Laron-type dwarfism

Laron syndrome, or Laron-type dwarfism, is an autosomal recessive disorder characterized by an insensitivity to growth hormone (GH), usually caused by a mutant growth hormone receptor. It causes a short stature and an increased sensitivity to insulin which means that diabetes mellitus type 2 is less likely to develop, and possibly cancer as well. It can be treated with injections of recombinant IGF-1. The principal feature of Laron syndrome is abnormally short stature (dwarfism). Physical symptoms include: prominent forehead, depressed nasal bridge, underdevelopment of mandible, truncal obesity, and micropenis in males. The breasts of females reach normal size, and in some are large in relation to body size. It has been suggested that hyperprolactinemia may contribute to the enlarged breast size. Seizures are frequently seen secondary to hypoglycemia. Some genetic variations decrease intellectual capacity. Laron syndrome patients also do not develop acne, except temporarily during treatment with IGF-1 (if performed). In 2011, it was reported that people with this syndrome in the Ecuadorian villages are resistant to cancer and diabetes and are somewhat protected against aging. This is consistent with findings in mice with a defective growth hormone receptor gene. Molecular genetic investigations have shown that this disorder is mainly associated with mutations in the gene for the GH receptor. These can result in defective hormone binding to the ectodomain or reduced efficiency of dimerization of the receptor after hormone occupancy. There are exceptionally low levels of insulin-like growth factor (IGF-1) and its principal carrier protein, insulin-like growth factor binding protein 3. A related condition involving postreceptor insensitivity to growth hormone has been associated with STAT5B. Laron syndrome can be diagnosed through biochemical analyses: basal GH levels are abnormally increased, while IGF-1 is low. When a GHRH test is performed, IGF-1 fails to increase. GHBP (growth hormone binding protein) levels are low in cases with mutations in the extracellular domain of the GH receptor and normal in cases with mutations in the intracellular domain. Genetic tests should be performed to make a precise etiological diagnosis. Administration of GH has no effect on IGF-1 production, therefore treatment is mainly by biosynthetic IGF-1. IGF-1 must be taken before puberty to be effective. The drug product Increlex (mecasermin), developed by the company Tercica, purchased by Ipsen, was approved by the US Food and Drug Administration in August 2005 for replacing IGF-1 in patients who are deficient.