LESSONS FROM 50 YEARS OF STUDY OF LARON SYNDROME

Objective: To describe the characteristics of untreated and recombinant insulin-like growth factor 1 (IGF-1)treated patients with the Laron syndrome (LS) as seen in our clinic over a period of over 50 years. In 1966, we reported a new disease, characterized by dwarfism (-4 to -10 height standard deviation score) typical facial features, small head circumference, obesity, and small genitalia. They resembled congenital growth hormone (GH) deficiency but had high levels of serum human GH and low IGF-1. Since then, our cohort grew to 69 patients, consisting of Jews of oriental origin, Muslins, and Christians originating from the Middle East or Mediterranean area. Many belong to consanguineous families. Methods: Molecular genetic investigations revealed that these patients had deletions or mutations in the GH receptor gene, but only individuals homozygous for this defect express the disease, coined Laron syndrome(LS; Online Mendelian Inheritance in Man# 262500). Results: During childhood, LS patients grow slowly, have a retarded bone age and sexual development, but reach full sexual development. The treatment of LS is recombinant IGF-1, which stimulates the linear growth but increases the degree of obesity. Adult-age patients with congenital IGF-1 deficiency are protected from cancer but can develop insulin resistance, glucose intolerance, diabetes, and cardiovascular disease. Due to pathologic changes in the brain related to the type of molecular defect in the GH receptor, they vary in their intellectual capacity. A number of LS patients marry, and with help of pregestational genetic diagnosis, have healthy children. Conclusion: LS is a unique disease model presenting a dissociation between GH and IGF-1 activity.