Risk and penetrance of primary hyperparathyroidism in multiple endocrine neoplasia type 2A families with mutations at codon 634 of the RET proto-oncogene. Groupe D'etude des Tumeurs à Calcitonine.

Germline mutations of the RET proto-oncogene are responsible for multiple endocrine neoplasia type 2, including multiple endocrine type 2A (MEN 2A), type 2B (MEN 2B), and familial medullary thyroid carcinoma. The relationship between specific mutations and syndromic features has been established. In particular, the risk for pheochromocytoma and hyperparathyroidism (HPT) in MEN 2A patients is clearly associated with the presence of the RET mutation at a specific position, i.e. at codon 634. Also, a correlation between a specific mutation, C634R, and the development of HPT has been suggested but is still controversial. To further investigate the relationship between specific mutations of codon 634 and the development of HPT, we studied a population of 188 individuals, carrying mutations at codon 634, namely C634R (65 patients belonging to 10 families), C634Y (80 patients belonging to 11 families), or the less frequent codon 634 mutations [i.e. C634S, C634F, C634G, or C634W (43 patients belonging to 9 families)]. In this series of patients, we defined an overall HPT prevalence of 19.1% and found that this prevalence did not vary significantly, with respect to the nature of the mutation. However, irrespective of the particular mutation, the prevalence of HPT showed a high interfamilial variability. The statistical model that best fitted with the observed data was in favor of the heterogeneity of the risk for HPT, with 40% of the families showing an HPT risk of 34% and 60% of the families showing an HPT risk of 9%. In addition, our study clearly demonstrated that HPT could be an early component of the disease and provided the first estimate of age-specific and mutation-specific HPT penetrance in individuals with mutations of codon 634 of the RET proto-oncogene.

Results of the calcitonin stimulation test in normal volunteers compared with genetically unaffected members of MEN 2A and familial medullary thyroid carcinoma families.

In the multiple endocrine neoplasia (MEN) type 2A and in the familial medullary thyroid carcinoma (FMTC), the recent development of genetic testing has provided new methods of identifying disease gene carriers. The use of sensitive immunoradiometric calcitonin (CT) assays led us to evaluate reference ranges of plasma CT responses after pentagastrin in healthy subjects in order to discuss the place of pentagastrin testing in the management of hereditary MTC. Basal and pentagastrin-stimulated CT concentrations were measured in 71 healthy volunteers--aged 20-67 years--and 76 genetically unaffected members of families with hereditary MTC--aged 4-61 years. In healthy subjects, CT peak values were below 30 ng/l in 68 cases and below 50 ng/l in 3 cases. In the genetically unaffected patients, CT peak values were below 15 ng/l in young patients and below 30 ng/l in patients older than 19 year excepted 5 men with stimulated CT levels ranging from 36.5 to 52 ng/l. In 2 of these 5, thyroidectomy revealed C-cell hyperplasia. Borderline test results are not sufficient to establish diagnosis of MTC and in these familial syndromes, management has to be based on the results of genetic testing. However, the determination of the upper normal limit for stimulated CT concentrations in young patients (< 15 ng/l) may help to identify the optimal moment for surgery.

Primary hyperparathyroidism in multiple endocrine neoplasia type IIa: retrospective French multicentric study. Groupe d'Etude des Tumeurs á Calcitonine (GETC, French Calcitonin Tumors Study Group), French Association of Endocrine Surgeons.

Primary hyperparathyroidism (PHPT) in multiple endocrine neoplasia (MEN) type IIa is rare, occurring in 20% to 30% of the patients. The aim of this study was to evaluate clinical findings, surgical therapy, and outcome for 56 patients affected by PHPT among 249 MEN-IIa patients collected from 84 families assembled by the Groupe d'Etude des Tumeurs á Calcitonine (GETC, French Calcitonin Tumors Study Group). This retrospective study was based on cases registered by the GETC (20 participating centers) from 1969 to 1994. Characteristics of PHPT in 56 patients (31 women, 25 men) with MEN-IIa were reviewed. All but two underwent cervicotomy. The median age at diagnosis was 37.6 years. PHPT was found concomitantly with medullary thyroid carcinoma (MTC) or pheochromocytoma in 43 patients (77%). PHPT was asymptomatic in 68% of the patients. Serum calcium levels ranged from 2.20 to 3.70 mmol/L (median 2.82 mmol/L; normal 2. 10-2.60 mmol/L). The number of parathyroid glands removed at surgery was 0 (n = 2), 1 (n = 24), 2 (n = 5), > 2 (n = 12), 4 (n = 11). Pathology (initial surgery) consisted of 24 adenomas, 4 double adenomas, and 25 hyperplasia. Cure after initial surgery was obtained in 89%, including a 22% incidence of hypoparathyroidism. There were 6 cases (11%) with persistent PHPT. With a mean follow-up of 6.4 years, five patients (9%) had recurrent PHPT. The results indicate that MEN-IIa-related PHPT is generally associated with mild, often asymptomatic hypercalcemia. Despite recurrences encountered 5 to 15 years after the first cervicotomy, resection of only macroscopically enlarged glands generally appears sufficient. Subtotal or total parathyroidectomy with autotransplantation is associated with a high rate of hypoparathyroidism.

