousands of genes was raised in T cells. Finally, we showed that inhibiting glutathione peroxidases activity increased the DNA damaging effect of H2O2 in thyrocytes. Conclusion: We propose that high H2O2 production in thyrocytes is matched with specific transcriptionally regulated antioxidant protection.

A 35-year-old woman was referred to the endocrinologist after measurement of an increased serum total testosterone above 8-fold the upper value of the normal range [6.5 ng/mL (N: 0.2–0.8)]. She spontaneously reported recent hair loss. Anamnesis reported a primary amenorrhea and a consanguineous family. At clinical examination, she was slightly overweight (height: 167 cm; weight: 77 kg; BMI: 28) with a normal breast development and adult external genitalia but no axillary or pubic hair. There was no hirsutism nor acne nor hyperseborrhea. Biology showed normal 17-hydroxy-progesterone (1.12 ng/mL) and elevated AMH [98 ng/mL (N: 1.5–6.5)]. Pelvic ultrasonography revealed an absence of uterus, a short vagina and bilateral intra-abdominal gonads without follicles nor individualized tumor. The absence of sexual hair contrasted with the high levels of total testosterone suggesting an androgen resistance. The elevated AMH suggested a testicular origin and explained the absence of uterus. Caryotype was 46,XY confirming the suspected diagnosis of complete insensitivity to androgens syndrome (CAIS). CAIS is a rare cause of primary amenorrhea with normal breast development. The medical management consists in bilateral gonadectomy after pubertal induction in order to prevent the risk of gonadal cancerization. The particularity of the present case is the atypical circumstances of diagnosis, which demonstrate the importance of the psychological care and the need of a multidisciplinary team. Indeed, our patient has a female phenotype without ambiguity and a female sexual and social identity despite her male genotype.

A 74-year-old man was admitted for sudden onset of severe pain in the left thoraco-abdominal flank. He had no palpitations and no headache. Clinically, the patient presented diaphoresis and his systolic blood pressure was measured at 240 mmHg. He had a history of hypertension treated by metoprolol, hydrochlorothiazide, felodipin and quinapril. ECG showed only signs of left ventricular hypertrophy. Biology was normal except a slight renal impairment. Thoraco-abdominal computed tomography performed to exclude an aortic dissection revealed a huge left adrenal mass (80 mm) with a left perirenal hematoma. Patient was admitted in intensive care unit to control blood pressure. At that time, pheochromocytoma was clinically suspected. Repeated 24-hour urine fractionated metanephrines and catecholamines measurements showed elevation of normetanephrine and noradrenalin levels at 3.2- and 1.6-fold the upper limit of the normal range respectively (in 3 independent urine collections). Despite no clear cut-offs for urinary (nor) metanephrines values, we considered these increased levels as compatible with the diagnosis of pheochromocytoma. 18F-FDG PET/CT imaging showed an FDG-avid adrenal lesion without pathological uptake elsewhere. A laparoscopic left adrenalectomy was performed and pathological examination concluded to an infiltration of the adrenal gland by a clear-cell renal cell carcinoma. The present case focuses on the atypical presentation of a renal cell carcinoma. The adrenergic symptoms combined to the increased urinary normetanephrine levels suggested the diagnosis of pheochromocytoma but were probably related to catecholamines release caused by the hemorrhage of the renal cell carcinoma within the adrenal medulla.

Primary macronodular bilateral adrenal hyperplasia (PMBAH) was incidentally identified in a 69-year-old woman who developed a biliary colic. She had a 30-year history of hypertension and was treated by three antihypertensive drugs. Concomitantly, one of her four sons was also referred after incidentally discover of a PMBAH. This 50-year-old man had developed, 1 year before, severe hypertension needing four antihypertensive drugs. Moreover, 2 years before, another son was also incidentally diagnosed for PMBAH through an ampulloma cure. This 49-year-old man had no hypertension but osteoporosis treated for many years. Hormonal evaluation showed in all three patients: basal suppressed ACTH, no plasma cortisol suppression after 1-mg over-night dexamethasone suppression test and aberrant adrenal sensitivity in response to several ligands (all data will be shown on poster). The mother underwent surgical resection of the biliary duct tumor. Histopathology is compatible with a neuroendocrine tumor. Immunostainings and genetic testing are still in progress. PBMAH is often genetically determined and several genes have been identified, ARMC5 being the last one. Illegitimate receptor expression is observed in the majority of PBMAH. However, the associated-tumors phenotype exhibited by this family does not enter into the spectrum of the described malignancies predisposing syndromes (no hyperparathyroidism). Anyway, investigations are continued in the others children and grandchildren. This case illustrates the phenotype variability within one family with a rare genetic cause of Cushing's syndrome and highlights the importance of a complete clinical characterization to permit phenotype-genotype correlations for a better knowledge of this disease.

DNA double-strand breaks (DSBs) are considered as one of the primary causes of cancer but their induction by hydrogen peroxide (H2O2) is still controversial. In this work, we studied whether the high levels of H2O2 produced in the thyroid to oxidize iodide could induce DNA modifications. Scores of DNA damage, in terms of strand breaks, were obtained by comet assay (alkaline condition for single-strand breaks (SSBs) and neutral condition for DSBs). We demonstrated that in a rat thyroid cell line (PCCl3), non-lethal concentrations of H2O2 (0.1–0.5 mmol/l) as well as irradiation (1–10 Gy) provoked a large number of SSBs (∼2–3 times control DNA damage values) but also high levels of DSBs (1.2–2.3 times control DNA damage values). We confirmed the generation of DSBs in this cell line and also in human thyroid in primary culture and in pig thyroid slices by measuring phosphorylation of histone H2AX. l-Buthionine-sulfoximine, an agent that depletes cells of glutathione, decreased the threshold to observe H2O2-induced DNA damage. Moreover, we showed that DNA breaks induced by H2O2 were more slowly repaired than those induced by irradiation. In conclusion, H2O2 causes SSBs and DSBs in thyroid cells. DSBs are produced in amounts comparable with those observed after irradiation but with a slower repair. These data support the hypothesis that the generation of H2O2 in thyroid could also play a role in mutagenesis particularly in the case of antioxidant defense deficiency.

