[Neuroendocrine neoplasms : a new era to the top of multidisciplinarity !] / Néoplasies neuroendocrines : une nouvelle ère a l'apogée de la multidisciplinarité !

Neuroendocrine neoplasms are histologically defined by a common neuroendocrine cellular phenotype. These are still considered as rare tumours even though their incidence is increasing. Heterogeneity is everywhere whether in the localization of the primitive cancer, the clinical presentation, the histological classification, the prognosis, as well as in therapeutic options, which clearly justifies specialized multidisciplinary care. Heterogeneity and scarcity explain the still fragmented nature of knowledge in this domain. Thanks to an increase in incidence, a desire for standardization of classification as well as the arrival of major therapeutic advances, such as vectorized internal radiotherapy, the future of neuroendocrine neoplasia seems more than promising and exciting. In our daily clinical practice at CHU Liège, we hope to bring our stone to the building by listing as many cases as possible in national and/or international databases, by centralizing therapeutic discussions within specific multidisciplinary concertations and by participating in multicenter study protocols.

Les néoplasies neuroendocrines sont définies histologiquement par un phénotype cellulaire neuroendocrine commun. Ces néoplasies sont toujours considérées comme des tumeurs rares, bien que leur incidence soit en constante augmentation. L'hétérogénéité est omniprésente, que ce soit dans la localisation du cancer primitif, la présentation clinique, la classification histologique, le pronostic ainsi que dans les diverses options thérapeutiques, justifiant impérativement une prise en charge pluridisciplinaire spécialisée. Cette hétérogénéité et cette rareté expliquent que les connaissances soient parcellaires. Grâce à une majoration d'incidence, une volonté d'uniformisation de classification ainsi que l'arrivée d'avancées thérapeutiques majeures, telles que la radiothérapie interne vectorisée, l'avenir des néoplasies neuroendocrines semble plus que prometteur et palpitant. En pratique clinique quotidienne au CHU de Liège, nous espérons apporter notre pierre à l'édifice en recensant un maximum de cas dans des bases de données nationales et/ou internationales, en centralisant les discussions thérapeutiques au sein de concertations multidisciplinaires dédiées et en participant à des protocoles d'études cliniques multicentriques.

[Chronic autoimmune gastritis : a multidisciplinary management]. / La gastrite chronique auto-immune : une prise en charge multidisciplinaire.

Chronic autoimmune gastritis (CAG) is a continuum of histological changes in gastric mucosa including: atrophy, intestinal metaplasia, dysplasia and finally, the occurrence of a neoplasm (gastric Neuroendocrine Tumors -NETs- and adenocarcinoma). The association with Hashimoto and Graves-Basedow disease is known as the thyrogastric autoimmune syndrome. While Helicobacter pylori (Hp) infection may be associated with CAG, the role of the gastric microbiota is ill-defined. The gastric hypochlorhydria determines a malabsorption of different micronutrients (iron, magnesium, calcium, vitamin B12) as well as drugs (thyroxine, etc.). Pernicious anemia is favoured by the deficit of parietal intrinsic factor that contributes to B12 malabsorption. Serology for Hp, serum pepsinogen I/II, increased gastrin levels, the presence of parietal cell antibodies and intrinsic factor antibodies may reveal CAG. High definition endoscopy associated with virtual chromoendoscopy seems promising for CAG diagnosis and follow-up. NETs type 1 treatment includes: endoscopic and surgical resection, somatostatin analogues and the recent availability of netazepide, a gastrin antagonist. We review herein advances in the treatment and diagnosis of CAG and associated autoimmune disorders, which may involve, in a multidisciplinary way, all practitioners.

