Published Date: August 8, 2015

Full Text Article

A New Homozygous IGF1R Variant Defines a Clinically Recognizable Incomplete Dominant form of SHORT Syndrome

Authors: Paolo Prontera, Lucia Micale, Alberto Verrotti, Valerio Napolioni, Gabriela Stangoni, Giuseppe Merla

Hum Mutat. 2015 Nov;36(11):1043-7. doi: 10.1002/humu.22853. Epub 2015 Aug 24.


Here, we describe a child, born from consanguineous parents, with clinical features of SHORT syndrome, high IGF1 levels, developmental delay, CNS defects, and marked progeroid appearance. By exome sequencing, we identified a new homozygous c.2201G>T missense mutation in the IGF1R gene. Proband's parents and other relatives, all heterozygous carriers of the mutation, presented with milder phenotype including high IGFI levels, short stature, and type 2 diabetes. Functional studies using patient's cell lines showed a lower IGF1R expression that leads to the alteration of IGF1R-mediated PI3K/AKT/mTOR downstream pathways, including autophagy. This study defines a clinically recognizable incomplete dominant form of SHORT syndrome, and provides relevant insights into the pathophysiological and phenotypical consequences of IGF1R mutations.

PMID: 26252249DOI: 10.1002/humu.22853