Germline mutations in the thyrotropin receptor gene cause non-autoimmune autosomal dominant hyperthyroidism.

The thyrotropin receptor (TSHR), a member of the large family of G protein-coupled receptors, controls both the function and growth of thyroid cells via stimulation of adenylyl cyclase. We report two different mutations in the TSHR gene of affected members of two large pedigrees with non-autoimmune autosomal dominant hyperthyroidism (toxic thyroid hyperplasia), that involve residues in the third (Val509Ala) and seventh (Cys672Tyr) transmembrane segments. When expressed by transfection in COS-7 cells, the mutated receptors display a higher constitutive activation of adenylyl cyclase than wild type. This new disease entity is the germline counterpart of hyperfunctioning thyroid adenomas, in which different somatic mutations with similar functional characteristics have been demonstrated.

Feminizing adreno-cortical carcinomas in male adults. A dire prognosis. Three cases in a series of 801 adrenalectomies and review of the literature.

UNLABELLED: We describe the clinical presentation, biochemical features, diagnostic criteria, clinical course and differential diagnosis in three cases of feminizing adreno-cortical carcinoma (FACC) with a review of the literature. PATIENTS: From 1970 throughout December 2003 among a series of 801 adrenalectomies, three had been performed for FACC. RESULTS: Age at presentation was 74, 63 and 23 years. Estradiol hypersecretion was observed in 3/3 patients, 17 OH progesterone was elevated in 2/3 patients and both of them had a diminution of testosterone, delta 4 androstenedione was elevated in 1/3 patients. Imaging studies suggested malignancy in 3/3 patients by the presence of necrosis, heterogeneity, calcifications, size of the tumor and compression of adjacent organs. All patients were stage III at presentation and had a Weiss score >or=6. Size and weight of the tumors were 30, 20, 15cm and 3750, 480 and 275g respectively. All 3 patients received mitotane and cortisone post-operatively and at follow up (7, 3 and 2 years) all 3 died of the disease. CONCLUSIONS: Feminizing adreno-cortical carcinomas in adults are exceedingly rare (1-2% of adreno-cortical carcinomas). Tumors are huge and even after surgery for cure their prognosis is worse than for other varieties of adreno-cortical carcinomas either secreting or non secreting. Early diagnosis and treatment may improve overall prognosis.

Association of myelodysplastic syndrome and relapsing polychondritis: further evidence.

We report five patients with both a myelodysplastic syndrome (MDS) and relapsing polychondritis (RP), that represented 0.6% of all MDS and 28% of all RP diagnosed over a period of 14 years. Ten other cases had previously been reported (four in detail), supporting a non-fortuitous association between the two disorders, already suggested for MDS and some other immunological disorders.

Long term treatment with the somatostatin analog SMS 201-995 in a patient with a thyrotropin- and growth hormone-secreting pituitary adenoma.

A patient with a mixed pituitary tumor secreting TSH and GH was treated, starting 3 months after partial adenomectomy, with the somatostatin analog SMS 201-995 for 8 months. Somatostatin itself inhibited TSH, GH, and alpha-subunit release by the tumor both in vivo and in vitro. Long term treatment with twice daily sc injections of SMS 201-995 resulted in decreased TSH secretion and lower serum thyroid hormone levels. However, euthyroidism was achieved only when the patient was treated with three daily 200-micrograms injections of SMS 201-995. After 30 weeks of SMS 201-995 therapy, TSH secretion increased, while GH secretion remained suppressed. After withdrawal for 6 months, SMS 201-995 (100 micrograms, sc, twice daily) again completely inhibited TSH secretion. SMS 201-995 did not alter the volume of the residual adenomatous tissue. We conclude that SMS 201-995 may be a valuable therapeutic agent for the management of patients with a thyrotroph adenoma. However, desensitization may occur during long term treatment.

Pseudohypoparathyroidism Ia and hypercalcitoninemia.