La gastrite chronique auto-immune (GAI) est un continuum d'altérations de la muqueuse gastrique incluant : atrophie, métaplasie intestinale, dysplasie et, enfin, la survenue d'une néoplasie (tumeurs neuroendocrines [NETs] gastriques et adénocarcinome). L'association avec la maladie de Hashimoto et de Graves-Basedow est connue comme syndrome thyrogastrique auto-immun. Alors que l'Helicobacter pylori (Hp) peut s'associer avec la GAI, le rôle du microbiote gastrique est mal défini. L'hypochlorhydrie gastrique détermine une malabsorption de micronutriments (fer, magnésium, calcium, vitamine B12) et de médicaments (thyroxine et autres). L'anémie de Biermer est favorisée par le déficit de production du facteur intrinsèque pariétal, contribuant à la malabsorption de B12. Un rapport diminué de pepsinogène I/II, une augmentation de la gastrine, la présence d'anticorps anti-cellule pariétale, les anticorps anti-facteur intrinsèque et la sérologie pour Hp contribuent à révéler précocement le diagnostic de GAI. L'endoscopie haute définition, associée à la chromoendoscopie virtuelle, semble prometteuse dans le diagnostic et dans le suivi. Le traitement des NETs gastriques de type 1, favorisées par la GAI, inclut : la résection endoscopique/chirurgicale, les analogues de la somatostatine et l'antagoniste de la gastrine nétazépide. Nous résumons ici les avancées diagnostiques et thérapeutiques dans la GAI et dans les affections associées : elles impliquent, de façon multidisciplinaire, l'ensemble des praticiens.

Histologically Proven Bronchial Neuroendocrine Tumors in MEN1: A GTE 51-Case Cohort Study.

OBJECTIVE: To evaluate the natural history of MEN1-related bronchial endocrine tumors (br-NETs) and to determine their histological characteristics, survival and causes of death. br-NETs frequency ranges from 3 to 13% and may reach 32% depending on the number of patients evaluated and on the criteria required for diagnosis. METHODS: The 1023-patient series of symptomatic MEN1 patients followed up in a median of 48.7 [35.5-59.6] years by the Groupe d'étude des Tumeurs Endocrines was analyzed using time-to-event techniques. RESULTS: br-NETs were found in 51 patients (4.8%, [95% CI 3.6-6.2%]) and were discovered by imaging in 86% of cases (CT scan, Octreoscan, Chest X-ray, MRI). Median age at diagnosis was 45 years [28-66]. Histological examination showed 27 (53%) typical carcinoids (TC), 16 (31%) atypical carcinoids (AC), 2 (4%) large cell neuroendocrine carcinomas (LCNEC), 3(6%) small cell neuroendocrine carcinomas (SCLC), 3(6%) TC associated with AC. Overall survival was not different from the rest of the cohort (HR 0.29, [95% CI 0.02-5.14]). AC tended to have a worse prognosis than TC (p = 0.08). Seven deaths were directly related to br-NETs (three AC, three SCLC and one LCNEC). Patients who underwent surgery survived longer (p = 10-4) and were metastasis free, while 8 of 14 non-operated patients were metastatic. There were no operative deaths. CONCLUSIONS: Around 5% of MEN1 patients develop br-NETs. br-NETs do not decrease overall survival in MEN1 patients, but poorly differentiated and aggressive br-NETs can cause death. br-NETs must be screened carefully. A biopsy is essential to operate on patients in time.

Distribution of adipose tissue: quantification and relationship with hepatic steatosis and vascular profiles of type 2 diabetic patients with metabolic syndrome.

AIM: As the distribution of fat is increasingly related to cardiovascular events, we examined whether or not abdominal-fat quantification using magnetic resonance imaging (MRI) software is reliable, and whether or not it is related to clinical markers of fat distribution as well as to metabolic and vascular status. METHODS: We recorded the anthropometric measurements of 34 obese type 2 diabetic patients with metabolic syndrome. The patients were enrolled to evaluate their abdominal (visceral and subcutaneous) adipose tissue by single-slice L3-L4 MRI. Manual and automated analyses were compared. The relationships between anthropometric measurements, biological markers and intima-media thickness of the common carotid artery were also assessed. RESULTS: We validated the automated software to quantify abdominal-fat deposition with MRI compared with manual measurements (r2=0.95). The waist-to-hip-circumference ratio (WHR) was the only clinical parameter that correlated with the proportion and quantity of visceral and subcutaneous abdominal-adipose tissue evaluated by MRI (r=0.60). In addition, fat repartition as evaluated by WHR was related to hepatic steatosis parameters (ferritin and ALAT) and to intima-media thickness, whereas simple waist circumference was not a determinant in these obese patients. We also showed that the adiponectin-to-leptin ratio was related to adipose tissue distribution. CONCLUSION: Distribution of abdominal fat, as evaluated by MRI, can be reflected by clinical determination of the WHR. Differences in regional accumulations of abdominal fat may be specifically related to variations in the risks of steatosis and vascular rigidity among obese type 2 diabetic patients.

