title: A New Homozygous IGF1R Variant Defines a Clinically Recognizable Incomplete Dominant form of SHORT Syndrome.
abstract: 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.
authors.affiliation: Medical Genetics Unit, University and Hospital of Perugia, Perugia, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Prontera
authors.affiliation: Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Micale
authors.affiliation: Department of Pediatrics, University of Perugia, Perugia, 06132, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Verrotti
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California.
authors.forename: Valerio
authors.initials: V
authors.lastname: Napolioni
authors.affiliation: Medical Genetics Unit, University and Hospital of Perugia, Perugia, Italy.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Stangoni
authors.affiliation: Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Merla
mesh_terms: D000328:Adult; D003241:Consanguinity; D059472:Exome; D005260:Female; D005799:Genes, Dominant; D006130:Growth Disorders / Q000175:diagnosis* / Q000235:genetics*; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D006934:Hypercalcemia / Q000175:diagnosis* / Q000235:genetics*; D007223:Infant; D008297:Male; D008659:Metabolic Diseases / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation; D009397:Nephrocalcinosis / Q000175:diagnosis* / Q000235:genetics*; D010641:Phenotype; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000235:genetics*
chemical_list: C000597236:IGF1R protein, human; D017451:Receptors, Somatomedin; D017526:Receptor, IGF Type 1
keywords: IGF1; IGF1R; PI3K; SHORT syndrome; neonatal progeroid syndrome