No abstract

Context Unlike homozygous variants, the implication of heterozygous variants on the leptin-melanocortin pathway in severe obesity has not been established. Objective To describe the frequency, the phenotype, and the genotype-phenotype relationship for heterozygous variants in LEP, LEPR, POMC, and PCSK1 in severe obesity. Methods In this retrospective study, genotyping was performed on at least one of the LEP, LEPR, POMC, and PCSK1 genes in 1,486 probands with severe obesity (600 children, 886 adults). The phenotype was collected in 60 subjects with heterozygous variants and 16 with homozygous variants. We analyzed variant frequency, Body Mass Index (BMI), age of obesity onset, food impulsivity, and endocrine abnormalities. Results The frequency of subjects with homozygous variants was 1.7% (n=26), and 6.7% (n=100) with heterozygous variants. Adults with homozygous variants had a higher BMI (66 versus 53 kg/m 2, p=0.015), an earlier onset of obesity (0.4 versus 5.4 years, p<0.001), more often food impulsivity (83% versus 42%, p=0.04), and endocrine abnormalities (75% versus 26%, p<0.01). The BMI was higher for subjects with high-impact heterozygous variants (61 versus 50 kg/m², p=0.045) and those with a second heterozygous variant on the pathway (65 versus 49 kg/m², p<0.01). In children, no significant differences were found for the age of obesity onset and BMI. Conclusions Heterozygous variants in LEP, LEPR, POMC, and PCSK1 are frequent in severe obesity and sometimes associated with a phenotype close to that of homozygotes. These data suggest a systematic search for variants in severe early-onset obesity, to discuss therapy that targets this key pathway.

Long-term outcomes in children undergoing intestinal transplantation remain unclear. Seventy-one children underwent intestinal transplantation in our center from 1989 to 2007. We report on 10-year posttransplant outcomes with (group 1, n = 26) and without (group 2, n = 9) a functional graft. Ten-year patient and graft survival rates were 53% and 36%, respectively. Most patients were studying or working, one third having psychiatric disorders. All patients in group 1 were weaned off parenteral nutrition with mostly normal physical growth and subnormal energy absorption. Graft histology from 15 late biopsies showed minimal abnormality. However, micronutrient deficiencies and fat malabsorption were frequent; biliary complications occurred in 4 patients among the 17 who underwent liver transplantation; median renal clearance was 87 mL/min/1.73 m 2. Four patients in group 1 experienced late acute rejection. Among the 9 patients in group 2, 4 died after 10 years and 2 developed significant liver fibrosis. Liver transplantation and the use of a 3-drug regimen including sirolimus or mycophenolate mofetil were associated with improved graft survival. Therefore, intestinal transplantation may enable a satisfactory digestive function in the long term. The prognosis of graft removal without retransplantation is better than expected. Regular monitoring of micronutrients, early psychological assessment, and use of sirolimus are recommended.