Pseudohypoparathyroidism Ia (PHP Ia) is characterized by resistance to PTH and many other stimuli because of deficiency of stimulatory G protein alpha-subunit. To determine the incidence, natural history, and mechanism of C cell dysfunction in PHP, calcitonin assays were performed in six patients with PHP Ia and four with pseudopseudohypoparathyroidism from three unrelated families. Controls included healthy subjects and patients with PHP Ib or hypoparathyroidism. The mean basal level of calcitonin was higher in PHP Ia patients than in controls (95.3 +/- 112.7 vs. 3.7 +/- 2.4 pg/mL; P = 0.005; n < 10). In PHP Ia patients, calcitonin levels rose over the normal range (30 pg/mL) after pentagastrin infusion in five patients and remained normal in one. Familial medullary thyroid carcinoma was clinically, biologically, and ultrasonographically ruled out over a mean follow-up exceeding 3 yr. Genomic screening for RET protooncogene mutations failed to reveal any anomaly. The calcitonin infusion test, which induced a significant increase in plasma cAMP in controls 30 and 60 min after infusion, failed to produce this response in PHP Ia patients, suggesting that the action of calcitonin was specifically impaired. PHP Ia may therefore be an independent etiology of hypercalcitoninemia and hyperresponsiveness to pentagastrin infusion.

Dopamine-secreting pheochromocytoma: an unrecognized entity? Classification of pheochromocytomas according to their type of secretion.

A pheochromocytoma that exclusively secretes dopamine (DA) rather than predominantly DA among a blend of catecholamines is as yet unreported. Of the 50 patients with pheochromocytoma who have undergone surgery, 32 underwent treatment within the last 5 years (when DA assay has been available). One half of these patients (15/32) exhibited DA secretion either in mixed catecholamines (12 patients) or exclusively (three patients). All three patients with exclusive DA-secreting tumors were normotensive. Without hypertension, the clinical investigation was a diagnostic challenge (unexplained cough or flank mass with inflammatory features). All three tumors were malignant and two were ectopic. Five of the 12 patients with mixed catecholamine-secreting tumors whose secretions included DA were hypertensive. Five other patients had flank mass and one had an unexplained cough. Tumors were rather large, and three of the tumors with mixed secretion were ectopic. Of the 12 patients, seven had tumors that were judged to be malignant. Three patients exhibited a dramatic decrease in blood pressure under alpha-blockade, which was not used in subsequent cases. Predominant or exclusive secretion of DA would explain the lack of hypertension due to its antiadrenergic action that inhibits the vasoconstrictive effects of other amines. Hypertension in patients with pheochromocytoma might depend on the ratio of DA/noradrenaline + adrenaline.

Essential hypertension: first reason for persistent hypertension after unilateral adrenalectomy for primary aldosteronism?

BACKGROUND: Despite cure of primary aldosteronism by surgical resection, hypertension persists postoperatively in 30% to 50% of patients. The aim of this study was to determine factors influencing long-term outcome of blood pressure after unilateral adrenalectomy for primary aldosteronism. METHODS: Records of 100 patients who underwent unilateral adrenalectomy for primary aldosteronism from 1970 through 1997 were reviewed. Patients were distributed in 2 groups according to whether blood pressure was normal (criteria of World Health Organization). Clinical, biochemical, and pathologic data were compared. RESULTS: All patients were biochemically cured. Blood pressure was normal in 56 patients and improved in 44 (mean follow-up, 69 and 59 months). Persistent hypertension correlated with age, known duration and seriousness of preoperative hypertension, family history of hypertension, no preoperative response to spironolactone, and contralateral adrenal hypertrophy. Gender, surgical approach, and pathologic findings were not predictive factors of blood pressure outcome. The prevalence of hypertension was almost the same in these postoperative patients as the prevalence of essential hypertension in a random population of the same age. CONCLUSIONS: Early unilateral adrenalectomy allows cure or improvement of hypertension in all patients with primary aldosteronism induced by unilateral excessive source of aldosterone secretion regardless of the pathologic findings. Persistent hypertension suggests that coexisting essential hypertension is present.

[Clinical manifestations and therapeutic approach in neurosarcoidosis]. / Manifestations cliniques et approche thérapeutique de la neurosarcoïdose: 40 cas.

