OBJECTIVE-The clinical expression of maturity-onset diabetes of the young (MODY)-3 is highly variable. This may be due to environmental and/or genetic factors, including molecular characteristics of the hepatocyte nuclear factor 1-␣ (HNF1A) gene mutation. RESEARCH DESIGN AND METHODS-We analyzed the mutations identified in 356 unrelated MODY3 patients, including 118 novel mutations, and searched for correlations between the genotype and age at diagnosis of diabetes. RESULTS-Missense mutations prevailed in the dimerizationand DNA-binding domains (74%), while truncating mutations were predominant in the transactivation domain (62%). The majority (83%) of the mutations were located in exons 1-6, thus affecting the three HNF1A isoforms. Age at diagnosis of diabetes was lower in patients with truncating mutations than in those with missense mutations (18 vs. 22 years, P ϭ 0.005). Missense mutations affecting the dimerization/DNA-binding domains were associated with a lower age at diagnosis than those affecting the transactivation domain (20 vs. 30 years, P ϭ 10 Ϫ4 ). Patients with missense mutations affecting the three isoforms were younger at diagnosis than those with missense mutations involving one or two isoforms (P ϭ 0.03). MODY3 is characterized by a severe insulin secretion defect, a retained sensitivity to sulfonylureas, a decreased renal threshold for glucose reabsorption, and, in rare families, the occurrence of liver adenomatosis (3-6). CONCLUSIONS-TheseThe clinical expression of MODY3 is highly variable from one family to another or even within the same family (7). HNF1A mutation carriers may be normoglycemic while their siblings may be hyperglycemic at a comparable age (8). Symptoms at diagnosis may be variable. Some patients have metabolic decompensation, while in others diabetes is diagnosed by systematic screening. The severity and the course of insulin secretion defect also vary since approximately one-third of the patients are treated with insulin after 15 years of diabetes duration, whereas others control their diabetes by diet or oral hypoglycemic agents (9).As in other monogenic diseases, this phenotype variability may be explained by environmental and/or additional genetic factors. Two studies have shown that age at diagnosis of diabetes in offspring carrying a HNF1A mutation was lower by 5-10 years when maternal diabetes was diagnosed before pregnancy, suggesting the role of exposure of the fetus to maternal hyperglycemia (10,11). Modifier genetic factors may also modulate the phenotype of the disease. Age at onset of diabetes is partly inheritable within MODY3 families, and putative genetic modifier loci have been mapped but not identified yet (12). In the same vein, it has been recently shown that germ line CYP1B1 Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0859.HNF1A, hepatocyte nuclear factor 1-␣; MODY, maturity-onset diabetes of the young.

We assessed the value of midnight salivary cortisol for the initial diagnosis of Cushing's syndrome. Sixty-three patients with various causes of Cushing's syndrome (37 with Cushing's disease, 17 with adrenal Cushing's syndrome, and nine with ectopic ACTH syndrome) and 54 control subjects with simple obesity were studied. All patients with Cushing's syndrome excreted more than 90 microg urinary free cortisol (UFC)/d (248 nmol/d), and all controls excreted less than 90 microg/d UFC. All patients with Cushing's syndrome had a midnight salivary cortisol concentration above 2.0 ng/ml (5.52 nmol/liter), whereas only three controls did so [2.0 ng/ml (5.52 nmol/liter); 2.05 ng/ml (5.66 nmol/liter); and 3.6 ng/ml (9.96 nmol/liter)]. This cut-off provides a sensitivity of 100% and a specificity of 96%. In patients with Cushing's syndrome, midnight salivary cortisol concentrations were correlated with UFC collected over the same period of time (0800-0800 h). Salivary cortisol measurements taken every 4 h showed a typical lack of circadian variation. The daily measurement of midnight salivary cortisol concentrations for 2 wk or more in five other out-patients (with obvious Cushing's disease, subclinical adrenal Cushing's syndrome, suspected Cushing's syndrome, pituitary incidentaloma, and prolactinoma) demonstrated the clinical utility of this factor. Measuring midnight salivary cortisol is an easy and noninvasive means of diagnosing hypercortisolism. Its diagnostic accuracy is identical to, if not better than, that of previously described gold standards.

No abstract