Exploration and management of adrenal incidentalomas. French Society of Endocrinology Consensus.

The French Society of Endocrinology convened a multidisciplinary panel of endocrinologists, radiologists, nuclear physicians and surgeons to address the appropriate evaluation and treatment of adrenal incidentalomas. The panel conducted a systematic review of medical literature on the following issues: epidemiology, natural history, radiological and scintigraphic evaluation, endocrine assessment, surgical management and appropriate follow-up. The following text reports the recommendations of experts on behalf of the French Society of Endocrinology. The authors emphasize the paucity of published scientific data that hampers evidence-based medicine recommendations. The crucial points of the French consensus are: the usefulness of CT-scanning evaluation of adrenal incidentalomas, the systematic screening for pheochromocytoma, the usefulness of the 1mg overnight dexamethasone test to screen for latent hypercortisolism, the difficulty to interpret mild biological abnormalities of the HPA axis, the consensus to remove surgically most of tumours greater than 4cm, the necessity to follow clinically glucorticoid tissular targets in the follow-up of non operated benign adrenocortical incidentalomas.

[Transoral resection of thyroid cancer metastasis to retropharyngeal lymph node]. / Abord transoral d'une adénopathie rétropharyngée métastatique d'un carcinome thyroïdien papillaire.

OBJECTIVES: Retropharyngeal lymph node metastasis from papillary thyroid carcinoma is uncommon. Traditional extirpative procedures include cervical, cervical-parotid, and transmandibular approaches. The authors report the case of a patient with a retropharyngeal node metastasis originating from papillary carcinoma of the thyroid gland that was successfully removed by a transoral approach. METHOD: A 49-year-old man presented for removal of a retropharyngeal lymph node metastasis measuring 21 mm x 27 mm from papillary thyroid carcinoma. Surgical excision was performed through a transoral approach using a surgical navigation system to assess the location of the node precisely. RESULT: The postoperative course was uneventful with return to a normal diet on the first postoperative day and hospital discharge on the second postoperative day. Three months after surgery, TSH-stimulated thyroglobulin was undetectable. CONCLUSION: The transoral approach to retropharyngeal space is a reliable procedure with low morbidity compared to other approaches. The limited surgical access provided by this approach should limit its use to removal of well-circumscribed lesions not invading adjacent structures.

Relevance of Ki-67 and prognostic factors for recurrence/progression of gonadotropic adenomas after first surgery.

OBJECTIVE: Gonadotropin-secreting pituitary adenomas carry a high risk of local recurrence or progression (R/P) of remnant tumor after first surgery. The clinical characteristics and the long-term outcome of these silent adenomas, which show no signs of endocrine hyperfunction, differ from those of other types of pituitary adenomas. However, to date, no study has focused specifically on gonadotropic adenomas. MATERIALS AND METHODS: To identify prognostic factors of R/P of remnants, we studied the postoperative outcome of 32 gonadotropic pituitary adenomas, defined on immunohistochemical staining, according to their clinical and radiological characteristics as well as the Ki-67 labeling index (LI). RESULTS: The Ki-67 LI failed to provide independent information for the identification of patients at risk of progression of remnants or recurrence. Multivariate survival analysis (Cox regression) showed that neither invasiveness nor remnant tumors nor hyposomatotropism influenced tumor recurrence. The strongest predicting factors of R/P were the antero-posterior (AP) diameter in the sagittal plane (P = 0.014), and the age of the patient at surgery (P = 0.047), with younger patients being at greater risk. Hazard ratios were 2.11 for each 5 mm increase in AP diameter and 0.57 for every 10 years of age. CONCLUSION: The two simple clinical criteria revealed by our study, the AP diameter of the tumor and the age of the patient, should be helpful in planning clinical management and radiological monitoring after first surgery of gonadotropic adenomas, while awaiting the identification of other pathological parameters.