Neurological impairment is a frequent cause of morbidity and mortality in patients with sarcoidosis. The aim of this study was to evaluate the clinical manifestations of the disease, the response to corticosteroids and alternative treatments. During a 5 year period, diagnosis of neurosarcoidosis was performed in 40 patients. We retrospectively analyzed clinical, laboratory data and response to treatments. Mean age was 41.3 years (range 17-72). Mean time of follow-up was 46 months. Neurologic signs were the first symptom in 50 p. 100 of cases and an isolated manifestation in 12.5 p. 100. Central nervous system impairment was seen in 60.7 p. 100, meningitis in 27 p. 100. Other clinical manifestations were cranial nerve palsies (27 p. 100), peripheral neuropathy (33 p. 100), myopathy (16 p. 100). Eighty percent of the patients were treated by corticosteroids. Because of a lack of efficacy 40 p. 100 of patient required alternative treatment (including methotrexate, cyclophosphamide, azathioprin, cyclosporin). Complete recovery was observed in only 27.5 p. 100 of cases confirming the severity of neurosarcoidosis. Forty percent of patients were clinically stable and 10 p. 100 worsened. No patient died. This study confirms that intensive initial treatment is often necessary to prevent irreversible lesions. Alternative treatment should be rapidly initiated in resistant forms.

[Alpha-methyl-paratyrosine in the treatment of malignant pheochromocytoma]. / L'alpha-méthyl-paratyrosine dans le traitement des phéochromocytomes malins.

Alpha-methyl-paratyrosine (Demser) is a specific inhibitor of tyrosine hydroxylation to dopa. It is administered orally and may be given in combination with symptomatic treatments to reduce the hypersecretion of catecholamines. We report two cases of malignant phaeochromocytoma in which this drug was used. A pharmacological study of the compound is presented, and the literature on its long-term use in the treatment of malignant phaeochromocytoma is reviewed. In our second patient, who received alpha-methyl-paratyrosine for 9 months, a study of changes in differential catecholamine excretion showed that the urinary catecholamines were redistributed, with an increase in the dopamine/norepinephrine ratio. An HPLC study of urinary excretion of catecholamines demonstrated that their levels cannot be significantly increased by excretion of alpha-methyl-paratyrosine or its metabolites.

[Postpartum thyroiditis. 31 cases]. / Les thyroïdites du post-partum. 31 cas.

Postpartum thyroiditis. 31 cases. Between 1977 and 1986, 29 women consulted in three internal medicine and endocrinology departments for clinical disorders which could be ascribed to 31 episodes of thyroiditis developed within 9 months of giving birth. Thyroiditis was diagnosed clinically on the basis of acute diffuse (11 cases) or nodular (7 cases) goitre formation, signs of dysthyroidism (16 cases) revealed by menstrual disturbances and/or galactorrhoea (11 cases). A thyrotoxic episode was observed in 9 patients; it was either without sequelae (5 cases) of followed by transient hypothyroidism (4 cases). In other patients transient hypothyroidism was observed in 11 cases and permanent hypothyroidism in 5 cases. Six patients showed no sign of dysthyroidism, and the diagnosis was made by immunological, cytological and/or histological examination of the thyroid gland. Circulating anti-thyroid antibodies were present in two-thirds of the patients. The results of radioisotope scanning varied according to the stage of the disease. In these patients, only the absence of goitre was predictive, in 4 out of 5 cases, of subsequent permanent hypothyroidism; in all other patients the prognosis was highly favourable, even without specific treatment.

[Thyroid dysfunctions related to amiodarone. Prospective survey with 116 patients]. / Dysfonctions thyroïdiennes liées à l'amiodarone. Enquête prospective chez 116 sujets.

Thyroid hormones, TSH and antithyroid antibodies were prospectively controlled in 116 patients treated with amiodarone. Hypothyroidism occurred in 4 patients (3.7%) mainly early (average = 6 months). Hyperthyroidism was seen among 13 patients (11.9%) and its prevalence was proportional to therapy duration.

[Initial manifestations and late diagnosis in chronic atrophic polychondritis: apropos of a series of 15 patients]. / Manifestations révélatrices et retard diagnostique dans la polychondrite chronique atrophiante: à propos d'une série de 15 malades.

An auricular or nasal chondritis or a saddle nose deformity are the initial manifestation in half of cases of relapsing polychondritis; the other initial manifestations are various and less evocative; polyarthritis, laryngo-tracheal symptoms, episcleritis which delay the diagnosis. From 15 cases of relapsing polychondritis, the diagnosis time from the first symptom are studied; this one is long, about 3 years and 6 months (from 3 months to 17 years) in 13/15 of the cases even if the first manifestation is typical (external chondritis). In two cases only, the diagnosis was established after the first attack. This late of diagnosis had socioeconomical impact and exposed to severe complications like tracheal chondritis.

