ESPE Abstracts (2014) 82 P-D-1-1-138

A Novel Homozygous Mutation of the IGF1 Receptor Gene (igf1r) in Two Siblings with Severe Short Stature, Intellectual Disability, Congenital Malformations, and Deafness

Isabelle Maystadta,b, Shayne F Andrewc, Jean De Schepperd, Nathalie Wauterse, Geert Mortierf, Valerie Benoîta, Pascal Josetg, Beatrice Onedag, Ron G Rosenfeldc, Anita Rauchg & Vivian Hwac

aInstitut de Pathologie et de Génétique, Center for Human Genetics, Gosselies, Charleroi, Belgium; bFaculty of Medicine, Université Namur, Namur, Belgium; cDepartment of Pediatrics, Oregon Health and Science University, Portland, Oregon, USA; dDepartment of Paediatric Endocrinology, Ghent University Hospital, Ghent, Belgium; eDepartment of Pediatrics, Hopital Civil de Charleroi, Charleroi, Belgium; fCenter for Medical Genetics, University of Antwerp, Antwerp, Belgium; gInstitute of Medical Genetics, University of Zurich, Zurich-Schwerzenbach, Switzerland

Background: Heterozygous mutations in the IGF1 receptor (IGF1R) are often associated with congenital IGF1 resistance, causing variable degrees of intrauterine growth retardation (IUGR) and postnatal short stature. To date, only one homozygous IGF1R mutation has been reported, in a child presenting with severe growth failure, mild intellectual impairment, microcephaly, dysmorphic features, and cardiac malformations.

Objective: We now report the clinical and functional characteristics of a second novel homozygous IGF1R mutation, identified in two siblings.

Patients and methods: The two siblings, an 11-year-old girl and a 7-year-old boy, with similar dysmorphic features, born from healthy consanguineous short Yemenite parents (mother’s height, 145 cm and father’s height, 160 cm), presented with severe IUGR (birth weight and length, −6 SDS) and postnatal growth failure (height, −5.5 SDS). Genetic causality (exome sequence analysis) and functional impacts of the mutation were evaluated.

Results: A moderate delayed bone age and epiphyseal abnormalities, normal basal growth hormone, elevated IGF1 and normal IGFBP3 concentrations were found. Severe microcephaly (head circumference, −7 SDS), mild intellectual disability, deafness, cardiac malformations, and a partial vermis hypoplasia were also documented in both patients. Fasting glucose levels were normal, but an impaired glucose tolerance without an hyperinsulinemic response were documented at OGTT. Exome sequencing identified a novel homozygous, in-frame p.711_714delAEKE deletion in IGF1R. Flow-cytometric analysis by FACS of live fibroblasts derived from the patients demonstrated normal expression and cell surface localization of the mutant IGF1R, which exhibited significantly reduced, but not abrogated, IGF1-induced signal transduction.

Conclusion: Homozygous IGF1R mutations that do not completely ablate IGF1R expression/functions can result in severe pre- and postnatal growth failure comparable to IGF1R compound heterozygotes. While a disturbed glucose tolerance appears a common finding, insulin reserve and bone maturation can be variable. Cardiac anomalies were observed in patients carrying homozygous, but not heterozygous, IGF1R mutations.