Comparison of different methods to assess body composition of weight loss in obese and diabetic patients.

Estimating body composition is important to understand the metabolic and cardiovascular effects of adiposity. Estimating changes in body compartments arising from weight loss strategies is equally important to evaluate their benefits and risks, particularly in frail populations (elderly or diabetic), and following bariatric surgery. Body compartments were evaluated in 50 obese subjects (25 diabetic, 25 non-diabetic) before and after a 7 kg weight loss obtained after 6 months of calorie restriction and orlistat. Fat and fat-free mass (FFM) were estimated by bioelectrical impedance analysis (BIA), dual X-ray absorptiometry (DXA), plethysmography (BodPod) and a combination of these in a 3- or 4-compartment model, the latter being considered the reference method. FFM hydration was the ratio of total body water (BIA) to FFM. FFM hydration was significantly higher than classical values (75.9+/-3.0%, P<0.0001), and decreased with weight loss (74.2+/-3.3%). Compared to the 4-compartment, the 3-compartment model gave the most accurate fat and FFM estimation. A significant bias was observed with DXA, BodPod or BIA. Compartment changes induced by weight loss were accurately evaluated by DXA, being particularly precise in the 3-compartment analysis. No effect of diabetes per se was observed. A 3- or 4-compartmental analysis is necessary to accurately estimate body composition and its changes during weight loss.

Endocrine function in a 48,XXYY adult with type 2 diabetes: case report with a review of the literature.

We present the clinical, biological, endocrinal and psychological characteristics of a 48,XXYY adult. The 43-year-old male examined is the first reported case of this XY polysomy concomitant with type 2 diabetes. Endocrine investigations suggested dysfunction of Leydig and Sertoli cells whereas the pituitary function appeared normal. We compare the phenotypic, behavioral and pathological features of the syndrome in our patient with other reports in the literature.

Cabergoline for Cushing's disease: a large retrospective multicenter study.

OBJECTIVE: The efficacy of cabergoline in Cushing's disease (CD) is controversial. The aim of this study was to assess the efficacy and tolerability of cabergoline in a large contemporary cohort of patients with CD. DESIGN: We conducted a retrospective multicenter study from thirteen French and Belgian university hospitals. METHODS: Sixty-two patients with CD received cabergoline monotherapy or add-on therapy. Symptom score, biological markers of hypercortisolism and adverse effects were recorded. RESULTS: Twenty-one (40%) of 53 patients who received cabergoline monotherapy had normal urinary free cortisol (UFC) values within 12 months (complete responders), and five of these patients developed corticotropic insufficiency. The fall in UFC was associated with significant reductions in midnight cortisol and plasma ACTH, and with clinical improvement. Compared to other patients, complete responders had similar median baseline UFC (2.0 vs 2.5xULN) and plasma prolactin concentrations but received lower doses of cabergoline (1.5 vs 3.5 mg/week, P < 0.05). During long-term treatment (>12 months), cabergoline was withdrawn in 28% of complete responders because of treatment escape or intolerance. Overall, sustained control of hypercortisolism was obtained in 23% of patients for 32.5 months (19-105). Nine patients on steroidogenesis inhibitors received cabergoline add-on therapy for 19 months (1-240). Hypercortisolism was controlled in 56% of these patients during the first year of treatment with cabergoline at 1.0 mg/week (0.5-3.5). CONCLUSIONS: About 20-25% of CD patients are good responders to cabergoline therapy allowing long-term control of hypercortisolism at relatively low dosages and with acceptable tolerability. No single parameter, including the baseline UFC and prolactin levels, predicted the response to cabergoline.

Reproductive outcome of women with 21-hydroxylase-deficient nonclassic adrenal hyperplasia.

