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.

Pituitary apoplexy and rivaroxaban.

Pituitary apoplexy (PA), defined by the occurrence of a massive hemorrhagic necrotic rearrangement within a pituitary adenoma, is rare. Its occurrence can be associated with certain risk factors, including anticoagulation. We report the first case of PA with rivaroxaban which is one of the new oral anticoagulants: a 73 year-old patient presenting with severe headache and visual field deterioration. Surgery was performed. Radiotherapy treatment was decided three months after surgery because of tumor residue.

Glycaemic control of Type 1 diabetes in clinical practice early in the 21st century: an international comparison.

AIMS: Improving glycaemic control in people with Type 1 diabetes is known to reduce complications. Our aim was to compare glycaemic control among people with Type 1 diabetes using data gathered in regional or national registries. METHODS: Data were obtained for children and/or adults with Type 1 diabetes from the following countries (or regions): Western Australia, Austria, Denmark, England, Champagne-Ardenne (France), Germany, Epirus, Thessaly and Thessaloniki (Greece), Galway (Ireland), several Italian regions, Latvia, Rotterdam (The Netherlands), Otago (New Zealand), Norway, Northern Ireland, Scotland, Sweden, Volyn (Ukraine), USA and Wales) from population or clinic-based registries. The sample size with available data varied from 355 to 173 880. Proportions with HbA1c < 58 mmol/mol (< 7.5%) and ≥ 75 mmol/mol (≥ 9.0%) were compared by age and sex. RESULTS: Data were available for 324 501 people. The proportions with HbA1c 58 mmol/mol (< 7.5%) varied from 15.7% to 46.4% among 44 058 people aged < 15 years, from 8.9% to 49.5% among 50 766 people aged 15-24 years and from 20.5% to 53.6% among 229 677 people aged ≥ 25 years. Sex differences in glycaemic control were small. Proportions of people using insulin pumps varied between the 12 sources with data available. CONCLUSION: These results suggest that there are substantial variations in glycaemic control among people with Type 1 diabetes between the data sources and that there is room for improvement in all populations, especially in young adults.

Genome-wide paternal uniparental disomy as a cause of Beckwith-Wiedemann syndrome associated with recurrent virilizing adrenocortical tumors.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome characterized by fetal macrosomia, macroglossia, and abdominal wall defects. BWS patients are at risk to develop Wilms tumor, neuroblastoma, hepatoblastoma, and adrenal tumors. A young woman with BWS features, but with inconclusive genetic evidence for the disease, came to clinical observation for signs of virilization at the age of 16 years. An adrenocortical tumor was diagnosed and surgically resected. The tumor underwent 2 local relapses that were also surgically treated. The patient was also operated to remove a breast fibroadenoma. SNP arrays were used to analyze chromosome abnormalities in normal and tumor samples from the patient and her parents. The patient presented genome-wide mosaic paternal uniparental disomy (patUPD) both in the adrenocortical and the breast tumors, with different degrees of loss of heterozygosity (LOH). The more recent relapses of the adrenocortical tumor showed a loss of part of chromosome 17p that was absent in the first tumor. Analysis of a skin biopsy sample also showed mosaic patUPD with partial LOH, while no LOH was detected in leukocyte DNA. This case shows that virilizing adrenocortical tumors may be a clinical feature of patients with BWS. The SNP array technology is useful to diagnose genome-wide patUPD mosaicism in BWS patients with an inconclusive molecular diagnosis and underlines the tumorigenic potential of the absence of the maternal genome combined with an excess of the paternal genome.

A new prognostic clinicopathological classification of pituitary adenomas: a multicentric case-control study of 410 patients with 8 years post-operative follow-up.

