ABSTRACT
The db/db mouse and the fa/fa rat are the archetypical leptin-resistant models due to mutant leptin receptors (9). Searches for similar genetic mutations in man, however, have been relatively fruitless except in rare circumstance. Clement et al. (13) have identified three morbidly obese sisters with very high leptin levels who are homozygous for a mutation in a splice donor site of the leptin receptor resulting in the loss of transmembrane and cytoplasmic domains because of exon skipping. These sisters were hyperphagic, had normal basal resting expenditure, and had hypogonadotropic hypogonadism with failure of pubertal development. However, unlike the above leptin-deficient patients, these sisters had mild growth retardation in early childhood with impaired basal and dynamic growth hormone secretion and decreased IGFI and IGF-BP3 levels (see Table 1). There was also evidence of hypothalamic hypothyroidism with only mildly raised insulin levels.
