Sequential cleavage of the precursor protein pre-pro-opiomelanocortin (POMC) generates the melanocortin peptides adrenocorticotrophin (ACTH), melanocyte-stimulating hormones (MSH) alpha, beta and gamma as well as the opioid-receptor ligand beta-endorphin. While a few cases of isolated ACTH deficiency have been reported (OMIM 201400), an inherited POMC defect has not been described so far. Recent studies in animal models elucidated a central role of alpha-MSH in the regulation of food intake by activation of the brain melanocortin-4-receptor (MC4-R; refs 3-5) and the linkage of human obesity to chromosome 2 in close proximity to the POMC locus, led to the proposal of an association of POMC with human obesity. The dual role of alpha-MSH in regulating food intake and influencing hair pigmentation predicts that the phenotype associated with a defect in POMC function would include obesity, alteration in pigmentation and ACTH deficiency. The observation of these symptoms in two probands prompted us to search for mutations within their POMC genes. Patient 1 was found to be a compound heterozygote for two mutations in exon 3 (G7013T, C7133delta) which interfere with appropriate synthesis of ACTH and alpha-MSH. Patient 2 was homozygous for a mutation in exon 2 (C3804A) which abolishes POMC translation. These findings represent the first examples of a genetic defect within the POMC gene and define a new monogenic endocrine disorder resulting in early-onset obesity, adrenal insufficiency and red hair pigmentation.

Chronic pancreatitis (CP) is a continuing or relapsing inflammatory disease of the pancreas. In approximately one-third of all cases, no aetiological factor can be found, and these patients are classified as having idiopathic disease. Pathophysiologically, autodigestion and inflammation may be caused by either increased proteolytic activity or decreased protease inhibition. Several studies have demonstrated mutations in the cationic trypsinogen gene (PRSS1) in patients with hereditary or idiopathic CP. It is thought that these mutations result in increased trypsin activity within the pancreatic parenchyma. Most patients with idiopathic or hereditary CP, however, do not have mutations in PRSS1 (ref. 4). Here we analysed 96 unrelated children and adolescents with CP for mutations in the gene encoding the serine protease inhibitor, Kazal type 1 (SPINK1), a pancreatic trypsin inhibitor. We found mutations in 23% of the patients. In 18 patients, 6 of whom were homozygous, we detected a missense mutation of codon 34 (N34S). We also found four other sequence variants. Our results indicate that mutations in SPINK1 are associated with chronic pancreatitis.

Nicotine and cotinine concentrations were measured in placental tissue during the first trimester, in amniotic fluid during the second trimester and in placental tissue and fetal serum at birth. These values were compared to the corresponding serum concentrations of the smoking mothers. Nicotine concentrations in the placentas (range 3.3-28 ng/g), in amniotic fluid (range 1.5-23 ng/ml) and in fetal serum (range 0.5- 25 ng/ml) were all higher than the corresponding maternal serum values: amniotic fluid/maternal vein serum concentration ratio 1.54 ± (SD) 0.27 (n = 23; week 16-24 of gestation), umbilical vein serum/matemal vein serum ratio 1.12 ± 0.30 (n = 26; at birth); placental tissue/matemal vein serum ratio 2.58 ± 1.30 (n = 17; at birth); these ratios were between 1.2 and 5 during week 10 of gestation (n = 3). The ratios did not depend on the time between the last cigarette smoked and sampling. Significant correlations were found between nicotine concentrations in amniotic fluid and maternal serum (r = 0.88), between fetal and maternal serum levels (r = 0.88) and between placental and maternal serum levels (r = 0.52). Cotinine concentrations in placental tissue (range 10-131 ng/g), amniotic fluid (range 5-188 ng/ml) and fetal serum (range 15-233 ng/ml) were lower than or similar to corresponding maternal serum levels. Our results indicate that the human fetus is exposed to higher nicotine concentrations than the smoking mothers.