Molecular characterization of a pediatric pheochromocytoma with suspected bilateral disease.

An 11-year-old boy with hypertension was suspected of having bilateral adrenal pheochromocytomas and hyperplasia. Molecular analysis of specific tumor suppressor genes and oncogenes excluded the familial syndromes, von Hippel-Lindau (VHL) disease and multiple endocrine neoplasia (MEN) type 2A. Further evaluation identified a unilateral adrenal pheochromocytoma with a VHL heterozygous somatic mutation (G695A) and loss of the maternal allele at 11p15.5-11p14 exclusively in the tumor tissue. Both reverse-transcriptase polymerase chain reaction and immunohistochemistry confirmed increased expression of IGF2 within the tumoral tissue, relative to a normal control adrenal gland. These results ruled out familial syndromes and suggested that the VHL mutation and the loss of maternal allele on chromosome 11 could have contributed to tumor development.

Are ectopic or abnormal membrane hormone receptors frequently present in adrenal Cushing's syndrome?

Twenty consecutive patients with adrenal Cushing's syndrome were studied with an in vivo protocol to determine the prevalence and diversity of the presence of ectopic or abnormal hormone receptors in their adrenal tissues. All six patients with bilateral ACTH-independent macronodular adrenal hyperplasia were found to have one or two abnormal adrenal receptors, including those for gastric inhibitory polypeptide, vasopressin (V1-vasopressin), beta-adrenergic agonists, LH/human CG, or serotonin 5-HT4. The presence of abnormal hormone receptors was found to be less frequently present in unilateral adenomas or carcinomas (3 of 14). The identification of abnormal adrenal hormone receptors can allow new pharmacological therapies of hypercortisolism. We suggest that the clinical screening for the presence of abnormal hormone receptors should be conducted in patients with adrenal Cushing's syndrome and, more particularly, in those with ACTH-independent macronodular adrenal hyperplasia, in the hope of offering medical therapy as an alternative to bilateral adrenalectomy.

Hyperfunctioning malignant thyroid nodule in an 11-year-old girl: pathologic and molecular studies.

We identified a papillary carcinoma in an 11-year-old girl with a hyperfunctioning thyroid nodule. A met453thr mutation in TSHR was found in the nodule but not in normal thyroid tissue or in leukocytes. This case documents that this activating mutation is associated with neoplasia.

The diversity of abnormal hormone receptors in adrenal Cushing's syndrome allows novel pharmacological therapies.

Recent studies from several groups have indicated that abnormal or ectopic expression and function of adrenal receptors for various hormones may regulate cortisol production in ACTH-independent hypercortisolism. Gastric inhibitory polypeptide (GIP)-dependent Cushing's syndrome has been described in patients with either unilateral adenoma or bilateral macronodular adrenal hyperplasia; this syndrome results from the large adrenal overexpression of the GIP receptor without any activating mutation. We have conducted a systematic in vivo evaluation of patients with adrenal Cushing's syndrome in order to identify the presence of abnormal hormone receptors. In macronodular adrenal hyperplasia, we have identified, in addition to GIP-dependent Cushing's syndrome, other patients in whom cortisol production was regulated abnormally by vasopressin, ss-adrenergic receptor agonists, hCG/LH, or serotonin 5HT-4 receptor agonists. In patients with unilateral adrenal adenoma, the abnormal expression or function of GIP or vasopressin receptor has been found, but the presence of ectopic or abnormal hormone receptors appears to be less prevalent than in macronodular adrenal hyperplasia. The identification of the presence of an abnormal adrenal receptor offers the possibility of a new pharmacological approach to control hypercortisolism by suppressing the endogenous ligands or by using specific antagonists for the abnormal receptors.

Abnormal expression and function of hormone receptors in adrenal Cushing's syndrome.

The initial description of GIP-dependent Cushing's syndrome suggested that abnormal or ectopic expression of adrenal receptors for various ligands may underlie other cases of ACTH-independent hypercortisolism. GIP-dependent Cushing's syndrome has been described in patients with unilateral adenomas or bilateral ACTH-independent macronodular adrenal hyperplasia (AIMAH) and results from the adrenal overexpression of non-mutated GIP receptor. In AIMAH, other patients were identified in whom regulation of cortisol production resulted from an abnormal adrenocortical response either to vasopressin, beta-adrenergic receptor agonists, hCG/LH, or serotonin 5-HT-4 receptor agonists. The identification of the presence of an abnormal adrenal receptor offers the possibility of a new pharmacological approach to control hypercortisolism by suppressing the endogenous ligands or by using specific antagonists of the abnormal receptor.