RET mutations in exons 13 and 14 of FMTC patients.

RET is a receptor tyrosine kinase gene which is responsible for three different inherited cancer syndromes namely multiple endocrine neoplasia type 2A (MEN 2A), type 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC) as well as for Hirschsprung disease (HSCR), a congenital disorder affecting the intestinal motility. Germ-line mutations in the RET exons 10 and 11 were demonstrated in the majority of the MEN 2A and FMTC patients. On the other hand, one codon of RET exon 16 is preferentially changed in MEN 2B patients. Recently, a germ-line mutation in the exon 13 was described in one FMTC family as well as in four sporadic MTCs. In the present study, we observed the same exon 13 mutation in two FMTC families. In addition, we identified a previously unreported substitution of RET exon 14 in two unrelated FMTC families. Both mutations segregate with the disease in these four FMTC families and involve the tyrosine kinase domain of RET. Haplotype analysis using polymorphic markers tightly linked to the RET gene indicates that in each pedigree the mutation arose as an independent event.

Phaeochromocytoma in multiple endocrine neoplasia type 2 A: survey of 100 cases.

OBJECTIVE: We report clinical, biochemical, morphological and histological data of phaeochromocytoma in 40 French families and in apparently sporadic cases of multiple endocrine neoplasia (MEN) type 2 A (medullary thyroid carcinoma, phaeochromocytoma, with or without hyperparathyroidism). DESIGN: This retrospective study was obtained from cases registered by the 'Groupe d'Etudes des Tumeurs à Calcitonine' from 1968 to 1990. We analysed the cases having sufficiently precise data on phaeochromocytoma with Pigas Software. PATIENTS: Characteristics of phaeochromocytoma in 100 patients with MEN 2 A were reviewed. Phaeochromocytoma was bilateral in 51%. The disease was inherited in 94 patients from 40 families (40 probands, 54 relatives), and was apparently sporadic in six. RESULTS: In this series, diagnostic circumstances were highly suggestive of phaeochromocytoma in 39.8% of the cases, whereas in 43.2%, diagnosis was made through systematic investigations of patients, either before (27.3%) or after (13.6%) thyroidectomy, or after discovery of hyperparathyroidism (2.3%). Fifteen per cent of patients were detected by family screening. Sudden death occurred in 8.9%, malignant phaeochromocytoma in 3%, and ectopic tissue in 4% of the cases. Urinary metanephrines appeared to be the most sensitive screening test. The extent of clinical symptoms was not associated with a particular hormonal pattern. Bilateral adrenalectomy was performed in 60% (in one step in 50%, in two steps in 10%). In these patients, bilateral histological lesions were observed in 92.5%. Simultaneous diagnosis for adrenal and thyroid disease was made in 73.4%, but phaeochromocytoma may be diagnosed before (9.6%) or after (17%) medullary thyroid carcinoma, with an interval greater than 2 years in 25 cases. CONCLUSION: Owing to variable clinical symptoms of phaeochromocytoma in these 100 cases of MEN 2 A, systemic biological adrenal assay is required. The search for phaeochromocytoma in medullary thyroid carcinoma (and vice versa) has to be systematically performed, even in apparently sporadic cases. Screening for phaeochromocytoma must be repeated for years, owing to the frequency of bilateral adrenal disease.

[Hypoglycemia induced by cibenzoline in the elderly]. / Hypoglycémie induite par la cibenzoline chez le sujet âgé.

Hypoglycaemia induced by class IA antiarrhythmic agents has been described. A case of cibenzoline-induced hypoglycaemia with favourable outcome is reported. The patient's age (84 years), increased renal impairment and malnutrition acted as facilitating factors. Blood insulin levels were normal in both absolute and relative values. Therapeutic overdosage in relation to age and renal function has been found in 20 out of 24 cases published or recorded by the French pharmacovigilance system. The mechanism of this hypoglycaemia is uncertain; absolute or relative hyperinsulinism has been detected in only 5 out of 14 controlled cases.

[Familial medullary thyroid cancer. Contribution of genealogy and genetics to the study of two families]. / Cancer médullaire familial de la thyroïde. Apport de la généalogie et de la génétique à l'étude de deux familles.

