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Germ-line mutations in the rearranged during transfection ( RET ) proto-oncogene are associated with thyroid cancer. These investigators studied presymptomatic patients 20 years of age or younger who had known RET mutations and had undergone prophylactic thyroidectomy. A significant age-related progression from C-cell hyperplasia to medullary thyroid carcinoma and to nodal metastasis was found in subgroups with certain mutations. Guidelines for the timing of thyroidectomy. Point mutations in the rearranged during transfection ( RET ) proto-oncogene 1 have emerged as the molecular basis of an array of distinct clinical phenotypes 2 , 3 as diverse as Hirschsprung's disease (aganglionosis of the submucosal and myenteric plexus of the colon), familial medullary thyroid carcinoma, and multiple endocrine neoplasia (MEN) type 2A (MEN-2A, characterized by medullary thyroid carcinoma, pheochromocytoma, and parathyroid adenoma) and type 2B (MEN-2B, characterized by medullary thyroid carcinoma, pheochromocytoma, intestinal ganglioneuromatosis, and skeletal deformity). 4 Encoding a receptor tyrosine kinase on chromosome 10q11.2, RET germ-line mutations in humans affect essentially four types of tissue, all of which originate from . . .

The prevention of medullary thyroid cancer in patients with multiple endocrine neoplasia type 2 syndrome has demonstrated the ability of molecular diagnosis and prophylactic surgery to improve patient outcomes. However, the other major neoplasia associated with multiple endocrine neoplasia type 2, phaeochromocytoma, is not as well characterised in terms of occurrence and treatment outcomes. In this study, we aimed to systematically characterise the outcomes of management of phaeochromocytoma associated with multiple endocrine neoplasia type 2. This multinational observational retrospective population-based study compiled data on patients with multiple endocrine neoplasia type 2 from 30 academic medical centres across Europe, the Americas, and Asia. Patients were included if they were carriers of germline pathogenic mutations of the RET gene, or were first-degree relatives with histologically proven medullary thyroid cancer and phaeochromocytoma. We gathered clinical information about patients'RET genotype, type of treatment for phaeochromocytoma (ie, unilateral or bilateral operations as adrenalectomy or adrenal-sparing surgery, and as open or endoscopic operations), and postoperative outcomes (adrenal function, malignancy, and death). The type of surgery was decided by each investigator and the timing of surgery was patient driven. The primary aim of our analysis was to compare disease-free survival after either adrenal-sparing surgery or adrenalectomy. 1210 patients with multiple endocrine neoplasia type 2 were included in our database, 563 of whom had phaeochromocytoma. Treatment was adrenalectomy in 438 (79%) of 552 operated patients, and adrenal-sparing surgery in 114 (21%). Phaeochromocytoma recurrence occurred in four (3%) of 153 of the operated glands after adrenal-sparing surgery after 6–13 years, compared with 11 (2%) of 717 glands operated by adrenalectomy (p=0·57). Postoperative adrenal insufficiency or steroid dependency developed in 292 (86%) of 339 patients with bilateral phaeochromocytoma who underwent surgery. However, 47 (57%) of 82 patients with bilateral phaeochromocytoma who underwent adrenal-sparing surgery did not become steroid dependent. The treatment of multiple endocrine neoplasia type 2-related phaeochromocytoma continues to rely on adrenalectomies with their associated Addisonian-like complications and consequent lifelong dependency on steroids. Adrenal-sparing surgery, a highly successful treatment option in experienced centres, should be the surgical approach of choice to reduce these complications. European Union, German Cancer Foundation, Arthur Blank Foundation, Italian Government, Charles University, Czech Ministry of Health, Nanjing Military Command, National Science Centre Poland, National Research Council for Scientific and Technological Development, and State of São Paulo Research Foundation.

Cushing’s disease, or pituitary ACTH dependent Cushing’s syndrome, is a rare disease responsible for increased morbidity and mortality. Signs and symptoms of hypercortisolism are usually non specific: obesity, signs of protein wasting, increased blood pressure, variable levels of hirsutism. Diagnosis is frequently difficult, and requires a strict algorithm. First-line treatment is based on transsphenoidal surgery, which cures 80% of ACTH-secreting microadenomas. The rate of remission is lower in macroadenomas. Other therapeutic modalities including anticortisolic drugs, radiation techniques or bilateral adrenalectomy will thus be necessary to avoid long-term risks (metabolic syndrome, osteoporosis, cardiovascular disease) of hypercortisolism. This review summarizes potential pathophysiological mechanisms, diagnostic approaches, and therapies.