Pituitary adenomas are currently classified by histological, immunocytochemical and numerous ultrastructural characteristics lacking unequivocal prognostic correlations. We investigated the prognostic value of a new clinicopathological classification with grades based on invasion and proliferation. This retrospective multicentric case-control study comprised 410 patients who had surgery for a pituitary tumour with long-term follow-up. Using pituitary magnetic resonance imaging for diagnosis of cavernous or sphenoid sinus invasion, immunocytochemistry, markers of the cell cycle (Ki-67, mitoses) and p53, tumours were classified according to size (micro, macro and giant), type (PRL, GH, FSH/LH, ACTH and TSH) and grade (grade 1a: non-invasive, 1b: non-invasive and proliferative, 2a: invasive, 2b: invasive and proliferative, and 3: metastatic). The association between patient status at 8-year follow-up and age, sex, and classification was evaluated by two multivariate analyses assessing disease- or recurrence/progression-free status. At 8 years after surgery, 195 patients were disease-free (controls) and 215 patients were not (cases). In 125 of the cases the tumours had recurred or progressed. Analyses of disease-free and recurrence/progression-free status revealed the significant prognostic value (p < 0.001; p < 0.05) of age, tumour type, and grade across all tumour types and for each tumour type. Invasive and proliferative tumours (grade 2b) had a poor prognosis with an increased probability of tumour persistence or progression of 25- or 12-fold, respectively, as compared to non-invasive tumours (grade 1a). This new, easy to use clinicopathological classification of pituitary endocrine tumours has demonstrated its prognostic worth by strongly predicting the probability of post-operative complete remission or tumour progression and so could help clinicians choose the best post-operative therapy.

Unilateral or bilateral adrenalectomy in PPNAD: six cases from a single family followed up over 40 years.

The most frequent endocrine Carney complex manifestation is a bilateral primary pigmented nodular adrenocortical disease and bilateral adrenalectomy (BA) is therefore its main treatment. In this study, a 40 years follow-up of six members of the same family with heterozygous PRKAR1A germline mutation, is reported over two generations. The first cases, two sisters with severe hyperandrogenism and Cushing syndrome (CS) diagnosed in 1972 at age 14 and 25, were successfully treated with unilateral adrenalectomy (UA). Their two brothers were then diagnosed, one with a CS-related severe osteoporosis treated with BA and the other with CS treated with UA. The second generation was diagnosed with CS signs at 7 and 21 years of age and were treated with BA and UA respectively. Out of the four patients treated with UA, the only event possibly related to CS was spontaneous episode of pulmonary embolism, 30 years after surgery. Hormonal evaluation revealed either eucortisolism in one patient or partial adrenal deficiency in two and mild hypercortisolism in one patient. For the two patients with BA, one of them accidentally died. The second one, surprisingly, recovered progressively normal cortisol secretion and circadian variation. Steroid substitution was stopped 6 years after her surgery and we demonstrated by iodocholesterol scintigraphy the presence of bilateral adrenal remnants. In conclusion, our results of long term evolution of PPNAD patients show that UA in this subset of patients could be considered to treat CS.

Dunnigan lipodystrophy syndrome: French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins).

Dunnigan syndrome, or Familial Partial Lipodystrophy type 2 (FPLD2; ORPHA 2348), is a rare autosomal dominant disorder due to pathogenic variants of the LMNA gene. The objective of the French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins), is to provide health professionals with a guide to optimal management and care of patients with FPLD2, based on a critical literature review and multidisciplinary expert consensus. The PNDS, written by members of the French National Reference Center for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), is available on the French Health Authority website (in French). Dunnigan syndrome is characterized by a partial atrophy of the subcutaneous adipose tissue and by an insulin resistance syndrome, associated with a risk of metabolic, cardiovascular and muscular complications. Its prevalence, assessed at 1/100.000 in Europe, is probably considerably underestimated. Thorough clinical examination is key to diagnosis. Biochemical testing frequently shows hyperinsulinemia, abnormal glucose tolerance and hypertriglyceridemia. Elevated hepatic transaminases (hepatic steatosis) and creatine phosphokinase, and hyperandrogenism in women, are common. Molecular analysis of the LMNA gene confirms diagnosis and allows for family investigations. Regular screening and multidisciplinary monitoring of the associated complications are necessary. Diabetes frequently develops from puberty onwards. Hypertriglyceridemia may lead to acute pancreatitis. Early atherosclerosis and cardiomyopathy should be monitored. In women, polycystic ovary syndrome is common. Overall, the management of patients with Dunnigan syndrome requires the collaboration of several health care providers. The attending physician, in conjunction with the national care network, will ensure that the patient receives optimal care through regular follow-up and screening. The various elements of this PNDS are described to provide such a support.