[Screening of multiple endocrine neoplasias type 1. Reflexions of the Study Group on Multiple Endocrine Neoplasias type 1]. / Dépistage des néoplasies endocriniennes multiples de type 1 (NEM 1). Réflexion du Groupe d'Etude des Néoplasies Endocriniennes Multiples de type 1 (GENEM 1).

The "Groupe d'Etude des Néoplasies Endocriniennes Multiples de type 1 (GENEM 1)" is a French group involved in a comprehensive multicentre study of Multiple Endocrine Neoplasia type 1 syndrome (NEM 1). The objectives of this group are to define diagnostic and therapeutic protocols and to carry out genetic research on NEM1. The first aim of physicians is to recognize the syndrome and to determine the appropriate screening especially into two circumstances: 1 degree In case of isolated and sporadic glandular disease -i-e-parathyroid glands, endocrine pancreas, antehypophysis, adrenal glands and neuroendocrine tumors? 2 degrees In case of very high probability of NEM 1 syndrome? This paper answers these two questions, based on the analysis of the first 150 cases collected by the GENEM 1.

[Hypertension in the elderly. Comparison of the efficacy and tolerability of labetalol and nifedipine. A multicenter, randomized, single-blind study]. / HTA du sujet âgé. Comparaison de l'efficacité et de la tolérance du labétalol et de la nifédipine. Etude multicentrique, randomisée, en simple insu.

This randomized multicentre study in elderly hypertensives with two unbalanced groups (2 patients under labetalol for 1 patient under nifedipine) compared the efficacy and safety of labetalol, whose dosage could be adjusted (1, 2, then 3 tablets/day) according to blood pressure level (BP greater than or equal to 160/95 mmHg), to that of nifedipine given at its recommended dosage (2 tablets/day). The treatment period lasted 6 weeks (D42). The main judgment criteria was the rate of patients with normalized BP under treatment (SBP less than 160 and DBP less than 95 mmHg). The analysis was carried out on 170 patients, 112 labetalol and 58 nifedipine. Both groups were homogeneous when entering into the study. The only difference was a higher rate of smokers in the nifedipine group compared with labetalol's (29% vs 13%). The rate of patients with normalized BP (SBP less than 160 and DBP less than 95 mmHg) were 66% in the labetalol group and 48% in the nifedipine's (p less than 0.05). Treatment withdrawals for all causes during the study were more frequent in the nifedipine group (19%) than in the labetalol's (6%). Treatment withdrawals for adverse events occurred in 3.5% of patients in the labetalol group and in 12% of the nifedipine's. The overall adverse events rate was 9% with labetalol and 29% with nifedipine (p less than 0.001). In this comparative study in elderly hypertensives, labetalol given in a dose titration schedule proved significantly superior to nifedipine, given at recommended maximal dosage, in terms of both BP control and side effects profile.(ABSTRACT TRUNCATED AT 250 WORDS)

[Phaeochromocytoma with hypokalaemia (two cases) (author's transl)]. / Phéochromocytome avec hypokaliémie. A propos de deux observations.

Two cases of phaeochromocytoma with hypokalaemia are reported. In the first, a carcinoma, hypokalaemia was potentially secondary to hyperreninaemia and hyperaldosteronism in association with probably paraneoplastic hypercorticism. The other was benign and the origin of isotopically demonstrated potassium deficiency was less clear, because hyperreninaemia, hyperaldosteronism and hypercortisolism were moderate.

Resistance to thyroid hormone in a family with no TRbeta gene anomaly: pathogenic hypotheses.

UNLABELLED: Syndromes of resistance to thyroid hormone (RTH) are almost always linked to a defective triiodothyronine-receptor B gene (TRB). Only six families with RTH exhibiting a normal TRB gene have been reported so far. We report another and discuss possible mechanisms. PATIENTS AND METHODS: We studied a kindred expressing a typical RTH phenotype. DNA was amplified and the TRB gene was sequenced. Linkage analysis assessed linkage between the TRB gene and RTH phenotype. RESULTS: Direct sequencing of the TRB gene failed to identify any anomaly in the coding exons. Linkage analysis demonstrated that the RTH phenotype was not linked to the TRB gene in this family. CONCLUSION: TRB1 and TRB2 genes were not defective in this family. Multiple mechanisms might account for this situation at the pre-receptor, receptor and post-receptor levels. The most likely hypothesis is the involvement of an abnormal nuclear cofactor serving a specific function in the regulation of thyroid hormone action.