CONTEXT: Because many women with 21-hydroxylase (21-OH)-deficient nonclassic adrenal hyperplasia (NCAH) carry at least one allele affected by a severe mutation of CYP21, they are at risk for giving birth to infants with classic adrenal hyperplasia (CAH). OBJECTIVE: Our objective was to determine the frequency of CAH and NCAH infants born to mothers with 21-OH-deficient NCAH. DESIGN AND SETTING: We conducted an international multicenter retrospective/prospective study. PATIENTS AND METHODS: The outcome of 203 pregnancies among 101 women with 21-OH-deficient NCAH was reviewed. The diagnosis of 21-OH-deficient NCAH was established by a basal or post-ACTH-stimulation 17-hydroxyprogesterone level of more than 10 ng/ml (30.3 nmol/liter). When possible, genotype analyses were performed to confirm CAH or NCAH in the offspring. RESULTS: Of the 203 pregnancies, 138 (68%) occurred before the mother's diagnosis of NCAH and 65 (32%) after the diagnosis. Spontaneous miscarriages occurred in 35 of 138 pregnancies (25.4%) before the maternal diagnosis of NCAH, and in only four of 65 pregnancies (6.2%) after the diagnosis (P < 0.002). Four (2.5%; 95% confidence interval, 0.7-6.2%) of the 162 live births were diagnosed with CAH. To date, 24 (14.8%; 95% confidence interval, 9.0-20.6%) children, 13 girls and 11 boys, have been diagnosed with NCAH. The distribution of NCAH children and their mothers varied significantly by ethnicity (P < 0.0001, for both). CONCLUSIONS: The risk of a mother with 21-OH-deficient NCAH for giving birth to a child affected with CAH is 2.5%; at least 14.8% of children born to these mothers have NCAH.

Clinical characterization of familial isolated pituitary adenomas.

CONTEXT: Familial pituitary adenomas occur rarely in the absence of multiple endocrine neoplasia type 1 (MEN1) and Carney complex (CNC). OBJECTIVE: Our objective was to characterize the clinical and genealogical features of non-MEN1/CNC familial isolated pituitary adenomas (FIPA). DESIGN AND SETTING: We conducted a retrospective study of clinical and genealogical characteristics of FIPA cases and performed a comparison with a sporadic population at 22 university hospitals in Belgium, Italy, France, and The Netherlands. RESULTS: Sixty-four FIPA families including 138 affected individuals were identified [55 prolactinomas, 47 somatotropinomas, 28 nonsecreting adenomas (NS), and eight ACTH-secreting tumors]. Cases were MEN1/PRKAR1A-mutation negative. First-degree relationships predominated (75.6%) among affected individuals. A single tumor phenotype occurred in 30 families (homogeneous), and heterogeneous phenotypes occurred in 34 families. FIPA cases were younger at diagnosis than sporadic cases (P = 0.015); tumors were diagnosed earlier in the first vs. the second generation of multigenerational families. Macroadenomas were more frequent in heterogeneous vs. homogeneous FIPA families (P = 0.036). Prolactinomas from heterogeneous families were larger and had more frequent suprasellar extension (P = 0.004) than sporadic cases. Somatotropinomas occurred as isolated familial somatotropinoma cases and within heterogeneous FIPA families; isolated familial somatotropinoma cases represented 18% of FIPA cases and were younger at diagnosis than patients with sporadic somatotropinomas. Familial NS cases were younger at diagnosis (P = 0.03) and had more frequently invasive tumors (P = 0.024) than sporadic cases. CONCLUSIONS: Homogeneous and heterogeneous expression of prolactinomas, somatotropinomas, NS, and Cushing's disease can occur within families in the absence of MEN1/CNC. FIPA and sporadic cases have differing clinical characteristics. FIPA may represent a novel endocrine neoplasia classification that requires further genetic characterization.

[Use of cabergoline in persisting Cushing's disease]. / Utilisation de la cabergoline dans la maladie de Cushing non contrôlée.