Surgery versus conservative care for Rathke's cleft cyst.

BACKGROUND: Rathke's cleft cysts are benign cystic lesions of the sellar region, which may cause headache, pituitary deficiencies and visual disturbances from mass effect. Their management is not standardized yet. This study is about establishing a consensus for medical care of RCC. MATERIAL AND METHODS: We performed a retrospective observational study of all patients that were diagnosed or followed for RCC between 2008 and 2018 (11 years), in the neurosurgical and the adult endocrine departments of our institution. The study's average time length of follow-up is 72.9 months (from 2 to 385 months). RESULTS: The 57 included patients were divided into 2 groups: group A, which included 39 patients that were conservatively managed and group B, which included 18 surgically treated patients. Group A showed either an improvement or a spontaneous resolution of headaches in 56.1% of the cases (P<0.01); a resolution of hyperprolactinemia in 70% of the cases (P=0.21); and of hypogonadism, ACTH deficiency, growth hormone deficiency in 100% of the cases. There was no spontaneous improvement of visual disturbances (P<0.01) or diabetes insipidus (P=0.29) during follow-up. Regarding group B, surgery allowed improvement or complete resolution of headaches in 60% of the cases; visual troubles in 100% of the cases (P<0.01); and hyperprolactinemia in 100% of the cases. Pituitary deficiencies were not improved by surgery. CONCLUSIONS: This study offers guidance in decision-making regarding the management of RCC patients. Surgery is particularly suitable for treating visual disturbances caused by RCC. Regular follow-up is more appropriate than surgery concerning headaches, hyperprolactinemia, endocrine disruptions and diabetes insipidus.

Practical implementation of automated closed-loop insulin delivery: A French position statement.

Automated closed-loop (CL) insulin therapy has come of age. This major technological advance is expected to significantly improve the quality of care for adults, adolescents and children with type 1 diabetes. To improve access to this innovation for both patients and healthcare professionals (HCPs), and to promote adherence to its requirements in terms of safety, regulations, ethics and practice, the French Diabetes Society (SFD) brought together a French Working Group of experts to discuss the current practical consensus. The result is the present statement describing the indications for CL therapy with emphasis on the idea that treatment expectations must be clearly defined in advance. Specifications for expert care centres in charge of initiating the treatment were also proposed. Great importance was also attached to the crucial place of high-quality training for patients and healthcare professionals. Long-term follow-up should collect not only metabolic and clinical results, but also indicators related to psychosocial and human factors. Overall, this national consensus statement aims to promote the introduction of marketed CL devices into standard clinical practice.

Discordant biological parameters of remission in acromegaly do not increase the risk of hypertension or diabetes: a study with the Liege Acromegaly Survey database.