[Loco-regional persistence and recurrences of operated differentiated thyroid cancers. 22 cases on 589 treated patients from 1964 to 1990, follow-up from 5 to 31 years]. / Persistance et récidives loco-régionales des cancers thyroïdiens différenciés opérés. 22 cas sur 589 patients traités de 1964 à 1990, suivis de 5 à 31 ans.

AIM OF THE STUDY: Evaluation of frequency and outcome of loco-regional persistance and recurrences of differentiated thyroid carcinomas after surgery. MATERIAL AND METHODS: from 1964 to December 1990, we operated and followed up more than 5 years (from 5 to 31 years): 589 thyroid cancers (309 papillary, 262 follicullar et 18 Hürthle cells); 145 patients were lost to follow-up (24%), 33% of them were microcarcinomas. Surgery consisted ultimately in 411 total thyroidectomies, 51 sub-total thyroidectomies, 113 lobectomies with isthmusectomies, 9 isthmusectomies or tumorectomies and 4 tracheotomies. Neck dissection was not routinely performed but rather selectively (n = 137). All Patients were put under suppressive hormone therapy. After total thyroidectomy, ablative 131 iodine was almost routinely done. All patients have been controlled by clinical examination, radio-iodine scanning and, since 1983, by sequential thyroglobulin assays. We have analysed the course of patients according to L. J. Degroot's staging (Stage I: Patient with intrathyroidal disease. Stage II: Patient with cervical node involvement. Stage III: Patient with extra-thyroidal neck invasive disease. Stage IV: Distant metastasis). RESULTS: Stage I, n = 383, Stage II, n = 96. Total = 479. Local recurrences in the bed of total thyroidectomy were exceptional: n = 2/323 (0.6%). Recurrences in the thyroid remnant after non total thyroidectomy were rare: n = 3/156 (2%). Cervical nodal recurrences were also rare: n = 7/479 (1.5%). Stage III (n = 73): 34/306 papillary, 9/78, well differentiated follicular, 25/175 poorly differentiated follicular. 2/9 follicular of other type and 3/18 hurtle cell. In 67 patients, the loco-regional sterilization was achieved, 5 of which were reoperated for nodal cervical metastasis. 6 patients died from continuing loco-regional disease and 10 presented distant metastases. 4 of which died from. Among opered patients are still alive (52/73 = 71,2%) no loco-regional recurrence persisted. CONCLUSION: The true problem is not recurrence but the persistance after surgery in stage III patients, despite the application of 1131. The determining factor of the persistance and recurrence is the initial stage of the carninomatous disease at the time of treatment.

[Apoptosis and the thyroid: the Fas pathway]. / Apoptose et thyroïde: le face à Fas.

THE APOPTOTIC FAS/FAS-L PATHWAY: Represents a major apoptotic pathway and involves the specific interaction between a membrane receptor, Fas, harbored by the target cell and a membrane ligand, Fas-L, harbored by the cytotoxic cell. FAS AND NORMAL THYROID GLAND: Normal thyrocytes express Fas receptor but not its ligand. The control of thyroid gland volume results from an equilibrium between the trophic action of TSH and thyrocyte apoptosis, which is limited to some extent by resistance to Fas activation by producing an inhibitor of the apoptotic signal transduction. FAS AND HASHIMOTO'S THYROIDITIS: Aberrant expression of Fas-L by thyrocytes induces their fratricide apoptosis. Thyroid-infiltrating lymphocytes are resistant to apoptosis by overexpressing the antiapoptotic protein Bcl2. FAS AND GRAVES' DISEASE: Autoantibody-dependant stimulation of the thyrotropin receptor favors goiter formation by reducing thyrocyte apoptosis. It induces repression of Fas expression and production of a soluble Fas, whose serum levels are correlated with clinical course. FAS AND THYROID CANCER: Tumoral cells are resistant to apoptosis by inhibiting the apoptotic signal transduction and exert Fas counter-attack by inducing apoptosis of antitumoral lymphocytes.