Analysis of RET proto-oncogene abnormalities in patients with MEN 2A, MEN 2B, familial or sporadic medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) may occur either as a sporadic or familial (FMTC) disease. Multiple endocrine neoplasia (MEN) type 2, inherited as an autosomal dominant disease, is characterized by coexistence of MTC with other endocrine neoplasia. Activating mutations of the RET proto-oncogene, involving the somatic or the germinal cell lineage, are found in both inherited and acquired forms. In this study, RET mutations were screened in 47 individuals either affected by MTC or belonging to families with hereditary MTC. Exons 10, 11, 13, 14, 15 and 16 of the RET gene were amplified by polymerase chain reaction and examined by DNA sequence and/or restriction enzyme analysis to detect mutations in purified amplicons. Six MEN 2A families with a germline mutation at codon 634, one FMTC family carrying a mutation at codon 618 and two MEN 2B families with a mutation at codon 918 were identified. In affected members of a MEN 2A family no known RET mutations were observed. Besides, we identified a germline mutation in a patient with apparently sporadic MTC and in two out of three sons, indicating the presence of a sporadic misclassified familial disease. In all of the families examined we were able to distinguish the affected vs unaffected (not at risk) members. A somatic mutation of codon 918 was detected in three out of ten patients with apparently sporadic MTC.

Atypical McCune-Albright syndrome associated with growth hormone-prolactin pituitary adenoma: natural history, long-term follow-up, and SMS 201-995--bromocriptine combined treatment results.

A 35-yr-old woman is described as having atypical McCune-Albright syndrome, associated with acromegaly and hyperprolactinemia due to pituitary adenoma. The patient did not present sexual precocity, but primary amenorrhea. After transphenoidal adenomectomy, the GH plasma levels returned to normal, whereas the PRL values decreased; bromocriptine therapy normalized PRL levels and induced ovulatory menses. After 4 uneventful yr the patient developed relapse of active acromegaly that did not recover after a second neurosurgical exploration. Bromocriptine treatment maintained normal PRL levels but did not significantly reduce GH ones; the association with long-acting somatostatin analog SMS 201-995 by continuous sc pump infusion induced definitive control of GH and somatomedin-C secretion. These results suggest an additive inhibitory effect on GH secretion exerted by the two drugs.

[The hypothalamic-hypophyseal-adrenal axis in obesity]. / Studio dell'asse ipotalamo-ipofisi-surrene (IIS) nell'obesità.

The HHA axis was assessed in 26 women with essential obesity using a CRF test, insulin hypoglycemia and oral glucose load. Basal values of ACTH and cortisol were similar in obese subjects and controls, whereas peak ACTH values following CRF administration were significantly lower in obese subjects. The net integrated areas under ACTH and cortisol curves after CRF injection were lower in obese subjects but not statistically significant. Glucose inhibited cortisol levels in controls but not in obese subjects. Insulin hypoglycemia provoked a ACTH and cortisol response in obese women which was significantly higher than that provoked by CRF. The lesser response of ACTH to CRF in obesity might be the result of an altered hypophyseal response to CRF mediated by other factors; in addition, the increased ACTH and cortisol response to the insulin stimulus compared to CRF observed in obese subjects leads to suppose that the metabolic stimulus involves the release of other factors.

Cardioembolic stroke in primary oxalosis with cardiac involvement.

Primary oxalosis is a rare disorder of oxalate metabolism, characterized by nephrocalcinosis, nephrolithiasis, and extrarenal deposition of calcium oxalate in several tissues, including the heart. We report the case of a 34-year-old man with sudden right hemiparesis and aphasia from the occlusion of the left middle cerebral artery. Clinical features and the results of laboratory investigations led to the diagnosis of primary oxalosis. Two-dimensional echocardiography disclosed the presence of massive intracardiac calcifications compatible with deposition of calcium oxalate. The absence of other causes of stroke strengthened a cause-and-effect relation between cardiac oxalosis and cerebral infarction. Consequently, cardiac oxalosis should be considered among possible occult cardiac sources of cerebral embolism.

Hyperthyroidism and high serum levels of TSH associated with pituitary tumour.

We report a 28-year-old male with persistent clinical and laboratory findings of hyperthyroidism associated with marked elevated serum levels of TSH and no response to TRH despite hemithyroidectomy and subsequent antithyroid drug therapy two years previous to admission to our hospital. Subsequent skull X-rays, CT scans and angiographic findings demonstrated the presence of a pituitary tumour. After operation and radiation therapy T3, T4 and TSH levels returned to normal values. Seven years later the patient is still euthyroid. We conclude that hyperthyroidism in our patient was due to excessive secretion of TSH by the pituitary tumour.

Neuroendocrine control of basal insulin secretion in man: a study with bromocriptine, clonidine and naloxone.

The effects of bromocriptine (CB-154, 2.5 mg po), clonidine (0.05 mg im) and naloxone (0.4 mg im), as well as the interaction between naloxone and CB-154 or clonidine on basal insulin secretion were studied in 6 normal men. Clonidine, naloxone and CB-154 plus naloxone lowered insulin plasma levels; CB-154 alone caused only a slight reduction, whereas clonidine plus naloxone did not affect insulin secretion. These results prove the existence of a complex neuroendocrine control of basal insulin secretion through dopaminergic, adrenergic and opiate mechanisms; they also suggest that the opiate inhibitory control of insulin release may be dissociated from the dopaminergic one, but may interact with the adrenergic one.

[Effects of interaction between 2-Br-alpha-ergocriptine (CB 154) and naloxone on the control of insulin secretion in normal men]. / Interazione fra 2-Br-alpha-ergocriptina (CB 154) e naloxone nel controllo della secrezione insulinica nell'uomo normale.

The effects of 2-Br-alpha-ergocriptine (CB 154, 2.5 mg per os) and naloxone (0.4 mg i.m.) as well as the interaction between these two drugs on insulin serum levels have been studied in six normal male volunteers. Both CB 154 and naloxone lower insulin serum levels, while a more clear-cut reduction is observed after CB 154 plus naloxone. These results are discussed in view of a possible involvement of dopaminergic and enkephalinergic systems in the control of insulin secretion at hypothalamic or pancreatic level.

A study on the effects of interaction between naloxone and 2-Br-alpha-ergocryptine or clonidine on luteinizing hormone, follicle-stimulating hormone, prolactin and thyroid-stimulating hormone levels in normal man serum.

The effects of 2-Br-alpha-ergocryptine (2.5 mg/osM), clonidine (50 microgram, intramuscularly) and naloxone (0.4 mg, intramuscularly) as well as the interaction between naloxone and 2-Br-alpha-ergocryptine or clonidine on luteinizing hormone (LH) follicle-stimulating hormone (FSH), prolactin (PL) and thyroid-stimulating hormone (TSH) serum levels in normal man have been studied. 2-Br-alpha-ergocryptine and clonidine clearly reduce and naloxone tends to reduce PL serum levels. TSH levels are lowered by naloxone as well by clonidine plus naloxone. The results obtained point also to a possible different pattern of LH and FSH secretion after naloxone, that is after opiate receptor blockade. The clonidine effects on PL secretion are discussed in the frame of a possible adrenergic control of the release of this hormone.