We studied gene expression profiles in two mouse models of human thyroid carcinoma: the Tg-RET/PTC3 (RP3) and Tg-E7 mice. RP3 fusion gene is the most frequent mutation found in the first wave post-Chernobyl papillary thyroid cancers (PTCs). E7 is an oncoprotein derived from the human papillomavirus 16 responsible for most cervical carcinoma in women. Both transgenic mice develop thyroid hyperplasia followed by solid differentiated carcinoma in older animals. To understand the different steps leading to carcinoma, we analyzed thyroid gene expression in both strains at different ages by microarray technology. Important biological processes were differentially regulated in the two tumor types. In E7 thyroids, cell cycle was the most up-regulated process, an observation consistent with the huge size of these tumors. In RP3 thyroids, contrary to E7 tumors, several human PTC characteristics were observed: overexpression of many immune-related genes, regulation of human PTC markers, up-regulation of EGF-like growth factors and significant regulation of angiogenesis and extracellular matrix remodeling-related genes. However, similarities were incomplete; they did not concern the overall gene expression and were not conserved in old animals. Therefore, RP3 tumors are partial and transient models of human PTC. They constitute a good model, especially in young animals, to study the respective role of the biological processes shared with human PTC and will allow testing drugs targeting these validated variables.

The aim of our work was to evaluate the number and final diagnosis of women with an elevation of total testosterone ≥ 1.6 ng/ml measured by direct RIA assay (normal range: 0.2–0.8 ng/ml). From the database of the lab (between 2004 and 2013), we analyzed data from 130 women. The distribution showed that over half patients had total testosterone 3 ng/ml, diagnosis were: unknown because of unavailable data (n = 3), men misclassified as women by data processing (n = 2), pregnancy with normal free testosterone index (n = 2), transgender patients (n = 2), androgen therapies in post-menopausal women (n = 3), congenital adrenal hyperplasia (n = 3), adrenocortical tumor (n = 1) and androgen insensitivity syndrome (n = 1). This last 24-year-old woman was initially referred for pelvic IRM because of suspicion of Mayer-Rokitansky-Kuster-Hauser syndrome. The patient had a normal female phenotype with breast development, no clinical signs of hyperandrogenism or virilization but primary amenorrhea. IRM showed absence of Mullerian structures (uterus, fallopian tubes) and presence of two gonads in the abdomen. Biology showed elevated total testosterone (8.4n = ng/ml) with normal SHBG conferring elevated free testosterone index, low oestradiol and normal LH and FSH. Karyotype analysis demonstrated a male chromosomal sex (46XY) confirming the diagnosis of complete androgen insensitivity. Finally, FISH analysis by using a SRY gene probe confirmed the presence of SRY gene on Y chromosome. In conclusion, a systematic analysis of the lab database was a tool to detect an external case for which both academic and multidisciplinary follow-up may be helpful.

In case of female hyperandrogenism, total testosterone assay is recommended as first-line test as it is, among androgens, the best predictor of tumour. A total testosterone above twice the upper normal value by direct assays requires exclusion of androgen producing tumour (virilizing ovarian/adrenal tumour). The aim of this work was to evaluate the number, the final diagnosis and the quality of care of women with an elevation of total testosterone ≥ 1.6 ng/ml measured by direct RIA assay (normal range :0.2–0.8 ng/ml). From the lab database (between 2004 and 2013), 130 women were identified. Testosterone measurement was asked by endocrinologists (25 %), gynaecologists (50%) and others (25%). In ascending order of total testosterone values, associated diagnosis were: hyperprolactinemia, unknown, PCOS, Cushing's disease, pregnancy, congenital adrenal hyperplasia, androgen therapies in post-menopausal women, men misclassified as women by data processing, transgender patients, adrenocortical tumour and androgen insensitivity syndrome. In our database, there was no virilizing ovarian tumour and only one case of adrenocortical tumour. The maximal total testosterone value was 3 ng/ml in PCOS group and 7 ng/ml in the adrenocortical tumour case. PCOS group concerns more than 30% of patients and corresponds probably to severe form of PCOS. In patients without diagnosis (∼ 20%), ovarian ultrasonography was performed in 50% of patients while adrenal imaging in only 15%. In conclusion, analyzing a hospital lab database is a way to create a registry of uncommon diseases. It permits also to assess and improve the quality of care in patients with rare disease or with lab values that require further assessment.

Hemophagocytic syndrome (HPS) is a clinical entity that combines non-specific clinical and biological features. The diagnosis is usually confirmed by a bone marrow examination. HPS may be primary or secondary to a malignancy or to an infectious or autoimmune disease. Since it was first described, various agents have been implicated, including viruses, bacteria, and parasites. In HIV patients, many cases occur with lymphoma or with a variety of opportunistic infections due to CMV, HHV8, Pneumocystis carinii, Mycobacterium tuberculosis, MAC, toxoplasmosis, and even pneumococcus. We report here a case of an AIDS patient presenting a HPS secondary to an extracerebral form of systemic toxoplasmosis that was only revealed by specific PCR in tissue other than the CNS.