Cabergoline is a dopaminergic agonist with demonstrated efficiency of for the treatment of prolactin-secreting pituitary tumors. It has also been reported effective for patients with hypercortisolism uncontrolled by conventional therapies. We describe the use of cabergoline in three patients with Cushing's disease, one of them presenting a silent ACTH-secreting pituitary tumor. Those patients underwent surgery and only one has been treated with radiation therapy. However persisting hypercortisolism motivated the use of cabergoline. We describe a decrease or a normalization in hypercortisolism; for one of the subjects, tumor growth seemed to be stopped. While cabergoline can induce a suppression of cortisol secretion or a corticotroph tumor shrinkage, the sites of action remain unclear.

Octreotide (long-acting release formulation) treatment in patients with graves' orbitopathy: clinical results of a four-month, randomized, placebo-controlled, double-blind study.

There are few effective, safe modalities for the management of Graves' ophthalmopathy (GO), a cell-mediated immune comorbidity of thyroid disease. Somatostatin analogs inhibit lymphocyte proliferation and activation, and accumulate in the orbital tissue of patients with GO. A double-blind, placebo-controlled study of a long-acting somatostatin analog [16 wk of long-acting release formulation of octreotide (octreotide-LAR)] was conducted in 51 patients with mild active GO with the aim of preventing deterioration and precluding the need for more aggressive therapeutic modalities, such as glucocorticoids or radiotherapy. No treatment effect was observed for the primary end point (a composite parameter defining the outcome as either success or failure on the basis of changes in class/grade of the severity index and Clinical Activity Scale of GO). The Clinical Activity Scale score was reduced for patients treated with octreotide-LAR, but without any significant difference with respect to patients receiving placebo. However, octreotide-LAR significantly reduced proptosis (as measured by exophthalmometry). This was associated with nonsignificant differences in favor of octreotide-LAR in a series of proptosis-related parameters: class III grade, opening of the upper eyelid, the difference in ocular pressure between primary position and upgaze, and extraocular muscle involvement. By magnetic resonance imaging evaluation the extraocular muscle volumes appeared reduced, but nonsignificantly. No significant correlation between the initial uptake of the somatostatin analog indium-labeled and the response to treatment was observed. One patient in the octreotide-LAR group developed gallstones. In this study, octreotide-LAR did not seem suitable to mitigate activity in mild GO. Surprisingly, it significantly reduced proptosis, one of the most debilitating symptoms of GO. Additional studies are warranted to define the benefit to risk ratio of the somatostatin analogs in this indication.

Telematic transmission of computerized blood glucose profiles for IDDM patients.

OBJECTIVE: To improve the analysis of self-monitoring of blood glucose (SMBG) and its communication between patients and physicians by a telematic transmission of computerized SMBG and to study the consequences of its use on glucose control of insulin-dependent diabetic (IDDM) patients. RESEARCH DESIGN AND METHODS: A prospective randomized crossover trial with two 3-mo periods, one with SMBG recorded on traditional booklets (booklet period) and another with computerized SMBG transmitted to a central data base through a telematic network (telematic period), comprised the study. During the latter phase, patients could receive computerized SMBG analysis on individual terminals connected to the telephone network (Minitel system). Blood glucose recordings and HbA1c were measured at inclusion and end of each period. Eleven pairs of IDDM patients on intensified insulin therapy were randomized within each pair to start with the telematic period (group A) or the booklet period (group B). RESULTS: Telematic transmissions were successful (less than 1% failure rate). Although initial HbA1c was low (6.7%), it declined during the telematic period (delta = -0.41%) compared with the booklet period (delta = +0.37%, P = 0.05). The percentage of low (less than 3.3 mM) blood glucose values correlated with HbA1c changes during the telematic period (r = 0.714, P = 0.0014) but not the booklet period. The patients favored the telematic tool to analyze SMBG. CONCLUSIONS: Telematic transmission of SMBG is feasible. It can improve SMBG analysis and perhaps glucose control, therefore offering a new way of communication between diabetic patients and their physicians.

[Thyroid cancers: from epidemiology to molecular biology]. / Les cancers de la thyroïde: de l'épidémiologie à la biologie moléculaire.

