Cushing's disease (CD) presents a marked female preponderance, but whether this skewed gender distribution has any relevance to the presentation and outcome of CD is not known. The aim of the present study was the comparison of clinical features, biochemical indices of hypercortisolism, and surgical outcome among male and female patients with CD. The study population comprised 280 patients with CD (233 females, 47 males) collected by the Italian multicentre study. Epidemiological data, frequency of clinical signs and symptoms, urinary free cortisol (UFC), plasma ACTH and cortisol levels, responses to dynamic testing, and surgical outcome were compared in female and male patients. Male patients with CD presented at a younger age, compared with females (30.5 +/- 1.93 vs. 37.1 +/- 0.86 yr, P < 0.01), with higher UFC and ACTH levels (434.1 +/- 51.96 vs. 342.1 +/- 21.01% upper limit of the normal range for UFC, P < 0.05; 163.9 +/- 22.92 vs. 117.7 +/- 9.59% upper limit of the normal range for ACTH, P < 0.05). No difference in ACTH and cortisol responses to CRH, gradient at inferior petrosal sinus sampling, and cortisol inhibition after low-dose dexamethasone was recorded between sexes. In contrast, the sensitivity of the high-dose dexamethasone test was significantly lower in male than in female patients. Of particular interest, symptoms indicative of hypercatabolic state were more frequent in male patients; indeed, males presented a higher prevalence of osteoporosis, muscle wasting, striae, and nephrolitiasis. Conversely, no symptom was more frequent in female patients with CD. Patients with myopathy, hypokalemia, and purple striae presented significantly higher UFC levels, compared with patients without these symptoms. Lastly, in male patients, pituitary imaging was more frequently negative and immediate and late surgical outcome less favorable. In conclusion, CD appeared at a younger age and with a more severe clinical presentation in males, compared with females, together with more pronounced elevation of cortisol and ACTH levels. Furthermore, high-dose dexamethasone suppression test and pituitary imaging were less reliable in detecting the adenoma in male patients, further burdening the differential diagnosis with ectopic ACTH secretion. Lastly, the postsurgical course of the disease carried a worse prognosis in males. Altogether, these findings depict a different pattern for CD in males and females.

Congenital hypothyroidism (CH), the most frequent form of preventable mental retardation, is predicted to have a relevant genetic origin. However, CH is frequently reported to be sporadic and candidate gene variations were found in <10% of the investigated patients. Here, we characterize the involvement of 11 candidate genes through a systematic Next Generation Sequencing (NGS) analysis. The NGS was performed in 177 unrelated CH patients (94 gland-in-situ; 83 dysgenesis) and in 3,538 control subjects. Non-synonymous or splicing rare variants (MAF < 0.01) were accepted, and their functional impact was predicted by a comprehensive bioinformatic approach and co-segregation studies. The frequency of variations in cases and controls was extended to 18 CH-unrelated genes. At least one rare variant was accepted in 103/177 patients. Monogenic recessive forms of the disease were found in five cases, but oligogenic involvement was detected in 39 patients. The 167 variations were found to affect all genes independently of the CH phenotype. These findings were replicated in an independent cohort of additional 145 CH cases. When compared to 3,538 controls, the CH population was significantly enriched with disrupting variants in the candidate genes (P = 5.5 × 10-7), but not with rare variations in CH-unrelated genes. Co-segregation studies of the hypothyroid phenotype with multiple gene variants in several pedigrees confirmed the potential oligogenic origin of CH. The systematic NGS approach reveals the frequent combination of rare variations in morphogenetic or functional candidate genes in CH patients independently of phenotype. The oligogenic origin represents a suitable explanation for the frequent sporadic CH occurrence.

Patients with KS are more prone to develop a severe and complex phenotype than nIHH. The presence of typical extra-gonadal defects and familiarity for PPO-IHH among the AO-IHH patients indicates a common predisposition with variable clinical expression. Overall, these findings improve the understanding of IHH and may have a positive impact on the management of patients and their families.

Differentiating Cushing's disease (CD) from pseudo-Cushing (PC) states may still be difficult in current practice. Because desmopressin (1-deamino-8D-arginine vasopressin, DDAVP), a vasopressin analogue, stimulates ACTH release in patients with CD but not in the majority of normal, obese, and depressed subjects, we investigated its ability to discriminate CD from PC states. One hundred seventy-three subjects (76 with active CD, 30 with PC, 36 with simple obesity, and 31 healthy volunteers) were tested with an iv bolus of 10 microg DDAVP. Sixty-one of these subjects also underwent a control study with saline. DDAVP induced marked ACTH and cortisol rises in CD (P < 0.005 vs. saline, for both ACTH and cortisol) but not in PC. A significant ACTH elevation occurred upon DDAVP administration also in normal and obese subjects, but it was much smaller than that observed in patients with CD (P < 0.0001). A peak absolute ACTH increase (> or =6 pmol/L), after DDAVP, allowed us to recognize 66 of 76 patients with CD and 88 of 97 subjects of the other groups. The same criterion correctly identified 18 of 20 patients with mild CD (24-h urinary free cortisol < or = 690 nmol/day) and 29 of 30 PC, resulting in a diagnostic accuracy of 94%, which was definitely higher than that displayed by urinary free cortisol, overnight 1-mg dexamethasone suppression test, and midnight plasma cortisol. In conclusion, the DDAVP test seems to be a useful adjunctive tool for the evaluation of hypercortisolemic patients chiefly because of its ability to differentiate mild CD from PC states.