Novel Genetic Mutation Linked to Rare Form of Short Stature

Published March 2016
EMBO Molecular Medicine

A team of international researchers, led by Andrew Dauber, MD, MMSc, director of the Cincinnati Center for Growth Disorders, has identified a new genetic mutation linked to a rare form of short stature in children.

The discovery gives endocrinologists around the world a new diagnosis to consider in children who present with idiopathic short stature, even in the presence of elevated concentrations of the insulin-like growth hormone IGF-I and IGFBP- 3.

“This is essentially a mutation that affects the bioavailability and activity of IGF-1,” Dauber says.

Dauber and co-researcher Vivian Hwa, PhD, worked with experts from Spain, Argentina, Denmark and throughout the U.S. to track down and study five children from two families that have the rare mutation. Their study appears in the March 2016 issue of EMBO Molecular Medicine.

In addition to short stature, these children exhibited small chins, mild microcephaly, longer fingers and toes, and elevated levels of IGF-1, ALS and IGFBP-3.

Using whole exome analysis, the team detected a loss-of-function mutation in the pregnancy-associated plasma protein A2, PAPP-A2. This mutation inhibits the body’s ability to cleave two of six specific IGF binding proteins, IGFBP-3 and -5, both of which are critical for the release of IGF-I for normal growth and development.

“These patients provide important insights into the regulation of longitudinal growth in humans, documenting the critical role of PAPP-A2 in releasing IGF-I from its binding proteins,” the authors wrote.

Dauber says the findings, duplicated in mouse models, also “indicate that understanding PAPP-A2 regulation and function will have important implications in both the clinical diagnosis of growth retardation and other areas of IGF-1 biology,” including insulin resistance, glucose control, cancer and longevity.