Experts increasingly recognize the hypothesis of "over-diagnosis" as the main factor of the raising incidence of thyroid cancers (TC). The detection of multiple microtumors, mainly of a papillary type, at a sub-clinical stage, with the use of sensitive detection methods supports this hypothesis. However, the intensive management and monitoring of these cancers failed to reduce mortality. Environmental and other risk factors cannot provide a sufficient explanation, as previously thought. In this context, the use of improved tools is needed, and the most promising perspective lies in molecular biology applied to thyroid cancer for diagnosis, evaluation of prognosis and treatment. The next generation sequencing (NGS) has demonstrated its diagnostic performances in recent clinical trials. Its interest in cases with indeterminate cytology is demonstrated and should help better targeting surgical indications. Its promising prognostic and therapeutic applications must be confirmed by additional studies. The integration of NGS in current practice should have a real medical, economic and scientific impact. Indeed, the exponential increase in our knowledge of molecular mechanisms of thyroid tumorigenesis strengthens the will to "reclassify" these cancers into molecular rather than histological subtypes, in order to offer patients more specific and targeted treatment.

Unraveling the intrafamilial correlations and heritability of tumor types in MEN1: a Groupe d'étude des Tumeurs Endocrines study.

BACKGROUND: MEN1, which is secondary to the mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Most studies demonstrated the absence of direct genotype-phenotype correlations. The existence of a higher risk of death in the Groupe d'étude des Tumeurs Endocrines-cohort associated with a mutation in the JunD interacting domain suggests heterogeneity across families in disease expressivity. This study aims to assess the existence of modifying genetic factors by estimating the intrafamilial correlations and heritability of the six main tumor types in MEN1. METHODS: The study included 797 patients from 265 kindred and studied seven phenotypic criteria: parathyroid and pancreatic neuroendocrine tumors (NETs) and pituitary, adrenal, bronchial, and thymic (thNET) tumors and the presence of metastasis. Intrafamilial correlations and heritability estimates were calculated from family tree data using specific validated statistical analysis software. RESULTS: Intrafamilial correlations were significant and decreased along parental degrees distance for pituitary, adrenal and thNETs. The heritability of these three tumor types was consistently strong and significant with 64% (s.e.m.=0.13; P<0.001) for pituitary tumor, 65% (s.e.m.=0.21; P<0.001) for adrenal tumors, and 97% (s.e.m.=0.41; P=0.006) for thNETs. CONCLUSION: The present study shows the existence of modifying genetic factors for thymus, adrenal, and pituitary MEN1 tumor types. The identification of at-risk subgroups of individuals within cohorts is the first step toward personalization of care. Next generation sequencing on this subset of tumors will help identify the molecular basis of MEN1 variable genetic expressivity.

Trabecular bone microarchitecture, bone mineral density, and vertebral fractures in male osteoporosis.

