A Primer on the Genetics of Medullary Thyroid Cancer

Medullary thyroid cancer is a rare type of neuroendocrine tumour that arises from the parafollicular cells (C cells) of the thyroid gland. It accounts for 3%–5% of thyroid cancer cases. Close to 25% of cases are familial, and 75% are considered sporadic. Familial cases are associated with a germline RET mutation; 43%–65% of sporadic cases harbour a somatic event in the gene. Germline RET mutations are associated with the autosomal-dominant inherited multiple endocrine neoplasia (MEN) 2A and 2B syndromes and the isolated familial medullary thyroid cancer syndrome. More than 100 RET codon mutations have been reported to date, with genotype–phenotype correlations that include the extent and aggressiveness of the medullary thyroid cancer and the presence of other features of the MEN2 syndromes. The latter include pheochromocytoma–paraganglioma, hyperparathyroidism, cutaneous lichen amyloidosis, and Hirschsprung disease. In this narrative review, we focus on RET proto-oncogene physiology and pathogenesis induced by germline and somatic RET mutations, the genotype–phenotype correlation, and the management and follow-up of patients with germline-mutated medullary thyroid cancer

Idiopathic central diabetes insipidus in a large cohort of patients: the hypopituitarism ENEA rare observational (HEROS) study

Central Diabetes Insipidus (CDI) is mainly associated with structural pathologies of the hypothalamic-pituitary area. Etiologies underlying CDI are identified in most patients, however idiopathic CDI is reported in 13-17% of cases after excluding other etiologies. The Hypopituitarism ENEA Rare Observational Study (HEROS study) retrospectively collected data of patients with idiopathic CDI from 14 pituitary centers in 9 countries. The cohort included 92 patients (59 females 64%), mean age at diagnosis was 35.4 ± 20.7 years, and a mean follow up of 19.1 ± 13.5 years following CDI diagnosis. In 6 women, diagnosis was related to pregnancy. Of 83 patients with available data on pituitary imaging, 40(48%) had normal sellar imaging, and 43(52%) had pathology of the posterior pituitary or the stalk, including loss of the bright spot, posterior pituitary atrophy or stalk enlargement. Anterior pituitary hormone deficiencies at presentation included hypogonadism in 6 (6.5%) patients (5 females), and hypocortisolism in one; during follow-up new anterior pituitary deficiencies developed in 6 patients. Replacement treatment with desmopressin was given to all patients except one, usually with an oral preparation. During follow up, no underlying disease causing CDI was identified in any patient. Patients with idiopathic CDI following investigation at baseline are stable with no specific etiology depicted during long-term follow-up