PURPOSE: Acromegaly is a rare disease due to growth hormone (GH)-secreting pituitary adenoma. GH and IGF-1 levels are usually congruent, indicating either remission or active disease; however, a discrepancy between GH and IGF-1 may occur. We aimed to evaluate the outcome of diabetes mellitus (DM) and hypertension (HT) in acromegalic patients with congruent GH and/or IGF-1 levels vs. discordant biochemical parameters. METHODS: Retrospective analysis of the data of 3173 patients from the Liege Acromegaly Survey (LAS) allowed us to include 190 patients from 8 tertiary referral centers across Europe, treated by surgery, with available data concerning DM and HT both at diagnosis and at the last follow-up (LFU). We recorded the number of anti-HT and anti-DM drugs used at the first evaluation and at LFU for every patient. RESULTS: Ninety-nine patients belonged to the REM group (concordant parameters), 65 patients were considered as GHdis (high random GH/controlled IGF-1), and 26 patients were considered as IGF-1dis (high IGF-1/controlled random GH). At diagnosis, 72 patients (37.8%) had HT and 54 patients had DM (28.4%). There was no statistically significant difference in terms of the number of anti-HT and anti-DM drugs at diagnosis versus LFU (mean duration: 7.3 ± 4.5 years) between all three groups. CONCLUSION: The long-term outcome of DM and HT in acromegaly does not tend to be more severe in patients with biochemical discordance in comparison with patients considered as in remission on the basis of concordant biological parameters, suggesting that patients with biochemical discordance do not require a closer follow-up.

Fertility and obstetrical complications in women with LMNA-related familial partial lipodystrophy.

OBJECTIVE: Familial partial lipodystrophy due to LMNA (lamin A/C) mutations is a rare disorder characterized by a selective loss of adipose tissue and insulin resistance. Dyslipidemia and severe diabetes often occur during its evolution. Only isolated and contradictory case reports have been published on the obstetrical prognosis in lipodystrophy. The aim of our study was to compare the fertility and occurrence of obstetrical complications of women with familial partial lipodystrophy due to LMNA (lamin A/C) mutations with those of nonaffected relatives, women from the general population, and women with polycystic ovary syndrome (PCOS). MATERIAL AND METHODS: Data were obtained from clinical follow-up of seven families with patients exhibiting mutations in LMNA (five R482W, one R482Q, one R439C) (14 affected among 48 women). RESULTS: The mean number of live children per woman was 1.7 in affected patients vs. 2.8 in nonaffected relatives. Fifty-four percent of LMNA-mutated women exhibited a clinical phenotype of PCOS, 28% suffered from infertility, 50% experienced at least one miscarriage, 36% developed gestational diabetes, and 14% experienced eclampsia and fetal death. Mean blood leptin level was significantly lower in LMNA-mutated patients than in nonaffected relatives (5.0 +/- 3.8 ng/ml vs 14.3 +/- 3.6; P < 0.001) despite similar body mass index (21.0 +/- 4.2 vs 22.4 +/- 2.2; P = 0.49). CONCLUSION: In these LMNA-linked lipodystrophic patients, the prevalence of PCOS, infertility, and gestational diabetes was higher than in the general population. Moreover, the prevalence of gestational diabetes and miscarriages was higher in lipodystrophic LMNA-mutated women than previously reported in PCOS women with similar body mass index. Women with lipodystrophies due to LMNA mutations are at high risk of infertility, gestational diabetes, and obstetrical complications and require reinforced gynecological and obstetrical care.

[What's new in the couple thyroid and heart in 2008?]. / Quoi de neuf dans le couple thyroïde et coeur en 2008 ?

Beginning in development and extending to adult physiology, a close relationship exists between the thyroid gland and the heart. They migrate together during ontogeny and possess common factors of transcriptions. Among them, Nkx2-5 whose mutations were recently described in patients with congenital hypothyroidism. The genomic impact of triiodothyronine (T3) on cardiac tissue allows the activation of synthesis of proteins belonging to the contractile device. The progress realized in the understanding of the mechanisms of cardiac remodelling strengthens the links between both organs : for example the recent discovery of interactions between some microARNs, activated in case of heart failure and the thyroid hormone receptor. There are numerous parallels between hypothyroidism and heart failure. The low- T3 syndrome are the single most significant predictor of cardiovascular and all-cause mortality in adults with heart disease and the treatment by T3 in these circumstances could allow improvement in cardiac function.

Prolactinoma and estrogens: pregnancy, contraception and hormonal replacement therapy.