A geneological study made it possible to establish a link between two medullary thyroid carcinoma families from Normandy totalling 9 sick subjects, and a probable link with a third family. The study contributed to the diagnosis of multiple endocrine neoplasia type IIa, whereas the condition had been diagnosed for 6 years as familial medullary thyroid carcinoma, without phaechromocytoma. Group in these two families together increased the number of subjects tested, thereby facilitating genetic link analysis and enabling the link with markers of the disease on chromosome 10 to be asserted. The genetic study can now be used to detect individuals at risk, and with regular laboratory tests the diagnosis will be made at the "precancerous" stage. A genealogical study going back to the family-founding couple will increase the population which will benefit from screening in this region north of Rouen.

[Eating disorders and obesity]. / Troubles du comportement alimentaire et obésité.

In most cases, obesity does not stem from a specific psychologic disturbance. Some obese people overeat, as do their family or their socio-professional peers, and this cannot be considered a pathologic behaviour. Many obese patients increase their energy intake when frustrated, anxious, or tired, like many normal individuals who enjoy a better weight regulation. But when obesity increases suddenly and/or severely in these circumstances, and in gross obesity, abnormal feeding behaviour is usually responsible: prandial or, more often extraprandial overeating (nibbling, gorging, binge eating, night eating, excess alcohol, carbohydrate craving). Serotoninergic mechanisms of the latter have focused wide interest. Conflicting situations and/or anxiety are usually a factor in child obesity. Deppreciated self-image and feelings of culpability, partly secondary to obesity itself and dietary failures often contribute to feeding disturbances, sometimes surreptitious, carrying a risk of vicious circle. But weight reduction itself, while improving self image, carries a risk of unmasking depressive tendencies, especially when too quick. Hence the importance of careful and comprehensive management.

[Pituitary adenoma treated with a somatostatin analog]. / Adénome thyréotrope traité par un analogue de la somatostatine.

We studied for over 7 months the use of SMS 201-995, in 1 woman with pituitary adenoma. Eight years after surgical and irradiation therapy, adenoma relapsed with hyperthyroidism (T4 L = 71pmol/l, TSH = 5.3 mU/l, subunit: 309 micrograms/l) and was complicated by meningitis. It was invasive and removed only partly. SMS therapy, 100 micrograms SC q 8 h, allowed partial reduction of clinical hyperthyroidism and decreased TSH and alpha subunit of 47%. Increased dosage and changing route of administration did not increase efficacy. A modest decrease of adenoma was probably caused by several reasons. In summary in an adenoma unusual by the extremely high value of alpha subunit in contrast with modest value of TSH, SMS therapy allowed partial control only.

[Latent and postpartum thyroiditis. Prospective study]. / Thyroïdite latente et post-partum. Etude prospective.

Thyroid evaluation was performed in 85 women at childbirth, then between 2 and 7 months, and 14 months later. Transient subclinical hypothyroidism was found in one woman; antithyroid antibodies were found in 10 and were persistent in 6, suggesting a late thyroiditis. For these 6 cases, 5 HLA typing showed 3 Locus DR4. The proportion of antithyroid antibody was the same in a reference population. This finding would be in agreement with the hypothesis of a latent thyroiditis, revealed by pregnancy. Relative iodine deficiency in France could explain the low frequency of post partum thyroiditis in the present study.

[Etiological diagnosis of syncope and brief loss of consciousness in patients over 65. Results of a multicenter prospective study of 188 cases]. / Diagnostic étiologique des lipothymies et pertes de connaissance brèves après 65 ans. Résultats d'une étude prospective multicentrique de 188 cas.

In a prospective multicentre study a series of 188 patients over 65 years of age admitted for syncope (90) or transient loss of consciousness (98) was collected. There were 120 women and 68 men; mean age was 78.7 +/- 6.6 years; 140 patients had a significant history mainly of arterial hypertension and coronary disease; 81 patients were taking drugs (4.1 on average) and notably diuretics, antihypertensive agents, antiarrhythmic agents, nitrites and psychotropic drugs. The most frequent diagnoses were arrhythmia (20.2 p. 100), postural hypotension (15.4 p. 100), reflex and vasodepressive syncope (12.2 p. 100) and coronary disease (5.3 p. 100). Taken together, these diagnoses could be divided into cardiac diseases (26.5 p. 100), extracardiac diseases (54.2 p. 100), diagnosis unknown (19 p. 100). The condition was iatrogenic in 45 patients (24 p. 100). The means by which the diagnosis was reached were studied: in two-thirds of the cases, careful physical examination and electrocardiography alone provided a diagnosis. Seven patients died during their stay in hospital. Among the 181 survivors 148 (81.7 p. 100) were discharged and returned home.