Some studies have indicated that the risk of fragility fractures in men increases as bone mineral levels decrease, but there is an overlap in the bone mineral density (BMD) measurements between patients with or without fractures. Furthermore, it has been suggested that the biomechanical competence of trabecular bone is dependent not only on the absolute amount of bone present but also on the trabecular microarchitecture. In the present study, 108 men (mean age 52.1 years) with lumbar osteopenia (T score < -2.5) were recruited to examine the relationships between BMD, architectural changes in trabecular bone, and the presence of vertebral fractures. Lumbar BMD was assessed from L2 to L4 in the anteroposterior view with dual-energy X-ray absorptiometry. At the upper left femur, hip BMD was measured at the transcervical site. Spinal X-ray films were analyzed independently by two trained investigators, and vertebral fracture was defined as a reduction of at least 20% in the anterior, middle, or posterior vertebral height. Transiliac bone biopsy specimens were obtained for all patients. Histomorphometric studies were performed on an image analyzer, and the following parameters were determined: trabecular bone volume (BV/TV), trabecular thickness (Tb.Th), number (Tb.N), and separation (Tb.Sp), interconnectivity index (ICI), characterization of the trabecular network (node count and strut analysis), and star volume of the marrow spaces. Spinal radiographs evidenced at least one vertebral crush fracture in 62 patients (group II) and none in 46 patients (group I). After adjusting for age, body mass index, and BMD, there were no significant differences between the two groups in BV/TV, Tb.Th, or star volume. In contrast, the mean values of ICI, free end-to-free end struts (FF/TSL), and Tb.Sp were significantly higher, whereas Tb.N and node-to-node struts (NN/TSL) were lower in patients with at least one vertebral fracture. Logistic regression analysis showed that only ICI, FF/TSL, NN/TSL, and Tb.N were significant predictors of the presence of vertebral fracture: odds ratios for an alteration of 1 SD ranged from 1.7 (1.0-3.2) for NN/TSL to 3.2 (1.1-10.1) for ICI. Patients with at least three vertebral fractures (n = 23) were categorized as "multiple fractures." The results of logistic regression showed that spine BMD, BV/TV, and all architectural parameters were significant predictors of multiple vertebral fractures: odds ratios for an alteration of 1 SD ranged from 2.2 (1.1-4.6) for star volume to 3.7 (1.4-9.7) for ICI. These results strongly suggest that bone trabecular microarchitecture is a major and independent determinant of vertebral fractures in middle-aged men with osteopenia.

Presence of renin, angiotensinogen, and converting enzyme in human pituitary lactotroph cells and prolactin adenomas.

Renin, angiotensinogen, and converting enzyme were detected in 10 normal human pituitary glands by immunohistochemical techniques. Renin was stained by polyclonal and monoclonal antibodies directed against human renin, and an antibody directed against the renin prosegment revealed the presence of prorenin. Immunoreactive angiotensinogen and angiotensin I-converting enzyme were found in the same cells as renin. Using serial sections and double immunohistochemical labeling with a PRL antiserum, all of the proteins of the renin-angiotensin system appeared to be localized within the lactotroph cells, and no component of the renin system was detected in any of the other pituitary cells. Renin, angiotensinogen, and angiotensin I-converting enzyme also were found in 6 PRL-secreting adenomas as well as in a mixed PRL/GH-secreting adenoma. The renin content of a PRL adenoma was about 1/100th that of a normal kidney. Renin activity could be blocked by an anticatalytic human renin antibody. No renin, angioten-sinogen, or angiotensin I-converting enzyme was found in 6 GH-secreting adenomas, 1 corticotroph adenoma, or 10 nonsecreting pituitary adenomas. The colocalization of proteins of the renin-angiotensin system suggests production of angiotensin II within the lactotroph cells and favors the hypothesis of a paracrine action of this peptide.

A case of male pseudohermaphroditism due to 17 alpha-hydroxylase deficiency and hormonal profiles in the nuclear family.

A genetic male with 17 alpha-hydroxylase deficiency is described. The patient, raised as a female, was seen at 17 yr of age for impuberism. She presented all the features of the classical severe form of the disease: complete female phenotype; hypertension; hypokalemia; elevated levels of plasma progesterone, 11-deoxycorticosterone, corticosterone (B), and ACTH; and suppression of renin and aldosterone production. Levels of 17-hydroxyprogesterone, 17-hydroxypregnenolone, and all androgens were barely detectable. Hormone steroid patterns were determined in basal conditions and after acute ACTH stimulation in the parents and the two unaffected brothers in order to identify the heterozygotes. Subtle abnormalities in B and aldosterone secretion were observed in the male members of the family. On the basis of an increased ratio of B to aldosterone the two brothers were assumed to be heterozygotes. The mother had normal basal and stimulated levels of B, deoxycorticosterone, and aldosterone. In the parents and two brothers the progesterone responses to ACTH were exaggerated. The most striking finding in the father and both brothers was the observation of increased basal plasma 17-hydroxyprogesterone, unresponsive to ACTH stimulation, suggesting a partial Leydig cell 17,20-lyase deficiency in the male heterozygotes of this family. This study shows that a short ACTH test can help to identify the heterozygotes in affected families, but the abnormalities found are more heterogeneous than previously suggested.