The stimulatory role of estrogen on prolactin secretion and on proliferation of lactotropic cells is well established in terms of physiology but could this phenomenon be extended to include harmful effects of estrogens on prolactinoma? The aim of this review is to provide an up-to-date assessment of this subject with regard to pregnancy, use of contraceptive pills and postmenopausal hormone replacement therapy. Dopamine agonists allow women presenting prolactinoma to recover their ovulation cycles and become pregnant. There is no adverse data concerning the safety of dopamine agonists such as bromocriptine, if the woman is treated during the first trimester of pregnancy but there is little information regarding the most recent treatments such as cabergoline or quinagolide. In women with microadenomas, pregnancy generally has little impact on their adenoma, delivery is normal and breast-feeding is allowed. Concerning macroprolactinomas, tumor progression during pregnancy is possible and endocrine follow-up remains necessary. Contraceptive pills containing estrogen and progestins are currently the best-tolerated and the most effective contraception. This type of contraceptive has long been avoided in patients presenting prolactinoma. While the literature has little to say on this subject and provides no adverse information, professional experience suggests that this attitude should be amended and that women presenting microprolactinoma should be allowed to use current contraceptive pills (containing 30 microg or less of ethinyl estradiol). The most important problem to overcome with this type of prescription, which masks the clinical consequences of hyperprolactinemia, is the possibility of overlooking hypophyseal disease that could result from this approach. The problem of macroprolactinoma is different; the possibility of prescribing contraceptive pills must be evaluated on a case-by-case basis and the impact of the drug on the adenoma must be very closely monitored. Estrogen replacement therapy in patients presenting hypogonadism should be attempted in patients with a history of prolactinoma and standard-monitoring precautions should be taken. In menopausal women, when replacement therapy is desirable, the presence of a microprolactinoma should not by itself avoid this prescription.

[A Multiple endocrine neoplasia type-1 observatory in a French-speaking area. A tool from the Endocrine Tumor study Group (GTE)]. / Observatoire francophone des néoplasies endocriniennes multiples de type 1. Un outil du Groupe d'étude des Tumeurs Endocrines (GTE).

Wermer's syndrome or Multiple Endocrine Neoplasia Type-1 (MEN1) is an autosomal dominant inherited disease, related to mutations in MEN1, an approximately 10-kb gene encoding menin, localized on chromosome 11q13. The Endocrine Tumor Group (GTE) has set up a MEN1 observatory of 1001 regularly followed MEN1 cases. This observatory aims at registering and evaluating MEN1 cases in a large cohort. Any new study on a particular unexplored aspect of the disease may be proposed by a physician to the GTE. This article describes the way to diagnose a new MEN1 case and to register it. Procedures for participating in a new study are presented. Some original results are quoted.

A multivariable prediction model for pegvisomant dosing: monotherapy and in combination with long-acting somatostatin analogues.

BACKGROUND: Effective treatment of acromegaly with pegvisomant (PEGV), a growth hormone receptor antagonist, requires an appropriate dose titration. PEGV doses vary widely among individual patients, and various covariates may affect its dosing and pharmacokinetics. OBJECTIVE: To identify predictors of the PEGV dose required to normalize insulin-like growth factor I (IGF-I) levels during PEGV monotherapy and in combination with long-acting somatostatin analogues (LA-SSAs). DESIGN: Two retrospective cohorts (Rotterdam + Liège Acromegaly Survey (LAS), total n = 188) were meta-analyzed as a form of external replication to study the predictors of PEGV dosing in addition to LA-SSA, the LAS (n = 83) was used to study the predictors of PEGV monotherapy dosing. Multivariable regression models were used to identify predictors of the PEGV dose required to normalize IGF-I levels. RESULTS: For PEGV dosing in combination with LA-SSA, IGF-I levels, weight, height and age, were associated with the PEGV normalization dosage (P ≤ 0.001, P ≤ 0.001, P = 0.028 and P = 0.047 respectively). Taken together, these characteristics predicted the PEGV normalization dose correctly in 63.3% of all patients within a range of ±60 mg/week (21.3% within a range of ±20 mg/week). For monotherapy, only weight was associated with the PEGV normalization dose (P ≤ 0.001) and predicted this dosage correctly in 77.1% of all patients within a range of ±60 mg/week (31.3% within a range of ±20 mg/week). CONCLUSION: In this study, we show that IGF-I levels, weight, height and age can contribute to define the optimal PEGV dose to normalize IGF-I levels in addition to LA-SSA. For PEGV monotherapy, only the patient's weight was associated with the IGF-I normalization PEGV dosage.