Background Familial hyperparathyroidism, especially Multiple Endocrine Neoplasia Type 1, is more likely to present with primary hyperparathyroidism (1° HPT) at a young age, mandating bilateral exploration of the parathyroid glands. However, the majority of young patients will not be gene carriers or have a family history. Recent evidence suggests that young adults under 40, in whom there is no suspicion of family history, can be managed with the same pre- and perioperative strategy as used for sporadic primary HPT of any age. Our aim was to evaluate the prevalence of mutations in the MEN1 gene in young adults under 40 who present with apparent sporadic 1° HPT. Methods A retrospective review was undertaken of all patients who underwent surgery for 1° HPT between 1993 and 2004. From a total of 1253 patients, 87 (6.2%) were under the age of 40. Thirty-three patients provided informed consent to a detailed personal and family history, physical examination, and genetic analysis of the MEN1 gene. Twelve patients were subsequently excluded as they were known gene carriers prior to surgery (10 MEN1 and 2 MEN2A patients). Twenty-one patients underwent genetic analysis. Results Of the 21 patients who consented to genetic analysis, the mean age was 30.8 years (range = 18–39 years with 43% younger than 30). These patients had no suspicious family or personal histories suggestive of a MEN phenotype. Fifteen patients presented with symptomatic hypercalcemia. All 21 patients underwent parathyroid surgery by conventional cervicotomy (12) or endoscopic parathyroidectomy in cases (9) where the parathyroid gland was localized preoperatively. Nineteen patients (91%) had uniglandular disease. Surgical cure was achieved in all patients. Of the 21 patients, only one patient (4.7%) was found to have a MEN1 gene mutation (exon 3, at codon 190, c;680_681delGGinsC). This patient was found to have double adenomas at surgery with subsequent histological confirmation. The overall prevalence of MEN1 mutation in all patients under 40 was 13%. Conclusion Although young age is often the only criterion to suspect MEN1, our results do not support routine MEN1 analysis in patients under 40. We propose that these patients be managed with the same preoperative and surgical approach as those presenting with sporadic 1° HPT of any age.

Mifepristone is the first and only available glucocorticoid receptor antagonist. It was initially mainly considered as a so-called ‘contragestive’ pill due to its antiprogestin activity. In this review, we summarize the results of mifepristone reported in the literature as a treatment of Cushing’s syndrome. Most of the patients were treated due to unsuccessful surgery and/or partially effective anticortisolic drugs. The majority of them presented a rapid decrease of clinical signs of hypercortisolism during the first month of treatment; about half experienced a reduction in their elevated blood pressure, and half of the diabetic patients presented improved blood glucose levels. Mifepristone treatment has 2 main drawbacks: (1) the blockade of glucocorticoid receptors leads to increased ACTH and cortisol levels, making it difficult to adapt the treatment and diagnose adrenal deficiency, and (2) increased cortisol levels can also lead to severe hypokalemia. Follow-up of efficacy should only be clinical (weight, blood pressure, skin lesions) and biological (regular blood potassium sampling). Dose adjustment will be performed based on these parameters. The lack of a large available prospective cohort of patients on mifepristone, and the scarcity of data on its long-term effects, does not allow recommending it as a first-line drug in the treatment of hypercortisolism. However, as mifepristone is a rapidly effective drug, it can play a role in the management of hypercortisolism. The main indication is the partial efficacy or bad tolerance of other well-known anticortisolic drugs, either by replacement (bad tolerance, lack of effectiveness) or addition (multimodal approach) of mifepristone.

Sporadic medullary thyroid carcinoma (SMTC) is usually diagnosed at a clinical stage often associated with lymph node involvement. Hence surgical treatment does not result in definitive cure in many patients. Studies have demonstrated that routine measurement of serum basal calcitonin (CT) in patients with nodular thyroid disease allows preoperative, early diagnosis of unsuspected SMTC. The aim of this work was to assess the results of surgery in patients operated on for subclinical SMTC detected preoperatively by measurement of serum CT. Results were compared with those obtained in patients with SMTCs diagnosed at a clinical stage and operated on during the same period. During a 4‐year period (1993–1996) 24 SMTCs were diagnosed and treated in our department. They were diagnosed at a clinical stage in 13 patients (group 1): palpable thyroid tumor (n= 11), palpable metastatic lymph node (n= 6), distant metastases (n= 4). In nine cases the diagnosis was made by both fine‐needle aspiration cytology and serum CT measurement. In the four other cases the initial cytology was incorrect, but the diagnosis was revised on the basis of elevated basal CT values. In 11 patients (group 2) presenting with nodular thyroid disease, SMTC was not clinically detectable. SMTC was preoperatively suspected by elevated CT levels: basal CT > 10 pg/ml and pentagastrin‐stimulated CT peak > 100 pg/ml. One patient in group 1 with distant metastases was not operated on. All of the other 12 patients underwent total thyroidectomy and extensive lymph node dissection. The mean size of the tumors was 27 mm. Lymph node involvement was found in nine patients. After surgery, CT levels returned to normal in five patients but remained elevated in five others; the two remaining patients died of distant metastases. All 11 patients in group 2 underwent total thyroidectomy and central neck dissection. None of the 11 patients had nodal extension. All 11 patients are biochemically cured. It was concluded that routine measurement of basal serum CT in those with nodular thyroid disease allows early, preoperative diagnosis of subclinical SMTC and improves the results of surgery.