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.

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.

[How to interprete hypercalcitoninemia?]. / Comment interpréter une hypercalcitoninémie?

PURPOSE: Today, calcitonin assay is used for the diagnosis of thyroid medullary cancer in the context of nodular thyroid disease. Calcitonin is an excellent marker of thyroid medullary cancer but some hypercalcitoninemia can also be related to other diseases, such as renal failure, endocrine tumors other than thyroid medullary cancer and sometimes to C cell hyperplasia, which is a not well-defined situation. Recent studies contributed to define calcitoninemia thresholds, which guide decision and avoid excessive invasive treatment. CURRENT KNOWLEDGE AND KEY POINTS: After a brief reminder of physiological role of calcitonin and assays, the difficulties encountered in interpreting hypercalcitoninemia and its potential causes other than thyroid medullary cancer are addressed. Recent studies, on large series, now allow a better knowledge of specificity and sensitivity of calcitonin measurement in patients with nodular thyroid disease and a well-argued management. FUTURE PROSPECTS AND PROJECTS: In the future, calcitonin dosage will be ordered even more frequently, as some authors recommend it for the diagnosis of thyroid nodule. It is up to us to know how to use this remarkable marker, by considering all possible situations of benign hypercalcitoninemia and reserving aggressive treatments for patients who really need them.

[Traumatic brain injury and pituitary insufficiency]. / Traumatisme crânien et insuffisance hypophysaire.

Until recently, hypopituitarism was not considered as a potential consequence of traumatic brain injury (TBI) since only few case reports were described. However, since 2000, preliminary studies have underlined such an association. Hypopituitarism may occur during the acute phase of TBI, months after or even many years later. Among the multiple deficiencies, GH deficiency appears to be the most frequently observed. However multiple bias are described in such studies, especially the small number of patients analyzed and the diagnosis relying on baseline values. Most recently, some studies analyzed 50 to 100 patients confirming that up to 50% of patients may be affected by such an association and underlined the necessity to propose a prospective evaluation since the evolution of hypopituitarism is highly variable during follow-up. It also appears necessary to describe this association to allow when necessary to secondarily propose hormonal substitutive treatment which might be discussed in such a context.

[Impact of systemic disease on the pituitary gland]. / Répercussions hypophysaires des maladies systémiques.

Systemic diseases located in hypothalamo-pituitary region can slowly induce pituitary deficiency, diabetes insipidus and morphological abnormalities. The aim of this study is to review recent clinical data about diagnosis of these rare diseases, with a focus on granulomatous diseases: histiocytosis and sarcoidosis. Recent clinical studies on histiocytosis have improved our knowledge about endocrine expression of the disease in children and in adults as well. Diabetes insipidus is the most frequent condition, described mainly in children. GH deficiency is the most frequent pituitary deficit in children and adult patients. During neurosarcoidosis, diabetes insipidus is the most frequent condition and gonadotropic deficiency is the most frequent deficit but GH has not been systematically studied. MRI allows visualisation of some lesions and is very useful to follow the disease course. Diagnosis of these diseases is made by clinical evaluation of all the sites and by pathological analysis of biopsies of peripheral lesions. While pituitary hormone replacement therapy does not seem to raise specific problems in these diseases, etiological treatments are not yet available and indications for antimitotic or immunomodulatory treatment are sometimes discussed.